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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was
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and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
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Avacopan wasunder investigation in clinical trial NCT02994927 (A Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis).
VFMCRP announces approval for TAVNEOS® (avacopan) for the treatment of ANCA-associated vasculitis in Japan
First orally administered therapy for the treatment of two types of ANCA-associated vasculitis approved in Japan
Partner Kissei to market TAVNEOS® in Japan, with launch expected as soon as possible following National Health Insurance (NHI) price listing
September 27, 2021 02:02 AM Eastern Daylight Time
ST. GALLEN, Switzerland–(BUSINESS WIRE)–Vifor Fresenius Medical Care Renal Pharma (VFMCRP) today announced that Japan’s Ministry of Health and Labor Welfare (MHLW) has granted its partner, Kissei Pharmaceutical Co., Ltd., marketing authorization approval for TAVNEOS® for the treatment of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the two main types of ANCA-associated vasculitis, a rare and severe autoimmune renal disease with high unmet medical need.
“We are delighted that TAVNEOS® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone”
“We are delighted that TAVNEOS® has been approved in Japan, the first market worldwide, and congratulate our partner Kissei for this significant milestone,” said Abbas Hussain, CEO of Vifor Pharma Group. “ANCA-associated vasculitis is officially designated an intractable disease in Japan, indicating a rare disease without any effective treatment but for which long-term treatment is required. There is significant unmet medical need of over 10,000 patients in Japan, and we believe in the potential of TAVNEOS® for treating it. We are confident that Kissei will fully focus on bringing this breakthrough treatment to this patient population, helping them lead better, healthier lives.”
The approval is based on the marketing authorization application filing by Kissei which was supported by positive clinical data from the pivotal phase-III trial ADVOCATE in a total of 331 patients with MPA and GPA in 18 countries and regions, including Japan. TAVNEOS® demonstrated superiority over standard of care at week 52 based on Birmingham Vasculitis Activity Score (BVAS).
VFMCRP holds the rights to commercialize TAVNEOS® outside the U.S.. In June 2017, VFMCRP granted Kissei the exclusive right to develop and commercialize TAVNEOS® in Japan. Kissei expects to begin to market TAVNEOS® as soon as possible following NHI price listing. Outside Japan, TAVNEOS is currently in regulatory review with various agencies, including the U.S. Food and Drug Administration and the European Medicines Agency.
About Vifor Pharma Group
Vifor Pharma Group is a global pharmaceuticals company. It aims to become the global leader in iron deficiency, nephrology and cardio-renal therapies. The company is a partner of choice for pharmaceuticals and innovative patient-focused solutions. Vifor Pharma Group strives to help patients around the world with severe and chronic diseases lead better, healthier lives. The company develops, manufactures and markets pharmaceutical products for precision patient care. Vifor Pharma Group holds a leading position in all its core business activities and consists of the following companies: Vifor Pharma and Vifor Fresenius Medical Care Renal Pharma (a joint company with Fresenius Medical Care). Vifor Pharma Group is headquartered in Switzerland, and listed on the Swiss Stock Exchange (SIX Swiss Exchange, VIFN, ISIN: CH0364749348).
Kissei Pharmaceutical Co., Ltd. is a Japanese pharmaceutical company with approximately 70 years of history. Based on its management philosophy, “contributing to society through high-quality, innovative pharmaceutical products” and “serving society through our employees”, Kissei is concentrating on providing innovative pharmaceuticals to patients worldwide as a strongly R&D-oriented corporation. Kissei is engaged in R&D and licensing activities in the field of nephrology/dialysis, urology, and unmet medical needs in other disease areas. Kissei has an established collaboration with VFMCRP for sucroferric oxyhydroxide which Kissei fully developed in Japan as P-TOL® (known as Velphoro® in Europe/US) for the treatment of hyperphosphatemia. Since the launch in 2015, the market share of P-TOL® has been steadily expanding in Japan. For more information about Kissei Pharmaceutical, please visit www.kissei.co.jp.
About ChemoCentryx Inc.
ChemoCentryx is a biopharmaceutical company developing new medications for inflammatory and autoimmune diseases and cancer. ChemoCentryx targets the chemokine and chemoattractant systems to discover, develop and commercialize orally-administered therapies. Besides ChemoCentryx’s lead drug candidate, avacopan, ChemoCentryx also has early stage drug candidates that target chemoattractant receptors in other inflammatory and autoimmunediseases and in cancer.
About ANCA-associated vasculitis
ANCA-associated vasculitis is a systemic disease in which over-activation of the complement pathway further activates neutrophils, leading to inflammation and destruction of small blood vessels. This results in organ damage and failure, with the kidney as the major target, and is fatal if not treated. Currently, treatment for ANCA-associated vasculitis consists of courses of non-specific immuno-suppressants (cyclophosphamide or rituximab), combined with the administration of daily glucocorticoids (steroids) for prolonged periods of time, which can be associated with significant clinical risk including death from infection.
About TAVNEOS® (avacopan)
Avacopan is an orally-administered small molecule that is a selective inhibitor of the complement C5a receptor C5aR1. By precisely blocking the receptor (the C5aR) for the pro-inflammatory complement system fragment, C5a on destructive inflammatory cells such as blood neutrophils, avacopan arrests the ability of those cells to do damage in response to C5a activation, which is known to be the driver of inflammation. Moreover, avacopan’s selective inhibition of only the C5aR1 leaves the beneficial C5a l pathway through the C5L2 receptor functioning normally.
ChemoCentryx is also developing avacopan for the treatment of patients with C3 Glomerulopathy (C3G) and hidradenitis suppurativa (HS). The U.S. Food and Drug Administration has granted avacopan orphan-drug designation for ANCA-associated vasculitis, C3G and atypical hemolytic uremic syndrome. The European Commission has granted orphan medicinal product designation for avacopan for the treatment of two forms of ANCA vasculitis: microscopic polyangiitis and granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), as well as for C3G. In October 2020, European Medicines Agency (EMA) accepted to review the Marketing Authorization Application (MAA) for avacopan for the treatment of patients with ANCA-associated vasculitis (granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)).
On May 6, 2021 the U.S. Food & Drug Administration’s (FDA’s) Arthritis Advisory Committee narrowly voted in support of avacopan, a C5a receptor inhibitor, for the treatment of adult patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. Although the panelists were excited about the possibility of a steroid-sparing therapy, some raised questions about whether results from the single phase 3 trial could adequately inform the risk/benefit assessment.1 The FDA will weigh the panel’s recommendation as it considers possible approval.
Treatment Needs for ANCA-Associated Vasculitis
ANCA-associated vasculitis is a rare, severe and sometimes fatal form of vasculitis characterized by inflammation of small vessels, often including those in the kidney. One factor that distinguishes it from other forms of vasculitis is the dominant role of neutrophils in its pathogenesis. From work in both animal and mouse models, we know activation of the alternative complement pathway plays a role in the disease pathogenesis, triggering attraction and activation of neutrophils in a complex feedback loop.1-3
Morbidity and mortality from ANCA-associated vasculitis has improved in recent decades, partly due to the introduction of new treatment regimens. The FDA approved rituximab for ANCA-associated vasculitis in 2011, and, in 2018, its label was extended to include maintenance therapy. Most patients with newly diagnosed ANCA-associated vasculitis are now started on a tapering dose of glucocorticoids, paired either with cyclophosphamide or rituximab, with a later follow-up maintenance dose of rituximab at around six months.
High doses of glucocorticoids are often used for remission induction, and they may also be employed as part of maintenance therapy, flare management and relapsing disease. This is a concern for practitioners, who hope to reduce the toxicity that results from glucocorticoid use, especially when given at high doses for prolonged periods.
Avacopan is the first drug to be specifically developed for a vasculitis indication. Other vasculitis therapies—such as tocilizumab for giant cell arteritis or rituximab for ANCA-associated vasculitis—were first approved for other diseases. Avacopan is an oral C5a receptor antagonist that selectively blocks the effects of C5a, thus dampening neutrophil attraction and activation. It does not have FDA approval for other indications, but has orphan drug status for ANCA-associated vasculitis (specifically for microscopic polyangiitis and granulomatosis with polyangiitis) and for C3 glomerulopathy, a rare kidney disease.
Arthritis Advisory Panel Meeting
The FDA generally requires evidence from at least two adequate and well-controlled phase 3 trials to establish effectiveness of a drug. However, it exercises regulatory flexibility in certain circumstances, such as for some rare diseases. In this case, it may consider the results of a well-designed single study if the evidence is statistically persuasive and clinically meaningful.4
Study design is a challenge for any manufacturer attempting to develop a product to potentially decrease steroid use because the FDA does not accept steroid sparing as an assessable outcome for clinical trials. For example, in the GiACTA trial, the phase 3 trial used as evidence for approval of tocilizumab for patients with giant cell arteritis, the biotechnology company Genentech wanted to give tocilizumab and demonstrate patients could then be safely taken off glucocorticoids. But the FDA required a more complicated multi-arm design.5
Other issues come up because of the way glucocorticoids have been used historically. Although they have been used for vasculitis since before drug licensing was introduced, glucocorticoids are not themselves licensed for ANCA-associated vasculitis, which brings up certain regulatory barriers in study design. Additionally, the efficacy of glucocorticoids in vasculitis to control disease activity or prevent relapse has never been officially quantified in a placebo-controlled trial.
ADVOCATE Design
For avacopan, ChemoCentryx based its application on a single phase 3 trial and two phase 2 trials.1-3 In pre-meeting documents and during the meeting itself, the company drew comparisons to the RAVE trial, used to establish the non-inferiority of rituximab to standard cyclophosphamide therapy in patients with ANCA-associated vasculitis.6 In this case, a single phase 3 trial (with supporting phase 2 data) was used as evidence for approval of rituximab.
The phase 3 trial of avacopan, ADVOCATE, used a similar, double-blind, double-dummy design.1 ADVOCATE included 331 patients with either new or relapsing ANCA-associated vasculitis. Half the participants received 30 mg of avacopan twice a day orally, as well as a prednisone placebo, out to the study’s end at 12 months. The other half received oral prednisone (tapered to 0 mg at five months) plus an avacopan placebo.
Additionally, patients received immunosuppressive treatment, either cyclophosphamide (35%) or rituximab (65%), at the discretion of the prescribing physician. Patients who had received cyclophosphamide also received follow-up azathioprine at week 15. But after initial treatment, no patients received maintenance rituximab, as would now be common practice.
Prior to enrollment, many participants were already receiving glucocorticoids as part of their treatment, to help get their disease under control. Thus, open-label prednisone treatment continued to be tapered for the early part of the trial in both groups up to the end of week 4. This had to be tapered to 20 mg or less of prednisone daily before beginning the trial, in both treatment groups.
As reported by the investigators, at week 26, the avacopan group was non-inferior to the prednisone group in terms of sustained remission. At the study’s conclusion at week 52, 66% of patients in the avacopan group were in sustained remission, as were 55% of those in the prednisone group. Thus, in terms of remission, avacopan was superior to glucocorticoids at week 52 (P=0.007).
The researchers also provided encouraging secondary endpoints related to a number of other parameters, including reduced glucocorticoid-related toxicities, fewer relapses, better quality of life measures and improvements in kidney functioning (e.g., glomerular filtration rate changes).
David R.W. Jayne, MD, a professor of clinical autoimmunity at the University of Cambridge and director of the Vasculitis and Lupus Service at Addenbrooke’s Hospital, Cambridge, England, was one of the ADVOCATE investigators and says that in the context of previous vasculitis trials, which have only rarely displayed positive effects from interventions, the ADVOCATE results are impressive.
“We’ve never seen quality-of-life benefits or [glomerular filtration rate] recovery benefits in other vasculitis trials, but we saw them consistently in this one,” says Dr. Jayne.
Example 1: Preparation of Free Base Crystalline Form of Compound 1
Crude Compound 1 was prepared essentially as described in WO 2016/053890.
A free base crystalline form of Compound 1 was prepared by dissolving 18 g of crude Compound 1 in 50 mL acetone with heating at 40° C. (a concentration of about ˜0.36 g/mL). The warm solution was passed through a 10 μm polyethylene filter. The solution was then loaded into rotary evaporator at 30° C. bath temperature and 180 rpm rotational speed. The solid collected was dried further in a 45° C. oven for 1 hour. The XRPD data of the crystalline form is shown in Error! Reference source not found., and the table of peaks measured are listed in Table 1, below.
Example 2: Preparing an Amorphous Form of Compound 1
Method 1
Crude Compound 1 was prepared essentially as described in WO 2016/053890.
Crude Compound 1 (15 grams) was dissolved into 40 mL of acetone at 40° C. temperature. The solution was spray dried using a Buchi B290 Spray Dryer, equipped with a peristaltic pump. The spray drying process was completed by using target inlet temperature of 80° C., target spray rate of 5 mL/min, and process gas flow rate of 20.60 CFM. The spray dried powder collected in the sample collection chamber was the amorphous form of Compound 1 as assessed by XRFD, shown in Error! Reference source not found.
Method 2 An amorphous form of Compound 1 was prepared by dissolving 1 g of the free base crystalline form of Compound 1 in 9 mL of acetone without any heating (a concentration of about ˜0.11 g/mL). The solution was passed through a 10 μm polyethylene filter by gravity. The solution was then loaded into rotary evaporator at 45° C. bath temperature and 220 rpm rotational speed. The solid collected was dried further in a 45° C. oven for 30 hour. The XRPD data of the starting material (in crystalline form) and the amorphous form produced from Method 2 are shown in Error! Reference source not found.A & FIG. 3B. The DSC data of the starting material (in crystalline form) and the amorphous form produced from Method 2 are shown in Error! Reference source not found. Experimental details related to DSC data collection are described in Example 3.
A 3-L round bottom flask equipped with a magnetic stirrer was charged with (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide (Compound 1, 250 g, 430 mmol) and MeCN (1.84 L, 8 vol). The resulting mixture was stirred and heated to 75° C. (internal temperature) for 30 min to form a clear solution, and filtered through polyethylene frit filter and rinsed with MeCN (230 mL). To this solution at 60° C. was slowly added a pre-filtered solution of benzenesulfonic acid hydrate (77.9 g, 442 mmol (based on monohydrate), 1.03 eq) in MeCN (276 mL, 3 vol) over 10 min and rinsed with MeCN (92 mL) (internal temperature dropped to 55° C.). The resulting solution was cooled to 50° C., seeded with besylate crystals of Compound 1 (˜100 mg) and slowly cooled to 45° C. over 1 h. The resulting mixture was slowly cooled to RT and stirred for 42 h. The solid was collected by filtration, washed with MeCN (230 mL×2), air-dried and then dried in an oven under vacuum at 50° C. overnight (48 h) to afford N-cyclopentyl-4-((2R,3S)-1-(2-fluoro-6-methylbenzoyl)-3-((4-methyl-3-(trifluoromethyl)phenyl)-carbamoyl)piperidin-2-yl)benzenaminium benzenesulfonate as off-white crystals, with a recovery yield of 266.5 g (84%). 1H NMR (400 MHz, DMSO-d 6) (RT) δ 10.44 (s, 1H), 7.90-7.83 (m, 1H), 7.65-6.95 (m, 14H), 6.42-6.34 (m, 1H), 6.05-5.00 (br, 1H), 3.85-3.70 (m, 1H), 3.22-3.00 (m, 3H), 2.38-2.28 (m, 4H), 2.20-1.40 (m, 15H); (65° C.) δ 10.22 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.68-6.70 (m, 15H), 6.44-6.35 (m, 1H), 3.72-3.65 (m, 1H), 3.25-2.98 (m, 3H), 2.40-2.28 (m, 4H), 2.22-1.40 (m, 15H). MS: (ES) m/z calculated for C 33H 36F 4N 3O 2 [M+H] + 582.3, found 582.2. A plot of the XRPD is shown in FIG. 1, and Table 1, below, summarizes significant peaks observed in the XRPD plot. HPLC (both achiral analytical and chiral): >99%. Elemental Analysis consistent with formula of C 39H 41F 4N 3O 5S, KF: 0.66%.
Example 11[0147] The following are representative compounds prepared and evaluated using methods similar to the examples herein. Characterization data is provided for the compounds below. Biological evaluation is shown in Figure 1 for these compounds and others prepared as described herein.(2R,3S)-2-(4-Cyclopentylaminophenyl)-l-(2-fluoro-6-methylbenzoyl)piperidine-3- carboxylic acid (4-methyl-3-trifluoromethylphenyl)amide
[0097]This example illustrates the preparation of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide by the method provided more generally in FIG. 1 (Scheme 1) using the reagents provided below:
[0098]Step 1:
[0099]An oven-dried 12 L, 3-necked flask equipped with a mechanical stirrer, condenser, and thermometer was charged with acrolein diethyl acetal (1127 g, 8.666 mole, 1.05 equiv.) and warmed up to 40° C. A mixture of solid ethyl 3-(4-nitrophenyl)-3-oxo-propanoate (1956 g, 8.253 mole) and (R)-(−)-2-phenylglycinol (>99.5% e.e., 1187 g, 8.666 mole, 1.05 equiv.) was added in portions over 40 min. to maintain a stirrable mixture at an internal temperature of approximately 40° C. After all solids were added, the mixture was stirred at 40° C. for 10 minutes. 4M HCl in dioxane (206.2 mL, 0.825 mole, 10 mol. %) was subsequently added through the condenser within 2 minutes and the internal temperature was increased to 70 OC. The reaction was stirred for 22 h whereupon LC-MS showed consumption of starting materials and enamine intermediate. The heating was turned off and ethanol (6.6 L) was added. The solution was then seeded with 4 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate and stirred at room temperature for 18 h. The solid was subsequently filtered off and 0.1 L of ethanol was used to rinse the flask and equipment onto the filter. The isolated solid was then washed three times on the filter with ethanol (250 mL each) and dried under vacuum to generate 1253 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate as a bright yellow solid (38% yield, 98.5% HPLC wt/wt purity, 0.15 wt % of EtOH).
[0100]Step 2:
[0101]260 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate (0.659 mol), 0.66 L of ethanol, and 56 g of palladium catalyst (10% Pd/C, Degussa type E101 NE/W, 50% wet, 21.5 wt. % of powder, 4.0 mol % Pd) were placed in a 2.2 L Parr bottle and purged with nitrogen. The bottle was mounted on a Parr shaker apparatus and hydrogen was added at a rate to keep the external temperature of the bottle below 30° C. After 4 hours, the consumption of hydrogen slowed down. The bottle was then shaken under 50 psi of hydrogen for 2 hours. 94 mL of glacial acetic acid (1.65 mol, 2.5 equiv.) was subsequently added to the bottle and the bottle was purged three times with hydrogen at 50 psi. The bottle was then shaken under 35-55 psi of hydrogen for 48 hours, keeping the temperature below 30° C. The bottle was removed from the apparatus and 55 mL of 12M HCl aq. was added (0.659 mol, 1 equiv.) followed by 87 mL of cyclopentanone (0.989 mol, 1.5 equiv.). The bottle was purged three times with hydrogen at 50 psi and then shaken under 50 psi of hydrogen for 16-20 hours. The mixture was removed from the apparatus and filtered through a fritted funnel containing celite (80 g) and then washed three times with 0.125 L of ethanol. 54.1 g of anhydrous sodium acetate (0.659 mol, 1 equiv.) was added and the mixture was concentrated in vacuo at 40-55° C. to remove 0.9 L of the volatile components. 2.0 L of acetonitrile was added and 2.0 L of volatile components were removed in vacuo. The crude material was diluted with 1.0 L of acetonitrile and mechanically stirred at r.t. for 30 minutes. The mixture was filtered through Celite (40 g) and the cake was washed with 0.28 L of acetonitrile. The combined filtrates gave a solution of the crude amine acetate (Solution A, e.e. =78%). Solutions A of two independent runs were combined for further processing.
[0102]In a 12-L 3-neck flask equipped with a mechanical stirrer, internal thermometer, and reflux condenser (−)-O,O′-di-p-toluoyl-L-tartaric acid (1.019 kg, 2.64 mol, 2 equiv.) was dissolved in 5.8 L of acetonitrile. The mixture was heated to 60° C. with stirring, followed by a quick addition of 1 L of Solution A. The resultant solution was seeded with 4 g of the crystalline ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) and stirred at 60° C. for 15 minutes. After 15 minutes at 60 OC the seed bed has formed. The remaining amount of Solution A was added over a period of 2.5 hours, maintaining an internal temperature at 60° C. When the addition was complete, the heat source was turned off and the mixture was stirred for 17 hours, reaching a final temperature of 22.5° C. The suspension was filtered and the solids were washed with 0.50 L of acetonitrile to rinse the equipment and transfer all solids onto the filter. The resultant wet solids were washed on the funnel with 3.0 L of acetonitrile and dried in a vacuum oven at 45° C. for 48 hours to provide 1.005 kg of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) as an off-white solid (70% yield, contains 1 wt. % of acetonitrile). The enantiomeric ratio of the product was 99.4:0.6.
[0103]Step 3:
[0104]In a 5 L 3-necked flask equipped with a mechanical stirrer and an addition funnel, solid anhydrous potassium carbonate (K2CO3, 226 g, 1.64 mol, 4.1 equiv.) was dissolved in H2O (0.82 L) and cooled to ambient temperature. MTBE (0.82 L) was added, followed by solid ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylate (−)-O,O′-di-p-toluoyl-L-tartaric acid salt (1:2) (436 g, 0.400 mol). The mixture was vigorously stirred at r.t. for 1 hour, then 2-fluoro-6-methylbenzoyl chloride (72.5 g, 0.420 mmol, 1.05 equiv.) in MTBE (0.14 L) was added dropwise over 1 hour. The product started precipitating from the reaction before addition of the acid chloride was completed. The reaction was vigorously stirred at r.t. for 30 minutes and monitored by LC-MS for the disappearance of starting material. The mixture was subsequently transferred to a 5 L evaporation flask using 0.3 L of MTBE to rinse the equipment and remove all solids. The mixture was concentrated in vacuo to remove the MTBE, then 0.3 L of heptane was added and the mixture was evaporated again to leave only the product suspended in aqueous solution. The flask was removed from the rotavap and water (0.82 L) and heptane (0.82 L) were added. The suspension was vigorously stirred for 16 hours using a mechanical stirrer. The contents were then filtered and the solid was washed with water (2×0.42 L) and heptane (0.42 L). The solid was dried in a vacuum oven at 45° C. to provide 172 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate as an off-white powder (95% yield).
