New Drug Approvals

Home » FDA 2017

Category Archives: FDA 2017

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Paypal donate

Blog Stats

  • 1,599,125 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,974 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,974 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 29 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 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 29 year tenure till date Aug 2016, Around 30 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 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, 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 13 lakh plus views on New Drug Approvals Blog in 212 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

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Voxilaprevir, فوكسيلابريفير , 伏西瑞韦 , Воксилапревир


Voxilaprevir.svgUNII-0570F37359.pngChemSpider 2D Image | voxilaprevir | C40H52F4N6O9S

Figure imgf000410_0002

Voxilaprevir

  • Molecular FormulaC40H52F4N6O9S
  • Average mass868.934 Da
 1535212-07-7 cas
(1R,18R,20R,24S,27S,28S)-N-[(1R,2R)-2-(Difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-28-ethyl-13,13-difluoro-7-methoxy-24-(2-methyl-2-propanyl)-22,25-dioxo-2,21-dioxa-4,11,2  ;3,26-tetraazapentacyclo[24.2.1.03,12.05,10.018,20]nonacosa-3(12),4,6,8,10-pentaene-27-carboxamide
Cyclopropanecarboxamide, N-[[[(1R,2R)-2-[5,5-difluoro-5-(3-hydroxy-6-methoxy-2-quinoxalinyl)pentyl]cyclopropyl]oxy]carbonyl]-3-methyl-L-valyl-(3S,4R)-3-ethyl-4-hydroxy-L-prolyl-1-amino-2-(difluoromethyl)-N-[(1-methylcyclopropyl)sulfonyl]-, cyclic (1→2)-ether, (1R,2R)-
(laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)– 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide
(laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)- 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide

8H-7,10-Methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide, N-[(1R,2R)-2-(difluoromethyl)-1-[[[(1-methylcyclopropyl)sulfonyl]amino]carbonyl]cyclopropyl]-5-(1 ,1-dimethylethyl)-9-ethyl-18,18-difluoro-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-14-methoxy-3,6-dioxo-, (1aR,5S,8S,9S,10R,22aR)-

GS-9857
UNII:0570F37359
Воксилапревир [Russian] [INN]
فوكسيلابريفير [Arabic] [INN]
伏西瑞韦 [Chinese] [INN]

Voxilaprevir is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with sofosbuvirand velpatasvir. The combination has the trade name Vosevi and has received a positive opinion from the European Committee for Medicinal Products for Human Use in June 2017.[1]

In July 18, 2017, Vosevi was approved by Food and drug administration.[2]

The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-1 12). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, MP., Clin. Liver Dis., 201 1 , 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 201 1 , 66, 1573-1686; Brody, H., Nature Outlook, 201 1 , 474, S1 -S7; Gordon, C. P., et al., J. Med. Chem. 2005, 48, 1 -20;

Maradpour, D., et al., Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al., Hepatology, 1996, 24, 1351 -4;

Domingo, et al., Gene 1985, 40, 1 -8; Martell, et al., J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1 -6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1 , 2, 3, and so on).

HCV is distributed worldwide with genotypes 1 , 2, and 3 predominate within the United States, Europe, Australia, and East Asia (Japan, Taiwan, Thailand, and China). Genotype 4 is largely found in the Middle East, Egypt and central Africa while genotype 5 and 6 are found predominantly in South Africa and South East Asia respectively (Simmonds, P. et al. J Virol. 84: 4597-4610, 2010).

The combination of ribavirin, a nucleoside analog, and interferon-alpha (a) (IFN), is utilized for the treatment of multiple genotypes of chronic HCV infections in humans. However, the variable clinical response observed within patients and the toxicity of this regimen have limited its usefulness. Addition of a HCV protease inhibitor (telaprevir or boceprevir) to the ribavirin and IFN regimen improves 12-week post-treatment virological response (SVR12) rates

substantially. However, the regimen is currently only approved for genotype 1 patients and toxicity and other side effects remain.

The use of directing acting antivirals to treat multiple genotypes of HCV infection has proven challenging due to the variable activity of antivirals against the different genotypes. HCV protease inhibitors frequently have compromised in vitro activity against HCV genotypes 2 and 3 compared to genotype 1 (See, e.g., Table 1 of Summa, V. et al., Antimicrobial Agents and Chemotherapy, 2012, 56, 4161 -4167; Gottwein, J. et al, Gastroenterology, 201 1 , 141 , 1067-1079).

Correspondingly, clinical efficacy has also proven highly variable across HCV genotypes. For example, therapies that are highly effective against HCV genotype 1 and 2 may have limited or no clinical efficacy against genotype 3.

(Moreno, C. et al., Poster 895, 61 st AASLD Meeting, Boston, MA, USA, Oct. 29 – Nov. 2, 2010; Graham, F., et al, Gastroenterology, 201 1 , 141 , 881 -889; Foster, G.R. et al., EASL 45th Annual Meeting, April 14-18, 2010, Vienna, Austria.) In some cases, antiviral agents have good clinical efficacy against genotype 1 , but lower and more variable against genotypes 2 and 3. (Reiser, M. et al.,

Hepatology, 2005, 41 ,832-835.) To overcome the reduced efficacy in genotype 3 patients, substantially higher doses of antiviral agents may be required to achieve substantial viral load reductions (Fraser, IP et al., Abstract #48, HEP DART 201 1 , Koloa, HI, December 201 1 .)

Antiviral agents that are less susceptible to viral resistance are also needed. For example, resistance mutations at positions 155 and 168 in the HCV protease frequently cause a substantial decrease in antiviral efficacy of HCV protease inhibitors (Mani, N. Ann Forum Collab HIV Res., 2012, 14, 1 -8;

Romano, KP et al, PNAS, 2010, 107, 20986-20991 ; Lenz O, Antimicrobial agents and chemotherapy, 2010, 54,1878-1887.)

In view of the limitations of current HCV therapy, there is a need to develop more effective anti-HCV therapies. It would also be useful to provide therapies that are effective against multiple HCV genotypes and subtypes.

Image result

Kyla BjornsonEda CanalesJeromy J. CottellKapil Kumar KARKIAshley Anne KatanaDarryl KatoTetsuya KobayashiJohn O. LinkRuben MartinezBarton W. PhillipsHyung-Jung PyunMichael SangiAdam James SCHRIERDustin SiegelJames G. TAYLORChinh Viet TranMartin Teresa Alejandra TrejoRandall W. VivianZheng-Yu YangJeff ZablockiSheila Zipfel
Applicant Gilead Sciences, Inc.

Kyla Ramey (Bjornson)

Kyla Ramey (Bjornson)

Senior CTM Associate at Gilead Sciences

……………………………………………………………………………….str1

PATENT

WO 2014008285

https://www.google.com/patents/WO2014008285A1?cl=en

26. A compound of Formula IVf:
Figure imgf000410_0002

RELATIVE SIMILAR EXAMPLE WITHOUT DIFLUORO GROUPS, BUT NOT SAME COMPD

Example 1. Preparation of (1 aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N- [(1 R,2R)-2-(difluoromethyl)-1 -{[(1 – methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo- 1 ,1 a,3,4,5,6,9,10,18,19,20,21 ,22,22a-tetradecahydro-8H-7,10- methanocyclopropa[18,19][1 ,10,3,6]dioxadiazacyclononadecino[1 1 ,12- b]quinoxaline-8-carboxamide.

Figure imgf000182_0001
Figure imgf000183_0001

Step 1 . Preparation of 1-1 : A mixture containing Intermediate B4 (2.03 g, 6.44 mmol), Intermediate E1 (1 .6 g, 5.85 mmol), and cesium carbonate (3.15 g, 9.66 mmol) in MeCN (40 mL) was stirred vigorously at rt under an atmosphere of Ar for 16 h. The reaction was then filtered through a pad of Celite and the filtrate concentrated in vacuo. The crude material was purified by silica gel

chromatography to provide 1-1 as a white solid (2.5 g). LCMS-ESI+ (m/z): [M- Boc+2H]+ calcd for C2oH27CIN3O4: 408.9; found: 408.6.

Step 2. Preparation of 1-2: To a solution 1 -1 (2.5 g, 4.92 mmol) in dioxane

(10 mL) was added hydrochloric acid in dioxane (4 M, 25 mL, 98.4 mmol) and the reaction stirred at rt for 5 h. The crude reaction was concentrated in vacuo to give 1-2 as a white solid (2.49 g) that was used in subsequently without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C2oH26CIN3O4: 407.9; found: 407.9.

