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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 GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
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EMA……Ogluo (glucagon), a hybrid medicine for the treatment of severe hypoglycaemia in diabetes mellitus. Hybrid applications rely in part on the results of pre-clinical tests and clinical trials of an already authorised reference product and in part on new data.
Ogluo will be available as 0.5 and 1 mg solution for injection. The active substance of Ogluo is glucagon, a pancreatic hormone (ATC code: H04AA01); glucagon increases blood glucose concentration by stimulating glycogen breakdown and release of glucose from the liver.
The benefits with Ogluo are its ability to restore blood glucose levels in hypoglycaemic subjects. The most common side effects are nausea and vomiting.
Ogluo is a hybrid medicine1 of GlucaGen/GlucaGen Hypokit; GlucaGen has been authorised in the EU since October 1962. Ogluo contains the same active substance as GlucaGen but is available as a ready-to-use formulation intended for subcutaneous injection.
1 Hybrid applications rely in part on the results of pre-clinical tests and clinical trials for a reference product and in part on new data.
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It works to raise the concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body.[3] It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose.[4] It is produced from proglucagon, encoded by the GCG gene.
The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes the liver to engage in glycogenolysis: converting stored glycogen into glucose, which is released into the bloodstream.[5] High blood-glucose levels, on the other hand, stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress.[6] Glucagon belongs to the secretin family of hormones.
Function
Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis.[7] Glucagon also decreases fatty acid synthesis in adipose tissue and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised to generate energy in tissues such as skeletal muscle when required.[8]
Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.
Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression (such as diabetes mellitus type 1).[9]
Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.[10]
Mechanism of action
Metabolic regulation of glycogen by glucagon.
Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane of the cell. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule. This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.
Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate from glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ𝛾. Gɑ separates from Gβ𝛾 and interacts with the transmembrane protein adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP binds to protein kinase A, and the complex phosphorylates phosphorylase kinase.[11] Phosphorylated phosphorylase kinase phosphorylates phosphorylase. Phosphorylated phosphorylase clips glucose units from glycogen as glucose 1-phosphate. Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose 2,6-bisphosphate.[12] The enzyme protein kinase A (PKA) that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose 2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose 2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis)[13] by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).
Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes.[14]
Physiology
Production
A microscopic image stained for glucagon
The hormone is synthesized and secreted from alpha cells (α-cells) of the islets of Langerhans, which are located in the endocrine portion of the pancreas. Production, which is otherwise freerunning, is suppressed/regulated by amylin, a peptide hormone co-secreted with insulin from the pancreatic β cells.[15] As plasma glucose levels recede, the subsequent reduction in amylin secretion alleviates its suppression of the α cells, allowing for glucagon secretion.
In rodents, the alpha cells are located in the outer rim of the islet. Human islet structure is much less segregated, and alpha cells are distributed throughout the islet in close proximity to beta cells. Glucagon is also produced by alpha cells in the stomach.[16]
Recent research has demonstrated that glucagon production may also take place outside the pancreas, with the gut being the most likely site of extrapancreatic glucagon synthesis.[17]
Elevated glucagon is the main contributor to hyperglycemic ketoacidosis in undiagnosed or poorly treated type 1 diabetes. As the beta cells cease to function, insulin and pancreatic GABA are no longer present to suppress the freerunning output of glucagon. As a result, glucagon is released from the alpha cells at a maximum, causing rapid breakdown of glycogen to glucose and fast ketogenesis.[29] It was found that a subset of adults with type 1 diabetes took 4 times longer on average to approach ketoacidosis when given somatostatin (inhibits glucagon production) with no insulin. Inhibiting glucagon has been a popular idea of diabetes treatment, however some have warned that doing so will give rise to brittle diabetes in patients with adequately stable blood glucose.[citation needed]
The absence of alpha cells (and hence glucagon) is thought to be one of the main influences in the extreme volatility of blood glucose in the setting of a total pancreatectomy.
History
In the 1920s, Kimball and Murlin studied pancreatic extracts, and found an additional substance with hyperglycemic properties. They described glucagon in 1923.[30] The amino acid sequence of glucagon was described in the late 1950s.[31] A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific radioimmunoassay was developed.[citation needed]
Etymology
Kimball and Murlin coined the term glucagon in 1923 when they initially named the substance the glucose agonist.[32]
^ Leinen RL, Giannini AJ (1983). “Effect of eyestalk removal on glucagon induced hyperglycemia in crayfish”. Society for Neuroscience Abstracts. 9: 604.
^ Claus TH, El-Maghrabi MR, Regen DM, Stewart HB, McGrane M, Kountz PD, Nyfeler F, Pilkis J, Pilkis SJ (1984). “The role of fructose 2,6-bisphosphate in the regulation of carbohydrate metabolism”. Current Topics in Cellular Regulation. 23: 57–86. doi:10.1016/b978-0-12-152823-2.50006-4. ISBN9780121528232. PMID6327193.
^ Skoglund G, Lundquist I, Ahrén B (November 1987). “Alpha 1- and alpha 2-adrenoceptor activation increases plasma glucagon levels in the mouse”. European Journal of Pharmacology. 143 (1): 83–8. doi:10.1016/0014-2999(87)90737-0. PMID2891547.
^ Honey RN, Weir GC (October 1980). “Acetylcholine stimulates insulin, glucagon, and somatostatin release in the perfused chicken pancreas”. Endocrinology. 107 (4): 1065–8. doi:10.1210/endo-107-4-1065. PMID6105951.
^ Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q (January 2006). “Intra-islet insulin suppresses glucagon release via GABA-GABAA receptor system”. Cell Metabolism. 3 (1): 47–58. doi:10.1016/j.cmet.2005.11.015. PMID16399504.
^ Krätzner R, Fröhlich F, Lepler K, Schröder M, Röher K, Dickel C, Tzvetkov MV, Quentin T, Oetjen E, Knepel W (February 2008). “A peroxisome proliferator-activated receptor gamma-retinoid X receptor heterodimer physically interacts with the transcriptional activator PAX6 to inhibit glucagon gene transcription”. Molecular Pharmacology. 73 (2): 509–17. doi:10.1124/mol.107.035568. PMID17962386. S2CID10108970.
^ Unger RH, Orci L (June 1981). “Glucagon and the A cell: physiology and pathophysiology (first two parts)”. The New England Journal of Medicine. 304 (25): 1518–24. doi:10.1056/NEJM198106183042504. PMID7015132.
^ Orskov C, Holst JJ, Poulsen SS, Kirkegaard P (November 1987). “Pancreatic and intestinal processing of proglucagon in man”. Diabetologia. 30 (11): 874–81. doi:10.1007/BF00274797 (inactive 2020-10-11). PMID3446554.
^ John AM, Schwartz RA (December 2016). “Glucagonoma syndrome: a review and update on treatment”. Journal of the European Academy of Dermatology and Venereology. 30 (12): 2016–2022. doi:10.1111/jdv.13752. PMID27422767. S2CID1228654.
^ Fasanmade OA, Odeniyi IA, Ogbera AO (June 2008). “Diabetic ketoacidosis: diagnosis and management”. African Journal of Medicine and Medical Sciences. 37 (2): 99–105. PMID18939392.
^ Bromer W, Winn L, Behrens O (1957). “The amino acid sequence of glucagon V. Location of amide groups, acid degradation studies and summary of sequential evidence”. J. Am. Chem. Soc. 79 (11): 2807–2810. doi:10.1021/ja01568a038.
On November 25, 2020, the Food and Drug Administration granted accelerated approval to naxitamab (DANYELZA, Y-mAbs Therapeutics, Inc.) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for pediatric patients one year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.
Efficacy was evaluated in patients with relapsed or refractory neuroblastoma in the bone or bone marrow enrolled in two single-arm, open-label trials: Study 201 (NCT 03363373) and Study 12-230 (NCT 01757626). Patients with progressive disease following their most recent therapy were excluded. Patients received 3 mg/kg naxitamab administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 µg/m2/day on days -4 to 0 and at 500 µg/m2/day on days 1 to 5. At the investigator’s discretion, patients were permitted to receive pre-planned radiation to the primary disease site in Study 201 and radiation therapy to non-target bony lesions or soft tissue disease in Study 12-230.