[0105]Step 4:
[0106]A 0.5 L 3-necked round-bottom flask was dried overnight in an oven at 200° C. and then cooled under a stream of nitrogen. The flask was equipped with a magnetic stir bar, nitrogen inlet, and a thermometer. The flask was charged with 30.2 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate (66.7 mmol), 11.5 mL of 4-methyl-5-trifluoromethylaniline (80 mmol, 1.2 equiv.) and 141 mL of dry toluene under an atmosphere of nitrogen. Nitrogen was bubbled through the resultant solution for 10 minutes and then the solution was warmed to 30° C. The oil bath was removed and 100 mL of a 2 M solution of AlMe3 in toluene (Aldrich, 200 mmol, 3 equiv.) was cannulated into the reaction mixture at a rate maintaining the reaction temperature between 35-40° C., a process that took approximately 45 minutes. The temperature of the reaction mixture was then increased to 55° C. over a period of 1 hour and the reaction mixture was stirred at 55° C. for 8 hours, whereupon all of the starting ester was consumed (monitored by LC-MS). The reaction was subsequently cooled overnight to ambient temperature and the solution was then cannulated into a mechanically stirred 1 L flask containing a solution of 67.8 g of sodium potassium tartrate tetrahydrate (240 mmol, 3.6 equiv.) in 237 mL of water, pre-cooled to 10 OC in an ice bath. The addition process took approximately 30 minutes, during which the reaction mixture self-heated to 57° C. The empty reaction flask was subsequently rinsed with 20 mL of dry toluene and the solution was combined with the quench mixture. The mixture was then cooled to r.t. with stirring, 91 mL of ethyl acetate was added, and the mixture was stirred an additional 15 minutes. The mixture was subsequently filtered through a pad of Celite and the filtrate was allowed to separate into two layers. The organic layer was then separated and washed with a solution of 5.7 g of sodium potassium tartrate tetrahydrate (20 mmol) in 120 mL of water and then with two 120 mL portions of water. The wet organic solution was concentrated in vacuo to a weight of ˜150 g and a solvent exchange with ethanol was performed maintaining a total volume of 0.2-0.3 L, until <1 mol. % toluene with respect to ethanol was observed by 1H NMR. The solution was then evaporated at elevated temperature to a weight of 223 g and heated to reflux. Mechanical stirring was initiated and 41 mL of water was added. The resulting solution was seeded with (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide crystals at 60 OC and then slowly cooled to r.t. over 2 hours. The slurry was subsequently stirred for 18 hours and the solids were filtered off. The solids were then washed with two 30 mL portions of 7:3 ethanol/water and dried in a vacuum oven for 24 hours at 50 OC to afford 31.0 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as off-white crystals (80% yield). Analytical data: HPLC purity: 99.59%; >99.8% d.e. and e.e. by HPLC; ICP-OES Pd: <1 ppm; Al: δ ppm; residual toluene by headspace GC-MS: 15 ppm; microash<0.1%; K—F 0.1%. 1H NMR (400 MHz, TFA-d) δ 7.91 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.58-6.82 (m, 8H), 6.75 (t, J=8.6 Hz, 1H), 4.10-4.00 (m, 1H), 3.60-3.47 (m, 1H), 3.45-3.41 (m, 1H), 3.33-3.25 (m, 1H), 2.44-2.22 (m, 7H), 2.04-1.92 (m, 4H), 1.82-1.69 (m, 7H), MS: (ES) m/z 582 (M+H+).
The present disclosure is directed to, inter alia, methods of treating ANCA-associated vasculitis (AAV) in a human in need thereof, the method comprising administering to the human a therapeutically effective amount of avacopan, having the structure shown below:
Announcement of Marketing Authorization Approval in Japan and Co-promotion Agreement of UPASITA® IV Injection Syringe for the Treatment of Secondary Hyperparathyroidism in Dialysis Patients
SANWA KAGAKU KENKYUSHO Co., Ltd. (Head Office: Nagoya, President and CEO : Shusaku Isono, Suzuken Group, ; “SANWA KAGAKU”) has received Marketing Authorization approval today for UPASITA® IV Injection Syringes (generic name: Upacicalcet Sodium Hydrate; “UPASITA®”) for the treatment of secondary hyperparathyroidism in patients on hemodialysis.
UPASITA® was created by Ajinomoto Pharmaceuticals Co., Ltd. (currently EA Phama Co., Ltd.) and developed by SANWA KAGAKU for the treatment of secondary hyperparathyroidism under a licensing agreement with EA Pharma. UPASITA® acts on calcium sensing receptor in the parathyroid and suppresses excessive secretions of parathyroid hormones (PTH). UPASITA® is administered by intravenous injection to dialysis patients through dialysis circuit by physicians or medical staffs upon completion of dialysis and such administration is expected to reduce the burden of patients with many oral medications whose drinking water volume is severely restricted.
Regarding provision of medical and drug information, SANWA KAGAKU entered into a co-promotion agreement in Japan with Kissei Pharmaceutical Co., Ltd. (Head Office: Matsumoto, Nagano; Chairman and CEO: Mutsuo Kanzawa ; “Kissei”). SANWA KAGAKU will handle the production, marketing, and distribution of the Product while SANWA KAGAKU and Kissei collaboratively promote it to medical institutions in the field in accordance with the agreement. Through the co-promotion activity in the field, SANWA KAGAKU and Kissei will contribute to the treatment of dialysis patients suffering from secondary hyperparathyroidism.
《Reference》
About secondary hyperparathyroidism (SHPT) SHTP is one of complications that occur as chronic kidney disease (chronic kidney failure) progresses and is a pathological condition where excessive PTH is secreted by the parathyroid gland. It has been reported that excessive secretion of parathyroid hormone promotes efflux of phosphorus and calcium from the bone into the blood, thereby increasing the risk of developing bone fractures and arteriosclerosis due to calcification of the cardiovascular system and affecting the vital prognosis.
Product Summary of UPASITA® IV Injection Syringe for Dialysis Brand name: UPASITA® IV Injection Syringe for Dialysis 25μg UPASITA® IV Injection Syringe for Dialysis 50μg UPASITA® IV Injection Syringe for Dialysis 100μg UPASITA® IV Injection Syringe for Dialysis 150μg UPASITA® IV Injection Syringe for Dialysis 200μg UPASITA® IV Injection Syringe for Dialysis 250μg UPASITA® IV Injection Syringe for Dialysis 300μg
Generic Name (JAN): Upacicalcet Sodium Hydrate
Date of Marketing Approval: June 23, 2021
Indications: Secondary hyperparathyroidism in patients on hemodialysis
Dosage and Administration: In adults, UPASITA® is usually administered into venous line of the dialysis circuit at the end of dialysis session during rinse back at a dose of 25 μg sodium upacicalcet 3 times a week as a starting dose. The starting dose can be 50 μg depending on the concentration of serum calcium. Thereafter, the dose may be adjusted in a range from 25 to 300 μg while parathyroid hormone (PTH) and serum calcium level should be carefully monitored in patients.
SYN
WO 2020204117
PATENT
WO 2011108724
WO 2011108690
JP 2013063971
WO 2016194881
JP 6510136
PATENT
WO 2016194881
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016194881&tab=FULLTEXT(Example 1) Synthesis of (2S) -2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 1 ) [Chemical formula 14] CDI 150. 2 g (926.6Mmol, 1.1 eq. vs Boc-DAP-O t Bu) to and stirred at 5 ° C. acetone was added 750mL (3.0L / kg). 250 g (842.6 mmol) of Boc-DAP-OtBu was added in two portions, and the mixture was washed with 125 mL (0.5 L / kg) of acetone. After stirring for 30 minutes, completion of the IC (imidazolylcarbonylation) reaction was confirmed by HPLC. 282.6 g (1263.8 mmol, 1.5 eq.) Of ACHB was added in 3 portions, and the mixture was washed with 125 mL (0.5 L / kg) of acetone. After raising the temperature to 30 ° C. and stirring for 18 hours, the completion of the urea conversion reaction was confirmed by HPLC. After cooling to 5 ° C., 124.5 mL (1432.4 mmol, 1.7 eq.) Of concentrated hydrochloric acid was added, and the mixture was stirred for 1 hour. The precipitated unwanted material was filtered and washed with 1000 mL (4.0 L / kg) of acetone. The filtrate was concentrated to 1018 g (4.1 kg / kg), the temperature was raised to 50 ° C., and 625.0 mL (7187 mmol, 8.5 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 30 minutes and confirming the completion of deprotection by HPLC, 750 mL of water was added (3.0 L / kg). This liquid was concentrated under reduced pressure to 1730 g (6.9 kg / kg) to precipitate a solid. After stirring at 20 ° C. for 14 hours, vacuum filtration was performed. The filtered solid was washed with 500 mL (2.0 L / kg) of acetone and then dried under reduced pressure at 60 ° C. for 6 hours to obtain 201.4 g of the target product (64.5%). 1H-NMR (400MHz, DMSO-d6): δ 8.3 (s, 1H), 8.2 (bs, 3H), 8.1 (d, 1H, J = 2.6Hz), 7.3 (t, 1H, J = 6.0Hz), 7.0 (d, 1H, J = 2.6Hz), 4.0-4.1 (m, 1H), 3.6-3.7 (m, 1H), 3.4-3.5 (m, 1H)[0026](Example 2) Synthesis of (2S) -2-amino-3-{[(3-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 2 ) [Chemical formula 15] CDI 120.2 g (741.2 mmol, 1. 600 mL (3.0 L / kg) of acetone was added to 1 eq. Vs Boc-DAP-OtBu), and the mixture was stirred at 5 ° C. 200 g (673.9 mmol) of Boc-DAP-OtBu was added in two portions, and the mixture was washed with 100 mL (0.5 L / kg) of acetone. After stirring for 30 minutes, the completion of the IC reaction was confirmed by HPLC. 175.0 g (1010.8 mmol, 1.5 eq.) Of ABS was added in 3 portions and washed with 100 mL (0.5 L / kg) of acetone. After raising the temperature to 30 ° C. and stirring for 18 hours, the completion of the urea conversion reaction was confirmed by HPLC. After cooling to 5 ° C., 99.6 mL (1145.4 mmol, 1.7 eq.) Of concentrated hydrochloric acid was added, and the mixture was stirred for 1 hour. The precipitated unwanted material was filtered and washed with 1400 mL (7.0 L / kg) of acetone. The filtrate was concentrated to 800.1 g (4.0 kg / kg), heated to 50 ° C., and then 500.0 mL (5750.0 mmol, 8.5 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 30 minutes and confirming the completion of deprotection by HPLC, 600 mL of water was added (3.0 L / kg). This liquid was concentrated under reduced pressure to 1653.7 g to precipitate a solid. After aging at 20 ° C. for 15 hours, vacuum filtration was performed. The filtered solid was washed with 400 mL (2.0 L / kg) of acetone and then dried under reduced pressure at room temperature for 6 hours to obtain 140.3 g of the desired product (net 132.2 g, 64.7%). 1H-NMR (400MHz, DMSO-d6): δ 8.8 (s, 1H), 8.2 (bs, 3H), 7.7 (s, 1H), 7.3-7.4 (m, 1H), 7.1-7.2 (m, 2H) , 6.3-6.4 (bs, 1H), 4.0-4.1 (bs, 1H), 3.6-3.7 (bs, 1H), 3.5-3.6 (bs, 1H)[0027](Example 3) Synthesis of (2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 3 ) [Chemical formula 16] CDI 14. To 4 g (88.8 mmol, 1.05 eq. Vs Boc-DAP-OtBu), 75 mL (3.0 L / kg vs DAP-OtBu) of acetone was added and stirred at 5 ° C. After adding 25 g (84.3 mmol) of Boc-DAP-OtBu in two portions and stirring for 30 minutes, the completion of the IC reaction was confirmed by HPLC. 26.1 g (118.0 mmol, 1.4 eq.) Of ACTS was added in 3 portions and washed with 25 mL (1.0 L / kg) of acetone. After the temperature was raised to 30 ° C., the mixture was stirred overnight, and the completion of the urea conversion reaction was confirmed by HPLC. After concentrating under reduced pressure at 10 kPa and 40 ° C. until the solvent was completely removed, 37.5 mL (1.5 L / kg) of water and 22.8 mL (257.6 mmol) of concentrated hydrochloric acid were added to perform deprotection for 2 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 5 ° C., 60 mL (2.4 L / kg) of MeCN was added, and the mixture was stirred overnight. Further, when 120 mL (4.8 L / kg) of MeCN was added, stratification occurred, so 10 mL (0.4 L / kg) of water and 2.5 mL (0.1 L / kg) of MeCN were added. The precipitated solid was filtered under reduced pressure, washed with 60 mL of MeCN / water (1/2), and then dried under reduced pressure at 60 ° C. for 14 hours to obtain 20.1 g of the desired product as a white solid (net18.3 g, yield 61). 0.8%). 1H-NMR (400MHz, DMSO-d6): δ 14.70-13.30 (bs, 1H), 8.27 (bs, 3H), 8.15 (s, 1H), 7.98 (d, 1H, J = 1.6Hz), 7.27 (d , 1H, J = 1.6Hz), 6.82 (t, 1H, J = 6.0Hz), 4.04 (bs, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 1H), 2.22 (s, 3H)[0028](Example 4) Synthesis of compound 3 using phenylchloroformate as a carbonyl group-introducing reagent (Step 1) [Chemical formula 17] MeCN 375 mL (7.5 L / kg vs ACTS), Py for 50 g (225.6 mmol) of ACTS. 38.1 mL (473.7 mmol, 2.1 eq.) Was added and stirred at 25 ° C. 29.9 mL (236.8 mmol, 1.05 eq.) Of ClCO 2 Ph (phenyl chloroformate) was added dropwise, and after stirring for 30 minutes, completion of the CM (carbamate) reaction was confirmed by HPLC. 68.9 g (232.4 mmol) of Boc-DAP-OtBu was added, 97.5 mL (699.3 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. The completion of the urea conversion reaction was confirmed by HPLC. Here, 103.5 g of the total amount of 517.43 g was used to move to the next step (down to ACTS 10 g scale). 30 mL of water was added and concentrated to 77.0 g at 40 ° C. and 5 kPa. After 100 mL (10 L / kg) of AcOEt was added and the liquid separation operation was performed, 30 mL of water was added to the organic layer and the liquid separation operation was performed again. The organic layer was concentrated to 47.6 g at 40 ° C. and 10 kPa, and then 15 mL (1.5 L / kg) of AcOEt and 100 mL (10 L / kg) of THF were added. Again, it was concentrated to 50.7 g and THF was added up to 146 g. When it was concentrated again to 35.5 g and added to AcOEt 30 mL (3 L / kg) and THF 100 mL (10 L / kg), a solid was precipitated. It was cooled to 5 ° C. and aged overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of THF, and then dried under reduced pressure at 40 ° C. for 3 hours overnight at 30 ° C. to obtain 24.9 g of the desired product as a white solid (net). 23.0 g, 83.6%). 1 H-NMR (400MHz, DMSO-d6): δ 8.86 (bs, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.25 (d, 1H, J = 1.6Hz), 7.14 (d, 1H, J = 7.6Hz), 6.60 (t, 1H, J = 5.6Hz), 4.00-3.90 (m, 1H), 3.60-3.50 (m, 1H), 3.30-3.20 (m, 1H), 3.15-3.05 (m, 6H), 2.19 (s, 3H), 1.50-1.30 (m, 18H), 1.20-1.10 (m, 9H)
(Step 2) [Chemical
formula 18] Compound 4 21.64 g (net. 20.0 g, 68 mL of water (3.4 L / kg vs. compound 4) vs. 32.8 mmol) ) Was added, the mixture was stirred at 50 ° C., and 12 mL (135.6 mmol, 4.1 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 1 hour, the temperature was raised to 70 ° C. to dissolve the precipitated solid. After confirming the completion of the reaction by HPLC, the mixture was cooled to 50 ° C. and aged for 1 hour, and then cooled to 5 ° C. over 4 hours. The precipitated solid was filtered under reduced pressure, washed with 40 mL (2.0 L / kg) of MeCN / water (2/1), and then dried under reduced pressure at 60 ° C. for 3 hours to obtain 11.2 g of the desired product as a white solid (11.2 g). net 10.5 g, 91.1%).[0029](Example 5) [Chemical formula 19] MeCN 10.0 mL (10.0 L / kg vs ACSS), Py 0.75 mL (9.25 mmol, 2.05 eq.) For 1.00 g (4.51 mmol) of ACTS. , And stirred at 8 ° C. After dropping 0.59 mL (4.74 mmol, 1.05 eq.) Of ClCO 2 Ph, raising the temperature to room temperature and stirring for 1 hour, completion of the CM conversion reaction was confirmed by HPLC. 1.33 g (4.51 mmol, 1.0 eq.) Of Boc-DAP-OtBu was added, 1.92 mL (13.76 mmol, 3.05 eq.) Of TEA was added dropwise, and the mixture was stirred at 40 ° C. for 1 hour. After confirming the completion of the urea conversion reaction by HPLC, the mixture was concentrated until the solvent was completely removed. 1.0 mL of water and 2.0 mL of concentrated hydrochloric acid (22.6 mmol, 5.0 eq.) Were added, and the mixture was stirred at 50 ° C. for 4 hours. After confirming the completion of deprotection by HPLC, MeCN 7.5 mL (7.5 L / kg), 1 M HCl aq. After adding 4.5 mL, the mixture was stirred at 5 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 3.0 mL (3.0 L / kg) of MeCN, and then dried at 60 ° C. overnight to obtain 1.28 g of the desired product as a white solid (net 1.18 g, 77). .0%).[0030](Example 6) (Step 1) 3-({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl} amino) -5-chloro-4-methylbenzene-1-sulfonic acid ( Synthesis of Compound 5 ) [Chemical formula 20] To 5 g (22.56 mmol) of ACTS, 37.5 mL (7.5 L / kg vs ACTS) of MeCN and 3.81 mL (47.38 mmol, 2.1 eq.) Of Py were added. The mixture was stirred at 25 ° C. 2.99 mL (23.68 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, and after stirring for 30 minutes, the completion of the CM reaction was confirmed by HPLC. 5.92 g (23.23 mmol, 1.03 eq.) Of Boc-DAP-OMe was added, 9.75 mL (69.93 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. 0.4 g (1.58 mmol, 0.07 eq.) Of Boc-DAP-OMe and 0.22 mL (1.58 mmol, 0.07 eq.) Of TEA were added, and the completion of the ureaization reaction was confirmed by HPLC. 7.32 mL (112.8 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 4 hours. After confirming the completion of deprotection by HPLC, the mixture was cooled to 25 ° C. and 37.5 mL (7.5 L / kg) of MeCN and 7.5 mL (1.5 L / kg) of water were added to precipitate a solid. It was cooled to 5 ° C. and aged for 16 hours. The precipitated solid was filtered under reduced pressure, washed with 20 mL (4.0 L / kg) of water / MeCN (1/2), and then dried under reduced pressure at 40 ° C. for 5 hours to obtain 7.72 g of the target product as a white solid (772 g of the target product). net 7.20 g, 87.3%). 1H-NMR (400MHz, DMSO-d6): δ 8.39 (bs, 3H), 8.16 (d, 1H, J = 1.2Hz), 7.90 (d, 1H, J = 1.6Hz), 7.28 (d, 1H, J = 1.6Hz), 6.78 (t, 1H, J = 5.6Hz), 4.20-4.10 (m, 1H), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H) , 2.21 (s, 3H) HRMS (FAB – ): calcd for m / z 364.0369 (MH), found The m / z 364.0395 (MH)
(step 2) [Formula 21]
compound 5 10.64 g (net Non 10.0 g, To 27.34 mmol), 18 mL of water (1.8 L / kg vs. compound 5 ) was added and stirred at 8 ° C. 3.42 mL (57.41 mmol, 2.1 eq.) Of a 48% aqueous sodium hydroxide solution was added dropwise, and the mixture was washed with 1.0 mL (1.0 L / kg) of water and then stirred at 8 ° C. for 15 minutes. After confirming the completion of hydrolysis by HPLC, the temperature was raised to 25 ° C. and 48% HBr aq. The pH was adjusted to 5.8 by adding about 3.55 mL. After confirming the precipitation of the target product by dropping 65 mL (6.5 L / kg) of IPA, the mixture was aged for 1 hour. 81 mL (8.1 L / kg) of IPA was added dropwise and aged at 8 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of IPA, and then dried under reduced pressure at 40 ° C. for 4 hours to obtain 10.7 g of the desired product as a white solid (net 9.46 g, 92. 6%). 1 H-NMR (400MHz, DMSO-d6): δ8.76 (s, 1H), 7.91 (d, 1H, J = 1.6Hz), 8.00-7.50 (bs, 2H), 7.24 (d, 1H, J = 1.6Hz), 7.20 (t, 1H, J = 5.6Hz), 3.58-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.23 (s, 3H)[0031](Example 7) (Step 1) [Chemical formula 22] For 10.0 g (45.1 mmol) of ACTS, 50 mL (5.0 L / kg vs ACTS) of MeCN, 7.46 mL (92.5 mmol, 2.05 eq. ) Was added, and the mixture was stirred at 8 ° C. 5.98 mL (47.4 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, the temperature was raised to 25 ° C., and the mixture was stirred for 1 hour, and then the completion of the CM reaction was confirmed by HPLC. 100 ml of acetone (10.0 L / kg vs ACTS) was added, the mixture was cooled to 8 ° C., and aged for 1 hour. The precipitated solid was filtered under reduced pressure, washed with 30 mL of acetone (3.0 L / kg vs ACTS), and then dried under reduced pressure at 60 ° C. for 2 hours to obtain 17.8 g of the target product (net 14.4 g as a free form). Quant). 1 H-NMR (400MHz, DMSO-d6): δ 9.76 (bs, 1H), 8.93-8.90 (m, 2H), 8.60-8.50 (m, 1H), 8.10-8.00 (m, 2H), 7.60 (s , 1H), 7.50-7.40 (m, 3H), 7.30-7.20 (m, 3H), 2.30 (s, 3H)
(Step 2) [Chemical 23]
Compound 6 To 5.0 g (11.9 mmol), 50 ml of acetonitrile and 3.53 g (11.9 mmol) of Boc-DAP-OtBu were added, and the mixture was stirred at 8 ° C. 3.5 ml (25 mmol) of triethylamine was added dropwise, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and 25 ml of ethyl acetate and 5 ml of water were added for extraction. The organic layer was washed with 5 ml of water, the solvent was distilled off, 50 ml of tetrahydrofuran was added, the mixture was cooled to 8 ° C., and aged for 1 hour. The precipitated solid was filtered under reduced pressure, washed with 10 ml of tetrahydrofuran, and dried under reduced pressure at 60 ° C. overnight to obtain 6.3 g of the desired product as a white solid.[0032](Example 8) [Chemical formula 24] For 1.08 g (4.89 mmol) of ACTS, 8.1 mL (7.5 L / kg vs ACTS) of MeCN and 827 μL (10.27 mmol, 2.1 eq.) Of Py were added. In addition, it was stirred at room temperature. ClCO 2 Ph 649 μL (5.14 mmol, 1.05 eq.) Was added dropwise, and the mixture was stirred for 30 minutes, and then the completion of the CM conversion reaction was confirmed by HPLC. 1.48 g (5.04 mmol, 1.03 eq.) Of Cbz-DAP-OMe HCl was added, 2.1 mL (15.17 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at room temperature for about 5 hours. After confirming the completion of the urea conversion reaction by HPLC, the mixture was concentrated until the solvent was completely removed. 15.0 mL of 30% HBr / AcOH was added, and the mixture was stirred at room temperature for 70 minutes, and the completion of deprotection was confirmed by HPLC. After concentration to dryness, 10 mL of water and 4 mL of AcOEt were added to carry out an extraction operation, and then the aqueous layer was stirred at room temperature overnight. The precipitated solid was filtered under reduced pressure, washed with 15 mL of water and 10 mL of AcOEt, and then dried at 40 ° C. for 3 hours to obtain 1.45 g of the desired product as a white solid (58.8%).[0033](Example 9) Synthesis of compound 7 ( methyl ester of compound 1 ) using phenyl chloroformate as a carbonyl group introduction reagent [Chemical formula 25] MeCN 73 mL (14.6 L) with respect to 5.00 g (22.4 mmol) of ACHB. / Kg vs ACHB), Py 3.8 mL (47 mmol, 2.1 eq.), Was added and stirred at 40 ° C. After adding 3.0 mL (24 mmol, 1.05 eq.) Of ClCO 2 Ph and stirring for 30 minutes, the completion of the CM conversion reaction was confirmed by HPLC. 5.87 g (23 mmol, 1.0 eq.) Of Boc-DAP-OMe was added, washed with a small amount of MeCN, 9.7 mL (70 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 40 ° C. for 3 hours. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (112 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 7 hours. Further, 1.5 mL (23 mmol, 1.0 eq.) Of MsOH was added, and the reaction was carried out at 50 ° C. overnight. After confirming the completion of deprotection by HPLC, 90 mL of acetone was added to the reaction solution, and the mixture was cooled to room temperature. The precipitated solid was obtained and dried under reduced pressure at 60 ° C. to obtain the desired product. 1 H-NMR (400MHz, DMSO-d6): δ 7.22 (m, 1H), 7.14 (m, 1H), 4.36 (m, 1H), 3.80 (s, 3H), 3.20-3.40 (m, 2H).[0034](Example 10) Synthesis of compound 5 using 4-chlorophenylchloroformate as a carbonyl group-introducing reagent [Chemical formula 26] For 5.00 g (22.6 mmol) of ACTS, 73 mL (14.6 L / kg vs ACTS) of MeCN, 3.8 mL (47 mmol, 2.1 eq.) Of Py was added and stirred at 40 ° C. After adding 3.25 mL (23.7 mmol, 1.05 eq.) Of 4-chloroformic acid 4-chlorophenylate and stirring at 40 ° C. for 1.5 hours, completion of the CM conversion reaction was confirmed by HPLC. Add 5.92 g (23.2 mol, 1.0 eq.) Of Boc-DAP-OMe, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (113 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 3.5 hours. After confirming the completion of deprotection by HPLC, the reaction solution was cooled to room temperature, 7.5 mL of water was added, the mixture was cooled to 8 ° C., and the mixture was stirred overnight. The precipitated solid was filtered, washed with a small amount of MeCN water, and dried at 60 ° C. overnight to obtain 6.94 g of the desired product as a white solid (84.1%).[0035](Example 11) Synthesis of compound 5 using 4-nitrophenyl chloroformate as a carbonyl group-introducing reagent [Chemical formula 27] 73 mL (14.6 L / kg vs. ACTS) of MeCN with respect to 5.00 g (22.6 mmol) of ACTS. , Py 3.8 mL (47 mmol, 2.1 eq.), And stirred at 40 ° C. 4.77 mL (23.7 mmol, 1.05 eq.) Of 4-nitrophenyl chloroformate was added dropwise, and the mixture was stirred at 40 ° C. for 3.5 hours, and then the completion of the CM reaction was confirmed by HPLC. Add 5.92 g (23.2 mmol, 1.0 eq.) Of Boc-DAP-OMe, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (113 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 3.5 hours. After confirming the completion of deprotection by HPLC, the reaction solution was cooled to room temperature, 7.5 mL of water was added, the mixture was cooled to 8 ° C., and the mixture was stirred overnight. The precipitated solid was filtered, washed with a small amount of MeCN water, and dried at 60 ° C. overnight to obtain 5.96 g of the desired product as a white solid (72.2%).[0036](Example 12) Synthesis of compound 3 using Boc-DAP-OH [Chemical 28] MeCN 73 mL (14.6 L / kg vs ACTS), Py 3.8 mL, relative to 5.00 g (22.6 mmol) of ACTS. (47 mmol, 2.1 eq.) Was added and stirred at 40 ° C. After adding 3.00 mL (23.8 mmol, 1.05 eq.) Of phenylchloroformate and stirring at 40 ° C. for 0.5 hours, the completion of the CM conversion reaction was confirmed by HPLC (CM conversion reaction product: 4.37 minutes). , ACTS: N.D.). Add 4.75 g (23.2 mmol, 1.0 eq.) Of Boc-DAP-OH, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea-forming reaction by HPLC (urea-forming reaction product: 3.81 minutes, CM-forming reaction product: 0.02 area% vs. urea-forming reaction product), the mixture was cooled to room temperature. By adding 7.3 mL (113 mmol, 5.0 eq.) Of MsOH, raising the temperature to 50 ° C., stirring for 4.5 hours, and further adding 1.5 mL (23 mmol, 1.0 eq.) Of MsOH, stirring for 1 hour. , The formation of the target product was confirmed by HPLC (Compound 3: 2.49 minutes, urea conversion reaction product: 0.50 area vs. compound 3, area of compound 3 with respect to the total area excluding pyridine: 71.0 area).