Step 3. Preparation of 1-3: To a DMF (35 mL) solution of 1-2 (2.49 g, 5.61 mmol), Intermediate D1 (1 .75 mg, 6.17 mmol) and DIPEA (3.9 mL, 22.44 mmol) was added COMU (3.12 g, 7.29 mmol) and the reaction was stirred at rt for 3 h. The reaction was quenched with 5% aqueous citric acid solution and extracted with EtOAc, washed subsequently with brine, dried over anhydrous MgSO , filtered and concentrated to produce 1 -3 as an orange foam (2.31 g) that was used without further purification. LCMS-ESI+ (m/z): [M]+ calcd for C35H49CIN4O7: 673.3; found: 673.7.

Step 4. Preparation of 1-4: To a solution of 1-3 (2.31 g, 3.43 mmol), TEA (0.72 mL, 5.15 mmol) and potassium vinyltrifluoroborate (0.69 mg, 5.15 mmol) in EtOH (35 mL) was added PdCI2(dppf) (0.25 g, 0.34 mmol, Frontier Scientific). The reaction was sparged with Argon for 15 min and heated to 80 °C for 2 h. The reaction was adsorbed directly onto silica gel and purified using silica gel chromatography to give 1 -4 as a yellow oil (1 .95 g). LCMS-ESI+ (m/z): [M+H]+ calcd for C37H53N4O7: 665.4; found: 665.3.

Step 5. Preparation of 1 -5: To a solution of 1 -4 (1 .95 g, 2.93 mmol) in

DCE (585 ml_) was added Zhan 1 B catalyst (0.215 g, 0.29 mmol, Strem) and the reaction was sparged with Ar for 15 min. The reaction was heated to 80 °C for 1 .5 h, allowed to cool to rt and concentrated. The crude product was purified by silica gel chromatography to produce 1 -5 as a yellow oil (1 .47 g; LCMS-ESI+ (m/z): [M+H]+ calcd for C35H49N4O7: 637.4; found: 637.3).

Step 6. Preparation of 1 -6: A solution of 1 -5 (0.97 g, 1 .52 mmol) in EtOH (15 ml_) was treated with Pd/C (10 wt % Pd, 0.162 g). The atmosphere was replaced with hydrogen and stirred at rt for 2 h. The reaction was filtered through Celite, the pad washed with EtOAc and concentrated to give 1 -6 as a brown foamy solid (0.803 g) that was used subsequently without further purification. LCMS-ESr (m/z): [M+H]+ calcd for C35H5i N4O7: 639.4; found: 639.3.

Step 7. Preparation of 1 -7: To a solution of 1 -6 (0.803 g, 1 .26 mmol) in DCM (10 ml_) was added TFA (5 ml_) and stirred at rt for 3 h. An additional 2 ml_ TFA was added and the reaction stirred for another 1 .5 h. The reaction was concentrated to a brown oil that was taken up in EtOAc (35 ml_). The organic solution was washed with water. After separation of the layers, sat. aqueous NaHCO3 was added with stirring until the aqueous layer reached a pH ~ 7-8. The layers were separated again and the aqueous extracted with EtOAc twice. The combined organics were washed with 1 M aqueous citric acid, brine, dried over anhydrous MgSO4, filtered and concentrated to produce 1 -6 as a brown foamy solid (0.719 g) that was used subsequently without further purification. LCMS-ESr (m/z): [M+H]+ calcd for C3i H43N4O7: 583.3; found: 583.4 .

Step 8. Preparation of Example 1 : To a solution of 1 -7 (0.200 g, 0.343 mmol), Intermediate A10 (0.157 g, 0.515 mmol), DMAP (0.063 g, 0.51 mmol) and DIPEA (0.3 ml_, 1 .72 mmol) in DMF (3 ml_) was added HATU (0.235 g, 0.617 mmol) and the reaction was stirred at rt o/n. The reaction was diluted with MeCN and purified directly by reverse phase HPLC (Gemini, 30-100% MeCN/H2O + 0.1 % TFA) and lyophilized to give Example 1 (1 18.6 mg) as a solid TFA salt. Analytic HPLC RetTime: 8.63 min. LCMS-ESI+ (m/z): [M+H]+ calcd for

C40H55F2N6O9S: 833.4; found: 833.5. 1H NMR (400 MHz, CD3OD) δ 9.19 (s, 1 H); 7.80 (d, J = 8.8 Hz, 1 H); 7.23 (dd, J = 8.8, 2.4 Hz, 1 H); 7.15 (d, J = 2.4 Hz, 1 H); 5.89 (d, J = 3.6 Hz, 1 H); 5.83 (td, JH-F = 55.6 Hz, J = 6.4 Hz, 1 H); 4.56 (d, J = 7.2 Hz, 1 H); 4.40 (s, 1 H) 4.38 (ap d, J = 7.2 Hz, 1 H); 4.16 (dd, J = 12, 4 Hz, 1 H); 3.93 (s, 3H); 3.75 (dt, J = 7.2, 4 Hz, 1 H); 3.00-2.91 (m, 1 H); 2.81 (td, J = 12, 4.4 Hz, 1 H); 2.63-2.54 (m, 1 H); 2.01 (br s, 2H); 1 .88-1 .64 (m, 3H); 1 .66-1 .33 (m, 1 1 H) 1 .52 (s, 3H); 1 .24 (t, J = 7.2 Hz, 3H); 1 .10 (s, 9H); 1 .02-0.96 (m, 2H); 0.96- 0.88 (m, 2H); 0.78-0.68 (m, 1 H); 0.55-0.46 (m, 1 H).

PATENT

US 20150175625

PATENT

US 20150175626

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=C6BE27513351D0F12E95BC8C04756872.wapp1nA?docId=WO2015100145&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The hepatitis C virus (HCV), a member of the hepacivirus genera within the Flaviviridae family, is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 2000, 32, 98-112). Consequently, a significant focus of current antiviral research is directed toward the development of improved methods for the treatment of chronic HCV infections in humans (Ciesek, S., von Hahn T., and Manns, MP., Clin. Liver Dis., 2011, 15, 597-609; Soriano, V. et al, J. Antimicrob. Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474, S1-S7; Gordon, C. P., et al, J. Med. Chem. 2005, 48, 1-20; Maradpour, D., et al, Nat. Rev. Micro. 2007, 5, 453-463).

Virologic cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV (Neumann, et al, Science 1998, 282, 103-7; Fukimoto, et al, Hepatology, 1996, 24, 1351-4; Domingo, et al, Gene 1985, 40, 1-8; Martell, et al, J. Virol. 1992, 66, 3225-9). HCV treatment is further complicated by the fact that HCV is genetically diverse and expressed as several different genotypes and numerous subtypes. For example, HCV is currently classified into six major genotypes (designated 1-6), many subtypes (designated a, b, c, and so on), and about 100 different strains (numbered 1, 2, 3, and so on).

HCV is distributed worldwide with genotypes 1, 2, and 3 predominate within the United States, Europe, Australia, and East Asia (Japan, Taiwan, Thailand, and China). Genotype 4 is largely found in the Middle East, Egypt and central Africa while genotype 5 and 6 are found predominantly in South Africa and South East Asia respectively (Simmonds, P. et al. J Virol. 84: [0006] There remains a need to develop effective treatments for HCV infections. Suitable compounds for the treatment of HCV infections are disclosed in U.S. Publication No. 2014-0017198, titled “Inhibitors of Hepatitis C Virus” filed on July 2, 2013 including the compound of formula I:

Example 1. Synthesis of (laR,5S,8S,9S,10R,22aR)-5-teri-butyl- V-[(lR,2R)-2-(difluoromethyl)- 1-{ [(1-methylcyclopr opyl)sulfonyl] carbamoyl} cyclopropyl] -9-ethyl- 18,18- difluoro-14-methoxy-3,6-dioxo-l,la,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19] [1,10,3,6] dioxadiazacyclononadecino[ll,12-6]quinoxaline-8- carboxamide (I) by route I

[0195] Compound of formula I was synthesized via route I as shown below:

