PROUD Indian WORLD RECORD VIEWS holder on THIS BLOG, ………live, by DR ANTHONY MELVIN CRASTO, Worldpeaceambassador, Worlddrugtracker, Helping millions, 100 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 45 lakh plus VIEWS on this blog in 227 countries, 7 CONTINENTS ……A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, [THIS BLOG HOLDS WORLD RECORD VIEWS ] A PROUD INDIAN
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
with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
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
He has total of 32 International and Indian awards
Tebipenem (brand name: Orapenem) is a broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. It was developed as a replacement drug to combat bacteria that had acquired antibiotic resistance to commonly used antibiotics.[1][2] Tebipenem is formulated as the estertebipenem pivoxil due to the better absorption and improved bioavailability of this form.[3] It has performed well in clinical trials for ear infection and looks likely to be further developed in future.[4] It is only marketed in Japan.[5] Tebipenem is the first carbapenem whose prodrug form, the pivalyl ester, is orally available.[6]
Tebipenem pivoxil, an oral carbapenem prodrug, was launched in Japan in 2009 by Meiji Seika Pharma for the treatment of bacterial infection in children. The drug candidate was originally developed at Wyeth Pharmaceuticals (now Pfizer) and was subsequently licensed to Meiji Seika.
Tebipenem pivoxil was approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Apr 22, 2009. It was developed and marketed as Orapenem® by Meiji Seika in Japan.
In 2017, the product was licensed to Spero Therapeutics by Meiji Seika Pharma for worldwide development and commercialization, except in Japan and certain Asian countries, where Meiji will retain rights.
In 2017, the FDA granted the drug qualified infectious disease product designation for complicated urinary tract infections (cUTI), diabetic foot infections (DFI) and community acquired bacterial pneumonia (CABP)
Tebipenem pivoxil is a broad-spectrum orally-administered antibiotic, from the carbapenem subgroup of β-lactam antibiotics. Carbapenems are a class of beta-lactam antibiotics, which act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. It is used to treat otorhinolaryngological infection, otitis media and bacterial pneumonia.
Orapenem® is available as granules for oral use, containing 100 mg Tebipenem pivoxil/g granules. According to the weight of children, 4 mg/kg, and twice a day after dinner.
Alternatively Bipei Nan ester (Tebipenempivoxil) (I), chemical name: (+) – (4R, 5S, 6S) -6 – [(lR) -l- hydroxyethyl] -4-methyl-7 – oxo-3 [[1- (2-thiazol-2-yl) -3-azetidinyl] thio] -1-azabicyclo [3. 2.0] hept-2-ene 2-carboxylic acid methyl -2- pivaloyl), of the formula:
[0003]
[0004] developed by the American company Pfizer, for Bipei Nan ester fine granules developed by the Japanese company Meiji, in February 2009 was approved in Japan, and listed in April 2009.Alternatively Bipei Nan prodrug esters are for Bipei Nan, the lower the water after oral administration of the parent drug esterase for Bipei Nan, penicillin-binding protein binding to bacteria (the PBP), inhibition of bacterial cell wall synthesis, and is the only can oral carbapenem antibiotics.
[0005] Alternatively esters Bipei Nan structural characteristics, is a C3-side chain is thiazolyl substituted azetidinyl group, while in the C2 position by matching volts carboxylic ester forming a prodrug, increased oral absorbability; its oral absorption is better than in most β_ lactam antibiotics already on the market now.Bipei Nan for a broad spectrum antibiotic; especially for the PRSP in recent years, mainly due to the infection caused by children (penicillin-resistant Streptococcus pneumoniae), MRSP (erythromycin-resistant Streptococcus pneumoniae) and Haemophilusinfluenzae (Haemophilus influenzae) showed a very strong antibacterial effect.Alternatively Bipei Nan as prodrugs compared to for Bipei Nan horses volts for Bipei Nan ester having a better absorption kinetics, has good stability.
[0006] TakeshiIsoda like literature SynthesesandPharmacokineticStudiesof ProdrugEstersfortheDevelopmentofOralCarbapenem, L-084 (TheJournalof Antibiotics (2006) 59, 241 – 247; doi:. 10 · 1038 / ja 2006. 34) discloses a method for the synthesis of ester Bipei Nan : the Bipei Nan Alternatively, benzyltriethylammonium chloride, and chloromethyl pivalate was dissolved in N, N- dimethylformamide was added a solution of N, N- diisopropylethylamine, in the reaction was stirred for 4h at 45 ° C, the reaction was cooled to complete 5 ° C, was added ethyl acetate and water, the mixture was adjusted with aqueous citric acid I.OM PH = 4, the organic phase was discarded, the aqueous phase was adjusted with potassium bicarbonate to PH = 7. 6, the mixture extracted with ethyl acetate, the organic phase was washed with water and aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, the residue was subjected to silica gel column to give a yellow solid which was slurried with ethyl acetate to give colorless crystals.The column chromatography method requires not only consume a large amount of organic solvent together IJ, and a long time, so this method is not suitable for industrial production. In addition, the resulting large solid slurried with ethyl acetate, a solid dispersion is not easy, affect the uniformity of the product.
[0007] Patent US5534510, EP0632039, JP10-195076 discloses a method for synthesizing Bipei Nan ester is: dissolved after lyophilization for Bipei Nan aqueous sodium bicarbonate, lyophilized solid was dissolved in N, N- two dimethylformamide, adding a specific acid, methyl iodide, LH stirred at room temperature, ethyl acetate was added the reaction was completed, the organic phase was washed with saturated aqueous sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, the solvent was removed, the residue was subjected Alternatively Bipei Nan silica gel column to give the ester.The Mr. Fang Fati Bipei Nan for Bipei Nan into the sodium salt of pivalic acid with methyl iodide, prior to lyophilization to remove water required for the reaction, or affect the subsequent reaction with methyl iodide pivalate, lyophilized difficult when enlarged and the operation will take longer, the method further column chromatography operations shall therefore not suitable for industrial production.