PATENT
JP 6510136
PATENT
WO 2020204117
Reference Example 1 Synthesis of 3-{[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate sodium (Compound A1) (Step 1) Synthesis of 3 -({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl} amino) -5-chloro-4-methylbenzene-1-sulfonic acid 3-amino- 37.5 mL (7.5 L / kg vs ACTS) of acetonitrile and 3.81 mL (47.38 mmol, 2.1 eq.) Of pyridine against 5 g (22.56 mmol) of 5-chloro-4-methylbenzenesulfonic acid (ACTS). Was added and stirred at 25 ° C. 2.99 mL (23.68 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, and after stirring for 30 minutes, the completion of the carbamate reaction was confirmed by HPLC. Add 5.92 g (23.23 mmol, 1.03 eq.) Of 3-amino-N- (tert-butoxycarbonyl) -L-alanine methyl ester hydrochloride and 9.75 mL (69.93 mmol, 3.1 eq.) Triethylamine. Was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. Add 0.4 g (1.58 mmol, 0.07 eq.) Of 3-amino-N- (tert-butoxycarbonyl) -L-alanine methyl ester hydrochloride and 0.22 mL (1.58 mmol, 0.07 eq.) Of triethylamine. Then, the completion of the urea conversion reaction was confirmed by HPLC. 7.32 mL (112.8 mmol, 5.0 eq.) Of methanesulfonic acid was added, the temperature was raised to 50 ° C., and the mixture was stirred for 4 hours. After confirming the completion of deprotection by HPLC, the mixture was cooled to 25 ° C. and 37.5 mL (7.5 L / kg) of acetonitrile and 7.5 mL (1.5 L / kg) of water were added to precipitate a solid. It was cooled to 5 ° C. and aged for 16 hours. The precipitated solid was filtered under reduced pressure, washed with 20 mL (4.0 L / kg) of water / acetonitrile (1/2), and then dried under reduced pressure at 40 ° C. for 5 hours to obtain 7.72 g of the desired product as a white solid (. net 7.20 g, 87.3%).
1 H-NMR (400MHz, DMSO-d6): δ 8.39 (bs, 3H), 8.16 (d, 1H, J = 1.2Hz), 7.90 (d, 1H, J = 1.6Hz), 7.28 (d, 1H, J = 1.6Hz), 6.78 (t, 1H, J = 5.6Hz), 4.20-4.10 (m, 1H), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H) ), 2.21 (S, 3H)HRMS (FAB – ): Calcd For M / Z 364.0369 (MH & lt;), Found M / Z 364.0395 (MH & lt;) (Step 2) (2) Compound obtained in step 1 of synthesis of 3-{[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate . To 64 g (net 10.0 g, 27.34 mmol), 18 mL of water (1.8 L / kg vs. the compound of Step 1) was added, and the mixture was stirred at 8 ° C. 3.42 mL (57.41 mmol, 2.1 eq.) Of a 48% aqueous sodium hydroxide solution was added dropwise, and the mixture was washed with 1.0 mL (1.0 L / kg) of water and then stirred at 8 ° C. for 15 minutes. After confirming the completion of hydrolysis by HPLC, the temperature was raised to 25 ° C. and 48% HBr aq. About 3.55 mL was added to adjust the pH to 5.8. After confirming the precipitation of the desired product by dropping 65 mL (6.5 L / kg) of isopropyl alcohol, the mixture was aged for 1 hour. 81 mL (8.1 L / kg) of isopropyl alcohol was added dropwise and the mixture was aged at 8 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of isopropyl alcohol, and then dried under reduced pressure at 40 ° C. for 4 hours to obtain 10.7 g of the desired product as a white solid (net 9.46 g, 92). .6%). 1 H-NMR (400MHz, DMSO-d6): δ8.76 (s, 1H), 7.91 (d, 1H, J = 1.6Hz), 8.00-7.50 (bs, 2H), 7.24 (d, 1H, J = 1.6Hz), 7.20 (t, 1H, J = 5.6Hz), 3.58-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.23 (s, 3H)
https://patents.google.com/patent/WO2012072663A1/enEXAMPLESExample 1 : Synthesis and isolation of (+)-2-amino-3,6-dihydro-4-dimethylamino-6- methyl-l,3,5-triazine hydrochloride by the process according to the invention
Preliminary step: Synthesis of racemic 2-amino-3,6-dihydro-4-dimethylamino- 6-methyl-l,3,5-triazine hydrochloride:
Metformin hydrochloride is suspended in 4 volumes of isobutanol. Acetaldehyde diethylacetal (1.2 eq.) and para-toluenesulfonic acid (PTSA) (0.05 eq) are added and the resulting suspension is heated to reflux until a clear solution is obtained. Then 2 volumes of the solvent are removed via distillation and the resulting suspension is cooled to 20°C. The formed crystals are isolated on a filter dryer and washed with isobutanol (0.55 volumes). Drying is not necessary and the wet product can be directly used for the next step.Acetaldehyde diethylacetal can be replaced with 2,4,6-trimethyl-l,3,5-trioxane (paraldehyde).- Steps 1 and 2: formation of the diastereoisomeric salt and isolation of the desired diastereoisomer
Racemic 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine hydrochloride wet with isobutanol (obtained as crude product from preliminary step without drying) and L-(+)-Tartaric acid (1 eq.) are dissolved in 2.2 volumes of methanol at 20-40°C. The obtained clear solution is filtered and then 1 equivalent of triethylamine (TEA) is added while keeping the temperature below 30°C. The suspension is heated to reflux, stirred at that temperature for 10 minutes and then cooled down to 55°C. The temperature is maintained at 55°C for 2 hours and the suspension is then cooled to 5- 10°C. After additional stirring for 2 hours at 5-10°C the white crystals are isolated on a filter dryer, washed with methanol (2 x 0.5 Vol) and dried under vacuum at 50°C. The yield after drying is typically in the range of 40-45%
– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt
γ ethanol HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt is suspended in 2 volumes of ethanol and 1.02 equivalents of HCl-gas are added under vacuum (-500 mbar). The suspension is heated to reflux under atmospheric pressure (N2) and 5% of the solvent is removed via distillation. Subsequent filtration of the clear colourless solution into a second reactor is followed by a cooling crystallization, the temperature is lowered to 2°C. The obtained suspension is stirred at 2°C for 3 hours and afterwards the white crystals are isolated with a horizontal centrifuge. The crystal cake is washed with ethanol and dried under vacuum at 40°C. The typical yield is 50-55% and the mother liquors can be used for the recovery of about 25-30%) of (+)-2-amino- 3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate.Example 2: Modification of the solvent of steps 3 and 4
– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt
HN^NH acetone HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt synthesized according to steps 1 and 2 of example 1 is suspended in 1 volume (based on total amount of (+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt) of acetone at 20°C. To this suspension 1.01 equivalents of 37% Hydrochloric acid are added. The suspension is heated to reflux under atmospheric pressure (N2) and water is added until a clear solution is obtained. 1.5 vol of acetone are added at reflux temperature. The compound starts crystallising and the obtained suspension is kept at reflux for 2 hours followed by a cooling crystallization to 0°C. The obtained suspension is stirred at 0°C for 2 hours and the white crystals are isolated by centrifugation. The crystal cake is washed with isopropanol and dried under vacuum at 40°C in a continuous drying oven.
ClassAmides; Analgesics; Antirheumatics; Drug conjugates; Glycosaminoglycans; Nonsteroidal anti-inflammatories
Mechanism of ActionCyclooxygenase inhibitors
RegisteredOsteoarthritis
Phase IITendinitis
23 Mar 2021Registered for Osteoarthritis in Japan (Intra-articular)
25 Sep 2020Phase II for Osteoarthritis is still ongoing in USA (Seikagaku Corporation pipeline, September 2020)
25 Sep 2020Phase II for Tendinitis is still ongoing in Japan (Seikagaku Corporation pipeline, September 2020)
In today’s aging society, osteoarthritis (hereinafter also referred to as “OA” in the present specification), which is a dysfunction caused by joint pain and joint degeneration, is the most common joint disease in the world. It is one of the major causes of physical disorders that interfere with daily life in the elderly. Further, as a disease accompanied by swelling and pain in joints, rheumatoid arthropathy (hereinafter, also referred to as “RA” in the present specification), which is polyarthritis, is known. In RA as well, when the condition progresses over a long period of time, cartilage and bones are destroyed and degeneration or deformation occurs, resulting in physical disorders that interfere with daily life, such as narrowing the range in which joints can be moved.
Currently, preparations using hyaluronic acid and its derivatives are used as medicines for arthropathy such as osteoarthritis and rheumatoid arthropathy. Hyaluronic acid preparations are usually formulated as injections, and for the purpose of improving dysfunction due to arthropathy and suppressing pain through the lubricating action, shock absorption action, cartilage metabolism improving action, etc. of hyaluronic acid, the affected knee, It is administered directly to joints such as the shoulders. Commercialized hyaluronic acid preparations include, for example, those containing purified sodium hyaluronate as an active ingredient (for example, Alz (registered trademark) and Svenir (registered trademark)). The preparation requires continuous administration of 3 to 5 times at a frequency of once a week. In addition, preparations containing crosslinked hyaluronan as an active ingredient require three consecutive doses once a week (for example, Synvisc®), or treatment is completed with a single dose. For single dose administration (eg, Synvisc-One®, Gel-One®, MONOVISC®) are known.On the other hand, steroids and non-steroidal anti-inflammatory compounds are known as quick-acting drugs, and are also used for treatments aimed at relieving joint pain caused by OA and RA. For example, the steroid triamcinolone acetonide has been used as a therapeutic target for joint diseases such as rheumatoid arthritis. Triamcinolone acetonide is commercially available as a drug that is injected intra-articularly and requires administration every 1 to 2 weeks for treatment. Further, as non-steroidal anti-inflammatory compounds, for example, ointments containing diclofenac sodium as an active ingredient and oral administration agents are known.It is also known that a mixture or a conjugate of hyaluronic acid or a derivative thereof and a steroid or a non-steroidal anti-inflammatory compound is used as an active ingredient. For example, a mixture of crosslinked hyaluronic acid and triamcinolone hexaacetonide (CINGAL®) has been commercialized as a single-dose drug. Further, a compound in which hyaluronic acid or a derivative thereof is linked to a steroid or a non-steroidal anti-inflammatory compound is also known. For example, Patent Documents 1 and 2 describe derivatives in which an anti-inflammatory compound is introduced into hyaluronic acid via a spacer. These aim to achieve both fast-acting pain relief and long-term pain relief through improvement of dysfunction. However, it has not yet reached the stage where it can be said that sufficient treatment methods for OA and RA have been established and provided.
<Synthesis Example> Aminoethanol-diclofenac-introduced sodium hyaluronate (test substance) was synthesized according to the method described in Examples of International Publication No. 2005/066241 (hyaluronic acid weight average molecular weight: 800,000, introduction rate). : 18 mol%). More specifically, it was synthesized by the following method. 2.155 g (10.5 mmol) of 2-bromoethylamine hydrobromide is dissolved in 20 mL of dichloromethane, 1.436 mL (10.5 mmol) of triethylamine is added under ice-cooling, and di-tert-butyl-dicarbonate (Boc) is added. 2 O) 2.299 g (10.5 mmol) of a dichloromethane solution of 5 mL was added and stirred. After stirring at room temperature for 90 minutes, ethyl acetate was added, and the mixture was washed successively with 5 wt% citric acid aqueous solution, water and saturated brine. After dehydration with sodium sulfate, the solvent was distilled off under reduced pressure to obtain Boc-aminoethyl bromide. 5 mL of a dimethylformamide (DMF) solution of 2.287 g (10.2 mmol) of Boc-aminoethyl bromide obtained above is ice-cooled, 6 mL of a DMF solution of 3.255 g (10.2 mmol) of diclofenac sodium is added, and the mixture is added at room temperature. Stirred overnight. The mixture was stirred at 60 ° C. for 11 hours and at room temperature overnight. Ethyl acetate was added, and the mixture was sequentially separated and washed with a 5 wt% aqueous sodium hydrogen carbonate solution, water, and saturated brine. After dehydration with sodium sulfate, ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (toluene: ethyl acetate = 20: 1 (v / v), 0.5% by volume triethylamine) to obtain Boc-aminoethanol-diclofenac. 2.108 g (4.80 mmol) of Boc-aminoethanol-diclofenac obtained above was dissolved in 5 mL of dichloromethane, 20 mL of 4M hydrochloric acid / ethyl acetate was added under ice-cooling, and the mixture was stirred for 2.5 hours. Diethyl ether and hexane were added and precipitated, and the precipitate was dried under reduced pressure. As a result, aminoethanol-diclofenac hydrochloride was obtained. Structure 1 was identified by-NMR H: 1 H-NMR (500 MHz, CDCl 3 ) [delta] (ppm) = 3.18 (2H,t, NH 2 CH 2 CH 2 O-), 3.94 (2H, s, Ph-CH 2 -CO), 4.37 (2H, t, NH 2 CH 2 CH 2 O-), 6.47-7.31 (8H, m, Aromatic H, NH). After dissolving 500 mg (1.25 mmol / disaccharide unit) of hyaluronic acid having a weight average molecular weight of 800,000 in 56.3 mL of water / 56.3 mL of dioxane, imide hydroxysuccinate (1 mmol) / 0.5 mL of water, water-soluble carbodiimide Hydrochloride (WSCI / HCl) (0.5 mmol) / water 0.5 mL, aminoethanol-diclofenac hydrochloride (0.5 mmol) / (water: dioxane = 1: 1 (v / v), 5 mL obtained above ) Was added in sequence, and the mixture was stirred all day and night. 7.5 mL of a 5 wt% sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the mixture was stirred for about 4 hours. 215 μL of a 50% (v / v) acetic acid aqueous solution was added to the reaction solution for neutralization, and then 2.5 g of sodium chloride was added and the mixture was stirred. 400 ml of ethanol was added to precipitate, and the precipitate was washed twice with an 85% (v / v) aqueous ethanol solution, twice with ethanol, and twice with diethyl ether, dried under reduced pressure overnight at room temperature, and aminoethanol-diclophenac. Introduction Sodium hyaluronate (test substance) was obtained. The introduction rate of diclofenac measured by a spectrophotometer was 18 mol%.
Anamorelin is a non-peptidic ghrelin mimetic Treatment of cancer anorexia and cancer cachexia
Anamorelin hydrochloride has been submitted New Drug Application (NDA) for the treatment of cachexia in non-small cell lung cancer (NSCLC) patients.
It was originally developed by Novo Nordisk, then it was licensed to Ono and Helsinn Therapeutics for the treatment of cachexia and anorexia in cancer patients.
Anamorelin hydrochloride has been submitted New Drug Application (NDA) for the treatment of cachexia in non-small cell lung cancer (NSCLC) patients.
It was originally developed by Novo Nordisk, then it was licensed to Ono and Helsinn Therapeutics for the treatment of cachexia and anorexia in cancer patients.
On 18 May 2017, the European Medicines Agency recommended the refusal of the marketing authorisation for the medicinal product, intended for the treatment of anorexia, cachexia or unintended weight loss in patients with non-small cell lung cancer. Helsinn requested a re-examination of the initial opinion. After considering the grounds for this request, the European Medicines Agency re-examined the opinion, and confirmed the refusal of the marketing authorisation on 14 September 2017.[8] The European Medicines Agency concluded that the studies show a marginal effect of anamorelin on lean body mass and no proven effect on hand grip strength or patients’ quality of life. In addition, following an inspection at clinical study sites, the agency considered that the safety data on the medicine had not been recorded adequately. Therefore, the agency was of the opinion that the benefits of anamorelin did not outweigh its risks.[9]
The chemical name of anamorelin hydrochloride is 2-Amino-N-((R)-1-((R)-3-benzyl-3-(1,2,2-trimethylhydrazine-1-carbonyl)piperidin-1-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-2-methylpropanamide hydrochloride corresponding to the molecular formula C31H42N6O3•HCl and has a relative molecular mass 583.16 g/mol and has the following structure:
The structure of the active substance was elucidated by a combination of 1 H-NMR, 13C-NMR, elemental analysis, FT-IR, UV and and mass spectrometry. Anamorelin HCl appears as a white to off-white hygroscopic solid, freely soluble in water, methanol and ethanol, sparingly soluble in acetonitrile and practically insoluble in ethyl acetate, isopropyl acetate and n-heptane. Its pka was found to be 7.79 and the partition coefficient 2.98. It has two chiral centres with the R,R absolute configuration, which is controlled in the active substance specification by chiral HPLC. Based on the presented data, neither anamorelin hydrochloride, nor any of its salts have been previously authorised in medicinal products in the European Union. Anamorelin is therefore considered as a new active substance.