Synthesis of intermediates for compound of formula I SEE PATENT

US  20150175626

str1

References

Patent ID Patent Title Submitted Date Granted Date
US2014343008 HEPATITIS C TREATMENT 2014-01-30 2014-11-20
US2014212491 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS 2014-01-30 2014-07-31
US2014017198 INHIBITORS OF HEPATITIS C VIRUS 2013-07-02 2014-01-16
US2015064253 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS 2014-01-30 2015-03-05
US2015150897 METHODS OF TREATING HEPATITIS C VIRUS INFECTION IN SUBJECTS WITH CIRRHOSIS 2014-12-01 2015-06-04
US2015175625 CRYSTALLINE FORMS OF AN ANTIVIRAL COMPOUND 2014-12-18 2015-06-25
US2015175626 SYNTHESIS OF AN ANTIVIRAL COMPOUND 2014-12-18 2015-06-25
US2015175646 SOLID FORMS OF AN ANTIVIRAL COMPOUND 2014-12-08 2015-06-25
US2015175655 INHIBITORS OF HEPATITIS C VIRUS 2013-07-02 2015-06-25
US2015361087 ANTIVIRAL COMPOUNDS 2015-06-09 2015-12-17
Patent ID Patent Title Submitted Date Granted Date
US2016120892 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS 2015-09-28 2016-05-05
US2016130300 INHIBITORS OF HEPATITIS C VIRUS 2016-01-15 2016-05-12
Voxilaprevir
Voxilaprevir.svg
Clinical data
Trade names Vosevi (combination with sofosbuvir and velpatasvir)
Identifiers
CAS Number
PubChemCID
ChemSpider
UNII
Chemical and physical data
Formula C40H52F4N6O9S
Molar mass 868.94 g·mol−1

FDA approves Vosevi for Hepatitis C

07/18/2017
The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis.

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis. Vosevi is a fixed-dose, combination tablet containing two previously approved drugs – sofosbuvir and velpatasvir – and a new drug, voxilaprevir. Vosevi is the first treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV. Some patients who suffer from chronic HCV infection over many years may have jaundice (yellowish eyes or skin) and develop complications, such as bleeding, fluid accumulation in the abdomen, infections, liver cancer and death.

There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the strain of the virus can help inform treatment recommendations. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small number of patients are infected with genotypes 4, 5 or 6.

The safety and efficacy of Vosevi was evaluated in two Phase 3 clinical trials that enrolled approximately 750 adults without cirrhosis or with mild cirrhosis.

The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug. Patients with genotypes 2, 3, 4, 5 or 6 all received Vosevi.

The second trial compared 12 weeks of Vosevi with the previously approved drugs sofosbuvir and velpatasvir in adults with genotypes 1, 2 or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug.

Results of both trials demonstrated that 96-97 percent of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.

Treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history.

The most common adverse reactions in patients taking Vosevi were headache, fatigue, diarrhea and nausea.

Vosevi is contraindicated in patients taking the drug rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Vosevi.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted approval of Vosevi to Gilead Sciences Inc

//////////Voxilaprevir, فوكسيلابريفير ,  伏西瑞韦 , Воксилапревир , fda 2017, GS 9857, gilead, 1535212-07-7

CCC1C2CN(C1C(=O)NC3(CC3C(F)F)C(=O)NS(=O)(=O)C4(CC4)C)C(=O)C(NC(=O)OC5CC5CCCCC(C6=NC7=C(C=C(C=C7)OC)N=C6O2)(F)F)C(C)(C)C
CC1(CC1)S(=O)(=O)NC(=O)[C@]2(C[C@H]2C(F)F)NC(=O)[C@@H]7[C@H](CC)[C@@H]3CN7C(=O)[C@@H](NC(=O)O[C@@H]6C[C@H]6CCCCC(F)(F)c4nc5ccc(OC)cc5nc4O3)C(C)(C)C
Advertisements

FDA approves Vosevi for Hepatitis C


07/18/2017
The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis.

The U.S. Food and Drug Administration today approved Vosevi to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis. Vosevi is a fixed-dose, combination tablet containing two previously approved drugs – sofosbuvir and velpatasvir – and a new drug, voxilaprevir. Vosevi is the first treatment approved for patients who have been previously treated with the direct-acting antiviral drug sofosbuvir or other drugs for HCV that inhibit a protein called NS5A.

“Direct-acting antiviral drugs prevent the virus from multiplying and often cure HCV. Vosevi provides a treatment option for some patients who were not successfully treated with other HCV drugs in the past,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV. Some patients who suffer from chronic HCV infection over many years may have jaundice (yellowish eyes or skin) and develop complications, such as bleeding, fluid accumulation in the abdomen, infections, liver cancer and death.

There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the strain of the virus can help inform treatment recommendations. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small number of patients are infected with genotypes 4, 5 or 6.

The safety and efficacy of Vosevi was evaluated in two Phase 3 clinical trials that enrolled approximately 750 adults without cirrhosis or with mild cirrhosis.

The first trial compared 12 weeks of Vosevi treatment with placebo in adults with genotype 1 who had previously failed treatment with an NS5A inhibitor drug. Patients with genotypes 2, 3, 4, 5 or 6 all received Vosevi.

The second trial compared 12 weeks of Vosevi with the previously approved drugs sofosbuvir and velpatasvir in adults with genotypes 1, 2 or 3 who had previously failed treatment with sofosbuvir but not an NS5A inhibitor drug.

Results of both trials demonstrated that 96-97 percent of patients who received Vosevi had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.

Treatment recommendations for Vosevi are different depending on viral genotype and prior treatment history.

The most common adverse reactions in patients taking Vosevi were headache, fatigue, diarrhea and nausea.

Vosevi is contraindicated in patients taking the drug rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Vosevi.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted approval of Vosevi to Gilead Sciences Inc

//////////////Vosevi, Gilead Sciences Inc, Priority Review, Breakthrough Therapy designations, fda 2017, sofosbuvir,  velpatasvir , voxilaprevir, Hepatitis B

FDA approves new treatment Endari (L-glutamine oral powder) for sickle cell disease


Image result for sickle cell disease
07/07/2017
The U.S. Food and Drug Administration today approved Endari (L-glutamine oral powder) for patients age five years and older with sickle cell disease to reduce severe complications associated with the blood disorder.

July 7, 2017

Release

The U.S. Food and Drug Administration today approved Endari (L-glutamine oral powder) for patients age five years and older with sickle cell disease to reduce severe complications associated with the blood disorder.

“Endari is the first treatment approved for patients with sickle cell disease in almost 20 years,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “Until now, only one other drug was approved for patients living with this serious, debilitating condition.”

Sickle cell disease is an inherited blood disorder in which the red blood cells are abnormally shaped (in a crescent, or “sickle,” shape). This restricts the flow in blood vessels and limits oxygen delivery to the body’s tissues, leading to severe pain and organ damage. According to the National Institutes of Health, approximately 100,000 people in the United States have sickle cell disease. The disease occurs most often in African-Americans, Latinos and other minority groups. The average life expectancy for patients with sickle cell disease in the United States is approximately 40 to 60 years.

The safety and efficacy of Endari were studied in a randomized trial of patients ages five to 58 years old with sickle cell disease who had two or more painful crises within the 12 months prior to enrollment in the trial. Patients were assigned randomly to treatment with Endari or placebo, and the effect of treatment was evaluated over 48 weeks. Patients who were treated with Endari experienced fewer hospital visits for pain treated with a parenterally administered narcotic or ketorolac (sickle cell crises), on average, compared to patients who received a placebo (median 3 vs. median 4), fewer hospitalizations for sickle cell pain (median 2 vs. median 3), and fewer days in the hospital (median 6.5 days vs. median 11 days).  Patients who received Endari also had fewer occurrences of acute chest syndrome (a life-threatening complication of sickle cell disease) compared with patients who received a placebo (8.6 percent vs. 23.1 percent).

Common side effects of Endari include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain and chest pain.

Endari received Orphan Drug designation for this use, which provides incentives to assist and encourage the development of drugs for rare diseases.  In addition, development of this drug was in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.

The FDA granted the approval of Endari to Emmaus Medical Inc.