[0008] Chinese patent CN102633801A disclosed for the preparation of esters Bipei Nan, including the following steps of: for Bipei Nan I. 37g, N, N- 11 ml of dimethylformamide, potassium carbonate 0 · 5g, tetrabutylphosphonium bromide 0 · 03g, reaction at 0 · 5h -KTC, Stuttgart dropwise at this temperature, methyl iodide 〇.88g acid, ethyl acetate was added the reaction was completed Ilml insolubles were filtered off, the filtrate was washed with water 22ml, water Ilml phase was extracted once with ethyl acetate, the combined ethyl acetate, washed with water and ethyl acetate are added 11 ml of water, adjusted to 3.5 with aqueous citric acid, phases were separated, the aqueous phase washed with ethyl acetate Ilml with the aqueous phase is added acetic acid 22ml ethyl ester, was adjusted to 7.5 with aqueous sodium bicarbonate, phase separation, washed with water and 22ml ethyl acetate, the ethyl acetate phase over anhydrous sodium sulfate was added 0. 5g, dried decolorizing charcoal, the filtrate was concentrated to a volume, stirring crystallization, cooling to 〇~5 ° C followed by stirring crystallization, filtration, and dried to give a white solid 〇.54g.Pivalate methyl iodide using the method of low-temperature reaction, post-treatment operation complicated, solvent volume, increasing both cost and environmental pollution, and methyl iodide pivalate unstable, expensive, not suitable for industrial production.
Example 1
[0029] Alternatively the Bipei Nan 18g, N, N- dimethylformamide 162mL, potassium 6. 54g, tetrabutylammonium bromide (λ45g, the reaction 60min, was added dropwise at this temperature at 25 ° C for chloromethyl pivalate 8. 93g, after the completion of the reaction, water was added and stirred for 10 minutes, 320ml, 160ml ethyl acetate was added to extract the aqueous phase extracted with ethyl acetate and once with 160ml ethyl acetate were combined, washed with water, phase separation, ethyl acetate washed with water 640ml paint ester, the ethyl acetate phase over anhydrous sodium sulfate was added 60g, decolorizing charcoal and dried, and the filtrate was concentrated, was added dropwise 25 ° C under stirring for crystallization 162mL isopropyl ether, filtered and dried to give a white solid 17. 64g. purity by HPLC 99.87%, the yield was 89.7%.
[0030] TBPN1HNMR data (CDCl3):. 5 989-5 978ppm (1H, d, 5 5, H-13.), 5 858-5 847ppm (1H, d, 5 5, Η-13.)… , 4 · 436-4. 390ppm (2H, m, H-22e, H-24e), 4. 232-4. 217ppm (2H, m, H-2, H-9), 4. 173-4. 146ppm (1H, m, H-21), 4. 039-3. 960ppm (4H, m, H-22a, H-24a, H-28), 3. 402-3. 372ppm (2H, t, 7. 5 , H-27), 3. 243-3. 230ppm (1H, m, H-3), 3. 199-3. 167ppm (1H, m, H-8), I. 348-1. 337ppm (3H, d, 5. 5, H-1), I. 24ppm (12H, m, H-17, H-18, H-19, H-10) ·
Abe, T.; Hayashi, K.; Mihira, A.; Satoh, C.; Tamai, S.; Yamamoto, S.; Hikida, M.; Kumagai, T.; Kitamura, M.
L-084, a new oral carbapenem: Synthesis and structure-activity relationships of C2-substituted 1beta-methylcarbapenems
38th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 24-27, San Diego) 1998, Abst F-64
CLIP
EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703
Halogenation of allylamine (I) with either bromine or sulfuryl chloride produced the corresponding (halomethyl)aziridines (II). Subsequent treatment of (II) with n-butyllithium at -78 C yielded 1-azabicyclobutane (III). Opening of the bicyclic system of (III) with formic acid followed by acid hydrolysis provided 3-hydroxyazetidine (IV). This was condensed with 2-(methylsulfanyl)thiazoline (V) to give thiazolinylazetidine (VI). Alternatively, 3-hydroxyazetidine (IV) was condensed with 2-chloroethyl isothiocyanate (VII) to give the intermediate thiourea (VIII), which cyclized to the thiazoline (VI). Conversion of the hydroxyl group of (VI) into the thioacetate (IX) was carried out by either coupling with thioacetic acid under Mitsunobu conditions or by conversion to mesylate (X) followed by displacement with potassium thioacetate. The required thiol (XI) was then obtained from (IX) by basic hydrolysis of the thioacetate ester.
1-azabicyclobutane (III) was opened with thioacetic acid with concomitant N-acetylation yielding (XII). Further acid hydrolysis of (XII) gave 3-mercaptoazetidine (XIII). Condensation of (XIII) with either 2-(methylthio)thiazoline (V) or 2-chloroethyl isothiocyanate (VII) then produced thiazolinylazetidine (XI).
A further procedure consisted in the opening of 1-azabicyclobutane (III) with 2-mercaptothiazoline (XIV) to give (XV). Subsequent rearrangement of (XV) in the presence of methanesulfonic acid produced thiazolinyl azetidine (XI).
Condensation of (phosphoryloxy)carbapenem (XVI) with 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (XI) gave thioether (XVII). The p-nitrobenzyl ester group of (XVII) was then deprotected with Zn powder to afford the target carboxylic acid.
Jump up^Kato, K.; Shirasaka, Y.; Kuraoka, E.; Kikuchi, A.; Iguchi, M.; Suzuki, H.; Shibasaki, S.; Kurosawa, T.; Tamai, I. (2010). “Intestinal Absorption Mechanism of Tebipenem Pivoxil, a Novel Oral Carbapenem: Involvement of Human OATP Family in Apical Membrane Transport”. Molecular Pharmaceutics. 7 (5): 1747–1756. doi:10.1021/mp100130b. PMID20735088.
Jump up^Sugita, R. (2013). “Good transfer of tebipenem into middle ear effusion conduces to the favorable clinical outcomes of tebipenem pivoxil in pediatric patients with acute otitis media”. Journal of Infection and Chemotherapy. 19 (3): 465–471. doi:10.1007/s10156-012-0513-5. PMID23393013.