The main efficacy outcome measures were confirmed overall response rate (ORR) per the revised International Neuroblastoma Response Criteria (INRC) and duration of response (DOR). Among 22 patients treated in the multicenter Study 201, the ORR was 45% (95% CI: 24%, 68%) and 30% of responders had a DOR greater or equal to 6 months. Among 38 patients treated in the single-center Study 12-230, the ORR was 34% (95% CI: 20%, 51%) with 23% of patients having a DOR greater or equal to 6 months. For both trials, responses were observed in either the bone, bone marrow or both.
The prescribing information contains a Boxed Warning stating that naxitamab can cause serious infusion-related reactions and neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). To mitigate these risks, patients should receive premedication prior to each naxitamab infusion and be closely monitored during and for at least two hours following completion of each infusion.
The most common adverse reactions (incidence ≥25% in either trial) in patients receiving naxitamab were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.
The recommended naxitamab dose is 3 mg/kg/day (up to 150 mg/day) on days 1, 3, and 5 of each treatment cycle, administered after dilution as an intravenous infusion in combination with GM-CSF, subcutaneously at 250 µg/m2/day on days -4 to 0 and at 500 µg/m2/day on days 1 to 5. Treatment cycles are repeated every 4 to 8 weeks.
This review used the Real-Time Oncology Review (RTOR) pilot program and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted accelerated approval based on overall response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.
FDA 11/25/2020, Imcivree, To treat obesity and the control of hunger associated with pro-opiomelanocortin deficiency, a rare disorder that causes severe obesity that begins at an early age Drug Trials Snapshot, 10MG/ML, SOLUTION;SUBCUTANEOUS, Orphan
DESCRIPTION
IMCIVREE contains setmelanotide acetate, a melanocortin 4 (MC4) receptor agonist. Setmelanotide is an 8 amino acid cyclic peptideanalog of endogenous melanocortin peptide α-MSH (alpha-melanocyte stimulating hormone).
The chemical name for setmelanotide acetate is acetyl-L-arginyl-L-cysteinyl-D-alanyl-Lhistidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2→8)-disulfide acetate. Its molecular formula is C49H68N18O9S2 (anhydrous, free-base), and molecular mass is 1117.3 Daltons (anhydrous, free-base).
The chemical structure of setmelanotide is:
IMCIVREE injection is a sterile clear to slightly opalescent, colorless to slightly yellow solution. Each 1 mL of IMCIVREE contains 10 mg of setmelanotide provided as setmelanotide acetate, which is a salt with 2 to 4 molar equivalents of acetate, and the following inactive ingredients: 100 mg N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-glycero-3phosphoethanolamine sodium salt, 8 mg carboxymethylcellulose sodium (average MWt 90,500), 11 mg mannitol, 5 mg phenol, 10 mg benzyl alcohol, 1 mg edetate disodium dihydrate, and Water for Injection. The pH of IMCIVREE is 5 to 6.
Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor. Setmelanotide binds to and activates MC4 receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects. Setmelanotide increases resting energy expenditure in both obese animals and humans. Setmelanotide has been reported to possess the following activity profile (cAMP, EC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM).
Setmelanotide, sold under the brand name Imcivree, is a medication for the treatment of obesity.[1]
The most common side effects include injection site reactions, skin hyperpigmentation (skin patches that are darker than surrounding skin), headache and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain), among others.[1] Spontaneous penile erections in males and adverse sexual reactions in females have occurred with treatment.[1] Depression and suicidal ideation have also occurred with setmelanotide.[1]
SYN
WO 2011060355
Medical uses
Setmelanotide is indicated for chronic weight management (weight loss and weight maintenance for at least one year) in people six years and older with obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance.[1] Setmelanotide is the first FDA-approved treatment for these genetic conditions.[1]
Setmelanotide is not approved for obesity due to suspected POMC, PCSK1, or LEPR deficiency with variants classified as benign (not causing disease) or likely benign or other types of obesity, including obesity associated with other genetic syndromes and general (polygenic) obesity.[1]
Setmelanotide has been reported to possess the following activity profile (cAMP, EC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM).[5] (19.6-fold selectivity for MC4 over MC3, the second target of highest activity.)
History
Setmelanotide was evaluated in two one-year studies.[1] The first study enrolled participants with obesity and confirmed or suspected POMC or PCSK1 deficiency while the second study enrolled participants with obesity and confirmed or suspected LEPR deficiency; all participants were six years or older.[1] The effectiveness of setmelanotide was determined by the number of participants who lost more than ten percent of their body weight after a year of treatment.[1]
The effectiveness of setmelanotide was assessed in 21 participants, ten in the first study and eleven in the second.[1] In the first study, 80 percent of participants with POMC or PCSK1 deficiency lost ten percent or more of their body weight.[1] In the second study, 46 percent of participants with LEPR deficiency lost ten percent or more of their body weight.[1]
The study also assessed the maximal (greatest) hunger in sixteen participants over the previous 24 hours using an eleven-point scale in participants twelve years and older.[1] In both studies, some, but not all, of participants’ weekly average maximal hunger scores decreased substantially from their scores at the beginning of the study.[1] The degree of change was highly variable among participants.[1]
The U.S. Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review.[1] The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc.[1]
Synthesis of Example 1i.e., Ac-Arg-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2
The title peptide having the above structure was assembled using Fmoc chemistry on an Apex peptide synthesizer (Aapptec; Louisville, Ky., USA). 220 mg of 0.91 mmol/g (0.20 mmoles) Rink Amide MBHA resin (Polymer Laboratories; Amherst, Mass., USA) was placed in a reaction well and pre-swollen in 3.0 mL of DMF prior to synthesis. For cycle 1, the resin was treated with two 3-mL portions of 25% piperidine in DMF for 5 and 10 minutes respectively, followed by 4 washes of 3-mL DMF—each wash consisting of adding 3 mL of solvent, mixing for 1 minute, and emptying for 1 minute. Amino acids stocks were prepared in NMP as 0.45M solutions containing 0.45M HOBT. HBTU was prepared as a 0.45M solution in NMP and DIPEA was prepared as a 2.73M solution in NMP. To the resin, 2 mL of the first amino acid (0 9 mmoles, Fmoc-Cys(Trt)-OH) (Novabiochem; San Diego, Calif., USA) was added along with 2 mL (0.9 mmoles) of HBTU and 1.5 mL (4.1 mmoles) of DIPEA. After one hour of constant mixing, the coupling reagents were drained from the resin and the coupling step was repeated. Following amino acid acylation, the resin was washed with two 3-mL aliquots of DMF for 1 minute. The process of assembling the peptide (deblock/wash/acylate/wash) was repeated for cycles 2-9 identical to that as described for cycle 1. The following amino acids were used: cycle 2) Fmoc-Trp(Boc)-OH (Genzyme; Cambridge, Mass., USA); cycle 3) Fmoc-Arg(Pbf)-OH (Novabiochem); cycle 4) Fmoc-DPhe-OH (Genzyme); cycle 5) Fmoc-His(Trt)-OH (Novabiochem); cycle 6) Fmoc-D-Ala-OH (Genzyme); cycle 7) Fmoc-Cys(Trt)-OH, (Novabiochem); and cycle 8) Fmoc-Arg(Pbf)-OH (Genzyme). The N-terminal Fmoc was removed with 25% piperidine in DMF as described above, followed by four 3-mL DMF washes for 1 minute. Acetylation of the N-terminus was performed by adding 0.5 mL of 3M DIPEA in NMP to the resin along with 1.45 mL of 0.45M acetic anhydride in NMP. The resin was mixed for 30 minutes and acetylation was repeated. The resin was washed with 3 mL of DMF for a total of 5 times followed with 5 washes with 5 mL of DCM each.
To cleave and deprotect the peptide, 5mL of the following reagent was added to the resin: 2% TIS/5% water/5% (w/v) DTT/88% TFA. The solution was allowed to mix for 3.5 hours. The filtrate was collected into 40 mL of cold anhydrous ethyl ether. The precipitate was pelleted for 10 minutes at 3500 rpm in a refrigerated centrifuge. The ether was decanted and the peptide was re-suspended in fresh ether. The ether workup was performed three times. Following the last ether wash, the peptide was allowed to air dry to remove residual ether.