SYN
OPRD
PATENT
WO 9958501
PATENT
WO 2001034593
https://patents.google.com/patent/WO2001034593A1/enExample 1A procedure for the preparation of the compound which is either 2-Amino-N-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1- (1 H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide
A one-necked round-bottom flask (1 I) equipped with a magnetic stirrer and addition funnel was charged with NaOH-pellets (15,6 g), tetrahydrofuran (400 ml) and ethylnipecotate (50 ml, 324 mmol). To the stirred mixture at room temperature was added dropwise a solution of Boc2O (84,9 g, 389 mmol) dissolved in tetrahydrofuran (150 ml) (1 hour, precipitation of white solid, NaOH-pellets dissolved, exoterm). The mixture was stirred overnight at room temperature. The mixture was added to EtOAc (500 ml) and H2O (2000 ml), and the aqueous layer was re-extracted with EtOAc (2 X 500 ml) and the combined organic layers were washed with brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to afford piperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (82,5 g) as a thin yellow oil.1H-NMR (300 MHz, CDCI3): δ 1,25 (t, 3H, CH3); 1 ,45 (s, 9H, 3 X CH3); 2,05 (m, 1H); 2,45 (m, 1H); 2,85 (m, 1 H); 3,95 (d (broad), 1 H); 4,15 (q, 2H, CH2)Step b3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tetf-butyl ester 3-ethyl ester (racemic mixture)
A three-necked round-bottom flask (2 I) equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was evacuated, flushed with nitrogen, charged with anhydrous tetrahydrofuran (500 ml) and cooled to -70 °C. Then lithium diisopropylamine (164 ml of a 2,0 M solution in tetrahydrofuran, 327 mmol) was added. To the stirred solution at -70 °C was added dropwise over 45 min. a solution of piperidine-1 ,3-dicarboxylic acid 1- tert-butyl ester 3-ethyl ester (80 g, 311 mmol) in anhydrous tetrahydrofuran (50 ml) (temperature between -70 °C and -60 °C, clear red solution). The mixture was stirred for 20 min. and followed by dropwise addition over 40 min. of a solution of benzylbromide (37 ml, 311 mmol) in anhydrous tetrahydrofuran (250 ml) (temperature between -70 °C and -60 °C). The mixture was stirred for 1 hour at -70 °C, and then left overnight at room temperature (pale orange).The reaction mixture was concentrated in vacuo to approx. 300 ml, transferred to a separating funnel, diluted with CH2CI2 (900 ml) and washed with H2O (900 ml). Due to poor separation the aqueous layer was re-extracted with CH2CI2 (200 ml), the combined organic layers were washed with aqueous NaHSO4 (200 ml, 10%), aqueous NaHCO3 (200 ml, saturated), H2O (200 ml), brine (100 ml), dried over MgSO4> filtered and concentrated in vacuo to afford an oil, which was dissolved in EtOAc(1):heptane(10) and aged overnight. The solids formed was removed by filtration, washed with heptane and dried in vacuo to give a racemic mixture of 3-benzylpiperidine-1 ,3-dicarboxylic acid 1-ter–butyl ester 3-ethyl ester (81 ,4 g). ■ HPLC (h8): Rt = 15,79 min.LC-MS: Rt = 7,67 min. (m+1) = 348,0Step c 3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester (racemic mixture)
3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (81 g, 233 mmol) was dissolved in EtOH (400 ml) and NaOH (400 ml, 16% aqueous solution) in a one neck round- bottom flask (1 L) equipped with a condenser and a magnetic stirrer. The mixture was refluxed for 10 h under nitrogen, and cooled to room temperature, concentrated in vacuo to approx. 600 ml (precipitation of a solid), diluted with H2O (400 ml), cooled in an icebath, and under vigorous stirring acidified with 4 M H2SO4 until pH = 3 (final temperature: 28 °C). The mixture was extracted with EtOAc (2 X 700 ml), and the combined organic layers were washed with brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to afford an oil, which was dissolved in EtOAc(1):heptane(10) and aged overnight. The crystals formed were removed by filtration, washed with heptane and dried in vacuo to give a racemic mixture of 3-benzylpiperidine-1 ,3-dicarboxylic acid 1-tetf-butyl ester (66,0 g)HPLC (h8): Rt = 12,85 min.LC-MS: Rt = 5,97 min. (m+1) = 320,0Chirale HPLC (Chiracel OJ, heptane(92):iPrOH(8):TFA(0,1)): Rt = 8,29 min. 46,5 % Rt = 13,69 min. 53,5 %Step d(3R)-3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-Benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester
(Resolution of 3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester)
3-Benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester (76 g, 238 mmol) was dissolved in EtOAc (3,0 L) in a one neck flask (5L) equipped with magnetic stirring. Then H2O (30 ml), R(+)-1-phenethylamine (18,2 ml, 143 mmol) and Et3N (13,2 ml, 95 mmol) were added and the mixture was stirred overnight at room temperature resulting in precipitation of white crystals (41 ,9 g), which were removed by filtration, washed with EtOAc and dried in vacuo. The precipitate was dissolved in a mixture of aqueous NaHSO4 (300 ml, 10%) and EtOAc (600 ml), layers were separated and the aqueous layer re-extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo to afford a colourless oil, which was dissolved in EtOAc(1):heptane(10) and aged overnight. The crystals that had been formed were removed by filtration, washed with heptane and dried in vacuo to give one compound which is either (3R)-3-benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-benzylpiperidine- 1,3-dicarboxylic acid 1-tert-butyl ester (27,8 g).Chirale HPLC (Chiracel OJ, heptane(92):iPrOH(8):TFA(0,1)):Rt = 7,96 min. 95,8 % eeStep e(3R)-3-Benzyl-3-(N,N’1N’-trimethylhvdrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester or (3S)-3-Benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester
Trimethylhydrazine dihydrochloride (15,3 g, 104 mmol) was suspended in tetrahydrofuran (250 ml) in a one-neck round-bottom flask (1 I) equipped with a large magnetic stirrer, and an addition funnel/nitrogen bubbler. The flask was then placed in a water-bath (temp: 10- 20°C), bromo-rrts-pyrrolydino-phosphonium-hexafluorophosphate (40,4 g, 86,7 mmol) was added, and under vigorous stirring dropwise addition of diisopropylethylamine (59 ml, 347 mmol). The mixture (with heavy precipitation) was stirred for 5 min., and a solution of the product from step d which is either (3R)-3-benzylpiperidine-1 ,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester (27,7 g, 86,7 mmol) in tetrahydrofuran (250 ml) was added slowly over 1 ,5 hour. The mixture was stirred overnight at room temperature. The reaction was diluted with EtOAc (1000 ml), washed with H2O (500 ml), aqueous NaHSO4, (200 ml, 10%), aqueous NaHCO3 (200 ml, saturated), brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to afford a thin orange oil. The mixture was dissolved in EtOAc (300 ml), added to SiO2 (150 g) and concentrated in vacuo to a dry powder which was applied onto a filter packed with SiO2 (150 g), washed with heptan (1 I) and the desired compound was liberated with EtOAc (2,5 I). After concentration in vacuo, the product which is either (3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)-piperidine-1- carboxylic acid tert-butyl ester or (3S)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)- piperidine-1-carboxylic acid tert-butyl ester (49 g) as an orange oil was obtained.HPLC (h8): Rt = 14,33 min.Ste f(3R)-3-Benzyl-piperidine-3-carboxylic acid trimethylhydrazide or (3S)-3-Benzyl-piperidine-3- carboxylic acid trimethylhydrazide
The product from step e which is either (3R)-3-Benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)-piperidine-1 -carboxylic acid tert-butyl ester or (3S)-3-Benzyl-3- (N,N’,N’-trimethylhydrazinocarbonyl)-piperidine-1 -carboxylic acid tert-butyl ester (56,7 g, 100,9 mmol) was dissolved in EtOAc (500 ml) (clear colourless solution) in a one-neck roundbottom flask (2L) equipped with magnetic stirring. The flask was then placed in a waterbath (temp: 10-20 °C), and HCI-gas was passed through the solution for 5 min. (dust- like precipitation). After stirring for 1 hour (precipitation of large amount of white crystals), the solution was flushed with N2 to remove excess of HCI. The precipitate was removed by gentle filtration, washed with EtOAc (2 X 100 ml), and dried under vacuum at 40 °C overnight to give the product which is either (3R)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide or (3S)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide (37,0 g).HPLC (h8): Rt = 7,84 min.Step q r(1 R)-2-r(3R)-3-Benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidin-1-vn-1-((1 H-indol-3- yl)methyl)-2-oxoethvncarbamic acid tert-butyl ester or .(1 R)-2-..3S)-3-Benzyl-3-(N,N’,N’- trimethylhvdrazinocarbonyl)piperidin-1-vn-1-((1 H-indol-3-yl)methyl)-2-oxoethyllcarbamic acid tert-butyl ester
Boc-D-Trp-OH (32,3 g, 106 mmol) was dissolved in dimethylacetamide (250 ml) in a one- neck roundbottom flask (500 ml) equipped with a magnetic stirrer and a nitrogen bubbler. The solution was cooled to 0-5 °C and 1-hydroxy-7-azabenzotriazole (14,4 g, 106 mmol), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (20,3 g, 106 mmol), N- methylmorpholine (11 ,6 ml, 106 mmol) were added. After stirring for 20 min. at 0-5 °C the product from step f which is either (3R)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide or (3S)-3-benzyl-piperidine-3-carboxylic acid trimethylhydrazide (37,0 g, 106 mmol) and N-methylmorpholine (24,4 ml, 223 mmol) were added. The reaction was stirred overnight at room temperature. The mixture was then added to EtOAc (750 ml) and washed with aqueous NaHSO4 (300 ml, 10 %). The layers were allowed to separate, and the aqueous layer was re-extracted with EtOAc (500 ml). The combined organic layers were washed with H2O (100 ml), aqueous NaHCO3 (300 ml, saturated), H2O (100 ml), brine (300 ml), dried over MgSO4, filtered and concentrated in vacuo to afford the product which is either [(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1H- indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester or [(1 R)-2-[(3S)-3-benzyl-3- (N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-((1 H-indol-3-yl)methyl)-2- oxoethyljcarbamic acid tert-butyl ester (56,7g) as an orange oil.HPLC (h8): Rt = 14,61 min.LC-MS: Rt = 7,35 min. (m+1 ) = 562,6Step h1 -f(2R)-2-Amino-3-(1 H-indol-3-yl)propionylH3R)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide or 1-f(2R)-2-Amino-3-(1 H-indol-3-yl)propionvn-(3S)-3-benzylpiperidine-3- carboxylic acid trimethylhydrazide
The product from step g which is either [(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)piperidin-1 -yl]-1 -((1 H-indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester or [(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1- yl]-1-((1 H-indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester (56,7 g, 100,9 mmol) was dissolved in EtOAc (500 ml) (clear colourless solution) in a one-neck round-bottom flask (2L) equipped with magnetic stirring. The flask was then placed in a water-bath (temp: 10-20 °C), and HCI-gas was passed through the solution for 10 min. (heavy precipitation of oil). The mixture was flushed with N2 to remove excess of HCI and then separated into an oil and an EtOAc-layer. The EtOAc-layer was discarded. The oil was dissolved in H2O (500 ml), CH2CI2 (1000 ml), and solid Na2CO3 was added until pH > 7. The layers were separated, and the organic layer was washed with H2O (100 ml), brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to afford the product which is either 1-[(2R)-2-amino-3-(1 H-indol- 3-yl)propionyl]-(3R)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide or 1-[(2R)-2- amino-3-(1H-indol-3-yl)propionyl]-(3S)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide (27 g) as an orange foam.HPLC (h8): Rt = 10,03 min.Step i(1-r(1 R)-2-r(3R)-3-Benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidin-1-vn-1-(1H-indol-3- ylmethyl)-2-oxo-ethylcarbamovπ-1 -methylethyl fcarbamic acid tert-butyl ester or1-r(1 R)-2-r(3S)-3-Benzyl-3-(N,N’.N’-trimethylhvdrazinocarbonyl)piperidin-1-vn-1-(1 H-indol-3- ylmethyl)-2-oxo-ethylcarbamovπ-1-methylethyl)carbamic acid tert-butyl ester
Boc-Aib-OH (11 ,9 g, 58,4 mmol) was dissolved in dimethylacetamide (125 ml) in a one-neck roundbottom flask (500 ml) equipped with a magnetic stirrer and nitrogen bubbler. To the stirred solution at room temperature were added 1-hydroxy-7-azabenzotriazole (7,95 g, 58,4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (11 ,2 g, 58,4 mmol), and diisopropylethylamine (13,0 ml, 75,8 mmol). After 20 min. (yellow with precipitation) a solution of the product from step h which is either 1-[(2R)-2-amino-3-(1 H-indol-3- yl)propionyl]-(3R)-3-benzylpiperidine-3:carboxylic acid trimethylhydrazide or 1-[(2R)-2- amino-3-(1 H-indol-3-yl)propionyl]-(3S)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide (27,0 g, 58,4 mmol) in dimethylacetamide (125 ml) was added. The reaction was stirred at room temperature for 3 h. The mixture was added to EtOAc (750 ml) and washed with aqueous NaHSO4 (300 ml, 10 %). The layers were allowed to separate, and the aqueous layer was re-extracted with EtOAc (500 ml). The combined organic layers were washed with H2O (100 ml), aqueous NaHCO3 (300 ml, saturated), H2O (100 ml), brine (300 ml), dried over MgSO4, filtered and concentrated in vacuo to approx. 500 ml. Then SiO2 (150 g) was added and the remaining EtOAc removed in vacuo to give a dry powder which was applied onto a filter packed with SiO2 (150 g), washed with heptan (1 L), and the desired compound was liberated with EtOAc (2,5 L). After concentration in vacuo, the product which is either {1-[(1 R)-2-[(3R)-3-benzyl-3-(N, N’, N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1- (1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester or {1-[(1R)-2-[(3S)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1 H-indol-3- ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester 33,9 g as an orange foam was obtained.HPLC (h8): Rt = 14,05 min.Step j2-Amino-N-r(1 R)-2-f(3R)-3-benzyl-3-(N,N’,N’-trimethylhvdrazinocarbonyl)piperidin-1-vπ-1- (1 H-indol-3-ylmethyl)-2-oxoethyll-2-methylpropionamide, fumarate or2-Amino-N-r(1 R)-2-r(3S)-3-benzyl-3-(N1N’1N’-trimethylhvdrazinocarbonyl)piperidin-1-yll-1- (1H-indol-3-ylmethyl)-2-oxoethvπ-2-methylpropionamide, fumarate
The product from step i which is either {1-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1- methylethyl}carbamic acid tert-butyl ester or {1-[(1 R)-2-[(3S)-3-benzyl-3-(N,N’,N’- trimethylhydrazinocarbonyl)piperidin-1 -yl]-1 -(1 H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1 – methylethyljcarbamic acid tert-butyl ester (23,8 g, 36,8 mmol) was dissolved in of EtOAc (800 ml) (clear yellow solution) in a one neck round-bottom flask (1L) equipped with magnetic stirring. The flask was then placed in a water-bath (temp: 10-20 °C), and HCI-gas was passed through the solution for 5 min. (dust-like precipitation). After stirring for 1 hour (precipitation of large amount of yellow powder), the solution was flushed with N2 to remove excess of HCI. The precipitate was removed by gentle filtration and dried under vacuum at 40 °C overnight.The non-crystallinic precipitate was dissolved in H2O (500 ml) and washed with EtOAc (100 ml). Then CH2CI2 (1000 ml) and solid Na2CO3 was added until pH > 7. The 2 layers were separated, and the aqueous layer was e-extracted with CH2CI2 (200 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and redissolved in EtOAc (500 ml) in a one neck round-bottom flask (1 L) equipped with magnetic stirring. A suspension of fumaric acid (3,67 g) in isopropanol (20 ml) and EtOAc (50 ml) was slowly added (5 min.), which resulted in precipitation of a white crystallinic salt. After 1 hour the precipitation was isolated by filtration and dried overnight in vacuum at 40 °C to give the fumarate salt of the compound which is either 2-amino-N-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1- yl]-1-(1 H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide or 2-amino-N-[(1 R)-2-[(3S)-3- benzyl-3-(N,N,,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1 H-indol-3-ylmethyl)-2- oxoethyl]-2-methylpropionamide (13,9 g) as a white powder.HPLC (A1): Rt = 33,61 min.HPLC (B1): Rt = 34,62 min. LC-MS: Rt = 5,09 min. (m+1) = 547,4 ClaimsHide Dependent 1. The compound obtainable by the procedure as described in example 1 , or a pharmaceutically acceptable salt thereof.2. The compound obtainable by the procedure as described in example 1 , and which compound is2-Amino-N-[(1 R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylhydrazinocarbonyl)piperidin-1-yl]-1- (1 H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide
or a pharmaceutically acceptable salt thereof.3. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.4. A pharmaceutical composition according to claim 3 for stimulating the release of growth hormone from the pituitary.5. A pharmaceutical composition according to claim 3 or claim 4 for administration to animals to increase their rate and extent of growth, to increase their milk and wool production, or for the treatment of ailments.6. A method of stimulating the release of growth hormone from the pituitary of a mammal, the method comprising administering to said mammal an effective amount of a compound according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof, or of a composition according to any one of claims 3 – 5.7. A method of increasing the rate and extent of growth, the milk and wool production, or for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or of a composition according to any one of claims 3-5.8. Use of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament.9. Use according to claim 8 wherein the medicament is for stimulating the release of growth hormone from the pituitary of a mammal.
Growth hormone is a major participant in the control of several complex physiologic processes, including growth and metabolism. Growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilization and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
The release of growth hormone from the pituitary is controlled, directly or indirectly, by number of hormones and neurotransmitters. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example, arginine, L-3,4-dihydroxyphenylalanine (1-Dopa), glucagon, vasopressin, PACAP (pituitary adenylyl cyclase activating peptide), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed. For example, U.S. Pat. Nos. 6,303,620 and 6,576,648 (the entire contents of which are incorporated herein by reference), disclose a compound: (3R)-1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide, having the following chemical structure:
(MOL)(CDX) which acts directly on the pituitary cells under normal experimental conditions in vitro to release growth hormone therefrom. This compound is also known under the generic name “anamorelin.” This growth hormone releasing compound can be utilized in vitro as a unique research tool for understanding, inter alia, how growth hormone secretion is regulated at the pituitary level. Moreover, this growth hormone releasing compound can also be administered in vivo to a mammal to increase endogenous growth hormone release.
Example 1
Crystallization of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide form A
0.0103 g of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-piperidinecarboxylic acid 1,2,2-trimethylhydrazide was dissolved in methanol (0.1 mL) in a glass vial. The glass vial was then covered with PARAFILM® (thermoplastic film) which was perforated with a single hole. The solvent was then allowed to evaporate under ambient conditions. An X-ray diffraction pattern showed the compound was crystalline ( FIG. 1).
PATENT
WO 2017067438
https://patents.google.com/patent/WO2017067438A1/enAnamorelin, whose chemical name is: (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2- Trimethylformylhydrazide is a compound that increases mammalian growth hormone levels and has a compound structure as shown in Formula I:
Cancer cachexia is a state of consumption in which patients lose a lot of weight and muscle mass. It is necessary for the treatment of cachexia because it weakens the patient, affects the quality of life and interferes with the patient’s treatment plan. The drug alamorelin produces the same effect as the so-called “starved hormone” ghrelin, which stimulates hunger. Alamolin is a mimetic of ghrelin, which is secreted by the stomach and is a ligand for growth hormone receptors. . Alamolin binds to this receptor, causing the release of growth hormone, causing a metabolic cascade that affects a variety of different factors, including fat-removing body weight, as well as blood sugar metabolism. Therefore, alamorelin can also enhance the appetite of patients and help patients stay healthy. The 2014 European Society of Medical Oncology (ESMO) in Madrid, Spain, announced that Alamolin is expected to be the first drug in history to effectively improve cancer cachexia.Alamolin is a drug developed by Helsinn Therapeutics (Switzerland) from Novo Nordisk for the development of a cachexia and anorexia for patients with cancer, including non-small cell lung cancer. It can also be used to treat hip fractures and preventive diseases. The strength of the elderly and the elderly has continued to decline. In two key, 12-week Phase III clinical trials (ROMANA 1, ROMANA 2), alamorelin can significantly increase the body fat loss, and is generally tolerated; the incidence of serious adverse drug reactions is less than 3%, mainly related to hyperglycemia and diabetes. Compared with the placebo group, alamorelin continued to increase body weight and improve cancer anorexia-cachexia-related symptoms and concerns; however, there was no significant difference in the improvement of grip strength between the alamolin group and the placebo group. Therefore, this product has excellent clinical value and market value.The polymorphic form of the drug free base and its preparation are reported as follows:Synthesis of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylmethyl is disclosed in the patent ZL99806010.0 A method for synthesizing hydrazide, and using [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylmethylcarbonyl)piperidin-1-yl tert-Butyl ester of 1-((1H-indol-3-yl)methyl)-2-oxoethyl]carbamate is dissolved in dichloromethane, then trifluoroacetic acid is added to remove tert-butyl formate After the base, the mixture was concentrated to remove the solvent, and then the product was extracted with dichloromethane, and the obtained extract was concentrated to dryness to give (3R)-1-(2-methylalanyl-D-color ammonia as an amorphous powder. Acyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide.Patent ZL00815145.8 discloses the synthesis of alamorelin and its compounds as pharmaceutically acceptable salts, relating to novel diastereomeric compounds, pharmaceutically acceptable salts thereof, compositions containing them and their use in therapy Lack of use of medical conditions caused by growth hormone. Synthesis of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformyl is disclosed in this patent. The synthesis method of hydrazine, and using [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylmethylcarbonylcarbonyl)piperidin-1-yl] 1-((1H-Indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester was dissolved in ethyl acetate, and then hydrogen chloride gas was passed to remove the tert-butyl formate protection group. , the solid is dissolved in water, and then the pH is adjusted to about 7 with sodium carbonate, and the product is extracted with dichloromethane; the extract phase is concentrated to obtain (3R)-1-(2-methylalanyl-D-tryptophan). -3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazide.Patent WO2006016995 discloses (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylmethyl as a medicament Crystalline polymorphs of hydrazides, methods of producing and separating these polymorphs, and pharmaceutical compositions and drug therapies containing these polymorphs, the crystalline polymorphs for direct application to the pituitary Gland cells release the growth hormone. This patent discloses (4R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazone 4 Crystal form: Form A, Form B, Form C and Form D. The patent also provides the preparation of 3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazone. The method of crystal form, especially the preparation method of Form C, in which the method of removing the tert-butyl formate protecting group of methanesulfonic acid in methanol is utilized without exception. As a well-known cause in the art, clinical studies have found that mesylate is genotoxic, and its DNA alkylation leads to mutagenic effects, in which methyl methanesulfonate and ethyl methanesulfonate have been reported. (eg document EMEA/44714/2008). The invention adopts hydrochloric acid or hydrogen chloride gas to remove the tert-butyl formate protecting group, avoids the method of removing methanesulfonic acid, thereby avoiding the risk of the genotoxic impurities in the process, and increasing the risk. The safety of the drug.(3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-three prepared by the patent ZL99806010.0 and the patent ZL00815145.8 Methyl formyl hydrazide, no data on the purity of its compounds, we found that (3R)-1-(2-methylalanyl-D-tryptophan)-3 was prepared by this method. -Benzyl-3-piperidine 1,2,2-trimethylformylhydrazide does not help to remove the impurities produced, and the purity of the obtained product is not high, and it is difficult to meet the medicinal requirements. And (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethyl obtained by the preparation method of the present invention. The crystal form of the formyl hydrazide has a purity of 99.8% and a single impurity of less than 0.1%, which fully meets the requirements for medicinal purity. Moreover, the crystal form is stable to conditions such as pressure, temperature, humidity and illumination, and the preparation method is simple in operation and suitable for industrial production.Example 1:300 g of [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylcarbamidocarbonyl)piperidin-1-yl]-1-(( 1H-Indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester was added to the reaction flask, and then 4 L of dichloromethane was added to the reaction flask, and the raw material was completely dissolved by stirring.Then, the reaction system is cooled to 10 ° C or lower in an ice bath, hydrogen chloride gas is continuously supplied to the reaction liquid, and solids are gradually precipitated, and the reaction is further maintained at about 10 ° C for 3 to 5 hours, and the sample is detected. After the reaction of the raw materials is completed, the reaction system is completed. 1.5 L of water was added thereto, the solid was completely dissolved, and then the pH was adjusted to about 8 with a 20% aqueous sodium hydroxide solution, and the layers were separated; the aqueous phase was extracted once more with dichloromethane, and the organic phases were combined.The organic phase was dried over anhydrous sodium sulfate for 3 hrs, filtered, and then evaporated to ethylamine 3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude 246 g, yield 97.2%. HPLC content (area normalization method) was 96.1%.Example 2:300 g of [(1R)-2-[(3R)-3-benzyl-3-(N,N’,N’-trimethylcarbamidocarbonyl)piperidin-1-yl]-1-(( 1H-Indol-3-yl)methyl)-2-oxoethyl]carbamic acid tert-butyl ester was added to the reaction flask, 36% concentrated hydrochloric acid was added to the reaction flask, and the reaction system was heated to 40 with stirring. The reaction was carried out at ° C to 50 for 3 hours.Then, the sample is detected. After the reaction of the raw material is completed, the reaction system is cooled to 10 or less, and 2.0 L of dichloromethane is added to the reaction system, and then the pH is adjusted to about 8 with a 20% aqueous sodium hydroxide solution, and the aqueous phase is further separated. It was extracted once with dichloromethane and the organic phases were combined.The organic phase was dried over anhydrous sodium sulfate for 3 hrs, filtered, and then evaporated to ethylamine 3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude 248 g, yield 98%. HPLC content (area normalization method) was 96.2%.Preparation of (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazone E crystal formExample 3Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10g was added to the reaction flask and 30 ml of N- was added.Methylpyrrolidone, stirred and dissolved completely. Then, 60 ml of water was added dropwise to the reaction flask at room temperature, and the reaction liquid was heated to 60 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cooled to below 20 ° C, filtered, and the filter cake was washed with a mixture of N-methylpyrrolidone / H 2 O; the cake was vacuum dried at about 55 ° C to obtain (3R)-1-(2-methylalanyl) -D-tryptophan)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 9.5 g), HPLC content (area normalization) 99.72%. The XRD pattern is shown in Fig. 1, the DSC chart is shown in Fig. 2, and the TGA pattern is shown in Fig. 3, where the crystal form is defined as the E crystal form. The DSC of the crystal form has an endotherm at 120.05, the TGA is heated at 60A, and the crystal loss of 5 is about 3.1%. Combined with the Karl Fischer method, the moisture content of the product is determined. 3.1% and 3.2% indicate that the sample is present as a monohydrate.Example 4:Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 30 ml of N,N-dimethylformamide was added, stirred, and dissolved completely. Then, 30 ml of water was added dropwise to the reaction flask at room temperature, and the reaction solution was heated to 50 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 h.Slowly cool to below 10 ° C, filter, filter cake washed with N, N-dimethylformamide / H 2 O mixture; vacuum cake dried at around 55 ° C to obtain (3R)-1-(2-A Alanyl-D-tryptophanyl-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 8.5 g), HPLC content (area normalization) ) 99.87%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 5:Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 30 ml of dimethyl sulfoxide was added, stirred, and dissolved completely. Then, 40 ml of water was added dropwise to the reaction flask at room temperature, and the reaction liquid was heated to 60 ° C, the solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cooled to below 10 ° C, filtered, and the filter cake was washed with a mixture of dimethyl sulfoxide / H 2 O; the cake was vacuum dried at about 50 ° C to obtain (3R)-1-(2-methylalanyl) -D-tryptophanyl-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 9.1 g), HPLC content (area normalization) 99.61%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 6Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 40 ml of 1,4-dioxane was added, stirred, and dissolved completely. Then, 50 ml of water was added dropwise to the reaction flask at room temperature, and the reaction solution was heated to 70 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cooled to below 10 ° C, filtered, and the filter cake was washed with a mixture of 1,4-dioxane/H 2 O; the cake was vacuum dried at about 50 ° C to obtain (3R)-1-(2-methyl alanyl-D-tryptophan-3-Benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 8.7 g), HPLC content (area normalization) 99.11%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 7Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 40 ml of N,N-dimethylacetamide was added, stirred, and dissolved completely. Then, 40 ml of water was added dropwise to the reaction flask at room temperature, and the reaction solution was heated to 70 ° C. The solution became cloudy, and was slowly cooled to about 50 ° C. Seed crystals were added thereto, and cooling was continued to gradually precipitate a solid.The reaction system was cooled to about 10 ° C, filtered, and the filter cake was washed with a mixture of N,N-dimethylacetamide/H 2 O; the cake was vacuum dried at about 50 ° C to obtain (3R)-1-(2- Methylalanyl-D-tryptophanyl-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 8.1 g), HPLC content (area normalized) Law) 99.78%. Upon comparison, it was confirmed that the solid was in the E crystal form.Example 7Taking the above amorphous (3R)-1-(2-methylalanyl-D-tryptophyl)-3-benzyl-3-piperidine 1,2,2-trimethylformylhydrazine crude product 10 g was added to the reaction flask, 50 ml of acetone was added, stirred, and dissolved completely. Then, 70 ml of water was added dropwise to the reaction flask at room temperature, and the reaction liquid was heated to 45 ° C. The solution became cloudy, and a white solid was gradually precipitated, and stirring was continued for 2 hours.Slowly cool to below 10 ° C, filter, filter cake washed with acetone / H 2 O mixture; filter cake vacuum dried at around 50 ° C to obtain (3R)-1-(2-methylalanyl-D-color Aminoacyl-3-phenylmethyl-3-piperidine 1,2,2-trimethylformylhydrazide (white solid, 9.3 g), HPLC content (area normalization) 98.9%. Upon comparison, it was confirmed that the solid was in the E crystal form.