Image result for Emmaus Medical Inc

Image result for sickle cell disease

/////////////FDA2017, Endari, Orphan Drug designation,  Emmaus Medical Inc., L-glutamine oral powder

FDA approves first subcutaneous C1 Esterase Inhibitor to treat rare genetic disease


06/22/2017

 

The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

The U.S. Food and Drug Administration today approved Haegarda, the first C1 Esterase Inhibitor (Human) for subcutaneous (under the skin) administration to prevent Hereditary Angioedema (HAE) attacks in adolescent and adult patients. The subcutaneous route of administration allows for easier at-home self-injection by the patient or caregiver, once proper training is received.

HAE, which is caused by having insufficient amounts of a plasma protein called C1-esterase inhibitor (or C1-INH), affects approximately 6,000 to 10,000 people in the U.S. People with HAE can develop rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. These attacks of swelling can occur spontaneously, or can be triggered by stress, surgery or infection.

“The approval of Haegarda provides a new treatment option for adolescents and adults with Hereditary Angioedema,” said Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research. “The subcutaneous formulation allows patients to administer the product at home to help prevent attacks.”

Haegarda is a human plasma-derived, purified, pasteurized, lyophilized (freeze-dried) concentrate prepared from large pools of human plasma from U.S. donors. Haegarda is indicated for routine prophylaxis to prevent HAE attacks, but is not indicated for treatment of acute HAE attacks.

The efficacy of Haegarda was demonstrated in a multicenter controlled clinical trial. The study included 90 subjects ranging in age from 12 to 72 years old with symptomatic HAE. Subjects were randomized to receive twice per week subcutaneous doses of either 40 IU/kg or 60 IU/kg, and the treatment effect was compared to a placebo treatment period. During the 16 week treatment period, patients in both treatment groups experienced a significantly reduced number of HAE attacks compared to their placebo treatment period.

The most common side effects included injection site reactions, hypersensitivity (allergic) reactions, nasopharyngitis (swelling of the nasal passages and throat) and dizziness. Haegarda should not be used in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to a C1-INH preparation or its inactive ingredients.

Haegarda received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs to treat rare diseases or conditions.

The FDA granted approval of Haegarda to CSL Behring LLC.

///////////Haegarda, C1 Esterase inhibitor, CSL Behring LLC,  fda 2017, orphan drug

FDA approves first generic Strattera (atomoxetine) for the treatment of ADHD


05/30/2017 04:49 PM EDT
The U.S. Food and Drug Administration today approved the first generic versions of Strattera (atomoxetine) to treat attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients.
05/30/2017
The U.S. Food and Drug Administration today approved the first generic versions of Strattera (atomoxetine) to treat attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients.

May 30, 2017

Release

The U.S. Food and Drug Administration today approved the first generic versions of Strattera (atomoxetine) to treat attention-deficit/hyperactivity disorder (ADHD) in pediatric and adult patients.

Apotex Inc., Teva Pharmaceuticals USA Inc., Aurobindo Pharma Limited and Glenmark Pharmaceuticals Limited today gained approval to market atomoxetine in multiple strengths.

“Today’s approvals mark an important step forward in bringing consumers additional treatments that have met the FDA’s rigorous standards,” said Kathleen Uhl, M.D., director of the Office of Generic Drugs in the FDA’s Center for Drug Evaluation and Research. “Quickly bringing generics to market so patients have more options to treat their conditions is a top priority for the FDA.”

Generic prescription drugs approved by the FDA have the same high quality and strength as brand-name drugs. Generic prescription drug manufacturing and packaging sites must pass the same quality standards as those of brand-name drugs.

ADHD is marked by an ongoing pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development.

In the clinical trials for atomoxetine in children and adolescents, the most common side effects reported were upset stomach, decreased appetite, nausea or vomiting, dizziness, tiredness, and mood swings. In the clinical trials in adults, the most common side effects reported were constipation, dry mouth, nausea, decreased appetite, dizziness, sexual side effects, and problems passing urine.

Atomoxetine must be dispensed with a patient Medication Guide that describes the drug’s uses and warnings. This medication has a boxed warning for the increased risk of suicidal ideation in children and adolescents. Patients taking this medication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes. Other important warnings include the risk of severe liver damage and potential for serious cardiovascular events.

////////// atomoxetine, Strattera, fda 2017, ADHD,

FDA approves first cancer treatment for any solid tumor with a specific genetic feature


05/23/2017
The U.S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated

May 23, 2017

Release

The U.S. Food and Drug Administration today granted accelerated approval to a treatment for patients whose cancers have a specific genetic feature (biomarker). This is the first time the agency has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated.

Keytruda (pembrolizumab) is indicated for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapy drugs.

“This is an important first for the cancer community,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

MSI-H and dMMR tumors contain abnormalities that affect the proper repair of DNA inside the cell. Tumors with these biomarkers are most commonly found in colorectal, endometrial and gastrointestinal cancers, but also less commonly appear in cancers arising in the breast, prostate, bladder, thyroid gland and other places. Approximately 5 percent of patients with metastatic colorectal cancer have MSI-H or dMMR tumors.

Keytruda works by targeting the cellular pathway known as PD-1/PD-L1 (proteins found on the body’s immune cells and some cancer cells). By blocking this pathway, Keytruda may help the body’s immune system fight the cancer cells. The FDA previously approved Keytruda for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.

Keytruda was approved for this new indication using the Accelerated Approvalpathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study is required to verify and describe anticipated clinical benefits of Keytruda, and the sponsor is currently conducting these studies in additional patients with MSI-H or dMMR tumors.

The safety and efficacy of Keytruda for this indication were studied in patients with MSI-H or dMMR solid tumors enrolled in one of five uncontrolled, single-arm clinical trials. In some trials, patients were required to have MSI-H or dMMR cancers, while in other trials, a subgroup of patients were identified as having MSI-H or dMMR cancers by testing tumor samples after treatment began. A total of 15 cancer types were identified among 149 patients enrolled across these five clinical trials. The most common cancers were colorectal, endometrial and other gastrointestinal cancers. The review of Keytruda for this indication was based on the percentage of patients who experienced complete or partial shrinkage of their tumors (overall response rate) and for how long (durability of response). Of the 149 patients who received Keytruda in the trials, 39.6 percent had a complete or partial response. For 78 percent of those patients, the response lasted for six months or more.

Common side effects of Keytruda include fatigue, itchy skin (pruritus), diarrhea, decreased appetite, rash, fever (pyrexia), cough, difficulty breathing (dyspnea), musculoskeletal pain, constipation and nausea. Keytruda can cause serious conditions known as immune-mediated side effects, including inflammation of healthy organs such as the lungs (pneumonitis), colon (colitis), liver (hepatitis), endocrine glands (endocrinopathies) and kidneys (nephritis). Complications or death related to allogeneic hematopoietic stem cell transplantation after using Keytruda has occurred.

Patients who experience severe or life-threatening infusion-related reactions should stop taking Keytruda. Women who are pregnant or breastfeeding should not take Keytruda because it may cause harm to a developing fetus or newborn baby. The safety and effectiveness of Keytruda in pediatric patients with MSI-H central nervous system cancers have not been established.

The FDA granted this application Priority Review designation, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted accelerated approval of Keytruda to Merck & Co.

///////////Keytruda, pembrolizumab, BIO MARKER, MERCK, FDA 2017

FDA approves first drug Actemra (tocilizumab) to specifically treat giant cell arteritis


Image result for actemra logo
05/22/2017
The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

May 22, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of subcutaneous Actemra (tocilizumab) to treat adults with giant cell arteritis. This new indication provides the first FDA-approved therapy, specific to this type of vasculitis.

“We expedited the development and review of this application because this drug fulfills a critical need for patients with this serious disease who had limited treatment options,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Giant cell arteritis is a form of vasculitis, a group of disorders that results in inflammation of blood vessels. This inflammation causes the arteries to narrow or become irregular, impeding adequate blood flow. In giant cell arteritis, the vessels most involved are those of the head, especially the temporal arteries (located on each side of the head). For this reason, the disorder is sometimes called temporal arteritis. However, other blood vessels, including large ones like the aorta, can become inflamed in giant cell arteritis. Standard treatment involves high doses of corticosteroids that are tapered over time.

The efficacy and safety of subcutaneous (injected under the skin) Actemra for giant cell arteritis were established in a double-blind, placebo-controlled study with 251 patients with giant cell arteritis. The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Sustained remission was defined as the absence of symptoms of giant cell arteritis, normalization of inflammatory laboratory tests, and tapering the use of prednisone (a steroid drug). A greater proportion of patients receiving subcutaneous Actemra with standardized prednisone regimens achieved sustained remission from Week 12 through Week 52 as compared to patients receiving placebo with standardized prednisone regimens. The cumulative prednisone dose was lower in treated patients with Actemra relative to placebo.