The peptide was dissolved in 10% acetonitrile and analyzed by mass spectrometry and reverse-phase HPLC employing a 30×4.6 cm C18 column (Vydac; Hesperia, Calif., USA) with a gradient of 2-60% acetonitrile (0.1% TFA) over 30 minutes. This analysis identified a product with ˜53% purity. Mass analysis employing electrospray ionization identified a main product containing a mass of 1118.4 corresponding to the desired linear product. The crude product (˜100 mg) was diluted to a concentration of 2 mg/mL in 5% acetic acid. To this solution, 0.5M iodine/methanol was added dropwise with vigorous stirring until a pale yellow color was achieved. The solution was vigorously stirred for another 10 minutes. Excess iodine was then quenched by adding 1.0M sodium thiosulfate under continuous mixing until the mixture was rendered colorless. The peptide was re-examined by mass spectrometry analysis and HPLC. Mass spectrometry analysis identified a main species with a mass of 1116.4 which indicated successful oxidation to form the cyclic peptide. The peptide solution was purified on a preparative HPLC equipped with a C18 column using a similar elution gradient. The purified product was re-analyzed by HPLC for purity (>95%) and mass spectrometry (1116.9 which is in agreement with the expected mass of 1117.3) and subsequently lyophilized. Following lyophilization, 28 mg of purified product was obtained representing a 24% yield.
The other exemplified peptides were synthesized substantially according to the procedure described for the above-described synthetic process. Physical data for select exemplified peptides are given in Table 1.
The acetate salt of Example 1 (200 mg, 0.18 mmole) was dissolved in 10 mL of water. Sodium pamoate (155 mg, 0.36 mmole) was dissolved in 10 mL of water. The two solutions were combined and mixed well. The precipitates were collected by centrifugation at 3000 rpm for 20 minutes, washed for three times with water, and dried by lyophilization.
^ Jump up to:abc Lee EC, Carpino PA (2015). “Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014)”. Pharmaceutical Patent Analyst. 4 (2): 95–107. doi:10.4155/ppa.15.1. PMID25853469.
^ Jackson VM, Price DA, Carpino PA (August 2014). “Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies”. Expert Opinion on Investigational Drugs. 23 (8): 1055–66. doi:10.1517/13543784.2014.918952. PMID25000213. S2CID23198484.
The peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It is being researched by Rhythm Pharmaceuticals for the treatment of obesity and diabetes. In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC4 receptor deficiency and associated symptoms such as excessive appetite and obesity. As of December 2014, the drug is in phase II clinical trials for obesity and PWS.
1: Lee EC, Carpino PA. Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014). Pharm Pat Anal. 2015;4(2):95-107. doi: 10.4155/ppa.15.1. PubMed PMID: 25853469.
2: Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, Zhao X, Ring M, Psota TL, Cone RD, Panaro BL, Gottesdiener KM, Van der Ploeg LH, Reitman ML, Skarulis MC. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015 Apr;100(4):1639-45. doi: 10.1210/jc.2014-4024. Epub 2015 Feb 12. PubMed PMID: 25675384; PubMed Central PMCID: PMC4399297.
3: Clemmensen C, Finan B, Fischer K, Tom RZ, Legutko B, Sehrer L, Heine D, Grassl N, Meyer CW, Henderson B, Hofmann SM, Tschöp MH, Van der Ploeg LH, Müller TD. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol Med. 2015 Feb 4;7(3):288-98. doi: 10.15252/emmm.201404508. PubMed PMID: 25652173; PubMed Central PMCID: PMC4364946.
4: Jackson VM, Price DA, Carpino PA. Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies. Expert Opin Investig Drugs. 2014 Aug;23(8):1055-66. doi: 10.1517/13543784.2014.918952. Epub 2014 Jul 7. Review. PubMed PMID: 25000213.
5: Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, Pranger L, Cowley MA, Grove KL, Culler MD. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013 Feb;62(2):490-7. doi: 10.2337/db12-0598. Epub 2012 Oct 9. PubMed PMID: 23048186; PubMed Central PMCID: PMC3554387.
6: Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, Culler MD, Yang H, Dixit VD, Butler AA. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009 Oct;30(10):1892-900. doi: 10.1016/j.peptides.2009.07.012. Epub 2009 Jul 29. PubMed PMID: 19646498; PubMed Central PMCID: PMC2755620.
External links
“Setmelanotide”. Drug Information Portal. U.S. National Library of Medicine.
The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell), infusion reactions, pneumonia (infection of the lungs), upper respiratory tract infection (such as nose and throat infections), diarrhoea and bronchitis (inflammation of the airways in the lungs).[3]
In the European Union it is indicated, in combination with pomalidomide and dexamethasone, for the treatment of adults with relapsed and refractory multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor (PI) and have demonstrated disease progression on the last therapy.[3]
Researchers started a Phase I study with isatuximab in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM). The results during the Phase I trial showed that 26 out of the 45 patients discontinued the treatment due to progression of the disease. The patients had already been heavily pretreated. The latter lead to a manageable safety profile where the dose of isatuximab in combination with pomalidomide and dexamethasone would be capped to the maximum of 10 mg/kg weekly every two weeks for future studies.[12]
Based on the remarkable findings during the Phase I trial, a Phase II trial was launched where researchers investigated isatuximab as a single agent in patients with MM. The heavily pretreated patients reacted well to the single administration of isatuximab during Phase II of the trial.[13]
A Phase III combination trial for plasma cell myeloma is comparing pomalidomide and dexamethasone with and without isatuximab is in progress with an estimated completion date of 2021.[medical citation needed]
Additionally, two Phase III trials were added in 2017. The first trial highlights whether there is an added value in the combination of isatuximab with bortezomib, lenalidomide and dexamethasone. The latter will be tested in patients with newly diagnosed MM who are not qualified for a transplant (IMROZ trial). The second trial evaluates the combinations of isatuximab with carfilzomib and dexamethasone compared to carfilzomib with dexamethasone. The second trial was designed for patients who were previously treated with one to three prior lines (IKEMA). There is currently[when?] no treatment for MM, however promising improvements have been made and the study is still ongoing.[14][15]
In March 2020, it was approved for medical use in the United States.[8][9][10]
The U.S. Food and Drug Administration (FDA) approved isatuximab-irfc in March 2020, based on evidence from a clinical trial (NCT02990338) of 307 subjects with previously treated multiple myeloma.[10] The trial was conducted at 102 sites in Europe, North America, Asia, Australia and New Zealand.[10]
The trial evaluated the efficacy and side effects of isatuximab-irfc in subjects with previously treated multiple myeloma.[10] Subjects were randomly assigned to receive either isatuximab-irfc (in combination with pomalidomide and low-dose dexamethasone) or active comparator (pomalidomide and low-dose dexamethasone).[10] Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity.[10] Both subjects and health care providers knew which treatment was given.[10] The trial measured the time patients lived without the cancer growing (progression-free survival or PFS).[10]
It was approved for medical use in the European Union in May 2020.[3]
Structure and reactivity
The structure of isatuximab consists of two identical immunoglobulin kappa light chains and also two equal immunoglobulin gamma heavy chains. Chemically, isatuximab is similar to the structure and reactivity of daratumumab, hence both drugs show the same CD38 targeting. However, isatuximab shows a more potent inhibition of its ectozyme function. The latter gives potential for some non-cross reactivity. Isatuximab shows action of an allosteric antagonist with the inhibition of the CD38 enzymatic activity. Additionally, isatuximab shows potential where it can induce apoptosis without cross linking.[16] Lastly, Isatuximab reveals direct killing activity when a larger increase in apoptosis is detected in CD38 expressing cancer cells. Furthermore, isatuximab demonstrated a dose dependent inhibition of CD38 enzymatic activity. However, daratumumab with the same experimental conditions shows a more limited inhibition without a dose response.[17]
Reactions
Isatuximab binds uniquely to an epitope on the CD38 receptor and is the only CD38 antibody which can start apoptosis directly.[18] Isatuximab binds to a different CD38 epitopeamino-acid sequence than does the anti-CD38 monoclonal antibody daratumumab.[19] The binding with the CD38 receptor is mainly via the gamma heavy chains and are more potent than other CD38 antibodies such as daratumumab which can inhibit the enzymatic activity of CD38. Moreover, isatuximab inhibits the hydrolase activity of CD38.[medical citation needed]