SYN
Reference：
1. Org. Process Res. Dev.2006, 10, 339–345.
Abstract
The rapid process development of a scaleable synthesis of the pseudotripeptide RC-1291 for preclinical and clinical evaluation is described. By employing a nontraditional N-to-C coupling strategy, the peptide chain of RC-1291 was assembled in high yield, with minimal racemization and in an economical manner by introducing the most expensive component last. A one-pot deprotection/crystallization procedure was developed for the isolation of RC-1291 free base, which afforded the target compound in excellent yield and with a purity of >99.5% without chromatographic purification.
(R,R)-2-Amino-N-[2-[3-benzyl-3-(N,N′,N′-trimethyl-hydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)- 2-oxo-ethyl]-2-methyl-propionamide (1). Crude 7 (911 g; 1.28 mol theoretical)10 was dissolved in methanol (4.12 L) in a 22-L round-bottom flask equipped with a mechanical stirrer, a temperature probe, a reflux condenser, a gas (N2) inlet, and an addition funnel. The solution was heated to 55 °C; then methanesulfonic acid (269.5 g, 2.805 mol) was added over a period of 15 min. (Caution: gas evolution!) The solution was then heated to 60 °C for a period of 1 h, after which HPLC analysis showed that no 7 remained. The temperature of the reaction mixture was increased to reflux (68-72 °C) over a period of 35 min, while simultaneously adding a solution of KOH (85%, 210.4 g, 3.187 mol) in water (4.12 L). The clear, slightly yellow solution was then allowed to cool to 20 °C at a rate of 5 °C/h. The free base of RC1291 (1) crystallized as a pale-yellow solid, which was isolated by filtration. The filter cake was washed with two portions of 50% aqueous methanol (500 mL each) and then dried under high vacuum at 20 ( 5 °C to afford 1 as an off-white, crystalline solid (595 g, 85% yield for two steps, >99.5% AUC by HPLC).
HRMS (ESI) calcd for C31H43N6O3 [M + H]+ 547.3397, found 547.3432.
Cachexia and muscle wasting are very common among patients suffering from cancer, chronic obstructive pulmonary disease, and other chronic diseases. Ghrelin stimulates growth hormone secretion via the ghrelin receptor, which subsequently leads to increase of IGF-1 plasma levels. The activation of the GH/IGF-1 axis leads to an increase of muscle mass and functional capacity. Ghrelin further acts on inflammation, appetite, and adipogenesis and for this reason was considered an important target to address catabolic conditions. We report the synthesis and properties of an indane based series of ghrelin receptor full agonists; they have been shown to generate a sustained increase of IGF-1 levels in dog and have been thoroughly investigated with respect to their functional activity.
Patent
https://patents.google.com/patent/EP2838892A1/enGrowth hormone is a major participant in the control of several complex physiologic processes including growth and metabolism. Growth hormone is known to have a number of effects on metabolic processes such as stimulating protein synthesis and mobilizing free fatty acids, and causing a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiencies in growth hormone can result in dwarfism and other severe medical disorders.The release of growth hormone from the pituitary gland is controlled directly and indirectly by a number of hormones and neurotransmitters. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin.The use of certain compounds to increase levels of growth hormone in mammals has previously been proposed. Anamorelin is one such compound. Anamorelin is a synthetic orally active compound originally synthesized in the 1990s as a growth hormone secretogogue for the treatment of cancer related cachexia. The free base of anamorelin is chemically defined as:® (3R) 1 -(2-methylaIanyl~D ryptophyl)~3-(phenylraethyl)~3~piperidineearboxylie acid 1 ,2,2trimethyihydrazide,* 3-{(2R)-3-{(3R)-3-benzyi-3-| (trimethylhydrazino)carbonyi]piperidin-l»yl}-2-[(2»met hylaianyl)amino]-3-ox.opropyi}-IH-indole, or• 2-Amino-N-[(lR)-2-[(3R)-3~benzyWcarbony piperidin- 1 -yl] – 1-( 1 H-indol-3 -yl^^and has the below chemical structure; U.S. Patent No. 6,576,648 to Artkerson reports a process of preparing anamorelin as the fumarate salt, with the hydrochloride salt produced as an intermediate in Step (j) of Example 1 . U.S. Patent No. 7,825, 138 to Lorimer describes a process for preparing crystal forms of the free base of anamorelin.There is a need to develop anamorelin monohydrochloride as an active pharmaceutical ingredient with reduced impurities and improved stability over prior art forms of anamorelin hydrochloride, such as those described in U.S. Patent No, 6,576,648, having good solubility, bioavailability and processabi!ity. There is also a need to develop methods of producing pharmaceutically acceptable forms of anamorelin monohydrochloride thai have improved yield over prior art processes, reduced residual solvents, and controlled distribution of chloride content,it has unexpectedly been discovered that the process of making the hydrochloride salt of anamorelin described in Step (j) of U.S. Patent No. 6.576,648 can result in excessive levels of chloride in the final product, and that this excess chloride leads to the long-term instability of the final product due at least, partially to an increase in the amount of the less stable dihydrochloride salt of anamorelin. Conversely, because anamorelin free base is less soluble in water than the hydrochloride salt, deficient chloride content in the final product can lead to decreased solubility of the molecule. The process described in U.S. Patent No, 6,576,648 also yields a final product that contains more than 5000 ppm (0.5%) of residual solvents, which renders the product less desirable from a pharmaceutical standpoint, as described in CH Harmonized Tripartite Guideline. See Impurities; Guideline for residual solvents Q3C(R3). in order to overcome these problems, methods have been developed which, for the first time, allow for the efficient and precise control of the reaction between anarnorehn tree base and hydrochloric acid in situ, thereby increasing the yield of anarnorehn monohydrochioride from the reaction and reducing the incidence of unwanted anamorelin dihydroeh ride. According to the method, the free base of anamorelin is dissolved in an organic solvent and combined with water and hydrochloric acid, with the molar ratio of anarnorehn and chloride tightly controlled to prevent an excess of chloride in the final product. The water and hydrochloric acid can be added either sequentially or at the same time as long as two separate phases are formed. Without wishing to be bound by any theory, it is believed thai as the anamorelin free base in the organic phase is protonated by the hydrochloric acid it migrates into the aqueous phase. The controlled ratio of anamorelin free base and hydrochloric acid and homogenous distribution in the aqueous phase allows for the controlled formation of the monohydrochioride salt over the dihydrochloride, and the controlled distribution of the resulting chloride levels within individual batches and among multiple batches of anamorelin monohydrochioride.Thus, in a fust embodiment the invention provides methods for preparing anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride comprising: (a) dissolving anamorelin free base in an organic solvent to form a solution; (b) mixing said solution with water and hydrochloric acid for a time sufficient to: (i) react said anamorelin free base with said hydrochloric acid, and (ii) form an organic phase and an aqueous phase; (c) separating the aqueous phase from the organic phase; and (d) isolating anamorelin monohydrochioride from the aqueous phase.In a particularly preferred embodiment, the molar ratio of anamorelin to hydrochloric acid used in the process is less than or equal to 1 : 1 , so as to reduce the production of anamorelin dihydrochloride and other unwanted chemical species. Thus, for example, hydrochloric acid can be added at a molar ratio of from 0,90 to 1 ,0 relative to said anamorelin, from 0.90 to 0.99, or from 0.93 to 0.97.n another particularly preferred embodiment, the anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride is isolated from the aqueous phase via spray drying, preferably preceded by distillation. This technique has proven especially useful in the manufacture of anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride because of the excellent reduction in solvent levels observed, and the production of a stable amorphous form of anamorelin monohydrochioride or a composition comprising anamorelin monohydrochioride. In other embodiments, the invention relates to the various forms of anamorelin monohvdrochloride and compositions comprising anamorelin monohvdrochloride produced by the methods of the present invention. In a first embodiment, which derives from the controlled chloride content among batches accomplished by the present methods, the invention provides anamorelin monohvdrochloride or a composition comprising anamorelin monohydrochloride having an inter-batch chloride content of from 5.8 to 6.2%, preferably from 5.8 to less than 6.2%. Alternatively, the invention provides anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having a molar ratio of chloride to anamorelin less than or equal to 1 : 1 , such as from 0.9 to 1.0 or 0.99, in yet another embodiment the invention provides an amorphous form of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride. Further descriptions of the anamorelin monohydrochloride and compositions comprising the anamorelin monohydrochloride are given in the detailed description which follows.EXAMPLE 1 . PREPARATION OF ANAMOREUN HYDROCHLORIDEVarious methods have been developed to prepare the hydrochloric acid salt of anarnorelin, with differing results.In a first method, which is the preferred method of the present invention, anarnorelin free base was carefully measured and dissolved in isopropyl acetate. Anarnorelin free base was prepared according to known method (e.g., U.S. Patent No, 6,576,648). A fixed volume of HCl in water containing various molar ratios (0.80, 0,95, 1.00 or 1.05) of HCl relative to the anarnorelin free base was then combined with the anamorelin/isopropyl acetate solution, to form a mixture having an organic and an aqueous phase, The aqueous phase of the mixture was separated from the organic phase and the resulting aqueous phase was concentrated by spray drying to obtain the batches of anarnorelin monohydrochloride (or a composition comprising anarnorelin monohydrochloride ) shown in Table 1 A.Approximately 150mg of the resulting spray dried sample of anarnorelin monohydrochloride (or composition comprising anarnorelin monohydrochloride) was accurately weighed out and dissolved in methanol (50mL). Acetic acid (5mL) and distilled water (5mL) were added to the mixture. The resulting mixture was potentiometricaJ ly titrated using 0,0 IN silver nitrate and the e dpoint was determined. A blank determination was also performed and correction was made, if necessary. The chloride content in the sample was calculated by the following formula. This measurement method of chloride content was performed without any cations other than proton (! ! ‘ ).Chloride content (%) = VxNx35.453x l 00x l 00/{Wx[1 00-(water content (%))-(residual solvent (%))]}V: volume at the endpoint (ml.)N; actual normality of 0.01 mol/L silver nitrate35.453 : atomic weight of ChlorineW: weight of sample (mg)TABLE 1 AHCl Chloride ContentThis data showed that anamorelin monohydrochlonde produced by a fixed volume of HCl in water containing 0.80 or 1 .05 molar equivalents of HC1 relative to anamorelin free base had levels of chloride thai were undesirable, and associated with product instability as shown in Example 3.Alternatively, a fixed volume of HCl in water containing 0.95 moles of HCl relative to anamorelin free base was used to prepare anamorelin monohydrochlonde (or composition comprising anamorelin monohydrochloride) as follows. Anamorelin free base (18.8g, 34.4mmoi) and isopropyl acetate (341.8g) were mixed in a 1000 mL flask. The mixture was heated at 40±5°C to confirm dissolution of the crystals and then cooled at 25±5°C. Distilled water (22.3g) and 3.6% diluted hydrochloric acid (33. Ig, 32.7mmoL 0.95 equivalents) were added into the flask and washed with distilled water. After 30 minutes stirring, the reaction was static for more than 15 minutes and the lower layer (aqueous layer) was transferred into a separate 250mL flask. Distilled water was added to the flask and concentrated under pressure at 50i5cC. The resulting aqueous solution was then filtered and product isolated by spray drying to afford anamorelin monohydrochlonde A (the present invention).The physical properties of anamorelin monohydrochloride A were compared to anamorelin monohydrochloride produced by a traditional comparative method (“anamorelin monohydrochloride B”) (comparative example). Anamorelin mono hydrochloride B in the comparative example was produced by bubbling HCl gas into isopropyl acetate to produce a 2M solution of HCl, and reacting 0.95 molar equivalents of the 2M HCl in isopropyl acetate with anamorelin free base. The physical properties of anamorelin monohydrochloride B are reported in Table IB. This data shows that when 0.95 equivalents of HCl is added to anamorelin free base, the chloride content (or amount of anamorelin dihydrochloride) is increased, even when a stoichiometric ratio of hydrochloride to anamorelin of less than 1 ,0 is used, possibly due to uncontrolled precipitation. In addition, this data shows that the concentration of residual solvents in anamorelin monohydrochloride B was greater than the concentration in anamorelin monohydrochloride A, TABLE I B A similar decrease in residual solvent concentration was observed when 2-methyltetrahydrofuran was used as the dissolving solvent for anamorelin free base instead of isopropvi acetate in the process for preparing spray dried anamorelin monohydrochloride A (data not reported).The residual solvent (organic volatile impurities) concentration (specifically isopropyl acetate) of anamorelin monohydrochloride in TABLE IB was measured using gas chromatography (GC-2010, Shimadzu Corporation) according to the conditions shown in TABLE 1 C,
^ Currow DC, Abernethy AP (April 2014). “Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome”. Future Oncology. 10 (5): 789–802. doi:10.2217/fon.14.14. PMID24472001.
^ Jump up to:abc Garcia JM, Polvino WJ (June 2009). “Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers”. Growth Hormone & IGF Research. 19 (3): 267–73. doi:10.1016/j.ghir.2008.12.003. PMID19196529.
^ Jump up to:ab Garcia JM, Boccia RV, Graham CD, Yan Y, Duus EM, Allen S, Friend J (January 2015). “Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials”. The Lancet. Oncology. 16 (1): 108–16. doi:10.1016/S1470-2045(14)71154-4. PMID25524795.
^ Jump up to:ab Garcia JM, Friend J, Allen S (January 2013). “Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study”. Supportive Care in Cancer. 21 (1): 129–37. doi:10.1007/s00520-012-1500-1. PMID22699302. S2CID22853697.
^ Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, Fearon KC (April 2016). “Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials”. The Lancet. Oncology. 17 (4): 519–531. doi:10.1016/S1470-2045(15)00558-6. PMID26906526.