The overall safety profile observed in the Actemra treatment groups was generally consistent with the known safety profile of Actemra. Actemra carries a Boxed Warning for serious infections. Patients treated with Actemra who develop a serious infection should stop that treatment until the infection is controlled. Live vaccines should be avoided during treatment with Actemra. Actemra should be used with caution in patients at increased risk of gastrointestinal perforation. Hypersensitivity reactions, including anaphylaxis and death, have occurred. Laboratory monitoring is recommended due to potential consequences of treatment-related changes in neutrophils (type of white blood cell), platelets, lipids and liver function tests.

Subcutaneous Actemra was previously approved for the treatment of moderate to severely active rheumatoid arthritis. Intravenous Actemra was also previously approved for the treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis. Intravenous administration is not approved for giant cell arteritis.

The FDA granted this application a Breakthrough Therapy designation and a Priority Review.

The FDA granted the supplemental approval of Actemra to Hoffman La Roche, Inc.

//////////Actemra, tocilizumab, fda 2017, Breakthrough Therapy designation, Priority Review,  supplemental approval, Hoffman La Roche, Inc.

FDA approves drug to treat ALS, Radicava (Edaravone) , эдаравон, إيدارافون , 依达拉奉 ,ラジカット,


Edaravone.svg

05/05/2017
The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

May 5, 2017

Release

The U.S. Food and Drug Administration today approved Radicava (edaravone) to treat patients with amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease.

“After learning about the use of edaravone to treat ALS in Japan, we rapidly engaged with the drug developer about filing a marketing application in the United States,” said Eric Bastings, M.D., deputy director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This is the first new treatment approved by the FDA for ALS in many years, and we are pleased that people with ALS will now have an additional option.”

ALS is a rare disease that attacks and kills the nerve cells that control voluntary muscles. Voluntary muscles produce movements such as chewing, walking, breathing and talking. The nerves lose the ability to activate specific muscles, which causes the muscles to become weak and leads to paralysis. ALS is progressive, meaning it gets worse over time. The Centers for Disease Control and Prevention estimates that approximately 12,000-15,000 Americans have ALS. Most people with ALS die from respiratory failure, usually within three to five years from when the symptoms first appear.

Radicava is an intravenous infusion given by a health care professional. It is administered with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles consist of dosing on 10 of 14 days, followed by 14 days drug-free.

The efficacy of edaravone for the treatment of ALS was demonstrated in a six-month clinical trial conducted in Japan. In the trial, 137 participants were randomized to receive edaravone or placebo. At Week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving a placebo.

The most common adverse reactions reported by clinical trial participants receiving edaravone were bruising (contusion) and gait disturbance.

Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug. Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.

The FDA granted this drug orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Radicava to Mitsubishi Tanabe Pharma America, Inc,

ChemSpider 2D Image | Edaravone | C10H10N2O

1-Phenyl-3-methyl-5-pyrazolone
3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- [ACD/Index Name]
89-25-8 [RN]
эдаравон [Russian]
إيدارافون [Arabic]
依达拉奉 [Chinese]
ラジカット,
MCI-186

Edaravone (brand name ラジカット, Radicut) is a nootropic and neuroprotective agent used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction.[1] It acts as a potent antioxidant and strongly scavenges free radicals, protecting against oxidative stress and neuronal apoptosis.[2][3][4] It has been marketed solely in Japan by Mitsubishi Pharma since 2001.[1] It is also marketed in India by Edinburgh Pharmaceuticals by the brand name Arone.

On June 26, 2015, Mitsubishi Tanabe Pharma Corporation announced it has received approval to market Radicut for treatment of ALS in Japan. The phase III clinical trial began in 2011 in Japan. The company was awarded Orphan Drug Designation for Radicut by the FDA and EU in 2015. Radicut is an intravenous drug and administrated 14 days followed by 14 days drug holiday.

The biotech company Treeway is developing an oral formulation of edaravone (TW001) and is currently in clinical development. Treeway was awarded orphan drug designation for edaravone by the EMA in November 2014 and FDA in January 2015.

Edaravone has been shown to attenuate methamphetamine– and 6-OHDA-induced dopaminergic neurotoxicity in the striatum and substantia nigra, and does not affect methamphetamine-induced dopamine release or hyperthermia.[5][6] It has also been demonstrated to protect against MPTP-mediated dopaminergic neurotoxicity to the substantia nigra, though notably not to the striatum.[7][8][9]

Image result for edaravone synthesis

Edaravone (CAS NO.: 89-25-8), with other name of 3-Methyl-1-phenyl-2-pyrazolin-5-one, could be produced through many synthetic methods.

Following is one of the synthesis routes: By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.

SYNTHESIS

Edaravone, chemical name: 3-methyl-1-phenyl-2-pyrazoline-5-one, of the formula: Formula: CiciHltlN2O, molecular weight: 174.20, the formula:

 

Figure CN101830852BD00031

[0004] Edaravone is a brain-protecting agent (free radical scavenger). Clinical studies suggest that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. In patients with acute cerebral infarction Edaravone suppressed reduce peri-infarct regional cerebral blood flow, so that the first concept of days after the onset of brain NAA glycerol content than the control group significantly increased. Preclinical studies suggest that rats after ischemia / reperfusion of ischemic intravenous edaravone, can prevent the progress of cerebral edema and cerebral infarction, and relieve the accompanying neurological symptoms, suppress delayed neuronal death. Mechanism studies suggest that edaravone can scavenge free radicals, inhibiting lipid peroxidation, thereby inhibiting brain cells, endothelial cells, oxidative damage nerve cells.

For the synthesis of edaravone reported some use of benzene and methyl ethyl ketone amide corpus obtained, but methyl ethyl ketone amide difficult to obtain and slow reaction, which now has basically been abandoned; some use benzene corpus and ethyl acetoacetate in ethanol (see US4857542A, Synthesis Example 1) or water (Dykhanov NN Ethyl and butyl acetoacetates, Med Prom SSSR, 1961,15 (1):. 42-45) refluxing the reaction of the reaction The resulting purity edaravone poor, and the yield is not high, only about 70%.

Edaravone, chemical name: 2,4_-dihydro-5-methyl-2-phenyl pyrazole -3H- – one, of the formula: CiciHltlN2O, molecular weight: 174.20, the formula:

Figure CN102285920BD00031

edaravone is a clear cerebral infarction harmful factors (free radicals), protection of new therapeutic agents for cerebral infarction nerve cells. Clinical studies have shown that N- acetyl aspartate (NAA) is a specific sign of the survival of nerve cells, dramatically reducing the initial content of cerebral infarction. When patients with acute cerebral infarction Edaravone, peri-infarct rCBF decrease has improved, and the first 28 days after the onset of brain NAA content was significantly higher than that in the control group glycerol. Mechanism studies suggest that edaravone can clear the brain is highly cytotoxic hydroxyl radicals, inhibiting the synthesis of lipids free radicals, which can suppress brain infarction after reperfusion edema, protecting brain from damage and improve nerve impairment symptoms, and the delayed neuronal death inhibition, to protect the brain.