The antibodies show signs of improving antitumor immunity by eliminating regulatory T cells, B cells and myeloid-derived suppressor cells. The difference in binding between isatuximab and daratumumab is in the recognition of the different amino acid groups. Isatuximab identifies 23 amino acids of CD38 to the contrary with daratumumab who has 27. The residue of Glu233 has a flexible sidechain and faces the N-terminal of Asp1 residue in the isatuximab light chain. The latter light chain of isatuximab is also flexible which makes the interaction between CD38/Glu233 and the Asp1 weaker than the other interactions between CD38 and isatuximab. The caspase-dependent apoptotic pathway and the lysosomal mediated cell death pathway in MM cells is induced by isatuximab. The MM cell death follows the downstream reactions of the lysosomal activation. The latter also activates the production of reactive oxygen species.[20]
Available forms
Isatuximab or isatuximab-irfc is available as a drug in an intravenous infusion form. Injection doses are 100 mg/5 mL (20 mg/mL) solution in single-dose vial or 500 mg/25 mL (20 mg/mL) solution in single-dose vial.[4]
Mechanism of action
Cancer of the blood that is distinguished by an overproduction of malignant plasma cells in the bone marrow is called multiple myeloma. The myeloma cells are marked with uniformed overexpression of CD38 surface glycoproteins. Although these proteins are also expressed on other myeloid and lymphoid cells, the extent is relatively minor compared to myeloma cells. The fact that CD38 glycoproteins carry out various important cellular functions, and that they are plentiful on the surface of myeloma cells, has made them an appealing target for multiple myeloma treatment.[21] CD38 was first described as an activation marker, but later the molecule displayed functions in adhesion to endothelial CD31 proteins, e.g. as an aiding component of the synapse complex, as well as an ectoenzyme implicated in the metabolism of extracellular NAD+ and cytoplasmic NADP. The tumour cells can evade the immune system, possibly due to adenosine, an immunosuppressive molecule that arises as a product of the ectoenzymatic activity of CD38.[22]
Isatuximab-irfc is an IgG1-derived monoclonal antibody that selectively binds to the CD38 that exists on the exterior of hematopoietic and multiple myeloma cells (as well as other tumor cells). This drug induces apoptosis of tumor cells and activates immune effector mechanisms such as complement dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). Isatuximab-irfc is able to stimulate natural killer (NK) cells in the absence of CD38-positive target tumor cells and blocks CD38-positive T-regulatory cells.[4] Furthermore, the NADase activity of CD38 is adjusted by isatuximab, similarly to other CD38 antibodies. Contrarily to daratumumab however, isatuximab can incite apoptosis directly without cross-linking, and in its binding epitope.[23] According to the FDA, isatuximab-irfc alone has reduced ADCC and direct tumor cell killing activity in vitro in comparison to when it is combined with pomalidomide. As well as increased anti-tumor activity as opposed to isatuximab-irfc or pomalidomide only in a human multiple myeloma xenograft model.[4]
Metabolism and toxicity
Metabolism
Isatuximab-irfc is likely to be metabolized through catabolic pathways into smaller peptides. When isatuximab is at a constant state it is expected that the ≥99% elimination will occur approximately two months after the last dose was administered. The clearance percentage diminished when the dosages were increased over time, as well as when multiple doses were administered. However, the elimination of isatuximab-irfc did not differ when applied as a single agent or as a combination therapy.[4]
Toxicity
A dose-limiting toxicity (DLT) has characterized been characterized as the development of any of the following: grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia or grade 4 thrombocytopenia lasting more than 5 days; grade ≥ 2 allergic reactions or hypersensitivity (i.e., infusion reactions); or any other toxicity considered to be dose-limiting by the investigators or sponsor. Grade ≤ 2 infusion reactions were excluded from the DLT definition, because, with suitable care, patients that suffered a grade 2 infusion reaction prior to completion of the infusion were able to finalize isatuximab administration.[23]
There is no recommended reduced dose of isatuximab-irfc. In the eventuality of hematological toxicity it may be necessary to delay administration so that the blood count may be recovered.[4] Although there is no counteracting agent for isatuximab, clinical experience with overdoses is seemingly nonexistent as well. Overdose symptoms will probably be in line with the side effects attached to isatuximab. Therefore, infusion reactions, gastrointestinal disturbances and an elevated risk of infections may occur. It is necessary to carefully monitor the patient in case of an overdose and to employ clinically indicated symptomatic and supportive procedures.[21]
No studies have been conducted with isatuximab concerning carcinogenicity, genotoxicity or fertility.[4]
Pregnancy
When given to pregnant women isatuximab-irfc can cause fetal injury, due to the mechanism of action. It can precipitate depletion of immune cells as well as decreased bone density in the fetus. Pregnant women are therefore notified of the potential risks to a fetus, and women that are able to reproduce are advised to use effective contraceptives during treatment and at least five months subsequent to the last dose of isatuximab-irfc.
Furthermore, it is not recommended to combine isatuximab-irfc with pomalidomide in women that are carrying a child, because pomalidomide may cause birth defects and death of the unborn child.[4]
Indications
Isatuximab is indicated as a CD38-directed cytolytic antibody. By inhibiting the enzymatic activity of CD38.
The binding of isatuximab to CD38 on multiple myeloma (MM) cells leads to a trigger to several mechanisms leading to direct apoptosis of target cancer cells. The triggered pathways are the caspase-dependent apoptotic and the lysosome-mediated cell death pathway in MM cells.[24]
It is used in a combination with dexamethasone and pomalidomide. The drug is thus to treat patients with multiple myeloma. Restrictions for the use of isatuximab is that the patients have to be adults who have at least received two previous treatments with lenalidomide and a proteasome inhibitor.[4]
Isatuximab is currently[when?] also being tested in a Phase II trial as a monotherapy against refractory/recurrent systemic light-chain amyloidosis.[24]
Efficacy and side effects
Efficacy
A Phase III study of patients with refractory and relapsed MM, who were resistant to lenalidomide and a proteasome inhibitor, and could not have received daratumumab, another anti-CD38 monoclonal antibody was published in 2019 (ICARIA-MM). The addition of isatuximab to pomalidomide and dexamethasone improved progression free survival to 11.5 months compared to 6.5 months, with an overall response rate of 63%.[25]
Side effects
Adverse reactions to isatuximab-irfc may include neutropenia, infusion-related reactions and/or secondary primary malignancies.[4] Of these three the most commonly occurring ones are the infusion-related reactions.[24] Examples of the most frequent symptoms of infusion-related reactions are dyspnea, cough, chills, and nausea, while the severest signs and symptoms included hypertension and dyspnea.[4]
Effects on animals
The activity of isatuximab has been researched in mouse tumor models. It has been proven that isatuximab leads to antitumor activity in MM cells. Furthermore, the combination of isatuximab and pomalidomide will lead to an extra enhanced antitumor activity in MM cells. Thus, pomalidomide in vivo and in vitro leads to an increase of the activity of isatuximab.[24]
Animal studies in reproduction toxicity have not yet been carried out. So, the risks of birth defects and miscarriage risks are unknown.[4]
^ Orlowski RZ, Goldschmidt H, Cavo M, Martin TG, Paux G, Oprea C, Facon T (20 May 2018). “Phase III (IMROZ) study design: Isatuximab plus bortezomib (V), lenalidomide (R), and dexamethasone (d) vs VRd in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM)”. Journal of Clinical Oncology. 36 (15_suppl): TPS8055. doi:10.1200/JCO.2018.36.15_suppl.TPS8055.
“Isatuximab”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02990338 for “Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients (ICARIA-MM)” at ClinicalTrials.gov
Bulevirtide is a 47-amino acid peptide with a fatty acid, a myristoyl residue, at the N-terminus and an amidated C-terminus. The active substance is available as acetate salt. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule and is present in a non-stoichiometric ratio. The chemical name of bulevirtide is (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. It corresponds to the molecular formula C248H355N65O72, its relative molecular mass is 5398.9 g/mol
Bulevirtide appears as a white or off-white hygroscopic powder. It is practically insoluble in water and soluble at concentrations of 1 mg/ml in 50% acetic acid and about 7 mg/ml in carbonate buffer solution at pH 8.8, respectively. The structure of the active substance (AS) was elucidated by a combination of infrared spectroscopy (IR), mass spectrometry (MS), amino acid analysis and sequence analysis Other characteristics studied included ultraviolet (UV) spectrum, higher order structure (1D- and 2D- nuclear magnetic resonance spectroscopy (NMR)) and aggregation (Dynamic Light Scattering). Neither tertiary structure nor aggregation states of bulevirtide have been identified. With regard to enantiomeric purity, all amino acids are used in L-configuration except glycine, which is achiral by nature. Two batches of bulevirtide acetate were evaluated for enanatiomeric purity and no relevant change in configuration during synthesis was detected.
Bulevirtide is manufactured by a single manufacturer. It is a chemically synthesised linear peptide containing only naturally occurring amino acids. The manufacturing of this peptide is achieved using standard solidphase peptide synthesis (SPPS) on a 4-methylbenzhydrylamine resin (MBHA resin) derivatised with Rink amide linker in order to obtain a crude peptide mixture. This crude mixture is purified through a series of washing and preparative chromatography steps. Finally, the purified peptide is freeze-dried prior to final packaging and storage. The process involves further four main steps: synthesis of the protected peptide on the resin while side-chain functional groups are protected as applicable; cleavage of the peptide from the resin, together with the removal of the side chain protecting groups to obtain the crude peptide; purification; and lyophilisation. Two chromatographic systems are used for purification. No design space is claimed. Resin, Linker Fmoc protected amino acids and myristic acid are starting materials in line with ICH Q11. Sufficient information is provided on the source and the synthetic route of the starting materials. The active substance is obtained as a nonsterile, lyophilised powder. All critical steps and parameters were presented and clearly indicated in the description of the manufacturing process. The process description includes also sufficient information on the type of equipment for the SPPS, in-process controls (IPCs). The circumstances under which reprocessing might be performed were clearly presented. No holding times are proposed. Overall the process is sufficiently described.
The finished product is a white to off white lyophilised powder for solution for injection supplied in single-use vials. Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide. The composition of the finished product was presented. The powder is intended to be dissolved in 1 ml of water for injection per vial. After reconstitution the concentration of bulevirtide net peptide solution in the vial is 2 mg/ml. The components of the formulation were selected by literature review and knowledge of compositions of similar products available on the market at that time, containing HCl, water, mannitol, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. All excipients are normally used in the manufacture of lyophilisates. The quality of the excipients complies with their respective Ph. Eur monographs. The intrinsic properties of the active substance and the compounding formulation do not support microbiological growth as demonstrated by the stability data. No additional preservatives are therefore needed.
Hepcludex is an antiviral medicine used to treat chronic (long-term) hepatitis delta virus (HDV) infection in adults with compensated liver disease (when the liver is damaged but is still able to work), when the presence of viral RNA (genetic material) has been confirmed by blood tests.
HDV is an ‘incomplete’ virus, because it cannot replicate in cells without the help of another virus, the hepatitis B virus. Because of this, patients infected with the virus always also have hepatitis B.
HDV infection is rare, and Hepcludex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 19 June 2015. For further information on the orphan designation, see EU/3/15/1500.
The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.[2]
Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.[2] By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.[2]
Bulevirtide was approved for medical use in the European Union in July 2020.[2]
Medical uses
Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.[2][3]
The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1[5][6] that can also dock to NTCP, blocking the virus’s entry mechanism.[7]
The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.[7]
References
^Deterding, K.; Wedemeyer, H. (2019). “Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta”. Aids Reviews. 21 (3): 126–134. doi:10.24875/AIDSRev.19000080. PMID31532397.
^Francisco, Estela Miranda (29 May 2020). “Hepcludex”. European Medicines Agency. Retrieved 6 August 2020.
^Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, et al. (May 2013). “The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus”. Journal of Hepatology. 58 (5): 861–7. doi:10.1016/j.jhep.2012.12.008. PMID23246506.
Pre-transplant treatment to make patients with donor specific IgG eligible for kidney transplantation
Immunosuppressant, Immunoglobulin modulator (enzyme)
Imlifidase is under investigation in clinical trial NCT02854059 (IdeS in Asymptomatic Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients).
Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)‑degrading enzyme of Streptococcus pyogenes.[1] It cleaves the heavy chains of all human IgG subclasses (but no other immunoglobulins), eliminating Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC).[1] Thus, imlifidase reduces the level of donor specific antibodies, enabling transplantation.[1]
The benefits with imlifidase are its ability to convert a positive crossmatch to a negative one in highly sensitized people to allow renal transplantation.[1] The most common side effects are infections and infusion related reactions.[1]
Per the CHMP recommendation, imlifidase will be indicated for desensitization treatment of highly sensitized adult kidney transplant people with positive crossmatch against an available deceased donor.[1] The use of imlifidase should be reserved for people unlikely to be transplanted under the available kidney allocation system including prioritization programmes for highly sensitized people.[1]
History
Imlifidase was granted orphan drug designations by the European Commission in January 2017, and November 2018,[3][4] and by the U.S. Food and Drug Administration (FDA) in both February and July 2018.[5][6]
In February 2019, Hansa Medical AB changed its name to Hansa Biopharma AB.[4]
Ge S, Chu M, Choi J, Louie S, Vo A, Jordan SC, et al. (October 2019). “Imlifidase Inhibits HLA Antibody-Mediated NK Cell Activation and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) In Vitro”. Transplantation. doi:10.1097/TP.0000000000003023. PMID31644495.
Somapacitan, also known as NNC0195-0092,3 is a growth hormone analog indicated to treat adults with growth hormone deficiency.2,6 This human growth hormone analog differs by the creation of an albumin binding site, and prolonging the effect so that it requires weekly dosing rather than daily.5
Somapacitan was granted FDA approval on 28 August 2020.7
The most common side effects include: back pain, joint paint, indigestion, a sleep disorder, dizziness, tonsillitis, swelling in the arms or lower legs, vomiting, adrenal insufficiency, hypertension, increase in blood creatine phosphokinase (a type of enzyme), weight increase, and anemia.[2]
It was approved for medical use in the United States in August 2020.[2][3][4]
Somapacitan (Sogroya) is the first human growth hormone (hGH) therapy that adults only take once a week by injection under the skin; other FDA-approved hGH formulations for adults with growth hormone deficiency must be administered daily.[2]
Medical uses
Somapacitan is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency.[2]
Contraindications
Somapacitan should not be used in people with active malignancy, any stage of diabetic eye disease in which high blood sugar levels cause damage to blood vessels in the retina, acute critical illness, or those with acute respiratory failure, because of the increased risk of mortality with use of pharmacologic doses of somapacitan in critically ill individuals without growth hormone deficiency.[2]
History
Somapacitan was evaluated in a randomized, double-blind, placebo-controlled trial in 300 particpants with growth hormone deficiency who had never received growth hormone treatment or had stopped treatment with other growth hormone formulations at least three months before the study.[2] Particpants were randomly assigned to receive injections of weekly somapacitan, weekly placebo (inactive treatment), or daily somatropin, an FDA-approved growth hormone.[2] The effectiveness of somapacitan was determined by the percentage change of truncal fat, the fat that is accumulated in the trunk or central area of the body that is regulated by growth hormone and can be associated with serious medical issues.[2]
At the end of the 34-week treatment period, truncal fat decreased by 1.06%, on average, among particpants taking weekly somapacitan while it increased among particpants taking the placebo by 0.47%.[2] In the daily somatropin group, truncal fat decreased by 2.23%.[2] Particpants in the weekly somapacitan and daily somatropin groups had similar improvements in other clinical endpoints.[2]
It was approved for medical use in the United States in August 2020.[2][4] The U.S. Food and Drug Administration (FDA) granted the approval of Sogroya to Novo Nordisk, Inc.[2][4]
A Trial Investigating the Safety, Tolerability, Availability and Distribution in the Body of Once-weekly Long-acting Growth Hormone (Somapacitan) Compared to Once Daily Norditropin NordiFlex® in Adults With Growth Hormone Deficiency
A Trial Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Dose of Long-acting Growth Hormone (Somapacitan) Compared to Daily Dosing of Norditropin® SimpleXx® in Children With Growth Hormone Deficiency
Investigating Efficacy and Safety of Once-weekly NNC0195-0092 (Somapacitan) Treatment Compared to Daily Growth Hormone Treatment (Norditropin® FlexPro®) in Growth Hormone Treatment naïve Pre-pubertal Children With Growth Hormone Deficiency
A Trial to Evaluate the Safety of Once Weekly Dosing of Somapacitan (NNC0195-0092) and Daily Norditropin® FlexPro® for 52 Weeks in Previously Human Growth Hormone Treated Japanese Adults With Growth Hormone Deficiency
Investigation of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Multiple Doses of Somapacitan in Subjects With Mild and Moderate Degrees of Hepatic Impairment Compared to Subjects With Normal Hepatic Function.
A Trial to Compare the Safety of Once Weekly Dosing of Somapacitan With Daily Norditropin® FlexPro® for 26 Weeks in Previously Human Growth Hormone Treated Adults With Growth Hormone Deficiency
Trial to Compare the Efficacy and Safety of NNC0195-0092 (Somapacitan) With Placebo and Norditropin® FlexPro® (Somatropin) in Adults With Growth Hormone Deficiency.
Investigation of Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Multiple Doses of Somapacitan in Subjects With Various Degrees of Impaired Renal Function Compared to Subjects With Normal Renal Function
A dose-finding trial evaluating the effect and safety of once-weekly treatment of somapacitan compared to daily Norditropin® in children with short stature born small for gestational age with no catch-up growth by 2 years of age or older
A randomised, multinational, active-controlled,(open-labelled), dose finding, (double-blinded), parallel group trial investigating efficacy and safety of once-weekly NNC0195-0092 treatment compared to daily growth hormone treatment (Norditropin® FlexPro®) in growth hormone treatment naïve pre-pubertal children with growth hormone deficiency
A multicentre, multinational, randomised, open-labelled, parallel-group, active-controlled trial to compare the safety of once weekly dosing of NNC0195-0092 with daily Norditropin® FlexPro® for 26 weeks in previously human growth hormone treated adults with growth hormone deficiency
A multicentre, multinational, randomised, parallel-group, placebo-controlled (double blind) and active-controlled (open) trial to compare the efficacy and safety of once weekly dosing of NNC0195-0092 with once weekly dosing of placebo and daily Norditropin® FlexPro® in adults with growth hormone deficiency for 35 weeks, followed by a 53-week open-label extension period
A randomised, open-labelled, active-controlled, multinational, dose-escalation trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of long-acting growth hormone (NNC0195-0092) compared to daily dosing of Norditropin® SimpleXx® in children with growth hormone deficiency
Phase 1
Ongoing, Completed
2013-12-09
///////////Somapacitan, PEPTIDE.2020 APPROVALS, FDA 2020, ソマパシタン, NN8640
Immunoglobulin G1, anti-(calcitonin gene-related peptide) (human-oryctolagus cuniculus monoclonal ALD403 heavy chain), disulfide with human-oryctolagus cuniculus monoclonal ALD403 kappa-chain, dimer
Approved 2020 fda
ALD403, UNII-8202AY8I7H
Humanized anti-calcitonin gene-related peptide (CGRP) IgG1 antibody for the treatment of migraine.
Eptinezumab, sold under the brand name Vyepti, is a medication for the preventive treatment of migraine in adults.[2] It is a monoclonal antibody that targets calcitonin gene-related peptides (CGRP) alpha and beta.[3][4] It is administered by intravenous infusion every three months.[2]
Eeptinezumab-jjmr was approved for use in the United States in February 2020.[5]
^Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. (November 2014). “Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial”. The Lancet. Neurology. 13 (11): 1100–1107. doi:10.1016/S1474-4422(14)70209-1. PMID25297013.
Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively. In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.
Alder announced one-year results from the PROMISE 1 studyin June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with 300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs, compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients. In addition, ~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released in June 2018. These results indicated that, after the first quarterly infusion, chronic migraine patients dosed with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6 fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.
Teriparatide is a form of parathyroid hormone consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic (promoting bone formation) agent[2] used in the treatment of some forms of osteoporosis.[3] It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone.
Recombinant teriparatide is sold by Eli Lilly and Company under the brand name Forteo/Forsteo. A synthetic teriparatide from Teva Generics has been authorised for marketing in European territories[4]. Biosimilar product from Gedeon Richter plc has been authorised in Europe[5]. On October 4, 2019 the US FDA approved a recombinant teriparatide product, PF708, from Pfenex Inc. PF708 is the first FDA approved proposed therapeutic equivalent candidate to Forteo.
Teriparatide (recombinant human parathyroid hormone) is a potent anabolic agent used in the treatment of osteoporosis. It is manufactured and marketed by Eli Lilly and Company.
Teriparatide is a recombinant form of parathyroid hormone. It is an effective anabolic (i.e., bone growing) agent used in the treatment of some forms of osteoporosis. It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone. Teriparatide is sold by Eli Lilly and Company under the brand name Forteo.
Indication
For the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. Also used to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.
Clinical trials indicate that teriparatide increases predominantly trabecular bone in the lumbar spine and femoral neck; it has less significant effects at cortical sites. The combination of teriparatide with antiresorptive agents is not more effective than teriparatide monotherapy. The most common adverse effects associated with teriparatide include injection-site pain, nausea, headaches, leg cramps, and dizziness. After a maximum of two years of teriparatide therapy, the drug should be discontinued and antiresorptive therapy begun to maintain bone mineral density.
Mechanism of action
Teriparatide is the portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34 of the complete molecule which contains amino acid sequence 1 to 84. Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. Daily injections of teriparatide stimulates new bone formation leading to increased bone mineral density.
Medical uses
Teriparatide has been FDA-approved since 2002.[6] It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year)[7] and reducing the risk of fragility fractures.[6][8] When studied, teriparatide only showed bone mineral density (BMD) improvement during the first 18 months of use. Teriparatide should only be used for a period of 2 years maximum. After 2 years, another agent such a bisphosphonate or denosumab should be used in cases of osteoporosis. [9]
Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture.[10]
Other
Teriparatide can be used off-label to speed fracture repair and treat fracture nonunions.[11] It has been reported to have been successfully used to heal fracture nonunions.[12] Generally, due to HIPAA regulations, it is not publicized when American athletes receive this treatment to improve fracture recovery.[11] But an Italian football player, Francesco Totti, was given teriparatide after a tibia/fibula fracture, and he unexpectedly recovered in time for the 2006 World Cup.[11] It has been reported that Mark Mulder used it to recover from a hip fracture Oakland A’s for the 2003 MLB playoffs[13] and Terrell Owens to recover from an ankle fracture before the 2005 Super Bowl.[13]
Administration
Teriparatide is administered by injection once a day in the thigh or abdomen.
Contraindications
Teriparatide should not be prescribed for people who are at increased risks for osteosarcoma. This includes those with Paget’s Diseaseof bone or unexplained elevations of serum alkaline phosphate, open epiphysis, or prior radiation therapy involving the skeleton. In the animal studies and in one human case report, it was found to potentially be associated with developing osteosarcoma in test subjects after over 2 years of use. [14]
Patients should not start teriparatide until any vitamin D deficiency is corrected. [15]
Adverse effects
Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain.[6] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans.[2] This may be because unlike humans, rat bones grow for their entire life.[2] The tumors found in the rat studies were located on the end of the bones which grew after the injections began.[15]After nine years on the market, there were only two cases of osteosarcoma reported.[7] This risk was considered by the FDA as “extremely rare” (1 in 100,000 people)[6] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000).[6]
Mechanism of action
Teriparatide is a portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids). Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. PTH increases serum calcium, partially accomplishing this by increasing bone resorption. Thus, chronically elevated PTH will deplete bone stores. However, intermittent exposure to PTH will activate osteoblasts more than osteoclasts. Thus, once-daily injections of teriparatide have a net effect of stimulating new bone formation leading to increased bone mineral density.[16][17][18]
Teriparatide is the first FDA approved agent for the treatment of osteoporosis that stimulates new bone formation.[19]
FDA approval
Teriparatide was approved by the Food and Drug Administration (FDA) on 26 November 2002, for the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. The drug is also approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.
Combined teriparatide and denosumab
Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture by increasing BMD. However, there is no evidence of fracture rate reduction in patients taking a teriparatide and denosumab combination. Moreover, the combination therapy group showed a significant decrease in their bone formation marker, indicating that denosumab, an antiresorptive agent, might actually counteract the effect of teriparatide, a bone formation anabolic agent, in bone formation. [20]
PATENT
KR 2011291
WO 2019077432
CN 109897099
CN 109879955
CN 109879954
CN 108373499
PATENT
WO-2020000555
Process for preparing teriparatide as parathyroid hormone receptor agonist, useful for treating osteoporosis in menopausal women. Appears to be the first filing from the assignee and the inventors on this compound, however, this invention was previously seen as a Chinese national filing published in 12/2013. Daiichi Sankyo , through its subsidiary Asubio Pharma , was developing SUN-E-3001 , a nasally administered recombinant human parathyroid hormone, for the treatment of osteoporosis.
Teriparatide is a 1-34 fragment of human parathyroid hormone, which has the same biological activity as human parathyroid hormone. Hypogonadous osteoporosis and osteoporosis in menopausal women have great market prospects.
Patent US6590081 uses a method of genetic recombination to obtain teriparatide. However, the genetic recombination method has problems such as complicated process, high cost and serious waste.
Patent CN201510005427 uses Wang resin or 2-Cl-CTC resin to synthesize teriparatide one by one from the C-terminus to the N-terminus, which belongs to the conventional solid-phase synthesis method. However, the reaction is incomplete when the method is coupled to the late stage, which makes purification of the final product difficult and the purity is not high.
Patent CN201310403743 is synthesized by one-by-one coupling method. Unlike patent CN201510005427, this patent ester-condenses the free hydroxyl of Ser at the 17-position with the carboxyl group of Asn at the 16-position, and then obtains teriparatide through O → N acyl transfer. Although this method can reduce the difficulty of coupling at subsequent sites by changing the spatial configuration of the target peptide, it still has the problem of many solid-phase coupling steps and difficult purification.
In patent CN201410262511, a pseudoproline dipeptide Fmoc-Asn (Trt) -Ser (ψ Me, Me Pro) -OH is used instead of the two amino acids at the original 16-17 positions for coupling one by one, and the final cleavage yields teriparatide. This method adopts the method of feeding pseudoproline dipeptide to avoid the generation of oxidative impurities, but it cannot avoid a variety of missing peptides due to the excessively long peptide chain. At the same time, the pseudoproline dipeptide is expensive and difficult to obtain.
Patent CN201511024053 uses multiple di- or tripeptide fragments to replace a single amino acid for coupling, and finally cleavages to obtain teriparatide. This method requires liquid phase synthesis to obtain 11 short peptide fragments, which are complicated in operation and low in production efficiency.
A method for preparing teriparatide includes:
[0016]
Step 1: Coupling 3-Fmoc-4-diaminobenzoic acid with a solid phase carrier, and then sequentially coupling Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc from the C-terminus to the N-terminus according to the peptide sequence -His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met -OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and PG- Ser (tBu) -OH, then benzimidazolone is closed by phenyl p-nitrochloroformate, and finally fragmented by salicylaldehyde and TFA to obtain fragment APG-Ser-Val-Ser-Glu-Ile-Gln-Leu- Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL;
[0017]
Step 2: Coupling Fmoc-Phe-OH with a solid support, and then coupling Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val in sequence from the C-terminus to the N-terminus according to the peptide sequence. -OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf ) -OH, Fmoc-Leu-OH, Fmoc-Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu)- OH, Fmoc-Met-OH and Fmoc-Ser (tBu) -OH, TFA cleavage to obtain fragment B Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp- Val-His-Asn-Phe-OH;
[0018]
Step 3: Coupling Fragment A and Fragment B, and then removing the protecting group of Ser at Fragment A to obtain a crude teriparatide peptide;
[0019]
Step 4: Purifying the teriparatide crude peptide to obtain teriparatide;
[0020]
Step 1 and Step 2 are not in order.
[0021]
Preferably, the solid phase carrier in step 1 is Rink Amide Resin or 2-Cl-CTC Resin.
[0022]
Preferably, the coupling agent in step 1 is HOBt / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.
[0023]
Preferably, the PG of PG-Ser (tBu) -OH in step 1 is a Msz protecting group, a Teoc protecting group, or a Fmoc protecting group.
[0024]
Preferably, the cracking lysing agent in step 1 is a mixed solution of TFA and water.
[0025]
Preferably, the solid phase support in step 2 is Wang Resin.
[0026]
Preferably, the coupling agent in step 2 is HOBt / DIPCDI, HOBt / DMAP / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.
[0027]
Preferably, the lysing lysing agent in step 2 is a mixed solution of TFA and TIS.
[0028]
Preferably, the specific operation of the coupling in step 3 is to dissolve in a pyridine / acetic acid buffer solution for 2-4 hours.
[0029]
Preferably, the specific operation of removing the protecting group of 1-Ser in the fragment A in step 3 is:
[0030]
When the PG of PG-Ser (tBu) -OH in the fragment A is the protecting group of Msz, the coupling of the fragment A and the fragment B is completed by adding TFA / ammonium iodide / dimethylsulfide to remove the protecting group Msz, and the ether precipitates;
[0031]
When the PG of PG-Ser (tBu) -OH in the fragment A is a Teoc protecting group, the fragment A and the fragment B are coupled and tetrabutylammonium fluoride is added to remove the protecting group Teoc;
[0032]
When the PG of PG-Ser (tBu) -OH in the fragment A is a Fmoc protecting group, the fragment A and the fragment B are coupled and diethylamine is added to remove the protecting group Fmoc.
[0033]
The method for preparing teriparatide in the present invention uses fragment condensation to prepare teriparatide. First synthesize the teriparatide peptide sequence 1-16 (fragment A) and the 17-34 peptide sequence (fragment B), and then couple the two fragments to obtain the crude teriparatide peptide. Riparide. The side chain of the fragment in the invention has no protecting group, has good solubility in water, does not have the problem of difficult coupling, simple operation, and high production efficiency. The obtained teriparatide product has high purity and is easy to purify. Experiments show that the crude peptide of teriparatide obtained by the present invention can obtain a purity of 80% and a total yield of 45%. After simple purification, the purity of spermeptide can reach 99.92%, and the single largest impurity is 0.05%. Compared with the prior art, the invention has the characteristics of high product quality, low cost, and suitability for industrial production.
Example 1: Synthesis of fragment one (Msz-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)
[0097]
Weigh 20.0 g (10 mmol) of Rink Amide Resin with a substitution degree of 0.5 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 18.7 g (50 mmol) ) 3-Fmoc-4-diaminobenzoic acid and 8.1 g (60 mmol) of HOBt were dissolved in DMF, 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and added to a solid-phase reaction column, and reacted at room temperature for 2 hours. The solution was removed by DMF Wash 3 times. The 20% piperidine solution was used to remove the Fmoc protecting group (reaction time 5 + 7 minutes), and DMF was washed 6 times.
[0098]
According to the peptide sequence of fragment one, the above steps of amino acid coupling and removal of the Fmoc protecting group are repeated, using the coupling agent HOBt / DIPCDI or HOBt / PyBop / DIPEA or HATU / HOAt / DIPEA or HOAt / PyAop / DIPEA or HBTU / HOBt / DIPEA, coupled Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu- OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Msz-Ser (tBu) -OH.
[0099]
Weigh 10.1 g (50 mmol) of phenyl p-nitrochloroformate in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 12.9 g (100 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Separately weigh 10.6 g (100 mmol) of sodium carbonate and 100 ml of salicylaldehyde in a mixed solution of DCM / THF (1: 3), add to the peptide resin, react at room temperature overnight, filter, and concentrate the filtrate under reduced pressure to dryness. Finally, it was cleaved with TFA / H 2 O (95: 5) for 2 hours and precipitated with ether to obtain 19.2 g of fragment one.
[0100]
Example 2: Synthesis of fragment two (Teoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)
[0101]
Weigh 16.7 g (10 mmol) of 2-Cl-CTC Resin with a substitution degree of 0.6 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 7.48 g (20 mmol) of 3-Fmoc-4-diaminobenzoic acid was dissolved in DMF, 5.2 g (40 mmol) of DIPEA was added under an ice bath, and the solid phase reaction column was added, and the reaction was performed at room temperature for 0 hours, and 6 ml of methanol was added to block the resin for 1 hour. The solution was removed and washed 6 times with DMF.
[0102]
Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH were sequentially coupled according to the peptide sequence of fragment two according to the method in Example 1. , F moc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Teoc-Ser (tBu) -OH.