RNA (recombinant 5′-[1,2-[(3′-O-methyl)m7G-(5’→5′)-ppp-Am]]-capped all uridine→N1-methylpseudouridine-substituted severe acute respiratory syndrome coronavirus 2 secretory signal peptide contg. spike glycoprotein S1S2-specifying plus 5′- and 3′-untranslated flanking region-contg. poly(A)-tailed messenger BNT162b2), inner salt
Nucleic Acid Sequence
Sequence Length: 42841106 a 1315 c 1062 g 801 umodified
Tozinameran is mRNA encoding full length of spike protein analog of SARS-CoV-2
Target Severe acute respiratory syndrome coronavirus 2 spike glycoprotein
Coronavirus disease – COVID-19
FORM
ROUTE
STRENGTH
Injection, suspension
Intramuscular
0.23 mg/1.8mL
Suspension
Intramuscular
30 mcg
NAME
INGREDIENTS
DOSAGE
ROUTE
LABELLER
MARKETING START
MARKETING END
Pfizer-BioNTech Covid-19 Vaccine
Pfizer-BioNTech Covid-19 Vaccine (0.23 mg/1.8mL)
Injection, suspension
Intramuscular
Pfizer Manufacturing Belgium NV
2020-12-12
Not applicable
NAME
DOSAGE
STRENGTH
ROUTE
LABELLER
MARKETING START
MARKETING END
Comirnaty
30 mcg
Intramuscular
Bio N Tech Manufacturing Gmb H
2021-01-06
Not applicable
Pfizer-BioNTech Covid-19 Vaccine
Suspension
30 mcg
Intramuscular
Biontech Manufacturing Gmbh
2020-12-14
Not applicable
Pfizer-BioNTech Covid-19 Vaccine
Injection, suspension
0.23 mg/1.8mL
Intramuscular
Pfizer Manufacturing Belgium NV
2020-12-12
Not applicable
The Pfizer–BioNTech COVID‑19 vaccine (pINN: tozinameran), sold under the brand name Comirnaty,[13] is a COVID-19 vaccine developed by the German company BioNTech in cooperation with Pfizer. It is both the first COVID-19 vaccine to be authorized by a stringent regulatory authority for emergency use[14][15] and the first cleared for regular use.[16]
Trials began in April 2020; by November, the vaccine had been tested on more than 40,000 people.[24] An interim analysis of study data showed a potential efficacy of over 90% in preventing infection within seven days of a second dose.[19][20] The most common side effects include mild to moderate pain at the injection site, fatigue, and headache.[25][26] As of December 2020, reports of serious side effects, such as allergic reactions, have been very rare,[a] and no long-term complications have been reported.[28]Phase III clinical trials are ongoing: monitoring of the primary outcomes will continue until August 2021, while monitoring of the secondary outcomes will continue until January 2023.[18]
In December 2020, the United Kingdom was the first country to authorize the vaccine on an emergency basis,[28] soon followed by the United States, the European Union and several other countries globally.[29][30][6][31][32]
BioNTech is the initial developer of the vaccine, and partnered with Pfizer for development, clinical research, overseeing the clinical trials, logistics, finances and for manufacturing worldwide with the exception of China.[33] The license to distribute and manufacture in China was purchased by Fosun, alongside its investment in BioNTech.[34][35] Distribution in Germany and Turkey is by BioNTech itself.[36] Pfizer indicated in November 2020, that 50 million doses could be available globally by the end of 2020, with about 1.3 billion doses in 2021.[20]
Pfizer has advanced purchase agreements of about US$3 billion for providing a licensed vaccine in the United States, the European Union, the United Kingdom, Japan, Canada, Peru, Singapore, and Mexico.[37][38] Distribution and storage of the vaccine is a logistics challenge because it needs to be stored at temperatures between −80 and −60 °C (−112 and −76 °F),[39] until five days before vaccination[38][39] when it can be stored at 2 to 8 °C (36 to 46 °F), and up to two hours at temperatures up to 25 °C (77 °F)[40][11] or 30 °C (86 °F).[41][42] In February 2021, Pfizer and BioNTech asked the U.S. Food and Drug Administration (FDA) to update the emergency use authorization (EUA) to permit the vaccine to be stored at between −25 and −15 °C (−13 and 5 °F) for up to two weeks before use.[43]
Development and funding
Before COVID-19 vaccines, a vaccine for an infectious disease had never before been produced in less than several years, and no vaccine existed for preventing a coronavirus infection in humans.[44] After the COVID-19 virus was detected in December 2019,[45] the development of BNT162b2 was initiated on 10 January 2020, when the SARS-CoV-2 genetic sequences were released by the Chinese Center for Disease Control and Prevention via GISAID,[46][47][48] triggering an urgent international response to prepare for an outbreak and hasten development of preventive vaccines.[49][50]
In January 2020, German biotech-company BioNTech started its program ‘Project Lightspeed’ to develop a vaccine against the new COVID‑19 virus based on its already established mRNA-technology.[24] Several variants of the vaccine were created in their laboratories in Mainz, and 20 of those were presented to experts of the Paul-Ehrlich-Institute in Langen.[51] Phase I / II Trials were started in Germany on 23 April 2020, and in the U.S. on 4 May 2020, with four vaccine candidates entering clinical testing. The Initial Pivotal Phase II / III Trial with the lead vaccine candidate ‘BNT162b2’ began in July. The Phase III results indicating a 95% effectiveness of the developed vaccine were published on 18 November 2020.[24]
BioNTech received a US$135 million investment from Fosun in March 2020, in exchange for 1.58 million shares in BioNTech and the future development and marketing rights of BNT162b2 in China,[35] Hong Kong, Macau and Taiwan.[52]
In June 2020, BioNTech received €100 million (US$119 million) in financing from the European Commission and European Investment Bank.[53] In September 2020, the German government granted BioNTech €375 million (US$445 million) for its COVID‑19 vaccine development program.[54]
Pfizer CEO Albert Bourla stated that he decided against taking funding from the US government’s Operation Warp Speed for the development of the vaccine “because I wanted to liberate our scientists [from] any bureaucracy that comes with having to give reports and agree how we are going to spend the money in parallel or together, etc.” Pfizer did enter into an agreement with the US for the eventual distribution of the vaccine, as with other countries.[55]
The study of BNT162b2 is a continuous-phase trial in Phase III as of November 2020.[18] It is a “randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals”.[18] The early-stage research determined the safety and dose level for two vaccine candidates, with the trial expanding during mid-2020 to assess efficacy and safety of BNT162b2 in greater numbers of participants, reaching tens of thousands of people receiving test vaccinations in multiple countries in collaboration with Pfizer and Fosun.[20][35]
The Phase III trial assesses the safety, efficacy, tolerability, and immunogenicity of BNT162b2 at a mid-dose level (two injections separated by 21 days) in three age groups: 12–15 years, 16–55 years or above 55 years.[18] For approval in the EU, an overall vaccine efficacy of 95% was confirmed by the EMA.[58] The EMA clarified that the second dose should be administered three weeks after the first dose.[59]
Efficacy endpoint
Vaccine efficacy (95% confidence interval) [%]
After dose 1 to before dose 2
52.4 (29.5, 68.4)
≥10 days after dose 1 to before dose 2
86.7 (68.6, 95.4)
Dose 2 to 7 days after dose 2
90.5 (61.0, 98.9)
≥7 days after dose 2 (subjects without evidence of infection prior to 7 days after dose 2)
Overall
95.0 (90.0, 97.9)
16–55 years
95.6 (89.4, 98.6)
≥55 years
93.7 (80.6, 98.8)
≥65 years
94.7 (66.7, 99.9)
The ongoing Phase III trial, which is scheduled to run from 2020 to 2022, is designed to assess the ability of BNT162b2 to prevent severe infection, as well as the duration of immune effect.[20][21][22]
Pfizer and BioNTech started a Phase II/III randomized control trial in healthy pregnant women 18 years of age and older (NCT04754594).[60] The study will evaluate 30 µg of BNT162b2 or placebo administered via intramuscular injection in 2 doses, 21 days apart. The Phase II portion of the study will include approximately 350 pregnant women randomized 1:1 to receive BNT162b2 or placebo at 27 to 34 weeks’ gestation. The Phase III portion of this study will assess the safety, tolerability, and immunogenicity of BNT162b2 or placebo among pregnant women enrolled at 24 to 34 weeks’ gestation. Pfizer and BioNTech announced on 18 February 2021 that the first participants received their first dose in this trial.[61]
The vaccine candidate BNT162b2 was chosen as the most promising among three others with similar technology developed by BioNTech.[18][62][56] Prior to choosing BNT162b2, BioNTech and Pfizer had conducted Phase I trials on BNT162b1 in Germany and the United States, while Fosun performed a Phase I trial in China.[17][63] In these Phase I studies, BNT162b2 was shown to have a better safety profile than the other three BioNTech candidates.[63]
Sequence
The modRNA sequence of the vaccine is 4,284 nucleotides long.[64] It consists of a five-prime cap; a five prime untranslated region derived from the sequence of human alpha globin; a signal peptide (bases 55–102) and two proline substitutions (K986P and V987P, designated “2P”) that cause the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression and stimulating neutralizing antibodies;[17][65] a codon-optimized gene of the full-length spike protein of SARS-CoV-2 (bases 103–3879); followed by a three prime untranslated region (bases 3880–4174) combined from AES and mtRNR1 selected for increased protein expression and mRNA stability[66] and a poly(A) tail comprising 30 adenosine residues, a 10-nucleotide linker sequence, and 70 other adenosine residues (bases 4175–4284).[64] The sequence contains no uridine residues; they are replaced by 1-methyl-3′-pseudouridylyl.[64]
Composition
In addition to the mRNA molecule, the vaccine contains the following inactive ingredients (excipients):[67][68][8]
The vaccine is supplied in a multidose vial as “a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection“.[11][12] It must be thawed to room temperature and diluted with normal saline before administration.[12]
Authorizations
Expedited
The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) gave the vaccine “rapid temporary regulatory approval to address significant public health issues such as a pandemic” on 2 December 2020, which it is permitted to do under the Medicines Act 1968.[70] It was the first COVID‑19 vaccine to be approved for national use after undergoing large scale trials,[71] and the first mRNA vaccine to be authorized for use in humans.[14][72] The United Kingdom thus became the first Western country to approve a COVID‑19 vaccine for national use,[73] although the decision to fast-track the vaccine was criticised by some experts.[74]
On 8 December 2020, Margaret “Maggie” Keenan, 90, from Fermanagh, became the first person to receive the vaccine.[75] In a notable example of museums documenting the pandemic, the vial and syringe used for that first dose were saved acquired by The Science Museum in London for its permanent collection.[76] By 20 December, 521,594 UK residents had received the vaccine as part of the national vaccination programme. 70% had been to people aged 80 or over.[77]
After the United Kingdom, the following countries expedited processes to approve the Pfizer–BioNTech COVID‑19 vaccine for use: Argentina,[78] Australia,[79] Bahrain,[80] Canada,[7][81] Chile,[82] Costa Rica,[83] Ecuador,[82] Hong Kong,[84] Iraq,[85] Israel,[86] Jordan,[87] Kuwait,[88] Mexico,[89] Oman,[90] Panama,[91] the Philippines,[92] Qatar,[93] Saudi Arabia,[32][94] Singapore,[95][96] the United Arab Emirates,[97] and the United States.[10]
In the United States, an emergency use authorization (EUA) is “a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID‑19 pandemic”, according to the FDA.[99] Following an EUA issuance, BioNTech and Pfizer are expected to continue the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) of the vaccine in the United States.[99][100][101] The United States Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) approved recommendations for vaccination of those aged 16 years or older.[102][103]
Standard
On 19 December 2020, the Swiss Agency for Therapeutic Products (Swissmedic) approved the Pfizer–BioNTech COVID‑19 vaccine for regular use, two months after receiving the application, stating that the vaccine fully complied with the requirements of safety, efficacy and quality. This is the first authorization under a standard procedure.[1][104] On 23 December, a Lucerne resident, a 90-year-old woman, became the first person to receive the vaccine in Switzerland.[105] This marked the beginning of mass vaccination in continental Europe.[106]
On February 23, 2021, the Brazilian Health Regulatory Agency approved the Pfizer–BioNTech COVID-19 vaccine under its standard marketing authorization procedure. It became the first COVID-19 vaccine to receive definitive registration rather than emergency use authorization in the country.[110]
Adverse effects
The adverse effect profile of the Pfizer–BioNTech COVID‑19 vaccine is similar to that of other adult vaccines.[20] During clinical trials, the side effects deemed very common[a] are (in order of frequency): pain and swelling at the injection site, tiredness, headache, muscle aches, chills, joint pain, and fever.[68] Fever is more common after the second dose.[68] These effects are predictable and to be expected, and it is particularly important that people be aware of this to prevent vaccine hesitancy.[111]
Severe allergic reaction has been observed in approximately 11 cases per million doses of vaccine administered.[112][113] According to a report by the US Centers for Disease Control and Prevention 71% of those allergic reactions happened within 15 minutes of vaccination and mostly (81%) among people with a documented history of allergies or allergic reactions.[112] The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) advised on 9 December 2020, that people who have a history of “significant” allergic reaction should not receive the Pfizer–BioNTech COVID‑19 vaccine.[114][115][116] On 12 December, the Canadian regulator followed suit, noting that: “Both individuals in the U.K. had a history of severe allergic reactions and carried adrenaline auto injectors. They both were treated and have recovered.”[67]
On 28 January 2021, the European Union published a COVID-19 vaccine safety update which found that “the benefits of Comirnaty in preventing COVID‑19 continue to outweigh any risks, and there are no recommended changes regarding the use the vaccine.”[113][117] No new side effects were identified.[113]
Manufacturing
A doctor holding the Pfizer vaccine
Pfizer and BioNTech are manufacturing the vaccine in their own facilities in the United States and in Europe in a three-stage process. The first stage involves the molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. In the United States, this stage is conducted at a small pilot plant in Chesterfield, Missouri[118] (near St. Louis). After four days of growth, the bacteria are killed and broken open, and the contents of their cells are purified over a week and a half to recover the desired DNA product. The DNA is stored in tiny bottles and frozen for shipment. Safely and quickly transporting the DNA at this stage is so important that Pfizer has used its company jet and helicopter to assist.[119]
The second stage is being conducted at plants in Andover, Massachusetts[120] in the United States, and in Germany. The DNA is used as a template to build the desired mRNA strands. Once the mRNA has been created and purified, it is frozen in plastic bags about the size of a large shopping bag, of which each can hold up to 5 to 10 million doses. The bags are placed on special racks on trucks which take them to the next plant.[119]
The third stage is being conducted at plants in Portage, Michigan[121] (near Kalamazoo) in the United States, and Puurs in Belgium. This stage involves combining the mRNA with lipid nanoparticles, then filling vials, boxing vials, and freezing them.[119]Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids.[122] As of November 2020, the major bottleneck in the manufacturing process was combining mRNA with lipid nanoparticles.[119]
In February 2021, Pfizer revealed this entire sequence initially took about 110 days on average from start to finish, and that the company was making progress on reducing that number to 60 days.[123] Vaccine manufacturers normally take several years to optimize the process of making a particular vaccine for speed and cost-effectiveness before attempting large-scale production.[123] Due to the urgency presented by the COVID-19 pandemic, Pfizer began production immediately with the process by which the vaccine had been originally formulated in the laboratory, then started to identify ways to safely speed up and scale up that process.[123]
BioNTech announced in September 2020 that it had signed an agreement to acquire from Novartis a manufacturing facility in Marburg, Germany, to expand their vaccine production capacity.[124] Once fully operational, the facility would produce up to 750 million doses per year, or over 60 million doses per month. The site will be the third BioNTech facility in Europe which currently produces the vaccine, while Pfizer operates at least four production sites in the United States and Europe.
Advance orders and logistics
Pfizer indicated in its 9 November press release that 50 million doses could be available by the end of 2020, with about 1.3 billion doses provided globally by 2021.[20] In February 2021, BioNTech announced it would increase production by more than 50% to manufacture two billion doses in 2021.[125]
In July 2020, the vaccine development program Operation Warp Speed placed an advance order of US$1.95 billion with Pfizer to manufacture 100 million doses of a COVID‑19 vaccine for use in the United States if the vaccine was shown to be safe and effective.[34][126][127][128] By mid-December 2020, Pfizer had agreements to supply 300 million doses to the European Union,[129] 120 million doses to Japan,[130] 40 million doses (10 million before 2021) to the United Kingdom,[22] 20 million doses to Canada,[131] an unspecified number of doses to Singapore,[132] and 34.4 million doses to Mexico.[133] Fosun also has agreements to supply 10 million doses to Hong Kong and Macau.[134] The Hong Kong government said it would receive its first batch of one million doses by the first quarter of 2021.[135]
BioNTech and Fosun agreed to supply Mainland China with a batch of 100 million doses in 2021, subject to regulatory approval. The initial supply will be delivered from BioNTech’s production facilities in Germany.[136]
The vaccine is being delivered in vials that, once diluted, contain 2.25 ml of vaccine (0.45 ml frozen plus 1.8ml diluent).[101] According to the vial labels, each vial contains five 0.3 ml doses, however excess vaccine may be used for one, or possibly two, additional doses.[101][137] The use of low dead space syringes to obtain the additional doses is preferable, and partial doses within a vial should be discarded.[101][138] The Italian Medicines Agency officially authorized the use of excess doses remaining within single vials.[139] As of 8 January 2021, each vial contains six doses.[68][140][141][138] In the United States, vials will be counted as five doses when accompanied by regular syringes and as six doses when accompanied by low dead space syringes.[142]
Temperature the Pfizer vaccine must be kept at to ensure effectiveness, roughly between −80 and −60 °C (−112 and −76 °F)
Logistics in developing countries which have preorder agreements with Pfizer—such as Ecuador and Peru—remain unclear.[38] Even high-income countries have limited cold chain capacity for ultracold transport and storage of a vaccine that degrades within five days when thawed, and requires two shots three weeks apart.[38] The vaccine needs to be stored and transported at ultracold temperatures between −80 and −60 °C (−112 and −76 °F),[39][22][38][143][144] much lower than for the similar Moderna vaccine. The head of Indonesia‘s Bio Farma Honesti Basyir stated that purchasing the vaccine is out of the question for the world’s fourth-most populous country, given that it did not have the necessary cold chain capability. Similarly, India’s existing cold chain network can only handle temperatures between 2 and 8 °C (36 and 46 °F), far above the requirements of the vaccine.[145][146]
In January 2021, Pfizer and BioNTech offered to supply 50 million doses of COVID‑19 vaccine for health workers across Africa between March and the end of 2021, at a discounted price of US$10 per dose.[147]
Name
BNT162b2 was the code name during development and testing,[17][148] tozinameran is the proposed international nonproprietary name (pINN),[149] and Comirnaty is the brand name.[1][2] According to BioNTech, the name Comirnaty “represents a combination of the terms COVID‑19, mRNA, community, and immunity.”[150][151]
The vaccine also has the common name “COVID‑19 mRNA vaccine (nucleoside-modified)”[2] and may be distributed in packaging with the name Pfizer–BioNTech COVID‑19 Vaccine.”[152]
The German company BioNTech partnered with Pfizer to develop and test a coronavirus vaccine known as BNT162b2, the generic name tozinameran or the brand name Comirnaty. A clinical trial demonstrated that the vaccine has an efficacy rate of 95 percent in preventing Covid-19.
A Piece of the Coronavirus
The SARS-CoV-2 virus is studded with proteins that it uses to enter human cells. These so-called spike proteins make a tempting target for potential vaccines and treatments.
The vaccine uses messenger RNA, genetic material that our cells read to make proteins. The molecule — called mRNA for short — is fragile and would be chopped to pieces by our natural enzymes if it were injected directly into the body. To protect their vaccine, Pfizer and BioNTech wrap the mRNA in oily bubbles made of lipid nanoparticles.
Lipid nanoparticles
surrounding mRNA
Because of their fragility, the mRNA molecules will quickly fall apart at room temperature. Pfizer is building special containers with dry ice, thermal sensors and GPS trackers to ensure the vaccines can be transported at –94°F (–70°C) to stay viable.
Entering a Cell
After injection, the vaccine particles bump into cells and fuse to them, releasing mRNA. The cell’s molecules read its sequence and build spike proteins. The mRNA from the vaccine is eventually destroyed by the cell, leaving no permanent trace.
VACCINE
PARTICLES
VACCINATED
CELL
Spike
protein
mRNA
Translating mRNA
Three spike
proteins combine
Spike
Cell
nucleus
Spikes
and protein
fragments
Displaying
spike protein
fragments
Protruding
spikes
Some of the spike proteins form spikes that migrate to the surface of the cell and stick out their tips. The vaccinated cells also break up some of the proteins into fragments, which they present on their surface. These protruding spikes and spike protein fragments can then be recognized by the immune system.
Spotting the Intruder
When a vaccinated cell dies, the debris will contain many spike proteins and protein fragments, which can then be taken up by a type of immune cell called an antigen-presenting cell.
Debris from
a dead cell
Engulfing
a spike
ANTIGEN-
PRESENTING
CELL
Digesting
the proteins
Presenting a
spike protein
fragment
HELPER
T CELL
The cell presents fragments of the spike protein on its surface. When other cells called helper T cells detect these fragments, the helper T cells can raise the alarm and help marshal other immune cells to fight the infection.
Making Antibodies
Other immune cells, called B cells, may bump into the coronavirus spikes on the surface of vaccinated cells, or free-floating spike protein fragments. A few of the B cells may be able to lock onto the spike proteins. If these B cells are then activated by helper T cells, they will start to proliferate and pour out antibodies that target the spike protein.
HELPER
T CELL
Activating
the B cell
Matching
surface proteins
VACCINATED
CELL
B CELL
SECRETED
ANTIBODIES
Stopping the Virus
The antibodies can latch onto coronavirus spikes, mark the virus for destruction and prevent infection by blocking the spikes from attaching to other cells.
ANTIBODIES
VIRUS
Killing Infected Cells
The antigen-presenting cells can also activate another type of immune cell called a killer T cell to seek out and destroy any coronavirus-infected cells that display the spike protein fragments on their surfaces.
ANTIGEN-PRESENTING CELL Presenting a spike protein fragment ACTIVATED KILLER T CELL INFECTED CELL Beginning to kill the infected cell
Remembering the Virus
The Pfizer-BioNTech vaccine requires two injections, given 21 days apart, to prime the immune system well enough to fight off the coronavirus. But because the vaccine is so new, researchers don’t know how long its protection might last.
First dose, 0.3ml
Second dose, 21 days later
A preliminary study found that the vaccine seems to offer strong protection about 10 days after the first dose, compared with people taking a placebo:
Cumulative incidence of Covid-19 among clinical trial participants 2.5% 2.0 People taking a placebo
1.5 1.0 Second dose First dose People taking the
Pfizer-BioNTech vaccine
0.5
0
1
2
3
4
8
12
16
Weeks after the first dose
It’s possible that in the months after vaccination, the number of antibodies and killer T cells will drop. But the immune system also contains special cells called memory B cells and memory T cells that might retain information about the coronavirus for years or even decades.
Each vial of the vaccine contains 5 doses of 0.3 milliliters. The vaccine must be thawed before injection and diluted with saline. After dilution the vial must be used within six hours.
A diluted vial of the vaccine at Royal Free Hospital in London.Jack Hill/Agence France-Presse
References
^ Jump up to:ab According to the British National Formulary and MedDRA conventions, side effects are “very common” when they occur in more than 1 in 10 instances; “common”, 1 in 100 to 1 in 10; “uncommon”, 1 in 1,000 to 1 in 100; “rare”, 1 in 10,000 to 1 in 1,000; and “very rare” when they occur in less than 1 in 10,000 instances.[27]
^ Jump up to:abcdef Clinical trial number NCT04368728 for “NCT04368728: Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals” at ClinicalTrials.gov
^ Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. (December 2020). “Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine”. The New England Journal of Medicine. 383 (27): 2603–2615. doi:10.1056/NEJMoa2034577. PMC7745181. PMID33301246. development of BNT162b2 was initiated on January 10, 2020, when the SARS-CoV-2 genetic sequence was released by the Chinese Center for Disease Control and Prevention and disseminated globally by the GISAID (Global Initiative on Sharing All Influenza Data) initiative
The Pfizer-BioNTech COVID-19 vaccine (Tozinameran, INN), also known as BNT162b2, is one of four advanced mRNA-based vaccines developed through “Project Lightspeed,” a joint program between Pfizer and BioNTech.2,3 Tozinameran is a nucleoside modified mRNA (modRNA) vaccine encoding an optimized full-length version of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. It is designed to induce immunity against SARS-CoV-2, the virus responsible for causing COVID-19.2 The modRNA is formulated in lipid nanoparticles for administration via intramuscular injection in two doses, three weeks apart.1,3
Tozinameran is undergoing evaluation in clinical trials in both the USA (NCT04368728) and Germany (NCT04380701).4,5 Tozinameran received fast track designation by the U.S. FDA on July 13, 2020.6 On December 11, 2020, the FDA issued an Emergency Use Authorization (EUA) based on 95% efficacy in clinical trials and a similar safety profile to other viral vaccines over a span of approximately 2 months.1 Tozinameran was granted an EUA in the UK on December 2, 2020,8 and in Canada on December 9, 20207 for active immunization against SARS-CoV-2.12
Currently, sufficient data are not available to determine the longevity of protection against COVID-19, nor direct evidence that the vaccine prevents the transmission of the SARS-CoV-2 virus from one individual to another.9 Fact sheets for caregivers, recipients, and healthcare providers are now available.10,11
Tozinameran has not yet been fully approved by any country. In both the UK and Canada, Tozinameran is indicated under an interim authorization for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals aged 16 years and older.7,8
On December 11, 2020, the U.S. Food and Drug Administration granted emergency use authorization (EUA) for Tozinameran to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients aged 16 years and above.9 Safety and immune response information for adolescents 12-15 years of age will follow, and studies to further explore the administration of Tozinameran in pregnant women, children under 12 years of age, and those in special risk groups will be evaluated in the future.1
This vaccine should only be administered where appropriate medical treatment for immediate allergic reactions are immediately available in the case of an acute anaphylactic reaction after vaccine administration.12 Tozinameran administration should be postponed in any individual suffering from an acute febrile illness. Its use should be carefully considered in immunocompromised individuals and individuals with a bleeding disorder or on anticoagulant therapy. Appropriate medical treatment should be readily available in case of an anaphylactic reaction following vaccine administration.7,8
Tozinameran contains nucleoside modified mRNA (modRNA) encapsulated in lipid nanoparticles that deliver the modRNA into host cells. The lipid nanoparticle formulation facilitates the delivery of the RNA into human cells.12 Once inside these cells, the modRNA is translated by host machinery to produce the SARS-CoV-2 spike (S) protein antigen, which is subsequently recognized by the host immune system. Tozinameran has been shown to elicit both neutralizing antibody and cellular immune responses to the S protein, which helps protect against subsequent SARS-CoV-2 infection.7,8
Tozinameran is a nucleoside modified mRNA (modRNA) vaccine encoding an optimized full-length version of the SARS-CoV-2 spike (S) protein, translated and expressed in cells in vaccinated individuals to produce the S protein antigen against which an immune response is mounted. As with all vaccines, protection cannot be guaranteed in all recipients, and full protection may not occur until at least seven days following the second dose.7,8
In U.S. clinical trials, the vaccine was 95% effective in preventing COVID-19; eight COVID-19 cases occurred in the vaccine group and 162 cases occurred in the placebo group. Of the total 170 COVID-19 cases, one case in the vaccine group and three cases in the placebo group were considered to be severe infections.1,9
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Perez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Tureci O, Nell H, Schaefer A, Unal S, Tresnan DB, Mather S, Dormitzer PR, Sahin U, Jansen KU, Gruber WC: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 10. doi: 10.1056/NEJMoa2034577. [PubMed:33301246]
PHASE 3, for the potential oral treatment of moderate-to-severe atopic dermatitis (AD)
Jak1 tyrosine kinase inhibitor
UPDATE…… JAPAN APPROVED, 2021, 2021/9/27, CIBINQO
ALSO
fda 2022, APPROVALS 2022, 1/14/2022
THE US
In February 2018, the FDA granted Breakthrough Therapy designation for the treatment of patients with moderate-to-severe AD
PHASEIII
In December 2017, a randomized, double-blind, placebo-controlled, parallel-group, phase III trial (NCT03349060; JADE Mono-1; JADE; B7451012; 2017-003651-29) of PF-04965842 began in patients aged 12 years and older (expected n = 375) with moderate-to-severe AD
PRODUCT PATENT
Pub. No.:
WO/2014/128591
International Application No.:
PCT/IB2014/058889
Publication Date:
28.08.2014
International Filing Date:
11.02.2014
EXPIRY Roughly 2034
form
powder
color
white to beige
solubility
DMSO: 10 mg/mL, clear
storage temp.
room temp
Biochem/physiol Actions
PF-04965842 is a Janus Kinase (JAK) inhibitor selective for JAK1 with an IC50value of 29 nM for JAK1 compared to 803 nM for JAK2, >10000 nM for JAK3 and 1250 nM for Tyk2. JAKs mediate cytokine signaling, and are involved in cell proliferation and differentiation. PF-04965842 has been investigated as a possible treatment for psoriasis.
Originator Pfizer
Class Skin disorder therapies; Small molecules
Mechanism of Action Janus kinase 1 inhibitors
Highest Development Phases
Phase IIIAtopic dermatitis
DiscontinuedLupus vulgaris; Plaque psoriasis
Most Recent Events
08 Mar 2018Phase-III clinical trials in Atopic dermatitis (In children, In adults, In adolescents) in USA (PO) (NCT03422822)
14 Feb 2018PF 4965842 receives Breakthrough Therapy status for Atopic dermatitis in USA
06 Feb 2018Pfizer plans the phase III JADE EXTEND trial for Atopic Dermatitis (In children, In adults, In adolescents) in March 2018 (PO) (NCT03422822)
This compound was developed by Pfizer for Kinase Phosphatase Biology research. To learn more about Sigma′s partnership with Pfizer and view other authentic, high-quality Pfizer compounds,
PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis.
Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been i mplicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune d iseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer’s disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation , survival, apoptosis, mitogenesis, cell cycle control, and cel l mobility implicated in the aforementioned and related diseases.
Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central role in cytoki ne signaling (Kisseleva et al., Gene, 2002, 285 , 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL- 10, IL- 19, IL-20, IL-22), the gp 130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT- 1//SF-3, G-CSF, CT- 1, Leptin, IL- 12 , I L-23), gamma C family (IL-2 , I L-7, TSLP, IL-9, IL- 15 , IL-21, IL-4, I L- 13), IL-3 family (IL-3 , IL-5 , GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF- 1, HGF), and G-protein coupled receptors (ATI).
Abrocitinib is quickly absorbed from the gut and generally reaches highest blood plasma concentrations within one hour. Only 1.0 to 4.4% of the dose are found unmetabolized in the urine.[4]
History
April 2016: initiation of Phase 2b trial
December 2017: initiation of JADE Mono-1 Phase 3 trial[5]
May 2018: Results of Phase 2b trial posted
October 2019: Results of Phase 3 trial presented[6]
June 2020: Results of second Phase 3 trial published[7]
Society and culture
Legal status
In October 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Cibinqo, intended for the treatment of atopic dermatitis.[8] The applicant for this medicinal product is Pfizer Europe MA EEIG.[8] In December 2021, the European Commission approved abrocitinib for the treatment of atopic dermatitis.[2][9]
In January 2022, the United States Food and Drug Administration (FDA) approved abrocitinib for adults with moderate-to-severe atopic dermatitis.[10]
Introduction The finished product is presented as immediate release film-coated tablets containing 50 mg, 100 mg or 200 mg of abrocitinib as active substance. Other ingredients are: Tablet core: microcrystalline cellulose (E460i), anhydrous dibasic calcium phosphate (E341ii), sodium starch glycolate and magnesium stearate (E470b). Film-coat: hypromellose (E464), titanium dioxide (E171), lactose monohydrate, macrogol (E1521), triacetin (E1518) and red iron oxide (E172). The product is available in high-density polyethylene (HDPE) bottles with polypropylene closure or polyvinylidene chloride (PVDC) blisters with aluminium foil lidding film, as described in section 6.5 of the SmPC.
The chemical name of abrocitinib is N-((1S,3S)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl)propane-1-sulfonamide corresponding to the molecular formula C14H21N5O2S. It has a relative molecular mass of 323.42 Daltons and the following structure depicted in Figure 1:
The chemical structure of abrocitinib was elucidated by a combination of UV/VIS and IR spectroscopy, mass spectrometry, NMR spectroscopy and X-ray diffraction. The active substance is a white to pale-purple or pale pink crystalline powder. It is non-hygroscopic and its solubility is pH dependent. Abrocitinib is classified as BCS Class II. The impact of particle size on finished product uniformity of dosage units and dissolution has been studied (see finished product section). Based on the abrocitinib finished product biopharmaceutics performance, stability, and manufacturing experience, the active substance particle size specification was established. Abrocitinib is an achiral molecule, but with 2 stereocentres. Only one crystalline anhydrous form (Form 1) of abrocitinib has been identified. This form has been the only form used in all toxicology and clinical studies. Extensive polymorph and hydrate screening have been conducted to investigate if additional solid forms of abrocitinib could be discovered. Abrocitinib, Form 1 was the only anhydrous crystalline form identified from these studies. No new anhydrous polymorphs, hydrates or amorphous solids of abrocitinib were isolated from these screens. Experiments with 1,4 dioxane and dimethyl sulfoxide yielded solvated forms of abrocitinib. When these solvated structures were subjected to high temperature, these materials desolvated and converted to Form 1, free base anhydrous form of abrocitinib. However, these are not relevant since the commercial crystallisation step does not utilise either of these solvent systems. It has been confirmed that the manufacturing process consistently yields polymorphic form I. This form is physically and chemically stable under normal manufacturing and storage conditions as well as under accelerated conditions. Hence the absence of control of form I is justified.
FDA
U.S. FDA Approves Pfizer’s CIBINQO® (abrocitinib) for Adults with Moderate-to-Severe Atopic Dermatitis
CIBINQO is a once-daily oral treatment with proven efficacy to manage symptoms for adults who have not yet found relief with current options
NEW YORK–(BUSINESS WIRE)– Pfizer Inc. (NYSE: PFE) announced today that the United States (U.S.) Food and Drug Administration (FDA) approved CIBINQO® (abrocitinib), an oral, once-daily, Janus kinase 1 (JAK1) inhibitor, for the treatment of adults living with refractory, moderate-to-severe atopic dermatitis (AD) whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.
CIBINQO is approved at the recommended doses of 100 mg and 200 mg, with the 200 mg dose being recommended for patients who are not responding to the 100 mg dose. Additionally, a 50 mg dose was approved to treat moderate-to-severe AD specifically in patients with moderate renal impairment (kidney failure), certain patients receiving treatment with inhibitors of cytochrome P450 (CYP) 2C19, or patients who are known or suspected to be poor metabolizers of CYP2C19. For patients with moderate renal impairment who are not responding to 50 mg once daily, 100 mg once daily may also be prescribed.
“The reality for patients living with chronic inflammatory skin disease such as moderate-to-severe atopic dermatitis is that many experience debilitating symptoms that are not managed by current treatment options. Today’s approval of CIBINQO will provide an important new oral option that could help those who have yet to find relief,” said Jonathan Silverberg, MD, PhD, MPH, Department of Dermatology, The George Washington University School of Medicine and Health Sciences. “In multiple large-scale clinical trials, CIBINQO demonstrated strong efficacy at clearing skin, improving itch, and managing the extent and severity of eczema, offering a benefit-risk profile that supports the use of this treatment in the FDA-approved patient population.”
The FDA approval was based on results of five clinical trials from a large-scale clinical trial program of more than 1,600 patients. The safety and efficacy of CIBINQO was evaluated in three randomized, placebo-controlled, Phase 3 trials. Additionally, safety was evaluated through a randomized, placebo-controlled, dose-ranging trial and an ongoing long-term open-label extension trial. Across the trials, CIBINQO demonstrated a consistent safety profile and profound improvements in skin clearance, extent of disease, and severity, as well as rapid improvement in itch after two weeks, for some people living with AD versus placebo. In addition, a higher proportion of subjects treated with CIBINQO in two monotherapy trials achieved improvement in itching at week 12 compared to placebo.
“The FDA’s approval offers hope to the millions of patients across the U.S. who are suffering daily with an immuno-inflammatory condition that can cause intense and persistent itching, pain, discomfort, and distress if left uncontrolled,” said Mike Gladstone, Global President of Pfizer Inflammation & Immunology. “CIBINQO, an efficacious once-daily pill, is a medical breakthrough made possible by Pfizer researchers and the people living with moderate-to-severe atopic dermatitis who participated in our clinical trials.”
“Atopic dermatitis is so much more than just a rash, and it goes beyond the surface of the skin. It’s a chronic condition that can both significantly disrupt patients’ daily lives and negatively impact their emotional well-being,” said Julie Block, President and CEO, National Eczema Association. “We appreciate Pfizer’s commitment to this resilient patient community and eagerly await the positive impact CIBINQO could have on the treatment landscape for moderate-to-severe atopic dermatitis.”
The most common adverse events reported in ≥5% of patients with CIBINQO included nasopharyngitis (12.4% with CIBINQO 100 mg, 8.7% with CIBINQO 200 mg, and 7.9%, with placebo), nausea (6%, 14.5%, and 2.1%, respectively), and headache (6%, 7.8%, and 3.5%, respectively).
The full prescribing information for CIBINQO can be found here. CIBINQO will be made available in the coming weeks.
Additional Details on the CIBINQO Clinical Trial Program
Five clinical trials in the CIBINQO JAK1 Atopic Dermatitis Efficacy and Safety (JADE) global development program were included in the New Drug Application (NDA) to support the FDA approval.
The safety and efficacy of CIBINQO was evaluated in three Phase 3, randomized, placebo-controlled clinical trials. The trials evaluated measures of improvements in skin clearance, itch, disease extent, and severity, including the Investigator Global Assessment (IGA), Eczema Area and Severity Index (EASI), and Peak Pruritus Numerical Ratings Scale (PP-NRS). In each of the trials, over 40% of patients had prior exposure to a systemic therapy:
JADE MONO-1 and JADE MONO-2: A pair of randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy and safety of two doses (100 mg and 200 mg once daily) of CIBINQO monotherapy in 778 patients 12 years of age and older with moderate-to-severe AD. The trials assessed the co-primary endpoints of IGA and EASI-75 responses at Week 12.
JADE COMPARE: A randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of two doses (100 mg and 200 mg once daily) of CIBINQO in 837 adult patients with moderate-to-severe AD on background topical medicated therapy. The trial also included an active control arm with dupilumab, a biologic treatment administered by subcutaneous injection, compared with placebo. The trial assessed the co-primary endpoints of IGA and EASI-75 responses at Week 12.
Select findings for CIBINQO 100 mg, 200 mg, and placebo follow (*p<0.01 or **p<0.001):
JADE MONO-1:
IGA Response Rate (Week 12): 24%*, 44%**, and 8%, respectively
EASI-75 Response Rate (Week 12): 40%**, 62%**, and 12%, respectively
JADE MONO-2
IGA Response Rate (Week 12): 28%**, 38%**, and 9%, respectively
EASI-75 Response Rate (Week 12): 44%**, 61%**, and 10%, respectively
JADE COMPARE
IGA Response Rate (Week 12): 36%**, 47%**, and 14%, respectively
EASI-75 Response Rate (Week 12): 58%**, 68%**, and 27%, respectively
Safety was additionally evaluated through a randomized dose-ranging trial and a long-term, open-label, extension trial (JADE EXTEND).
U.S. IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS
Serious Infections
Patients treated with CIBINQO may be at increased risk for developing serious infections that may lead to hospitalization or death. The most frequent serious infections reported with CIBINQO were herpes simplex, herpes zoster, and pneumonia.
If a serious or opportunistic infection develops, discontinue CIBINQO and control the infection.
Reported infections from Janus kinase (JAK) inhibitors used to treat inflammatory conditions:
Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Test for latent TB before and during therapy; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.
Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral (including herpes zoster), and other infections due to opportunistic pathogens.
Avoid use of CIBINQO in patients with an active, serious infection, including localized infections. The risks and benefits of treatment with CIBINQO should be carefully considered prior to initiating therapy in patients with chronic or recurrent infections or those who have resided or traveled in areas of endemic tuberculosis or endemic mycoses.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIBINQO, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Consider yearly screening for patients in highly endemic areas for TB. CIBINQO is not recommended for use in patients with active TB. For patients with a new diagnosis of latent TB or prior untreated latent TB, or for patients with a negative test for latent TB but who are at high risk for TB infection, start preventive therapy for latent TB prior to initiation of CIBINQO.
Viral reactivation, including herpes virus reactivation (eg, herpes zoster, herpes simplex), was reported in clinical studies with CIBINQO. If a patient develops herpes zoster, consider interrupting CIBINQO until the episode resolves. Hepatitis B virus reactivation has been reported in patients receiving JAK inhibitors. Perform viral hepatitis screening and monitoring for reactivation in accordance with clinical guidelines before starting therapy and during therapy with CIBINQO. CIBINQO is not recommended for use in patients with active hepatitis B or hepatitis C.
Mortality
In a large, randomized postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another JAK inhibitor to TNF blocker treatment, a higher rate of all-cause mortality (including sudden cardiovascular death) was observed with the JAK inhibitor. CIBINQO is not approved for use in RA patients.
Malignancies
Malignancies, including non-melanoma skin cancer (NMSC), were reported in patients treated with CIBINQO. Lymphoma and other malignancies have been observed in patients receiving JAK inhibitors used to treat inflammatory conditions. Perform periodic skin examination for patients who are at increased risk for skin cancer. Exposure to sunlight and UV light should be limited by wearing protective clothing and using broad-spectrum sunscreen.
In a large, randomized postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. CIBINQO is not approved for use in RA patients. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.
Major Adverse Cardiovascular Events
Major adverse cardiovascular events were reported in patients treated with CIBINQO. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. CIBINQO is not approved for use in RA patients. Patients who are current or past smokers are at additional increased risk. Discontinue CIBINQO in patients that have experienced a myocardial infarction or stroke.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with CIBINQO, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.
Thrombosis
Deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients treated with CIBINQO. Thrombosis, including PE, DVT, and arterial thrombosis have been reported in patients receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of overall thrombosis, DVT, and PE were observed when compared with TNF blockers. CIBINQO is not approved for use in RA patients.
Avoid CIBINQO in patients that may be at increased risk of thrombosis. If symptoms of thrombosis occur, discontinue CIBINQO and treat patients appropriately.
Contraindication
CIBINQO is contraindicated in patients taking antiplatelet therapies, except for low-dose aspirin (≤81 mg daily), during the first 3 months of treatment.
Laboratory Abnormalities
Hematologic Abnormalities: Treatment with CIBINQO was associated with an increased incidence of thrombocytopenia and lymphopenia. Prior to CIBINQO initiation, perform a complete blood count (CBC). CBC evaluations are recommended at 4 weeks after initiation and 4 weeks after dose increase of CIBINQO. Discontinuation of CIBINQO therapy is required for certain laboratory abnormalities.
Lipid Elevations: Dose-dependent increase in blood lipid parameters were reported in patients treated with CIBINQO. Lipid parameters should be assessed approximately 4 weeks following initiation of CIBINQO therapy, and thereafter patients should be managed according to clinical guidelines for hyperlipidemia. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Immunizations
Prior to initiating CIBINQO, complete all age-appropriate vaccinations as recommended by current immunization guidelines, including prophylactic herpes zoster vaccinations. Avoid vaccination with live vaccines immediately prior to, during, and immediately after CIBINQO therapy.
Renal Impairment
Avoid use in patients with severe renal impairment or end stage renal disease, including those on renal replacement therapy.
Hepatic Impairment
Avoid use in patients with severe hepatic impairment.
Adverse Reactions
Most common adverse reactions (≥1%) in subjects receiving 100 mg and 200 mg include: nasopharyngitis, nausea, headache, herpes simplex, increased blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis.
Most common adverse reactions (≥1%) in subjects receiving either 100 mg or 200 mg also include: impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, herpes zoster, and thrombocytopenia.
Use in Pregnancy
Available data from pregnancies reported in clinical trials with CIBINQO are not sufficient to establish a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise females of reproductive potential that CIBINQO may impair fertility.
There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIBINQO during pregnancy. Pregnant women exposed to CIBINQO and health care providers are encouraged to call 1-877-311-3770.
Lactation
Advise women not to breastfeed during treatment with CIBINQO and for one day after the last dose.
Indication
CIBINQO is indicated for the treatment of adults with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable.
Limitations of Use: CIBINQO is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.
About CIBINQO® (abrocitinib)
CIBINQO is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD, including interleukin IL-4, IL-13, IL-31, IL-22, and thymic stromal lymphopoietin (TSLP).
In addition to receiving regulatory approval in the U.S., CIBINQO has received marketing authorization in the European Union, Great Britain, Japan, Korea, the United Arab Emirates, Norway, Iceland, and Singapore.
About Atopic Dermatitis
AD is a chronic skin disease characterized by inflammation of the skin and skin barrier defects.i,ii Most people know AD is a skin condition. But many don’t realize it can be caused in part by an abnormal immune response beneath the skin. This dysregulated immune response is thought to contribute to inflammation within the skin and the signs of AD on the surface. Lesions of AD are characterized by erythema (red/pink or discolored skin patches, depending on normal skin color), itching, lichenification (thick/leathery skin), induration (hardening)/papulation (formulation of papules), and oozing/crusting.i,ii
AD is one of the most common inflammatory skin diseases, affecting approximately 5-10% of adults in the U.S.iii,iv Approximately 1 in 3 adults with AD have moderate-to-severe disease.v,vi
About Pfizer Inflammation & Immunology
At Pfizer Inflammation & Immunology, we strive to deliver breakthroughs that enable freedom from day-to-day suffering for people living with autoimmune and chronic inflammatory diseases, which can be debilitating, disfiguring and distressing, dramatically affecting what they can do. With a focus on immuno-inflammatory conditions in Rheumatology, Gastroenterology and Medical Dermatology, our current portfolio of approved medicines and investigational molecules spans multiple action and delivery mechanisms, from topicals to small molecules, biologics and biosimilars. The root cause of many immunological diseases is immuno-inflammation, which requires specifically designed agents. Our differentiated R&D approach resulted in one of the broadest pipelines in the industry, where we purposefully match molecules to diseases where we believe they can make the biggest difference. Building on our decades-long commitment and pioneering science, we continue to advance the standard of care for patients living with immuno-inflammatory diseases and are working hand-in-hand with patients, caregivers and the broader healthcare community on healthcare solutions for the many challenges of managing chronic inflammatory diseases, allowing patients to live their best lives.
Pfizer Inc.: Breakthroughs that Change Patients’ Lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety, and value in the discovery, development, and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments, and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments, and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.
There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2 , JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly
paired JAK kinase in this context and is required for signaling by γ-common (IL-2Rγ) cytokine receptors, IL—6 receptor family, Type I, II and III receptor families and IL- 10 receptor family. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J.
J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285 , 1-24 (2002); O’Shea, J . J., et al., Ceil , 109, (suppl .) S121-S131 (2002)) while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);
Parganas E., et al., Cell, 93(3), 385-95 (1998)).
Tofacitinib (1), baricitinib (2), and ruxolitinib (3)
SYNTHESIS 5+1 =6 steps
Main synthesis
Journal of Medicinal Chemistry, 61(3), 1130-1152; 2018
INTERMEDIATE
CN 105732637
ONE STEP
CAS 479633-63-1, 7H-Pyrrolo[2,3-d]pyrimidine, 4-chloro-7-[(4- methylphenyl)sulfonyl]-
Pfizer Receives Breakthrough Therapy Designation from FDA for PF-04965842, an oral JAK1 Inhibitor, for the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis
Wednesday, February 14, 2018 8:30 am EST
Dateline:
NEW YORK
Public Company Information:
NYSE:
PFE
US7170811035
“We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”
NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) today announced its once-daily oral Janus kinase 1 (JAK1) inhibitor PF-04965842 received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD). The Phase 3 program for PF-04965842 initiated in December and is the first trial in the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) global development program.
“Achieving Breakthrough Therapy Designation is an important milestone not only for Pfizer but also for patients living with the often devastating impact of moderate-to-severe atopic dermatitis, their providers and caregivers,” said Michael Corbo, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development. “We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”
Breakthrough Therapy Designation was initiated as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) signed in 2012. As defined by the FDA, a breakthrough therapy is a drug intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such drug.1
About PF-04965842 and Pfizer’s Kinase Inhibitor Leadership
PF-04965842 is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD including interleukin (IL)-4, IL-13, IL-31 and interferon gamma.
Pfizer has established a leading kinase research capability with multiple unique kinase inhibitor therapies in development. As a pioneer in JAK science, the Company is advancing several investigational programs with novel selectivity profiles, which, if successful, could potentially deliver transformative therapies for patients. Pfizer has three additional kinase inhibitors in Phase 2 development across multiple indications:
PF-06651600: A JAK3 inhibitor under investigation for the treatment of rheumatoid arthritis, ulcerative colitis and alopecia areata
PF-06700841: A tyrosine kinase 2 (TYK2)/JAK1 inhibitor under investigation for the treatment of psoriasis, ulcerative colitis and alopecia areata
PF-06650833: An interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor under investigation for the treatment of rheumatoid arthritis
Working together for a healthier world®
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.
DISCLOSURE NOTICE: The information contained in this release is as of February 14, 2018. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.
This release contains forward-looking information about PF-04965842 and Pfizer’s ongoing investigational programs in kinase inhibitor therapies, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical trial commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable clinical trial results, including unfavorable new clinical data and additional analyses of existing data; risks associated with preliminary data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for any potential indication for PF-04965842 or any other investigational kinase inhibitor therapies; whether and when any such applications may be approved by regulatory authorities, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted, and, if approved, whether PF-04965842 or any such other investigational kinase inhibitor therapies will be commercially successful; decisions by regulatory authorities regarding labeling, safety and other matters that could affect the availability or commercial potential of PF-04965842 or any other investigational kinase inhibitor therapies; and competitive developments.
A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov and www.pfizer.com.
LC/MS m/z (M + H+) calcd for C14H22N5O2S: 324. Found: 324. Anal. Calcd for C14H21N5O2S: C, 51.99; H, 6.54; N, 21.65; O, 9.89; S, 9.91. Found: C, 52.06; H, 6.60; N, 21.48; O, 10.08; S, 9.97.
Schmieder, G.; Draelos, Z.; Pariser, D.; Banfield, C.; Cox, L.; Hodge, M.; Kieras, E.; Parsons-Rich, D.; Menon, S.; Salganik, M.; Page, K.; Peeva, E.Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled studyBr. J. Dermatol.2017, DOI: 10.1111/bjd.16004
Compound 25, N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide is available through MilliporeSigma (cat. no. PZ0304).
CLIP
REFERENCES
1: Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, Kieras E, Parsons-Rich D, Menon S, Salganik M, Page K, Peeva E. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2017 Sep 26. doi: 10.1111/bjd.16004. [Epub ahead of print] PubMed PMID: 28949012
2 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.
Originator Pfizer
Class Anti-inflammatories; Antipsoriatics; Pyrimidines; Pyrroles; Skin disorder therapies; Small molecules; Sulfonamides
Mechanism of Action Janus kinase 1 inhibitors
Phase III Atopic dermatitis
Discontinued Lupus vulgaris; Plaque psoriasis
21 May 2019Pfizer initiates enrolment in a phase I trial in Healthy volunteers in USA (PO) (NCT03937258)
09 May 2019 Pfizer plans a phase I pharmacokinetic and drug-drug interaction trial in healthy volunteers in May 2019 (NCT03937258)
30 Apr 2019 Pfizer completes a phase I trial (In volunteers) in USA (PO) (NCT03626415)
^ Jump up to:abcde“Cibinqo EPAR”. European Medicines Agency (EMA). 11 October 2021. Retrieved 17 December 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^Clinical trial number NCT03349060 for “Study to Evaluate Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-1)” at ClinicalTrials.gov
“Abrocitinib”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03349060 for “Study to Evaluate Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-1)” at ClinicalTrials.gov
Clinical trial number NCT03575871 for “Study Evaluating Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-2)” at ClinicalTrials.gov
{{ClinicalTrialsGov|NCT03720470|Study Evaluating Efficacy and Safety of PF-04965842 and Dupilumab in Adult Subjects With Moderate to Severe Atopic Dermatitis on Background Topical Therapy (JADE Compare)}
The U.S. Food and Drug Administration today approved Azedra (iobenguane I 131) injection for intravenous use for the treatment of adults and adolescents age 12 and older with rare tumors of the adrenal gland (pheochromocytoma or paraganglioma) that cannot be surgically removed (unresectable), have spread beyond the original tumor site and require systemic anticancer therapy. This is the first FDA-approved drug for this use.
update………APPROVED JAPAN 2021, 2021/9/27, Raiatt MIBG-I 131
July 30, 2018
Release
The U.S. Food and Drug Administration today approved Azedra (iobenguane I 131) injection for intravenous use for the treatment of adults and adolescents age 12 and older with rare tumors of the adrenal gland (pheochromocytoma or paraganglioma) that cannot be surgically removed (unresectable), have spread beyond the original tumor site and require systemic anticancer therapy. This is the first FDA-approved drug for this use.