 The first is by phenylhydrazine and methyl ethyl ketone amide (National API process compilation, 1980.737-739) condensation reaction in water at 50 ° C, a yield of up to 97%, but the raw material ketone amide ( CH3C0CH2C0NH2) are not readily available. Formula I

Edaravone synthetic route for the reaction:

Figure CN102285920BD00032

[0008] The second is to phenylhydrazine and ethyl acetoacetate in ethanol or water at reflux the reaction, sodium bisulfite as the preparation of the catalyst. From the perspective of the chemical reaction, acetyl ethyl ketone amide more than hydrazine reacted with benzene and ethyl acetoacetate more readily available, the price is cheaper, but lower reaction yield of about 70%. Formula 2 for the synthesis route Edaravone reaction formula:

Figure CN102285920BD00041

PATENT

https://www.google.com/patents/CN101830852B?cl=en

Figure CN101830852BD00041

1 Edaravone Synthesis Example [0023] Example

[0024] (1) Weigh benzene hydrochloride corpus 13. 5g (94mmol), was added to IOOml water, stirred for 0.5 hours, sodium hydroxide was added an equimolar 3. 76g, stirred for 0.5 hours; [0025] ( 2) To the reaction solution was added dropwise ethyl acetoacetate 11. 7g (90mmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 15. 5g;

[0026] (3) The crude product was added 30ml volume ratio of 2: 1 isopropanol – water, 2g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 14 a white crystalline powder. 8g, yield 90%, mpU9 ° C, with a purity of 99.9% 0

2 Edaravone Synthesis Example [0027] Example

[0028] (1) Weigh 15g of benzene hydrochloride corpus (I (Mmmol), was added to 120ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 4. 16g, stirred for 0.5 hours;

[0029] (2) To the reaction solution was added dropwise 13g of ethyl acetoacetate (lOOmmol), the reaction exotherm, the reaction was heated to reflux for 2.5 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 16. 7g;

(3) The crude product was added 40ml volume ratio of 2: 1 isopropanol – water, 2. 5g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature to precipitate a white solid, as a white crystalline powder 16. lg, a yield of 88.9%, mpU8 ° C, with a purity of 99.9% 0

3 Edaravone Synthesis Example [0031] Example

[0032] (1) Weigh 22g of benzene hydrochloride corpus (152mm0l), was added to 200ml of water and stirred for 0.5 hours, sodium hydroxide was added an equimolar 6. 08g, stirred for 0.5 hours;

[0033] (2) To the reaction solution was added dropwise 19g of ethyl acetoacetate (146mm0l), the reaction exotherm, the reaction was heated to reflux for 3 hours, heating was stopped, cooled to room temperature with stirring, filtered and dried to give a pale yellow granular crude 24. Sg;

[0034] (3) The crude product was added 50ml volume ratio of 2: 1 isopropanol – water, 3g of activated carbon was added and refluxed for 1 hour, filtered hot, cooled to room temperature a white solid was precipitated to give 23 a white crystalline powder. 2g, a yield of 87. 8%, mpU8 ° C, with a purity of 99.9% 0

[0035] Comparative Example

[0036] The ethyl acetoacetate 65g (0. 5mol) and 180ml of anhydrous ethanol mixed, with stirring at 50 ° C was added dropwise benzyl corpus 54g (0. 5mol) and a solution consisting of 30ml absolute ethanol, dropwise at reflux for 2 Bi hours, ethanol was distilled off 60ml, cooled, suction filtered, washed crystals with cold absolute ethanol twice, and dried in vacuo to give pale yellow crystals 70g. Recrystallized twice from absolute ethanol to give pale yellowish white crystals 56g (yield 65%).

PATENT

https://www.google.com/patents/CN102285920B?cl=en

Example 1: Preparation of phenylhydrazine edaravone.

[0024] a. Weigh 5.1g phenylhydrazine (47mmol), was added under stirring to water containing 45mL round-bottom flask, take appropriate concentrated hydrochloric acid solution was adjusted to pH 6.0 with PH meter.

[0025] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, was added 1.5g sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0026] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 85% yield, 99.2% purity 0

[0027] Example 2: Preparation of phenylhydrazine hydrochloride edaravone.

[0028] a. Weigh 6.8g phenylhydrazine hydrochloride (47mmol), was added under stirring to water containing 45mL round-bottomed flask, the pH of the solution adjusted to 6.0 with aqueous ammonia.

[0029] b. To the above solution was slowly added dropwise ethyl acetoacetate 5.85g (45mmol), the reaction exotherm, 1.25g was added sodium dithionite (Na2S2O6), heated to 105 ° C to room temperature until reflux After 3h, heating was stopped, and then stirred, cooling, filtration, and dried to give a pale yellow granular edaravone crude.

[0030] c. With anhydrous ethanol recrystallization, filtration, and dried to obtain a white crystalline powder that is refined edaravone, 84% yield, with a purity of 99.2%. [0031] Comparative Example:

Under the [0032] state of agitation will phenylhydrazine 10.2g (94mmol) added to a round bottom flask equipped with IOOmL water in an appropriate amount of concentrated hydrochloric acid was dubbed the volume ratio of 1: 1 aqueous hydrochloric acid, with a PH adjusting pH of the solution was measured 6.0. After weighing Ethylacetoacetate 11.7g (90mmol) added to the reaction mixture, the reaction was exothermic and cooling to room temperature, sodium bisulfite (NaHSO3), heated to 105 ° C under reflux for 3h, the hot solution Water was added into the beaker and mechanical stirring, cooling, filtration, and dried to give the yellow edaravone crude, 73% yield, with a purity of 99.1%.

Figure CN102285920BD00042

CLIP

http://www.rsc.org/suppdata/books/184973/9781849739634/bk9781849739634-chapter%204.2.3.pdf

Edaravone:

IR (KBr) max/cm-1 : 3431, 3129, 1602, 1599, 1580;

1 H NMR (300 MHz, CDCl3): δ 7.86 (d, J = 7.5 Hz, 2H, ArH), 7.40 (m, 2H, ArH), 7.18 (m, 1H, ArH), 3.41 (d, J =0.6 Hz, 2H, CH2), 2.19 (s, 3H, CH3);

13C NMR (75 MHz, CDCl3): 170.6, 156.4, 130.1, 128.8, 125.0, 118.9, 43.1, 17.0;

1 H NMR (300 MHz, DMSO-d6): δ 11.5 (bs, 1H, NH), 7.71 (m, 2H, ArH), 7.40 (m, 2H, ArH), 7.22 (m, 1H, ArH), 5.36 (s, 1H, CH), 2.12 (s, 3H, CH3);

13C NMR (75 MHz, DMSO-d6):171.7, 158.9, 148.7, 139.2, 138.6, 129.3,125.4, 124.8, 118.4, 43.5, 17.1, 14.2.

These values are in accordance with the previous published in literature1 .

In the carbon spectrum in DMSO presented in Figure SM 4.2.3.1.8 is evident the presence of the two major tautomeric structures of edaravone, signals are identified by different colours in both structures in the figure. Also in the IR analysis of the solid material (Figure SM 4.2.3.1.9) is possible to see either the NH form (max/cm-1, 3129), the OH form (max/cm- 1 , 3431) and the C=O (max/cm-1, 1599) of the enol and keto tautomeric forms of edaravone.

1. S. Pal, J. Mareddy and N. S. Devi, J.  Braz. Chem. Soc., 2008, 19, 1207.

CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532008000600023

We have shown that the short reaction time, in combination with good yields can make microwave assisted reaction of hydrazines with β-ketoesters ideal for a rapid entry to pyrazolones. All the compounds synthesized are characterized by spectroscopic (1H NMR, IR and MS) data. While determination of tautomeric composition of compound 3 is quite challenging as eight possible tautomeric forms need to be considered, interestingly, two major tautomeric forms of compound 3a was observed in two different solvents. For example, it exists as 1,2-dihydro pyrazolone (T-1Figure 2) in DMSO and 2,4-dihydro form (T-2Figure 2) in chloroform as indicated by 1H NMR spectra (Figure 3). The olefinic proton of T-1 appeared at 5.36 δ whereas the methylene hydrogens appeared at 3.43 δ in case of T-2. Additionally, the NH proton of T-1 at 11.40 δ was not observed incase of T-2 confirmed the absence of NH in the 2,4-dihydro form. Existence of two major tautomeric forms was also observed in case compound 3b (see 1H NMR data in the experimental section). However, X-ray study on single crystal of 2-(4-chlorophenyl)-5-methyl-1,2-dihydro pyrazol-3-one (3i) indicates that 2-aryl pyrazol-3-ones e.g. 3a-b3e-f and 3i exist as 1,2-dihydro form in crystal state. 27 It is mention worthy that the aryl ring of all these 2-aryl pyrazol-3-ones remain twisted with respect to the pyrazole plane as indicated by the crystallographic data of 3i [the dihedral angle between the pyrazole and benzene ring planes was found to be 15.81 (11)º].27

 

 

 

5-Methyl-2-phenyl-1,2-dihydro pyrazol-3-one (3a)

mp 125-127 ºC (lit21 126-130 ºC); 

IR (KBr) νmax/cm-1: 3127, 1597, 1525, 1498, 1454;

 1H NMR (400 MHz, DMSO-d6δ 11.40 (bs, 1H), 7.71-7.69 (m, 2H), 7.42-7.38 (m, 2H), 7.21-7.18 (m, 1H), 5.36 (s, 1H), 2.10 (s, 3H); 

13C NMR (50 MHz, DMSO-d6δ 170.6, 156.2, 138.1, 128.8 (2C), 124.9, 118.9 (2C), 43.1, 16.9; 

Mass (CI, m/z) 175 (M+1, 100).