Jump up^Rossi, S, ed. (7 August 2014). “Tebipenem Pivoxil”. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 April 2015.
In 2012, tesirine (SG3249) was developed by Spirogen, as a drug linker combining a set of desired properties: fast and straightforward conjugation to antibody cysteines by maleimide Michael addition, good solubility in aqueous/DMSO (90/10) systems, and a traceless cleavable linker system delivering the highly potent pyrrolobenzodiazepine (PBD) DNA cross-linker SG3199
This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody–drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody–drug conjugates in multiple clinical trials, four of them pivotal
Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody–drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.
In 2018, it was approved in Japan for treatment of secondary hyperparathyroidism in patients on dialysis.[3]
useful as calcium-sensitive receptor (CaSR) agonists for treating hyperparathyroidism. a CaSR agonist, being developed by Kyowa Hakko Kirin, under license from Mitsubishi Tanabe, for treating secondary hyperparathyroidism (phase 2 clinical, as of March 2015).
The present invention provides a novel crystal form of an arylalkylamine
compound. Specifically, a novel crystal form of
4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid has
excellent stability, and is therefore useful as an active ingredient for
a medicine. The present invention also provides an industrially
advantageous method for producing an arylalkylamine compound.
The present invention provides a novel crystal form of an arylalkylamine compound. Specifically, a novel crystal form of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1- yl)phenylacetic acid has excellent stability, and is therefore useful as an active ingredient for a medicine. The present invention also provides an industrially advantageous method for producing an arylalkylamine compound.
(1) To a mixed solution containing 33.5 g of 3-hydroxypiperidine and 62.7 ml of triethylamine dissolved in 250 ml of methylene chloride was added dropwise a solution of 55.7 ml of benzyloxycarbonyl chloride in 150 ml of methylene chloride, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous citric acid and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate.
MS•APCI (m/z): 236 [M+H]+
(2) 800 ml of a solution of 52.4 ml of oxalyl chloride in methylene chloride was cooled to −78° C., 53.2 ml of DMSO was added dropwise to the solution, and the mixture was stirred at −78° C. for 0.5 hour. A solution of 75.5 g of benzyl 3-hydroxypiperidine-1-carboxylate dissolved in 200 ml of methylene chloride was added dropwise to the mixture, and further 293 ml of triethylamine was added dropwise to the same, and the mixture was stirred for 16 hours while a temperature thereof was gradually raised to room temperature. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated to obtain 83.7 g of 1-benzyloxycarbonyl-3-piperidone. MS•APCI (m/z): 234 [M+H]+
(3) To a solution of 83.7 g of 1-benzyloxycarbonyl-3-piperidone dissolved in 1.2 liters of methylene chloride was added 55.0 g of (R)-(+)-1-(1-naphthyl)ethylamine, and after the mixture was stirred at room temperature for 2 hours, 69 ml of acetic acid and 160 g of sodium triacetoxy borohydride were added to the mixture, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous sodium hydroxide to make the mixture basic, and then, chloroform was added to the mixture, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 98.7 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
(4) To a solution of 40.95 g of triphosgene dissolved in 800 ml of methylene chloride was added dropwise a mixed solution containing 80.6 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate and 86.6 ml of triethylamine dissolved in 200 ml of methylene chloride at 0° C., and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added water, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was washed with 200 ml of diethyl ether, and the crystal collected by filtration was recrystallized from chloroform and diethyl ether to obtain 48.9 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.
Further, the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=8:1→0:1) to obtain 5.82 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate and 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate.
(5) To a solution containing 54.6 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 700 ml of tetrahydrofuran was added 350 ml of water, and the mixture was stirred under reflux for 15 hours. After tetrahydrofuran was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added thereto, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to obtain 24.3 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
(6) To a solution containing 24.2 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10% wet), and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 40 hours. Palladium carbon was removed, and the solvent was evaporated, the residue was washed with ethyl acetate-chloroform (10:1), and collected by filtration to obtain 15.3 g of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine (the following Reference example Table, Reference example 3.001(a)). MS•APCI (m/z): 255 [M+H]+
(7) By using 14.5 g of benzyl (S)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (5) to obtain 4.74 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
Moreover, by using 4.7 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (6) to obtain 2.89 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine. MS•APCI (m/z): 255 [M+H]+
(8) To a solution of 3.46 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine dissolved in 15 ml of methanol was added dropwise 20 ml of a solution of 4M hydrochloric acid in ethyl acetate, and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, washed and dried to obtain 3.33 g of (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine dihydrochloride
Kyowa Hakko Kirin Announces Commencement of Phase 2b Clinical Study of KHK7580 in Patients with Secondary Hyperparathyroidism in Japan
Tokyo, Japan, August 29, 2014 — Kyowa Hakko Kirin Co., Ltd. (Tokyo: 4151, President and CEO: Nobuo Hanai, “Kyowa Hakko Kirin”) today announced the initiation of a phase 2b clinical study evaluating KHK7580 for secondary hyperparathyroidism patients receiving hemodialysis in Japan.
This randomized, placebo-controlled, double-blind, parallel-group, multi-center study is designed to evaluate efficacy and safety in cohorts comprising KHK7580, its placebo and cinacalcet and initial dose of KHK7580 for secondary hyperparathyroidism patients receiving hemodialysis.
KHK7580 is a small molecular compound produced by Mitsubishi Tanabe Pharma Corporation (President & Representative Director, CEO: Masayuki Mitsuka, “Mitsubishi Tanabe Pharma”). Kyowa Hakko Kirin signed a license agreement of KHK7580 with Mitsubishi Tanabe Pharma for the rights to cooperative research, develop, market and manufacture the product in Japan and some part of Asia on March 2008.
The Kyowa Hakko Kirin Group is contributing to the health and prosperity of the world’s people by pursuing advances in life sciences and technology and creating new value.
KHK 7580 …..example 3.008 2HCl MS · APCI: 375[M + H]+ in …
The calcimimetic agent, KHK-7580, currently entering Phase III clinical trials, has now been given the INN (WHO) generic name, evocalcet. Its chemical structure has also now been published and it is, in fact, correct as proposed by Dr. Crasto (Well Done!!):
Name: Evocalcet
CAS#: 870964-67-3
Chemical Formula: C24H26N2O2
Exact Mass: 374.19943
Evocalcet is a calcium-sensing receptor agonist. The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. The calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone (PTH). CaSR is expressed in all of the organs of the digestive system. CaSR plays a key role in gastrointestinal physiological function and in the occurrence of digestive disease. High dietary Ca2+ may stimulate CaSR activation and could both inhibit tumor development and increase the chemotherapeutic sensitivity of cancer cells in colon cancer tissues. (Last update: 12/15/2015).
Patisiran was granted orphan drug designation in the U.S. and Japan for the treatment of familial amyloid polyneuropathy. Fast track designation was also granted in the U.S. for this indication. In the E.U., orphan drug designation was assigned to the compound for the treatment of transthyretin-mediated amyloidosis (initially for the treatment of familial amyloid polyneuropathy)
Patisiran is a second-generation siRNA therapy targeting mutant transthyretin (TTR) developed by Alnylam for the treatment of familial amyloid polyneuropathy. The product is delivered by means of Arbutus Biopharma’s (formerly Tekmira Pharmaceuticals) lipid nanoparticle technology
“A lot of people think it’s winter out there for RNAi. But I think it’s springtime.” — Alnylam CEO John Maraganore, NYT, February 7, 2011.
Patisiran — designed to silence messenger RNA and block the production of TTR protein before it is made — is number 6 on Clarivate’s list of blockbusters set to launch this year, with a 2022 sales forecast of $1.22 billion. Some of the peak sales estimates range significantly higher as analysts crunch the numbers on a disease that afflicts only about 30,000 people worldwide.
Transthyretin (TTR) is a tetrameric protein produced primarily in the liver.
Mutations in the TTR gene destabilize the protein tetramer, leading to misfolding of monomers and aggregation into TTR amyloid fibrils (ATTR). Tissue deposition results in systemic ATTR amyloidosis (Coutinho et al, Forty years of experience with type I amyloid neuropathy. Review of 483 cases. In: Glenner et al, Amyloid and Amyloidosis, Amsterdam: Excerpta Media, 1980 pg. 88-93; Hou et al., Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of
neurodegeneration. FEBS J 2007, 274: 1637-1650; Westermark et al, Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 1990, 87: 2843-2845). Over 100 reported TTR mutations exhibit a spectrum of disease symptoms.
[0004] TTR amyloidosis manifests in various forms. When the peripheral nervous system is affected more prominently, the disease is termed familial amyloidotic
polyneuropathy (FAP). When the heart is primarily involved but the nervous system is not, the disease is called familial amyloidotic cardiomyopathy (FAC). A third major type of TTR amyloidosis is called leptomeningeal/CNS (Central Nervous System) amyloidosis.
[0005] The most common mutations associated with familial amyloid polyneuropathy
(FAP) and ATTR-associated cardiomyopathy, respectively, are Val30Met (Coelho et al, Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012, 79: 785-792) and Vall22Ile (Connors et al, Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin VI 221 amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J 2009, 158: 607-614). [0006] Current treatment options for FAP focus on stabilizing or decreasing the amount of circulating amyloidogenic protein. Orthotopic liver transplantation reduces mutant TTR levels (Holmgren et al, Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 1991, 40: 242-246), with improved survival reported in patients with early-stage FAP, although deposition of wild-type TTR may continue (Yazaki et al, Progressive wild-type transthyretin deposition after liver transplantation preferentially occurs into myocardium in FAP patients. Am J Transplant 2007, 7:235-242; Adams et al, Rapid progression of familial amyloid polyneuropathy: a multinational natural history study Neurology 2015 Aug 25; 85(8) 675-82; Yamashita et al, Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology 2012, 78: 637-643; Okamoto et al., Liver
transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients’ survival. Liver Transpl 2009, 15: 1229-1235; Stangou et al, Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy: implications for amyloid fibrillogenesis. Transplantation 1998, 66:229-233; Fosby et al, Liver transplantation in the Nordic countries – An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013. Scand J Gastroenterol. 2015 Jun; 50(6):797-808.
Transplantation, in press).
[0007] Tafamidis and diflunisal stabilize circulating TTR tetramers, which can slow the rate of disease progression (Berk et al, Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA 2013, 310: 2658-2667; Coelho et al., 2012; Coelho et al, Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol 2013, 260: 2802-2814; Lozeron et al, Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid polyneuropathy. Eur J Neurol 2013, 20: 1539-1545). However, symptoms continue to worsen on treatment in a large proportion of patients, highlighting the need for new, disease-modifying treatment options for FAP.
[0008] Description of dsRNA targeting TTR can be found in, for example,
International patent application no. PCT/US2009/061381 (WO2010/048228) and
International patent application no. PCT/US2010/05531 1 (WO201 1/056883). Summary
[0009] Described herein are methods for reducing or arresting an increase in a
Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in a human subject by administering an effective amount of a transthyretin (TTR)-inhibiting composition, wherein the effective amount reduces a concentration of TTR protein in serum of the human subject to below 50 μg/ml or by at least 80%. Also described herein are methods for adjusting a dosage of a TTR- inhibiting composition for treatment of increasing NIS or Familial Amyloidotic Polyneuropathy (FAP) by administering the TTR- inhibiting composition to a subject having the increasing NIS or FAP, and determining a level of TTR protein in the subject having the increasing NIS or FAP. In some embodiments, the amount of the TTR- inhibiting composition subsequently administered to the subject is increased if the level of TTR protein is greater than 50 μg/ml, and the amount of the TTR- inhibiting composition subsequently administered to the subject is decreased if the level of TTR protein is below 50 μg/ml. Also described herein are formulated versions of a TTR inhibiting siRNA.
PATENT
WO 2016203402
PAPERS
Annals of Medicine (Abingdon, United Kingdom) (2015), 47(8), 625-638.
Pharmaceutical Research (2017), 34(7), 1339-1363
Annual Review of Pharmacology and Toxicology (2017), 57, 81-105
CLIP
Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults
Aug 10,2018
− First and Only FDA-approved Treatment Available in the United States for this Indication –
− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with Reversal of Neuropathy Impairment Compared to Baseline in Majority of Patients –
− Improvement in Specified Measures of Quality of Life and Disease Burden Demonstrated Across Diverse, Global Patient Population –
− Alnylam to Host Conference Call Today at 3:00 p.m. ET. −
CAMBRIDGE, Mass.–(BUSINESS WIRE)–Aug. 10, 2018– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the United States Food and Drug Administration (FDA) approved ONPATTRO™ (patisiran) lipid complex injection, a first-of-its-kind RNA interference (RNAi) therapeutic, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO is the first and onlyFDA-approved treatment for this indication. hATTR amyloidosis is a rare, inherited, rapidly progressive and life-threatening disease with a constellation of manifestations. In addition to polyneuropathy, hATTR amyloidosis can lead to other significant disabilities including decreased ambulation with the loss of the ability to walk unaided, a reduced quality of life, and a decline in cardiac functioning. In the largest controlled study of hATTR amyloidosis, ONPATTRO was shown to improve polyneuropathy – with reversal of neuropathy impairment in a majority of patients – and to improve a composite quality of life measure, reduce autonomic symptoms, and improve activities of daily living.
ONPATTRO™ (patisiran) packaging and product vial (Photo: Business Wire)
“Alnylam was founded on the vision of harnessing the potential of RNAi therapeutics to treat human disease, and this approval heralds the arrival of an entirely new class of medicines. We believe today draws us ever-closer to achieving our Alnylam 2020 goals of becoming a fully integrated, multi-product biopharmaceutical company with a sustainable pipeline,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “With the potential for the sequential launches of several new medicines in the coming years, we believe we have the opportunity to meaningfully impact the lives of people around the world in need of new approaches to address serious diseases with significant unmet medical needs.”
“Today’s historic approval marks the arrival of a first-of-its kind treatment option for a rare and devastating condition with limited treatment options,” said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “We extend our deepest gratitude to the patients who participated in the ONPATTRO clinical trials and their families and caregivers who supported them. We are also grateful for the tireless efforts of the investigators and study staff, without whom this important milestone would not have been possible. We also look forward to working with the FDA to potentially expand the ONPATTRO indication in the future.”
The FDA approval of ONPATTRO was based on positive results from the randomized, double-blind, placebo-controlled, global Phase 3 APOLLO study, the largest-ever study in hATTR amyloidosis patients with polyneuropathy. Results from the APOLLO study were published in the July 5, 2018, issue of The New England Journal of Medicine.
In APOLLO, the safety and efficacy of ONPATTRO were evaluated in a diverse, global population of hATTR amyloidosis patients in 19 countries, with a total of 39 TTR mutations. Patients were randomized in a 2:1 ratio to receive intravenous ONPATTRO (0.3 mg per kg of body weight) or placebo once every 3 weeks for 18 months. The study showed that ONPATTRO improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status and autonomic symptoms relative to placebo in adult patients with hATTR amyloidosis with polyneuropathy. The primary endpoint of the APOLLO study was the modified Neuropathy Impairment Score +7 (mNIS+7), which assesses motor strength, reflexes, sensation, nerve conduction and postural blood pressure.
Patients treated with ONPATTRO had a mean 6.0-point decrease (improvement) in mNIS+7 score from baseline compared to a mean 28.0-point increase (worsening) for patients in the placebo group, resulting in a mean 34.0-point difference relative to placebo, after 18 months of treatment.
While nearly all ONPATTRO-treated patients experienced a treatment benefit relative to placebo, 56 percent of ONPATTRO-treated patients at 18 months of treatment experienced reversal of neuropathy impairment (as assessed by mNIS+7 score) relative to their own baseline, compared to four percent of patients who received placebo.
Patients treated with ONPATTRO had a mean 6.7-point decrease (improvement) in Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) score from baseline compared to a mean 14.4-point increase (worsening) for patients in the placebo group, resulting in a mean 21.1-point difference relative to placebo, after 18 months of treatment.
As measured by Norfolk QoL-DN, 51 percent of patients treated with ONPATTRO experienced improvement in quality of life at 18 months relative to their own baseline, compared to 10 percent of the placebo-treated patients.
Over 18 months of treatment, patients treated with ONPATTRO experienced significant benefit vs. placebo for all other secondary efficacy endpoints, including measures of activities of daily living, walking ability, nutritional status, and autonomic symptoms.
The most common adverse events that occurred more frequently with ONPATTRO than with placebo were upper respiratory tract infections and infusion-related reactions. To reduce the risk of infusion-related reactions, patients received premedications prior to infusion.
“FDA approval of ONPATTRO represents an entirely new approach to treating patients with polyneuropathy in hATTR amyloidosis and shows promise as a new era in patient care,” said John Berk, M.D., Associate Professor of Medicine at Boston University School of Medicine and assistant director of the Amyloidosis Center at Boston University School of Medicine. “Given the strength of the APOLLO data, including data showing the possibility of halting or improving disease progression in many patients, ONPATTRO holds tremendous promise for people living with this disease.”
“For years I have witnessed the tragic impact of hATTR amyloidosis on generations of families. Today, we celebrate the FDA approval of ONPATTRO,” said Muriel Finkel, President of Amyloidosis Support Groups. “It’s extremely gratifying to see promising science translate into a treatment option that will allow patients to potentially experience an improvement in their disease and an improvement in their overall quality of life.”
“Today’s approval is significant in so many respects. It means the hATTR amyloidosis community of patients, families, caregivers and healthcare professionals in the United States now has a treatment option that offers renewed hope,” said Isabelle Lousada, Founder and Chief Executive Officer of the Amyloidosis Research Consortium. “With an FDA-approved treatment now available, I am more optimistic than ever that we can increase awareness of this rare disease and encourage more people to get tested and receive the proper diagnosis.”
ONPATTRO is expected to be available for shipment to healthcare providers in the U.S. within 48 hours.
Alnylam is committed to helping people access the medicines they are prescribed and will be offering comprehensive support services for people prescribed ONPATTRO through Alnylam Assist™. Visit AlnylamAssist.com for more information or call 1-833-256-2748.
ONPATTRO was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations. On July 27, patisiran received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy under accelerated assessment by the European Medicines Agency. The recommended Summary of Product Characteristics (SmPC) for the European Union (EU) includes data on secondary and exploratory endpoints. Expected in September, the European Commission will review the CHMP recommendation to make a final decision on marketing authorization, applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway. Regulatory filings in other markets, including Japan, are planned beginning in mid-2018.
About ONPATTRO™ (patisiran) lipid complex injection
ONPATTRO was approved by the U.S. Food and Drug Administration (FDA) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO is the first and only RNA interference (RNAi) therapeutic approved by the FDA for this indication. ONPATTRO utilizes a novel approach to target and reduce production of the TTR protein in the liver via the RNAi pathway. Reducing the TTR protein leads to a reduction in the amyloid deposits that accumulate in tissues. ONPATTRO is administered through intravenous (IV) infusion once every 3 weeks following required premedication and the dose is based on actual body weight. Home infusion may be an option for some patients after an evaluation and recommendation by the treating physician, and may not be covered by all insurance plans. Regardless of the setting, ONPATTRO infusions should be performed by a healthcare professional. For more information about ONPATTRO, visit ONPATTRO.com.
About hATTR Amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis represents a major unmet medical need with significant morbidity and mortality. The median survival is 4.7 years following diagnosis. Until now, people living with hATTR amyloidosis in the U.S. had no FDA-approved treatment options.
Alnylam Assist™
As part of Alnylam’s commitment to making therapies available to those who may benefit from them, Alnylam Assist will offer a wide range of services to guide patients through treatment with ONPATTRO, including financial assistance options for eligible patients, benefit verification and claims support, and ordering assistance and facilitation of delivery via specialty distributor or specialty pharmacy. Patients will have access to dedicated Case Managers who can provide personalized support throughout the treatment process and Patient Education Liaisons to help patients gain a better understanding of the disease. Visit AlnylamAssist.com for more information.
About RNAi
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. RNAi therapeutics are a new class of medicines that harness the natural biological process of RNAi. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach in developing medicines to improve the care of patients with genetic and other diseases.
About Alnylam
Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to improve the lives of people afflicted with rare genetic, cardio-metabolic, and hepatic infectious diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust discovery platform. ONPATTRO, available in the U.S. for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults, is Alnylam’s first U.S. FDA-approved RNAi therapeutic. Alnylam has a deep pipeline of investigational medicines, including three product candidates that are in late-stage development. Looking forward, Alnylam will continue to execute on its “Alnylam 2020” strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam employs over 800 people worldwide and is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam or on LinkedIn.
First treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients
The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment
The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.
“This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms. In this case, the effects of the disease cause a degeneration of the nerves, which can manifest in pain, weakness and loss of mobility,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses. We’re committed to advancing scientific principles that enable the efficient development and review of safe, effective and groundbreaking treatments that have the potential to change patients’ lives.”
RNA acts as a messenger within the body’s cells, carrying instructions from DNA for controlling the synthesis of proteins. RNA interference is a process that occurs naturally within our cells to block how certain genes are expressed. Since its discovery in 1998, scientists have used RNA interference as a tool to investigate gene function and its involvement in health and disease. Researchers at the National Institutes of Health, for example, have used robotic technologies to introduce siRNAs into human cells to individually turn off nearly 22,000 genes.
This new class of drugs, called siRNAs, work by silencing a portion of RNA involved in causing the disease. More specifically, Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.
Affecting about 50,000 people worldwide, hATTR is a rare condition. It is characterized by the buildup of abnormal deposits of protein fibers called amyloid in the body’s organs and tissues, interfering with their normal functioning. These protein deposits most frequently occur in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands and feet. Amyloid deposits can also affect the functioning of the heart, kidneys, eyes and gastrointestinal tract. Treatment options have generally focused on symptom management.
Onpattro is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.
“There has been a long-standing need for a treatment for hereditary transthyretin-mediated amyloidosis polyneuropathy. This unique targeted therapy offers these patients an innovative treatment for their symptoms that directly affects the underlying basis of this disease,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.
The efficacy of Onpattro was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.
The most common adverse reactions reported by patients treated with Onpattro are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea (difficulty breathing) and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). Onpattro leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.
The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
Approval of Onpattro was granted to Alnylam Pharmaceuticals, Inc.
The U.S. Food and Drug Administration today approved Annovera (segesterone acetate and ethinyl estradiol vaginal system), which is a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the first vaginal ring contraceptive that can be used for an entire year. Annovera is a reusable donut-shaped (ring), non-biodegradable, flexible vaginal system that is placed in the vagina for three weeks followed by one week out of the vagina, at which time women may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).
The U.S. Food and Drug Administration today approved Annovera (segesterone acetate and ethinyl estradiol vaginal system), which is a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the first vaginal ring contraceptive that can be used for an entire year. Annovera is a reusable donut-shaped (ring), non-biodegradable, flexible vaginal system that is placed in the vagina for three weeks followed by one week out of the vagina, at which time women may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).
“The FDA is committed to supporting innovation in women’s health and today’s approval builds on available birth control options,” states Victor Crentsil, M.D., acting deputy director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.
Annovera is washed and stored in a compact case for the seven days not in use. Annovera does not require refrigeration prior to dispensing and can withstand storage temperatures up to 30°C (86°F).
The efficacy and safety of Annovera were studied in three, open label clinical trials with healthy women ranging from 18 to 40 years of age. Based on the results, about two to four women out of 100 women may get pregnant during the first year they use Annovera.
All hormonal contraception carries serious risks. Annovera carries a boxed warning relating to cigarette smoking and serious cardiovascular events. Women over 35 who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.
Annovera is contraindicated and should not be used in women with:
A high risk of arterial or venous thrombotic diseases;
Current or history of breast cancer or other estrogen- or progestin-sensitive cancer;
Liver tumors, acute hepatitis, or severe (decompensated) cirrhosis;
Undiagnosed abnormal uterine bleeding;
Hypersensitivity to any of the components of Annovera; and
Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.
The most common side effects in women using Annovera are similar to those of other combined hormonal contraceptive products and include headache/migraine, nausea/vomiting, yeast infections, abdominal pain, dysmenorrhea (painful menstruation), breast tenderness, irregular bleeding, diarrhea and genital itching.
The FDA is requiring postmarketing studies to further evaluate the risks of venous thromboembolism, and the effects of CYP3A modulating drugs and tampon use on the pharmacokinetics of Annovera.
The FDA granted approval of Annovera to The Population Council, Inc.
/////////////fda 2018, Annovera, segesterone acetate, ethinyl estradiol, vaginal system
First treatment for the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients
The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment
The U.S. Food and Drug Administration today approved Onpattro (patisiran) infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adult patients. This is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR, a rare, debilitating and often fatal genetic disease characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. It is also the first FDA approval of a new class of drugs called small interfering ribonucleic acid (siRNA) treatment.
“This approval is part of a broader wave of advances that allow us to treat disease by actually targeting the root cause, enabling us to arrest or reverse a condition, rather than only being able to slow its progression or treat its symptoms. In this case, the effects of the disease cause a degeneration of the nerves, which can manifest in pain, weakness and loss of mobility,” said FDA Commissioner Scott Gottlieb, M.D. “New technologies like RNA inhibitors, that alter the genetic drivers of a disease, have the potential to transform medicine, so we can better confront and even cure debilitating illnesses. We’re committed to advancing scientific principles that enable the efficient development and review of safe, effective and groundbreaking treatments that have the potential to change patients’ lives.”
RNA acts as a messenger within the body’s cells, carrying instructions from DNA for controlling the synthesis of proteins. RNA interference is a process that occurs naturally within our cells to block how certain genes are expressed. Since its discovery in 1998, scientists have used RNA interference as a tool to investigate gene function and its involvement in health and disease. Researchers at the National Institutes of Health, for example, have used robotic technologies to introduce siRNAs into human cells to individually turn off nearly 22,000 genes.
This new class of drugs, called siRNAs, work by silencing a portion of RNA involved in causing the disease. More specifically, Onpattro encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins.
Affecting about 50,000 people worldwide, hATTR is a rare condition. It is characterized by the buildup of abnormal deposits of protein fibers called amyloid in the body’s organs and tissues, interfering with their normal functioning. These protein deposits most frequently occur in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands and feet. Amyloid deposits can also affect the functioning of the heart, kidneys, eyes and gastrointestinal tract. Treatment options have generally focused on symptom management.
Onpattro is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping patients better manage the condition.
“There has been a long-standing need for a treatment for hereditary transthyretin-mediated amyloidosis polyneuropathy. This unique targeted therapy offers these patients an innovative treatment for their symptoms that directly affects the underlying basis of this disease,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research.
The efficacy of Onpattro was shown in a clinical trial involving 225 patients, 148 of whom were randomly assigned to receive an Onpattro infusion once every three weeks for 18 months, and 77 of whom were randomly assigned to receive a placebo infusion at the same frequency. The patients who received Onpattro had better outcomes on measures of polyneuropathy including muscle strength, sensation (pain, temperature, numbness), reflexes and autonomic symptoms (blood pressure, heart rate, digestion) compared to those receiving the placebo infusions. Onpattro-treated patients also scored better on assessments of walking, nutritional status and the ability to perform activities of daily living.
The most common adverse reactions reported by patients treated with Onpattro are infusion-related reactions including flushing, back pain, nausea, abdominal pain, dyspnea (difficulty breathing) and headache. All patients who participated in the clinical trials received premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) to reduce the occurrence of infusion-related reactions. Patients may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). Onpattro leads to a decrease in serum vitamin A levels, so patients should take a daily Vitamin A supplement at the recommended daily allowance.
The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
Approval of Onpattro was granted to Alnylam Pharmaceuticals, Inc.
The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.
The U.S. Food and Drug Administration today approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. The drug is indicated for adults with Fabry disease who have a genetic mutation determined to be responsive (“amenable”) to treatment with Galafold based on laboratory data. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.
“Thus far, treatment of Fabry disease has involved replacing the missing enzyme that causes the particular type of fat buildup in this disease. Galafold differs from enzyme replacement in that it increases the activity of the body’s deficient enzyme,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research.
Fabry disease is an inherited disorder caused by mutations (alterations) in the alpha-galactosidase A (GLA) gene located on the X-chromosome. Fabry disease is rare and affects both males and females. It is estimated that classic Fabry disease (the most severe type) affects approximately one in 40,000 males. The later-onset type is more frequent, and in some populations, may occur in one in 1,500 to 4,000 males. Patients with Fabry disease develop slowly progressive kidney disease, cardiac hypertrophy (enlargement of the heart), arrhythmias (abnormal heart rhythm), stroke and early death.
The efficacy of Galafold was demonstrated in a six-month, placebo-controlled clinical trial in 45 adults with Fabry disease. In this trial, patients treated with Galafold over six months had a greater reduction in globotriaosylceramide (GL-3) in blood vessels of the kidneys (as measured in kidney biopsy samples) as compared to patients on placebo.The safety of Galafold was studied in four clinical trials which included a total of 139 patients with Fabry disease.
The most common adverse drug reactions in patients taking Galafold in clinical trials were headache, nasal and throat irritation (nasopharyngitis), urinary tract infection, nausea, and fever (pyrexia).
Galafold was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and where a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. A further study is required to verify and describe the clinical benefits of Galafold, and the sponsor will be conducting a confirmatory clinical trial of Galafold in adults with Fabry disease.
Galafold was granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug, if approved, would provide a significant improvement in treating, diagnosing or preventing a serious condition over available therapies. Galafold also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted approval of Galafold to Amicus Therapeutics U.S., Inc.
A macrolide antibiotic produced by Streptomyces ambofaciens. The drug is effective against gram-positive aerobic pathogens, N. gonorrhoeae, and staphylococci. It is used to treat infections caused by bacteria and Toxoplasma gondii.