“Many patients with these ultra-rare cancers can be treated with surgery or local therapies, but there are no effective systemic treatments for patients who experience tumor-related symptoms such as high blood pressure,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Patients will now have an approved therapy that has been shown to decrease the need for blood pressure medication and reduce tumor size in some patients.”
Pheochromocytomas are rare tumors of the adrenal glands. These glands are located right above the kidneys and make hormones including stress hormones called epinephrines and norepinephrines. Pheochromocytomas increase the production of these hormones, leading to hypertension (high blood pressure) and symptoms such as headaches, irritability, sweating, rapid heart rate, nausea, vomiting, weight loss, weakness, chest pain or anxiety. When this type of tumor occurs outside the adrenal gland, it is called a paraganglioma.
The efficacy of Azedra was shown in a single-arm, open-label, clinical trial in 68 patients that measured the number of patients who experienced a 50 percent or greater reduction of all antihypertensive medications lasting for at least six months. This endpoint was supported by the secondary endpoint, overall tumor response measured by traditional imaging criteria. The study met the primary endpoint, with 17 (25 percent) of the 68 evaluable patients experiencing a 50 percent or greater reduction of all antihypertensive medication for at least six months. Overall tumor response was achieved in 15 (22 percent) of the patients studied.
The most common severe side effects reported by patients receiving Azedra in clinical trials included low levels of white blood cells (lymphopenia), abnormally low count of a type of white blood cells (neutropenia), low blood platelet count (thrombocytopenia), fatigue, anemia, increased international normalized ratio (a laboratory test which measures blood clotting), nausea, dizziness, hypertension and vomiting.
As it is a radioactive therapeutic agent, Azedra includes a warning about radiation exposure to patients and family members, which should be minimized while the patient is receiving Azedra. The risk of radiation exposure is greater in pediatric patients. Other warnings and precautions include a risk of lower levels of blood cells (myelosuppression), underactive thyroid, elevations in blood pressure, renal failure or kidney injury and inflammation of lung tissue (pneumonitis). Myelodysplastic syndrome and acute leukemias, which are cancers of the blood and bone marrow, were observed in patients who received Azedra, and the magnitude of this risk will continue to be studied. Azedra can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception after receiving Azedra. Radiation exposure associated with Azedra may cause infertility in males and females.
The FDA granted this application Fast Track, Breakthrough Therapy and Priority Review designations. Azedra also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of Azedra to Progenics Pharmaceuticals, Inc.
AdreView (iobenguane I 123 Injection) is a sterile, pyrogen-free radiopharmaceutical for intravenous injection. Each mL contains 0.08 mg iobenguane sulfate, 74 MBq (2 mCi) of I 123 (as iobenguane sulfate I 123) at calibration date and time on the label, 23 mg sodium dihydrogen phosphate dihydrate, 2.8 mg disodium hydrogen phosphate dihydrate and 10.3 mg (1% v/v) benzyl alcohol with a pH of 5.0 – 6.5. Iobenguane sulfate I 123 is also known as I 123 meta-iodobenzlyguanidine sulfate and has the following structural formula:
Physical Characteristics
Iodine 123 is a cyclotron-produced radionuclide that decays to Te 123 by electron capture and has a physical half-life of 13.2 hours.
Iobenguane I-131 is a guanidine analog with specific affinity for tissues of the sympathetic nervous system and related tumors. The radiolabeled forms are used as antineoplastic agents and radioactive imaging agents. (Merck Index, 12th ed) MIBG serves as a neuron-blocking agent which has a strong affinity for, and retention in, the adrenal medulla and also inhibits ADP-ribosyltransferase.
Iobenguane i-131 is a Radioactive Diagnostic Agent. The mechanism of action of iobenguane i-131 is as a Radiopharmaceutical Activity.
Iobenguane I-131 is an I 131 radioiodinated synthetic analogue of the neurotransmitter norepinephrine. Iobenguane localizes to adrenergic tissue and, in radioiodinated forms, may be used to image or eradicate tumor cells that take up and metabolize norepinephrine.
The radioisotope of iodine used for the label can be iodine-123 (for imaging purposes only) or iodine-131 (which must be used when tissue destruction is desired, but is sometimes used for imaging also).
Pheochromocytoma seen as dark sphere in center of the body (it is in the left adrenal gland). Image is by MIBG scintigraphy, with radiation from radioiodine in the MIBG. Two images are seen of the same patient from front and back. Note dark image of the thyroid due to unwanted uptake of iodide radioiodine from breakdown of the pharmaceutical, by the thyroid gland in the neck. Uptake at the side of the head are from the salivary glands. Radioactivity is also seen in the bladder, from normal renal excretion of iodide.
It localizes to adrenergic tissue and thus can be used to identify the location of tumors[2] such as pheochromocytomas and neuroblastomas. With I-131 it can also be used to eradicate tumor cells that take up and metabolize norepinephrine.
Thyroid precautions
Thyroid blockade with (nonradioactive) potassium iodide is indicated for nuclear medicine scintigraphy with iobenguane/mIBG. This competitively inhibits radioiodine uptake, preventing excessive radioiodine levels in the thyroid and minimizing the risk of thyroid ablation ( in the case of I-131). The minimal risk of thyroid carcinogenesis is also reduced as a result.
The FDA-approved dosing of potassium iodide for this purpose are as follows: infants less than 1 month old, 16 mg; children 1 month to 3 years, 32 mg; children 3 years to 18 years, 65 mg; adults 130 mg.[3] However, some sources recommend alternative dosing regimens.[4]
Not all sources are in agreement on the necessary duration of thyroid blockade, although agreement appears to have been reached about the necessity of blockade for both scintigraphic and therapeutic applications of iobenguane. Commercially available iobenguane is labeled with iodine-123, and product labeling recommends administration of potassium iodide 1 hour prior to administration of the radiopharmaceutical for all age groups,[5] while the European Associated of Nuclear Medicine recommends (for iobenguane labeled with either I-131 or I-123,) that potassium iodide administration begin one day prior to radiopharmaceutical administration, and continue until the day following the injection, with the exception of newborns, who do not require potassium iodide doses following radiopharmaceutical injection.[4]
Product labeling for diagnostic iodine-131 iobenguane recommends potassium iodide administration one day before injection and continuing 5 to 7 days following.[6] Iodine-131 iobenguane used for therapeutic purposes requires a different pre-medication duration, beginning 24–48 hours prior to iobenguane injection and continuing 10–15 days following injection.[7]
Alternative imaging modality for pheochromocytoma
The FDOPAPET/CT scan has proven to be nearly 100% sensitive for detection of pheochromocytomas, vs. 90% for MIBG scans.[8][9][10] Centers which offer FDOPA PET/CT, however, are rare.
Clinical trials
Iobenguane I 131 for cancers
Iobenguane I 131 (as Azedra) has had a clinical trial as a treatment for malignant, recurrent or unresectable pheochromocytoma and paraganglioma, and the US FDA has granted it a Priority Review.[11]
Percent Composition: C 34.93%, H 3.66%, I 46.13%, N 15.28%
Literature References: Norepinephrine analog with specific affinity for tissues of sympathetic nervous system and related tumors; prepd as 123I and 131I labeled forms. Prepn and imaging studies: D. M. Wieland et al.,J. Nucl. Med.21, 349 (1980); eidem,US4584187 (1986). Improved synthesis: P. A. P. M. van Doremalen, A. G. M. Janssen, J. Radioanal. Nucl. Chem. Lett.96, 97 (1985). Metabolism in man: T. J. Mangner et al.,J. Nucl. Med.27, 37 (1986). HPLC determn in serum and urine: D. Schwabe et al.,J. Chromatogr.487, 177 (1989). Radiopharmacokinetics: S. Ertl et al.,Nucl. Med. Commun.8, 643 (1987). Clinical evaluation of myocardial imaging: D. Fagret et al.,Eur. J. Nucl. Med.15, 624 (1989). Diagnostic use in pheochromocytoma: B. Shapiro et al.,J. Nucl. Med.26, 576 (1985); therapeutic use: M. Krempf et al.,J. Clin. Endocrinol. Metab.72, 455 (1991). Symposia on therapeutic and diagnostic use in neuroblastoma: Advances in Neuroblastoma Research2, A. E. Evans et al., Eds. (Alan R. Liss, Inc., New York, 1988) p 643-726; Med. Pediatr. Oncol.15, 157-228 (1987). Review of pharmacology: J. C. Sisson, D. M. Weiland, Am. J. Physiol. Imaging1, 96-103 (1986); of biodistribution and clinical studies: A. R. Wafelman et al.,Eur. J. Nucl. Med.21, 545-559 (1994); of therapeutic use in neural crest tumors: L. Troncone, V. Rufini, Anticancer Res.17, 1823-1832 (1997).
Derivative Type: Sulfate
Molecular Formula: (C8H10IN3)2.H2SO4
Molecular Weight: 648.26
Percent Composition: C 29.64%, H 3.42%, I 39.15%, N 12.96%, S 4.95%, O 9.87%
Properties: Colorless crystals from water + ethanol, mp 166-167°.
Melting point: mp 166-167°
Therap-Cat: Radiolabeled forms as antineoplastic; diagnostic aid (radioactive imaging agent).
Jump up^Scarsbrook AF, Ganeshan A, Statham J, et al. (2007). “Anatomic and functional imaging of metastatic carcinoid tumors”. Radiographics. 27 (2): 455–77. doi:10.1148/rg.272065058. PMID17374863.
Jump up^Kowalsky RJ, Falen, SW. Radiopharmaceuticals in Nuclear Pharmacy and Nuclear Medicine. 2nd ed. Washington DC: American Pharmacists Association; 2004.
Jump up^6-[18FFluorodopamine Positron Emission Tomographic (PET) Scanning for Diagnostic Localization of Pheochromocytoma. Pacek et al. 2001] full text
Jump up^Luster M, Karges W, Zeich K, Pauls S, Verburg FA, Dralle H; et al. (2010). “Clinical value of (18)F-fluorodihydroxyphenylalanine positron emission tomography/computed tomography ((18)F-DOPA PET/CT) for detecting pheochromocytoma”. European journal of nuclear medicine and molecular imaging. 37 (3): 484–93. doi:10.1007/s00259-009-1294-7. PMID19862519.
BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.
Abaloparatide is indicated to treat postmenopausal women with osteoporosis who are more susceptible to bone fractures.[2]
Dosage
The dose recommended is 80mcg subcutaneous injection once a day, administered in the periumbilical area using a prefilled pen device containing 30 doses.[4]
Warnings and Precautions
Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[5] However, whether abaloparatide-SC will cause osteosarcoma in humans is unknown. Thus, the use of abaloparatide is not recommended for individuals at increased risk of osteosarcoma. Additionally, its use is not advised for more than 2 years during a patient’s lifetime.[4][6]
Side Effects
The most common side effects reported by more than 2% of clinical trials subjects are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo.[4]
Pharmacology
Abaloparatide is 34 amino acid synthetic analog of PTHrP. It has 41% homology to parathyroid hormone (PTH) (1-34) and 76% homology to parathyroid hormone-related protein (PTHrP) (1-34).[7] It works as an anabolic agent for the bone, through selective activation of the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor (GPCR) expressed in the osteoblasts and osteocytes. Abaloparatide preferentially binds the RG conformational state of the PTH1R, which in turn elicits a transient downstream cyclic AMP signaling response towards to a more anabolic signaling pathway.[8][9]
History
Preclinical studies
Abaloropatide was previously known as BA058 and BIM-44058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovarectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term[10] and long-term[11] daily subcutaneous injection of abaloparatide compared to controls. Recent studies indicated a dose-dependent increased in bone mass and strength in long-term abalorapatide treatment.[12] However, it was also indicated that prolonged abalorapatide-SC treatment leads to increased incidence of osteosarcoma.[5] To date, there is no yet evidence for increased risk of bone tumors due to prolonged abalorapatide systemic administration in humans. Based on this preclinical data, the FDA does not advised the use of abaloparatide-SC for more than 2 years, or in patients with history of Paget disease and/or other conditions that exacerbates the risk of developing osteosarcoma.[4]
Clinical Trials
Phase II trials were initiated in 2008. A 24-week randomized trial was conducted in postmenopausal women with osteoporosis (n=222) assessing bone mass density (BMD) changes as the primary endpoint.[13] Significant BMD increase at doses of 40 and 80 mcg were found in the lumbar spine, femur and hips of abaloparatide-treated participants compared to placebo. Additionally, abaloparatide showed superior anabolic effects on the hips compared to teriparatide.[14]
In the phase III (2011-2014) Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, a 18-months randomized, multicenter, double-blinded, placebo-controlled study evaluated the long-term efficacy of abaloparatide compared to placebo and teriparatide in 2,463 postmenopausal women (± 69 years old).[2] Women who received daily injections of abaloparatide experienced substantial reduction in the incidence of fractures compared to placebo. Additionally, greater BMD increase at 6, 12 and 18 months in spinal, hips and femoral bones was observed in abaloparatide compared to placebo and teriparatide-treated subjects.[3]
Participants who completed 18 months of abaloparatide or placebo in the ACTIVE study were invited to participate in an extended open-labeled study – ACTIVExtend study (2012-2016).[15] Subjects (n=1139) received additional 2 years of 70 mg of alendronate, Vitamin D (400 to 800 IU), and calcium (500–1000 mg) supplementation daily. Combined abaloparatide and alendronate therapy reduced significantly the incidence of vertebral and nonvertebral fractures.[16]
A clinical trial assessing the effectiveness of abaloparatide in altering spinal bone mineral density (BMD) in male subjects is expected to start in the first quarter of 2018. If successful, Radius Health aims to submit a sNDA to expand the use of abaloparatide-SC to treat men with osteoporosis.[17]
In addition to the injectable form of abaloparatide, a transdermal patch is also in development.[1]
Commercialization
As previously noted, abaloparatide-SC is manufactured by Radius Health, Inc. (Nasdaq: RDUS), a biomedical company based in Waltham, Massachusetts. This company is focused on the development of new therapeutics for osteoporosis, cancer and endocrine diseases. Abaloparatide is the only drug currently marketed by Radius Health. RDUS reported that sales for abaloparatide were $3.5million for the third quarter of 2017.[17] The company announced a net loss of $57.8 million, or $1.31 per share for the third quarter of 2017, compared to $19.2 million for the same quarter of 2016.[18] The net loss most likely reflects the substantial expenses associated with the preparation and launching of abaloparatide into the US market in May 2017.
In July 2017, Radius Health licensed rights to Teijin Limited for abaloparatide-SC manufacture and commercialization in Japan. Teijin is developing abaloparatide-SC under agreement with Ipsen Pharma S.A.S., and is conducting a phase III clinical trial in Japanese patients with osteoporosis.[19]
Regulatory Information
Radius Health filed a Marketing Authorization Application (MAA) in November 2015,[20] which was validated in December, 2015, and still under regulatory assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). As in July 2017, the CHMP issued a second Day-180 List of Outstanding Issues, which Radius is addressing with the CHMP.[17]
In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May, 2016.[21] A Prescription Drug User Fee Act (PDUFA) date was initially granted in March 30, 2016, but then extended to June 30, 2017.[22] As previously stated, abaloparatide injection was approved for use in postmenopausal osteoporosis on April 28, 2017.[6]
Intellectual Property
Radius Health currently holds three patents on abaloparatide-SC, with expiration dates from 2027-2028.[23] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2).
As previously mentioned, Teijin Limited was granted use of Radius Health intellectual property in July 2017, for the development, manufacture and commercialization of abaloparatide-sc in Japan.
The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.
May 27, 2016
Release
The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.
Prostate cancer is the second leading cause of death from cancer in U.S. men. In patients with suspected cancer recurrence after primary treatment, accurate staging is an important objective in improving management and outcomes.
“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, M.D., Ph.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Axumin is shown to provide another accurate imaging approach for these patients.”
Two studies evaluated the safety and efficacy of Axumin for imaging prostate cancer in patients with recurrent disease. The first compared 105 Axumin scans in men with suspected recurrence of prostate cancer to the histopathology (the study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. Radiologists onsite read the scans initially; subsequently, three independent radiologists read the same scans in a blinded study.
The second study evaluated the agreement between 96 Axumin and C11 choline (an approved PET scan imaging test) scans in patients with median PSA values of 1.44 ng/mL. Radiologists on-site read the scans, and the same three independent radiologists who read the scans in the first study read the Axumin scans in this second blinded study. The results of the independent scan readings were generally consistent with one another, and confirmed the results of the onsite scan readings. Both studies supported the safety and efficacy of Axumin for imaging prostate cancer in men with elevated PSA levels following prior treatment.
Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure to patients and healthcare providers during administration. Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.
The most commonly reported adverse reactions in patients are injection site pain, redness, and a metallic taste in the mouth.
Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom
The non-natural amino acid [ F]-l-amino-3-fluorocyclobutane-l-carboxylic acid
([18F]-FACBC, also known as [18F]-Fluciclovine) is taken up specifically by amino acid transporters and has shown promise for tumour imaging with positron emission tomography (PET).
A known synthesis of [18F]-FACBC begins with the provision of the protected precursor compound 1 -(N-(t-butoxycarbonyl)amino)-3 –
[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester. This precursor compound is first labelled with [18F]-fluoride:
II before removal of the two protecting groups:
IT III
EP2017258 (Al) teaches removal of the ethyl protecting group by trapping the [18F]- labelled precursor compound (II) onto a solid phase extraction (SPE) cartridge and incubating with 0.8 mL of a 4 mol/L solution of sodium hydroxide (NaOH). After 3 minutes incubation the NaOH solution was collected in a vial and a further 0.8 mL 4 mol/L NaOH added to the SPE cartridge to repeat the procedure. Thereafter the SPE cartridge was washed with 3 mL water and the wash solution combined with the collected NaOH solution. Then 2.2 mL of 6 mol/L HCl was then added with heating to 60°C for 5 minutes to remove the Boc protecting group. The resulting solution was purified by passing through (i) an ion retardation column to remove Na+ from excess NaOH and Cl~ from extra HCl needed to neutralise excess of NaOH to get a highly acidic solution before the acidic hydrolysis step, (ii) an alumina column, and (iii) a reverse-phase column. There is scope for the deprotection step(s) and/or the
purification step in the production of [18F]-FACBC to be simplified.
Example 1: Synthesis of f FIFACBC
No-carrier- added [18F]fluoride was produced via the 180(p,n)18F nuclear reaction on a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo). Irradiations were performed using a dual-beam, 30μΑ current on two equal Ag targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6 ml of > 96% [180]water (Marshall Isotopes). Subsequent to irradiation and delivery to a hotcell, each target was washed with 1.6 ml of [160]water (Merck, water for GR analysis), giving approximately 2-5 Gbq in 3.2 ml of [160]water. All radiochemistry was performed on a commercially available GE FASTlab™ with single-use cassettes. Each cassette is built around a one-piece-moulded manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connection with five prefilled vials, one water bag (100 ml) as well as various SPE cartridges and filters. Fluid paths are controlled with nitrogen purging, vacuum and the three syringes. The fully automated system is designed for single-step fluorinations with cyclotron-produced [18F]fluoride. The FASTlab was programmed by the software package in a step-by-step time-dependent sequence of events such as moving the syringes, nitrogen purging, vacuum, and temperature regulation. Synthesis of
[18F]FACBC followed the three general steps: (a) [18F]fluorination, (b) hydrolysis of protection groups and (c) SPE purification.
Vial A contained K222 (58.8 mg, 156 μπιοΐ), K2C03 (8.1 mg, 60.8 μπιοΐ) in 79.5% (v/v)
MeCN(aq) (1105 μΐ). Vial B contained 4M HC1 (2.0 ml). Vial C contained MeCN
(4.1ml). Vial D contained the precursor (48.4 mg, 123.5 μιηοΐ) in its dry form (stored at -20 °C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml). The 30 ml product collection glass vial was filled with 200 mM trisodium citrate (10 ml). Aqueous
[18F]fluoride (1-1.5 ml, 100-200 Mbq) was passed through the QMA and into the 180-
H20 recovery vial. The QMA was then flushed with MeCN and sent to waste. The trapped [18F]fluoride was eluted into the reactor using eluent from vial A (730 μΐ) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 μΐ, vial C). Approximately 1.7 ml of MeCN was mixed with precursor in vial D from which 1.0 ml of the dissolved precursor (corresponds to 28.5 mg, 72.7 mmol precursor) was added to the reactor and heated for 3 min at 85°C. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was washed with water, and then incubated with 2M NaOH (2.0 ml) for 5 min after which the 2M NaOH was sent to waste. The labelled intermediate (without the ester group) was then eluted off the tC18 cartridge into the reactor using water. The BOC group was hydrolysed by adding 4M HC1 (1.4 ml) and heating the reactor for 5 min at 60 °C. The reactor content with the crude [18F]FACBC was sent through the HLB and Alumina cartridges and into the 30 ml product vial. The HLB and Alumina cartridges were washed with water (9.1 ml total) and collected in the product vial. Finally, 2M NaOH (0.9 ml) and water (2.1 ml) was added to the product vial, giving a purified formulation of [18F]FACBC with a total volume of 26 ml. Radiochemical purity was measured by radio-TLC using a mixture of MeCN:MeOH:H20:CH3COOH (20:5:5: 1) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [18F]FACBC fraction divided by the total used [18F]fluoride activity (decay corrected). Total synthesis time was 43 min.
The RCY of [18F]FACBC was 62.5% ± 1.93 (SD), n=4.
/////FDA, diagnostic imaging agent, recurrent prostate cancer, fda 2016, Axumin, marketed, Blue Earth Diagnostics, Ltd., Oxford, United Kingdom, fluciclovine F 18
Date of issue of marketing authorisation valid throughout the European Union
22/05/2017
Contact address:
Blue Earth Diagnostics Ltd
215 Euston Road
London NW1 2BE
United Kingdom
Manufacture, characterisation and process controls
The active substance fluciclovine (18F) is prepared from the precursor AH113487 by nucleophilic substitution
of a triflate group by 18F-fluoride, followed by two deprotection steps. Due to the short half-life of the 18Ffluorine
radioisotope, each batch is prepared on the day of clinical use.
The active substance is prepared in a proprietary automated synthesiser unit. The synthesiser module is
computer-controlled. A fluid path for synthesis is provided in the form of a single use cassette (FASTlab). The
cassette contains 3 reagent vials and 3 solid phase cartridges. Two other reagent vials are supplied
separately as they have a recommended storage temperature of 2-8°C. These 2 vials are inserted into the
cassette on the day of production.
Assessment report
EMA/237809/2017 Page 13/90
Fluciclovine (18F) is produced in a continuous operation from the precursor AH113487. Due to the radioactive
nature of the process, and the short half-life of [18F] fluorine, intermediates are not isolated and there is no
opportunity for operator intervention or in-process testing. Control of the synthesis of fluciclovine (18F) from
the precursor is achieved through the automated synthesis platform, which is pre-programmed with
synthesis parameters optimised for the process. On-board detectors record transfers of radioactivity through
the fluid path at critical points and monitor temperature and pressure as appropriate so that the operator
may track the progress of the synthesis.
The active substance fluciclovine (18F) progressses immediately to purification, formulation and dispensing as
the finished product within a single, continuous operation. Validation of the manufacturing process for
fluciclovine (18F) is therefore described as part of finished product validation.
The characterisation of the active substance is in accordance with the EU guideline on chemistry of new
active substances.
As mentioned, the manufacture of the active substance and finished product takes place in a single,
continuous process. The active substance is not isolated at any point. Therefore, relevant information about
impurities is given only for the finished product.
For the same reason, information for the container closure system is provided only for the finished product.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004197/WC500230836.pdf
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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