1H NMR (400 MHz, CDCl3)δ 7.85 (d, J 8.3 Hz, 2H), 7.40-7.37 (m, 2H), 7.24-7.18 (m, 1H), 3.43 (s, 2H), 2.20 (s, 3H).

21. Makhija, M. T.; Kasliwal, R. T.; Kulkarni, V. M.; Neamati, N.; Bioorg. Med. Chem. 200412, 2317.         [ Links ]

CN101830852A Mar 22, 2010 Sep 15, 2010 海南美兰史克制药有限公司 Edaravone compound synthesized by new method
CN102060771A Nov 18, 2009 May 18, 2011 南京长澳制药有限公司 Edaravone crystal form and preparation method thereof
CN102180834A Mar 24, 2011 Sep 14, 2011 江苏正大丰海制药有限公司 Preparation method for edaravone

References

  1. ^ Jump up to:a b Doherty, Annette M. (2002). Annual Reports in Medicinal Chemistry, Volume 37 (Annual Reports in Medicinal Chemistry). Boston: Academic Press. ISBN 0-12-040537-7.
  2. Jump up^ Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A (March 2004). “[Research and development of the free radical scavenger edaravone as a neuroprotectant]”. Yakugaku Zasshi (in Japanese). 124 (3): 99–111. doi:10.1248/yakushi.124.99. PMID 15049127.
  3. Jump up^ Higashi Y, Jitsuiki D, Chayama K, Yoshizumi M (January 2006). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases”. Recent Patents on Cardiovascular Drug Discovery. 1 (1): 85–93. doi:10.2174/157489006775244191. PMID 18221078.
  4. Jump up^ Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N (2006). “Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury”. CNS Drug Reviews. 12 (1): 9–20. doi:10.1111/j.1527-3458.2006.00009.x. PMID 16834755.
  5. Jump up^ Yuan WJ, Yasuhara T, Shingo T, et al. (2008). “Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons”. BMC Neuroscience. 9: 75. doi:10.1186/1471-2202-9-75. PMC 2533664Freely accessible. PMID 18671880.
  6. Jump up^ Kawasaki T, Ishihara K, Ago Y, et al. (August 2006). “Protective effect of the radical scavenger edaravone against methamphetamine-induced dopaminergic neurotoxicity in mouse striatum”. European Journal of Pharmacology. 542 (1-3): 92–9. doi:10.1016/j.ejphar.2006.05.012. PMID 16784740.
  7. Jump up^ Kawasaki T, Ishihara K, Ago Y, Baba A, Matsuda T (July 2007). “Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger, prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the substantia nigra but not the striatum”. The Journal of Pharmacology and Experimental Therapeutics. 322 (1): 274–81. doi:10.1124/jpet.106.119206. PMID 17429058.
  8. Jump up^ Yokoyama H, Takagi S, Watanabe Y, Kato H, Araki T (June 2008). “Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice”. Journal of Neural Transmission (Vienna, Austria : 1996). 115 (6): 831–42. doi:10.1007/s00702-008-0019-6. PMID 18235988.
  9. Jump up^ Yokoyama H, Yano R, Aoki E, Kato H, Araki T (September 2008). “Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice”. Metabolic Brain Disease. 23 (3): 335–49. doi:10.1007/s11011-008-9096-3. PMID 18648914.

External links

Edaravone
Edaravone.svg
Edaravone ball-and-stick model.png
Clinical data
Trade names Radicut
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Rx-only (JP)
Identifiers
Synonyms MCI-186
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.001.719
Chemical and physical data
Formula C10H10N2O
Molar mass 174.20 g/mol
3D model (Jmol)
////////// Radicava, edaravone, fda 2017, Lou Gehrig’s disease, amyotrophic lateral sclerosis,  Mitsubishi Tanabe, orphan drug designation89-25-8, эдаравон, إيدارافون , 依达拉奉 ,ラジカット,
O=C1CC(=NN1c1ccccc1)C

FDA approves first treatment for a form of Batten disease, Brineura (cerliponase alfa)


Image result
04/27/2017
The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

The U.S. Food and Drug Administration today approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.

“The FDA is committed to approving new and innovative therapies for patients with rare diseases, particularly where there are no approved treatment options,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Approving the first drug for the treatment of this form of Batten disease is an important advance for patients suffering with this condition.”

CLN2 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), collectively referred to as Batten disease. CLN2 disease is a rare inherited disorder that primarily affects the nervous system. In the late infantile form of the disease, signs and symptoms typically begin between ages 2 and 4. The initial symptoms usually include language delay, recurrent seizures (epilepsy) and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects essential motor skills, such as sitting and walking. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Batten disease is relatively rare, occurring in an estimated two to four of every 100,000 live births in the United States.

Brineura is an enzyme replacement therapy. Its active ingredient (cerliponase alfa) is a recombinant form of human TPP1, the enzyme deficient in patients with CLN2 disease. Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a specific surgically implanted reservoir and catheter in the head (intraventricular access device). Brineura must be administered under sterile conditions to reduce the risk of infections, and treatment should be managed by a health care professional knowledgeable in intraventricular administration. The recommended dose of Brineura in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion, followed by an infusion of electrolytes. The complete Brineura infusion, including the required infusion of intraventricular electrolytes, lasts approximately 4.5 hours. Pre-treatment of patients with antihistamines with or without antipyretics (drugs for prevention or treatment of fever) or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion.

The efficacy of Brineura was established in a non-randomized, single-arm dose escalation clinical study in 22 symptomatic pediatric patients with CLN2 disease and compared to 42 untreated patients with CLN2 disease from a natural history cohort (an independent historical control group) who were at least 3 years old and had motor or language symptoms. Taking into account age, baseline walking ability and genotype, Brineura-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.

The safety of Brineura was evaluated in 24 patients with CLN2 disease aged 3 to 8 years who received at least one dose of Brineura in clinical studies. The safety and effectiveness of Brineura have not been established in patients less than 3 years of age.

The most common adverse reactions in patients treated with Brineura include fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure.

Brineura should not be administered to patients if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, health care providers should discontinue infusion of Brineura and refer to the device manufacturer’s labeling for further instructions. Additionally, health care providers should routinely test patient CSF samples to detect device infections. Brineura should also not be used in patients with ventriculoperitoneal shunts (medical devices that relieve pressure on the brain caused by fluid accumulation).

Health care providers should also monitor vital signs (blood pressure, heart rate, etc.) before the infusion starts, periodically during infusion and post-infusion in a health care setting. Health care providers should perform electrocardiogram (ECG) monitoring during infusion in patients with a history of slow heart rate (bradycardia), conduction disorder (impaired progression of electrical impulses through the heart) or structural heart disease (defect or abnormality of the heart), as some patients with CLN2 disease can develop conduction disorders or heart disease. Hypersensitivity reactions have also been reported in Brineura-treated patients. Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. If anaphylaxis occurs, infusion should be immediately discontinued and appropriate treatment should be initiated.

The FDA will require the Brineura manufacturer to further evaluate the safety of Brineura in CLN2 patients below the age of 2 years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess Brineura treated CLN2 patients for a minimum of 10 years.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Brineura also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is also receiving a Rare Pediatric Disease Priority Review Voucherunder a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the tenth rare pediatric disease priority review voucher issued by the FDA since the program began.

The FDA granted approval of Brineura to BioMarin Pharmaceutical Inc.

////////Brineura, cerliponase alfa, fda 2017, Batten disease, BioMarin Pharmaceutical Inc, Priority Review,  Breakthrough Therapy designations, Orphan Drug designation,

FDA approves first drug Ingrezza (valbenazine) to treat tardive dyskinesia


Valbenazine.svg

Valbenazine

  • Molecular FormulaC24H38N2O4
  • Average mass418.569 Da
(2R,3R,11bR)-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl L-valinate
(2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-yl L-valinate
1025504-45-3 cas
L-Valine, (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-yl ester
NBI-98854
Image result for valbenazine
Valbenazine ditosylate. RN: 1639208-54-0. UNII: 5SML1T733B, Molecular Formula, C24-H38-N2-O4.2C7-H8-O3-S, Molecular Weight, 762.9806

(2R,3R,11bR)-9,10-Dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo(a)quinolizin-2-yl L-valinate bis(4-methylbenzenesulfonate)

and

Valbenazine dihydrochloride
1639208-51-7

04/11/2017
The U.S. Food and Drug Administration today approved Ingrezza (valbenazine) capsules to treat adults with tardive dyskinesia. This is the first drug approved by the FDA for this condition.