Spiramycin is a macrolide antimicrobial agent with activity against gram-positive organisms, including Streptococcus pyogenes (group A beta-hemolytic streptococci), S. viridans, Corynebacterium diphtheriae, and methicillin-sensitive Staphylococcus aureus. Spiramycin is a 16-membered ring macrolide. It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium species. Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action.
Spiramycin is a macrolide antibiotic and antiparasitic It is used to treat toxoplasmosis and various other infections of soft tissues. Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2]
Spiramycin has been used in Europe since the year 2000 under the trade name “Rovamycine”, produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacıbaşı İlaç, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.
Spiramycin is a 16-membered ring macrolide. It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibiotic action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium species. Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration
Literature References: Antibiotic substance classified in the erythromycin-carbomycin group and produced by Streptomyces ambofaciens from soil of northern France: Cosar et al.,C.R. Seances Soc. Biol. Ses Fil.234, 1498 (1952); Pinnert-Sindico et al.,Antibiot. Annu.1954-1955, 724; Ninet, Verrier, US2943023 (1960 to Rhône-Poulenc), see alsoUS3000785 (1961 to Rhône-Poulenc). Antibacterial activity and toxicity: H. Sous et al.,Arzneim.-Forsch.8, 386 (1958). Separation into 3 components named spiramycin I, II and III: Preud’homme, Charpentier, US2978380 and US3011947 (1961 to Rhône-Poulenc). Structure: Kuehne, Benson, J. Am. Chem. Soc.87, 4660 (1965). Revised structure: Omura et al.,ibid.91, 3401 (1969); Mitscher et al.,J. Antibiot.26,55 (1973). Revised configuration at C-9: Freiberg et al.,J. Org. Chem.39, 2474 (1974). Symposium on pharmacology, antibacterial spectrum, and clinical efficacy: J. Antimicrob. Chemother.22, Suppl. B, 1-213 (1988).
Properties: Amorphous base, slightly sol in water. [a]D20 -80° (methanol). uv max (ethanol): 231 nm. Sol in most organic solvents. Active on gram-positive bacteria and rickettsiae. Cross resistance between microorganisms resistant to erythromycin and carbomycin. LD50 in rats (mg/kg): 9400 orally; 1000 s.c.; 170 i.v. (Sous).
The U.S. Food and Drug Administration today approved Poteligeo (mogamulizumab-kpkc) injection for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.
The U.S. Food and Drug Administration today approved Poteligeo (mogamulizumab-kpkc) injection for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. This approval provides a new treatment option for patients with MF and is the first FDA approval of a drug specifically for SS.
“Mycosis fungoides and Sézary syndrome are rare, hard-to-treat types of non-Hodgkin lymphoma and this approval fills an unmet medical need for these patients,” 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. “We are committed to continuing to expedite the development and review of this type of targeted therapy that offers meaningful treatments for patients.”
Non-Hodgkin lymphoma is a cancer that starts in white blood cells called lymphocytes, which are part of the body’s immune system. MF and SS are types of non-Hodgkin lymphoma in which lymphocytes become cancerous and affect the skin. MF accounts for about half of all lymphomas arising from the skin. It causes itchy red rashes and skin lesions and can spread to other parts of the body. SS is a rare form of skin lymphoma that affects the blood and lymph nodes.
Poteligeo is a monoclonal antibody that binds to a protein (called CC chemokine receptor type 4 or CCR4) found on some cancer cells.
The approval was based on a clinical trial of 372 patients with relapsed MF or SS who received either Poteligeo or a type of chemotherapy called vorinostat. Progression-free survival (the amount of time a patient stays alive without the cancer growing) was longer for patients taking Poteligeo (median 7.6 months) compared to patients taking vorinostat (median 3.1 months).
The most common side effects of treatment with Poteligeo included rash, infusion-related reactions, fatigue, diarrhea, musculoskeletal pain and upper respiratory tract infection.
Serious warnings of treatment with Poteligeo include the risk of dermatologic toxicity, infusion reactions, infections, autoimmune problems (a condition where the immune cells in the body attack other cells or organs in the body), and complications of stem cell transplantation that uses donor stem cells (allogeneic) after treatment with the drug.
The FDA granted this application Priority Review and Breakthrough Therapydesignation. Poteligeo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted this approval to Kyowa Kirin, Inc.
///////////////// Poteligeo, mogamulizumab-kpkc, fda 2018, Kyowa Kirin, Priority Review, Breakthrough Therapy designation, Orphan Drug designation
On July 31, 2018, the Food and Drug Administration approved lusutrombopag (Mulpleta, Shionogi Inc.) for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.
Approval was based on two randomized, double-blind, placebo-controlled trials (L-PLUS 1 and L-PLUS 2, NCT02389621) involving 312 patients with chronic liver disease and severe thrombocytopenia who were undergoing an invasive procedure and had a platelet count less than 50 x 109/L. Patients were randomized 1:1 to receive 3 mg of lusutrombopag or placebo once daily for up to 7 days.
In L-PLUS 1, 78% of patients (38/49) receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure, compared with 13% (6/48) who received placebo (95% CI for treatment difference: 49%, 79%; p<0.0001). In L-PLUS 2, 65% (70/108) of patients who received lusutrombopag required no platelet transfusion prior to the primary invasive procedure or rescue therapy for bleeding from randomization through 7 days after the procedure, compared with 29% (31/107) receiving placebo (95% CI for treatment difference: 25%, 49%; p<0.0001).
The most common adverse reaction in ≥ 3% of patients was headache.
The recommended lusutrombopag dosage is 3 mg orally once daily with or without food for 7 days.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.
Follow the Oncology Center of Excellence on Twitter @FDAOncology.
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703
1-azabicyclobutane (III) was opened with thioacetic acid with concomitant N-acetylation yielding (XII). Further acid hydrolysis of (XII) gave 3-mercaptoazetidine (XIII). Condensation of (XIII) with either 2-(methylthio)thiazoline (V) or 2-chloroethyl isothiocyanate (VII) then produced thiazolinylazetidine (XI).
NCT02216656
ONPATTRO™ (patisiran) packaging and product vial (Photo: Business Wire)
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