[0103]
Weigh 6.1 g (30 mmol) of phenyl p-nitrochloroformate and dissolve it in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 7.7 g (60 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Another 6.4 g (60 mmol) of sodium carbonate and 60 ml of salicylaldehyde dissolved in a mixed solution of DCM / THF (1: 1) were added to the peptide resin, reacted at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure to dryness. Finally, it was cleaved with TFA / H2O (95: 5) for 2 hours and precipitated with ether to obtain 10.5 g of fragment two.
[0104]
Example 3: Synthesis of fragment three (Fmoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)
[0105]
Fmoc-Ser (tBu) -OH was used for serine at position 1. Other synthetic methods were the same as in Example 1.
[0106]
Example 4: Synthesis of fragment four (Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH)
[0107]
Weigh 62.5 g (50 mmol) of Wang Resin with a degree of substitution of 0.8 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 3 minutes, then weigh 19.37 g (50 mmol) of Fmoc-Phe- OH, 8.1 g (60 mmol) of HOBt and 6.1 g (5 mmol) of DMAP were dissolved in DMF. 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and the solid phase reaction column was added. The mixture was reacted at room temperature for 2 hours and washed with DMF 6 times. 79.1 g (1000 mmol) of pyridine and 102.1 g (1000 mmol) of acetic anhydride were added to seal the resin for 6 hours, washed with DMF 6 times, and the methanol was shrunk and dried to obtain 71.4 g of Fmoc-Phe-WangResin. .
[0108]
According to the method in Example 1, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val-OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf) -OH, Fmoc-Leu-OH, Fmoc- Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Met-OH and Fmoc-Ser ( tBu) -OH, the obtained peptide resin was cleaved with TFA / TIS (95: 5) for 2 hours, and the ether was precipitated to obtain 23.2 g of fragment four.
[0109]
Example 5: Synthesis of crude teriparatide
[0110]
19.2 g (10 mmol) of fragment 1 obtained in Example 1 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 2 hours, and concentrated under reduced pressure to Dry, add TFA / ammonium iodide / dimethylsulfide (90: 5: 5) to react for 30 minutes, and diethyl ether precipitates to obtain 37 g of teriparatide crude peptide, purity 80.10%, weight yield 90%. The purity test results are shown in Figure 2 and Table 1.
[0111]
Example 6: Synthesis of crude teriparatide
[0112]
21.9 g (10 mmol) of fragment 2 obtained in Example 2 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), and reacted at room temperature for 3 hours, and then 26.15 g was added. Tetrabutylammonium fluoride (100 mmol) was reacted overnight to obtain the teriparatide crude peptide solution for direct purification. The purity of the crude peptide was 67.97%. The purity test results are shown in Figure 3 and Table 1.
[0113]
Example 7: Synthesis of crude teriparatide
[0114]
21.5 g (10 mmol) of fragment 3 obtained in Example 3 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 4 hours, and concentrated under reduced pressure to Dry, add methanol to dissolve, then add 14.63 g of diethylamine (200 mmol), react at room temperature for 2 hours, and concentrate to dryness under reduced pressure to obtain 45 g of teriparatide crude peptide, purity 63.22%, weight yield 109%. The purity test results are shown in Figure 4 and Table 1.
[0115]
Example 8: Purification of crude teriparatide
[0116]
The crude teriparatide peptide obtained in Example 5 was purified by HPLC with a wavelength of 220 nm, a chromatographic column was a reversed-phase C18 column, a 0.1% TFA solution, and acetonitrile were used as mobile phases. The target fractions were collected, concentrated by rotary evaporation, and lyophilized. 18.5 g of teriparatide spermidine was obtained, with a purity of 99.92%, a single maximum impurity of 0.05%, and a total yield of 45%. The purity test results are shown in Figure 5 and Table 1.
[0117]
The crude teriparatide peptide obtained in Example 6 was purified under the same conditions as described above to obtain 14.8 g of teriparatide spermeptide with a purity of 99.76%, a single maximum impurity of 0.07%, and a total yield of 36%.
[0118]
The crude teriparatide peptide obtained in Example 7 was purified under the same conditions as described above to obtain 14.0 g of teriparatide spermeptide with a purity of 99.73%, a single maximum impurity of 0.06%, and a total yield of 34%.
^Saag KG, Shane E, Boonen S, et al. (November 2007). “Teriparatide or alendronate in glucocorticoid-induced osteoporosis”. The New England Journal of Medicine. 357 (20): 2028–39. doi:10.1056/NEJMoa071408. PMID18003959.
^Murad, M. H.; Drake, M. T.; Mullan, R. J.; Mauck, K. F.; Stuart, L. M.; Lane, M. A.; Abu Elnour, N. O.; Erwin, P. J.; Hazem, A.; Puhan, M. A.; Li, T.; Montori, V. M. (2012). “Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis”. Journal of Clinical Endocrinology & Metabolism. 97(6): 1871–1880. doi:10.1210/jc.2011-3060. PMID22466336.
^O’Connor KM. Evaluation and Treatment of Osteoporosis. Med Clin N Am. 2016; 100:807-26
^Díez-Pérez A, Marin F, Eriksen EF, Kendler DL, Krege JH, Delgado-Rodríguez M (September 2018). “Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis”. Bone. 120: 1–8. doi:10.1016/j.bone.2018.09.020. PMID30268814.
^Selye, H (1932). “On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol”. Endocrinology. 16 (5): 547–558. doi:10.1210/endo-16-5-547.
^Dempster, D. W.; Cosman, F.; Parisien, M.; Shen, V.; Lindsay, R. (1993). “Anabolic actions of parathyroid hormone on bone”. Endocrine Reviews. 14 (6): 690–709. doi:10.1210/edrv-14-6-690. PMID8119233.
FORTEO (teriparatide [rDNA origin] injection) contains recombinant human parathyroid hormone (1- 34), and is also called rhPTH (1-34). It has an identical sequence to the 34 N-terminal amino acids(the biologically active region) of the 84-amino acid human parathyroid hormone.
Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:
Teriparatide (rDNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. FORTEO is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.
Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.
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SP ROT +3.8 ° Conc: 1.032 g/100mL; methanol; Wavlenght: 589.3 nm, Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues
Peptides (New York, NY, United States) (2005), 26, (8), 1441-1453., https://doi.org/10.1016/j.peptides.2005.03.022
FOR FREE FORM +19.6 °, Conc: 0.998 g/100mL; : N,N-dimethylformamide; 589.3 nm
presumed to be under license from Banyu , was investigating BQ-788, a selective endothelin receptor B (ETRB) antagonist, for treating metastatic melanoma. By December 2009, the drug was in validation.
Also claimed is their use as an ETBR antagonist and for treating cancers, such as brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma and squamous cell carcinoma. Represent a first filing from ENB Therapeutics Inc and the inventors on these deuterated forms of BQ-788. Melcure SarL ,
SYN
By Brosseau, Jean-Philippe et alFrom Peptides (New York, NY, United States), 26(8), 1441-1453; 2005
N-(cw-2,6-Dimethylpiperidinocarbonyl)-y-methylleucylD-l-(methoxycarbonyl)tryptophanyl-D-norleucine Sodium Salt (1, BQ-788). To a solution of 15 (3.5 g, 5.5 mmol) in methanol (50 mL) was slowly added 5% aqueous NaHCOs (300 mL) over a period of 30 min. The solution was stirred until clarity was achieved (30 min, 23 °C). The solution was diluted with water (200 mL), and the resulting solution was passed through a C18 (60 mL) cartridge preequilbrated in water. BQ-788 (1) was eluted with methanol (2 x 50 mL), concentrated under reduced pressure, resuspended in water (50 mL), and lyophilized to quantitatively yield compound 1 as a white powder:
Novel deuterated analogs of a substituted heterocyclic compound, particularly BQ-788 , processes for their preparation and compositions and combinations comprising them are claimed.
By He, John X.; Cody, Wayne L.; Doherty, Annette M., From Journal of Organic Chemistry (1995), 60(25), 8262-6
Journal of medicinal chemistry (1996), 39(12), 2313-30.
References
^Okada, M; Nishikibe, M (Winter 2002). “BQ-788, a selective endothelin ET(B) receptor antagonist”. Cardiovascular drug reviews. 20 (1): 53–66. PMID12070534.
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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This article incorporates text from this source, which is in the 
Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively. In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.