April 11, 2017

Release

The U.S. Food and Drug Administration today approved Ingrezza (valbenazine) capsules to treat adults with tardive dyskinesia. This is the first drug approved by the FDA for this condition.

Tardive dyskinesia is a neurological disorder characterized by repetitive involuntary movements, usually of the jaw, lips and tongue, such as grimacing, sticking out the tongue and smacking the lips. Some affected people also experience involuntary movement of the extremities or difficulty breathing.

“Tardive dyskinesia can be disabling and can further stigmatize patients with mental illness,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Approving the first drug for the treatment of tardive dyskinesia is an important advance for patients suffering with this condition.”

Tardive dyskinesia is a serious side effect sometimes seen in patients who have been treated with antipsychotic medications, especially the older medications, for long periods to treat chronic conditions, such as schizophrenia and bipolar disorder. Tardive dyskinesia can also occur in patients taking antipsychotic medications for depression and certain medications for gastrointestinal disorders and other conditions. It is unclear why some people who take these medications develop tardive dyskinesia yet others do not.

The efficacy of Ingrezza was shown in a clinical trial of 234 participants that compared Ingrezza to placebo. After six weeks, participants who received Ingrezza had improvement in the severity of abnormal involuntary movements compared to those who received placebo.

Ingrezza may cause serious side effects including sleepiness and heart rhythm problems (QT prolongation). Its use should be avoided in patients with congenital long QT syndrome or with abnormal heartbeats associated with a prolonged QT interval. Those taking Ingrezza should not drive or operate heavy machinery or do other dangerous activities until it is known how the drug affects them.

The FDA granted this application Fast Track, Priority Review and Breakthrough Therapy designations.

The FDA granted approval of Ingrezza to Neurocrine Biosciences, Inc.

Valbenazine (INN,[1]:114 proposed trade name Ingrezza) is the first drug approved by the FDA[2] for use in the treatment of tardive dyskinesia.[3][4] Clinical trials are underway to evaluate its efficacy in the treatment of Tourette’s syndrome.[5][6] It acts as a vesicular monoamine transporter 2 (VMAT2) inhibitor.[7]

Pharmacology

Mechanism of action

Valbenazine is known to cause reversible reduction of dopamine release by selectively inhibiting pre-synaptic human vesicular monoamine transporter type 2 (VMAT2). In vitro, valbenazine shows great selectivity for VMAT2 and little to no affinity for VMAT1 or other monoamine receptors.[8] Although the exact cause of tardive dyskinsia is unknown, it is hypothesized that it may result from neuroleptic-induced dopamine hypersensitivity.[9] By selectively reducing the ability of VMAT2 to load dopamine into synaptic vesicles,[10] the drug reduces overall levels of available dopamine in the synaptic cleft, ideally alleviating the symptoms associated with dopamine hypersensitivity. The importance of valbenazine selectivity inhibiting VMAT2 over other monoamine transporters is that VMAT2 is mainly involved with the transport of dopamine, and to a much lesser extent other monoamines such as norepinephrine, serotonin, and histamine. This selectivity is likely to reduce the likelihood of “off-target” adverse effects which may result from the upstream inhibition of these other monoamines.[11]

Society and culture

Commercial aspects

Valbenazine is produced by Neurocrine Biosciences, a company based in San Diego. In addition to the late-stage clinical trials studying valbenazine, Neurocrine Biosciences (partnered with AbbVie Inc.) also has another product, elagolix (a hormone antagonist), undergoing clinical trials.[12] Following the initiation of these trials, on 5 May 2016 Neurocrine reported revenues of $15 million for the first quarter of 2016.[13] The company now focuses on filing the valbenazine new drug application as they prepare for the commercial launch of the drug for the treatment of tardive dyskinesia.Neurocrine’s expenses have risen steadily since May 2015, primarily due to the pre-commercialization activities for valbenazine. [14]

Intellectual property

While Neurocrine Biosciences does not currently hold a final patent for valbenazine or elagolix, they do hold a patent for the VMAT2 inhibitor [9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido-[2,1-a]isoquinolin-2-yl]methanol and related compounds, which includes valbenazine.[15]

ChemSpider 2D Image | Valbenazine | C24H38N2O4

References

  1.  “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 71” (PDF). World Health Organization. Retrieved 18 November 2016.
  2.  Newswire, MultiVu – PR. “Neurocrine Announces FDA Approval of INGREZZA TM (valbenazine) Capsules as the First and Only Approved Treatment for Adults with Tardive Dyskinesia (TD)”. Multivu. Retrieved 2017-04-11.
  3.  Ben Adams (Aug 30, 2016). “Neurocrine submits valbenazine NDA early, set for 2017 approval”. fiercebiotech.com.
  4.  “Safety and Tolerability Study of NBI-98854 for the Treatment of Tardive Dyskinesia – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2016-11-13.
  5. Jump up^ “Tourette Syndrome Clinical Trials | Neurocrine Biosciences”. http://www.neurocrine.com. Retrieved 2016-11-13.
  6. Jump up^ “Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov. Retrieved 2016-11-13.
  7. Jump up^ O’Brien, C. F.; Jimenez, R; Hauser, R. A.; Factor, S. A.; Burke, J; Mandri, D; Castro-Gayol, J. C. (2015). “NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: A randomized, double-blind, placebo-controlled study”. Movement Disorders. 30 (12): 1681–7. doi:10.1002/mds.26330. PMC 5049616Freely accessible. PMID 26346941.
  8. Jump up^ “NBI-98854 – VMAT2 Inhibitor | Tics in Children Treatment | Neurocrine Biosciences”. http://www.neurocrine.com. Retrieved 2016-11-13.
  9. Jump up^ “tardive-dyskinesia”. http://www.priory.com. Retrieved 2016-11-13.
  10. Jump up^ Purves, Dale, et al. Neuroscience. Sinauer Associates. 087893646
  11.  “NBIX: NDA for Valbenazine in Tardive Dyskinesia to be Filed in 2016…”. Retrieved 2016-11-13.
  12.  “Endocrine & Movement Disorder R&D | About | Neurocrine Biosciences”. http://www.neurocrine.com. Retrieved 2016-11-14.
  13.  “NBIX: NDA for Valbenazine in Tardive Dyskinesia to be Filed in 2016…”. Retrieved 2016-11-20.
  14.  “Press Release | Neurocrine Biosciences, Inc.”. phoenix.corporate-ir.net. Retrieved 2016-11-20.
  15.  “[9,10-dimethoxy-3-(2-methylpropyl)-1h,2h,3h,4h,6h,7h,11bh-pyrido-[2,1-a]isoquinolin-2-yl]methanol And Compounds, Compositions And Methods Relating Thereto”. Retrieved 2016-11-20.
1 to 3 of 3
Patent ID Patent Title Submitted Date Granted Date
US8039627 SUBSTITUTED 3-ISOBUTYL-9, 10-DIMETHOXY-1, 3, 4, 6, 7, 11B-HEXAHYDRO-2H-PYRIDO[2, 1-A]ISOQUINOLIN-2-OL COMPOUNDS AND METHODS RELATING THERETO 2008-07-10 2011-10-18
US8357697 Substituted 3-isobutyl-9, 10-dimethoxy-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrido[2, 1-A]isoquinolin-2-ol compounds and methods relating thereto 2011-09-20 2013-01-22
US2016068526 BENZOQUINOLONE INHIBITORS OF VMAT2 2014-01-28 2016-03-10
Valbenazine
Valbenazine.svgImage result for valbenazine
Clinical data
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
Synonyms NBI-98854
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C24H38N2O4
Molar mass 418.58 g·mol−1
3D model (Jmol)
////////fda 2017, Ingrezza, valbenazine, tardive dyskinesia, Fast Track, Priority Review ,  Breakthrough Therapy designations, 1025504-45-3, NBI-98854, 
%d bloggers like this: