Treatment for primary biliary cholangitis

11433,050

17/512950

October 28, 2021

The present invention provides therapeutic compound for prevention and treatment of primary biliary cholangitis, (PBC). Specifically, the present invention provides pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of PBC. [chemical expression included]

Cadila Healthcare Ltd. (Gujarat, IN)

Cadila Healthcare Ltd. (Gujarat, IN)

1. A method of treating primary biliary cholangitis, comprising administering orally and once daily to a human in need thereof about 2 mg or about 4 mg of saroglitazar magnesium salt, to treat the primary biliary cholangitis; wherein saroglitazar is represented by: [chemical expression included]

2. The method of claim 1 , wherein about 4 mg saroglitazar magnesium salt is administered.

3. The method of claim 1 , wherein about 2 mg saroglitazar magnesium salt is administered.

4. The method of claim 1 , wherein saroglitazar magnesium salt is the sole therapeutic agent for treating the primary biliary cholangitis.

5. The method of claim 1 , wherein administering occurs for at least 16 weeks.

6. A method of treating primary biliary cholangitis, comprising administering orally and once daily to a human in need thereof a pharmaceutical formulation in the form of a tablet or a capsule, the pharmaceutical formulation comprising about 2 mg or about 4 mg of saroglitazar magnesium salt; and a pharmaceutical excipient, to treat the primary biliary cholangitis; wherein saroglitazar is represented by: [chemical expression included]

7. The method of claim 6 , wherein saroglitazar magnesium salt is the sole therapeutic agent in the pharmaceutical formulation.

8. The method of claim 6 , wherein saroglitazar magnesium salt is the sole therapeutic agent for treating the primary biliary cholangitis.

9. The method of claim 6 , wherein the pharmaceutical formulation comprises about 2 mg saroglitazar magnesium salt.

10. The method of claim 6 , wherein the pharmaceutical formulation comprises about 4 mg saroglitazar magnesium salt.

4231938 November 1980 Monaghan et al.
4346227 August 1982 Terahara et al.
4444784 April 1984 Hoffman et al.
5273995 December 1993 Roth
5354772 October 1994 Kathawala
6166063 December 2000 Villhauer
6395767 May 2002 Robl et al.
6699871 March 2004 Edmondson et al.
6987123 January 2006 Lohray et al.
7041837 May 2006 Lohray et al.
7323491 January 2008 Lohray et al.
7407955 August 2008 Himmelsbach et al.
8110598 February 2012 Lohray et al.
8212057 July 2012 Lohray et al.
8558009 October 2013 Lohray et al.
8772342 July 2014 Darteil et al.
9610277 April 2017 Patel
9656954 May 2017 Jain et al.
9783495 October 2017 Pandey et al.
9814697 November 2017 Patel et al.
10098868 October 2018 Patel
10385017 August 2019 Desai
10435363 October 2019 Dwivedi et al.
2003/0199498 October 2003 Lohray et al.
2003/0236254 December 2003 Lohray et al.
2007/0238776 October 2007 Lohray et al.
2009/0196923 August 2009 Mandal et al.
2011/0275669 November 2011 Lohray et al.
2012/0121729 May 2012 Paterson et al.
2013/0338209 December 2013 Gambhire et al.
2015/0132289 May 2015 Ellis et al.
2016/0068484 March 2016 Jain et al.
2016/0107989 April 2016 Dwivedi et al.
2016/0136131 May 2016 Patel et al.
2016/0166539 June 2016 Patel et al.
2016/0194280 July 2016 Dwivedi et al.
2016/0207884 July 2016 Dwivedi et al.
2017/0087127 March 2017 Patel et al.
2017/0088514 March 2017 Gambhire et al.
2017/0266158 September 2017 Patel et al.
2017/0320823 November 2017 Jain et al.
2018/0008616 January 2018 Pruzanski
102010012223 September 2011
1586571 October 2005
1910/MUM/2013 December 2014
1850/MUM/2015 May 2015
4430/MUM/2015 November 2015
4431/MUM/2015 November 2015
WO-1991/019702 December 1991
WO-1994/001420 January 1994
WO-1994/013650 June 1994
WO-1995/003038 February 1995
WO-1995/017394 June 1995
WO-1996/004260 February 1996
WO-1996/004261 February 1996
WO-1996/033998 October 1996
WO-1997/025042 July 1997
WO-1997/036579 October 1997
WO-1999/008501 February 1999
WO-1999/016758 April 1999
WO-1999/019313 April 1999
WO-1999/020614 April 1999
WO-2000/023417 April 2000
WO-2000/023445 April 2000
WO-2000/023451 April 2000
WO-2001/053257 July 2001
WO-2002/024625 March 2002
WO-2003/009841 February 2003
WO-2005/031335 April 2005
WO-2012/104869 August 2012
WO-2012/145569 October 2012
WO-2014/174524 October 2014
WO-2014/195967 December 2014
WO-2015/001573 January 2015
WO-2015/011730 January 2015
WO-2015/029066 March 2015
WO-2015/033357 March 2015
WO-2016/127019 August 2016
WO-2016/181409 November 2016
WO-2017/089979 June 2017
WO-2017/089980 June 2017

Stephen et al. Journal of Pharmaceutical Science, 1977, pp. 1-18. cited by examiner
“Sodium Stearyl Fumarate”, obtained on Jun. 23, 2015. Retrieved from the Internet: , 4 pages. cited by applicant
Acdisol Product Overview (year 2005). cited by applicant
Angulo et al. (2000) “Oral Budesonide in the Treatment of Patients with Primary Biliary Cirrhosis With a Suboptimal Response to Ursodeoxycholic Acid,” Hepatotogy 31 (2):318-323. cited by applicant
Angulo, P. (2007) “GI Epidemiology: nonalcoholic fatty liver disease,” Aliment. Pharmacol. Ther. 25(8)883-889. cited by applicant
Anonymous “IND Minutes draft 19 07 12” Retrieved on Oct. 15, 2013 from the Internet from URL: http://www.docstoc.com/docs/145152750/IND-Minutes-draft-19-07-12 (1 page). cited by applicant
Anonymous “Lipaglyn™ Discovery, Development & Preclinical Studies” Retrieved on Oct. 15, 2013 from the Internet from URL: http://webcache.googleusercontent.com/search?q=cache:RGrhmY0HM3sJ:lipaglyn.com/downloads/Lipaglyn_Preclinical_Studies.ppsx (25 pages). cited by applicant
Anonymous International Nonproprietary Names for Pharmaceutical Substances (INN); Jan. 1, 2012; Retrieved from the internet: URL: http://www.who.int/medicines/publications/druginformation/issues/PL_108.pdf; Retrieved on Oct. 15, 2013; pp. 401-471. cited by applicant
Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition” 88-92. cited by applicant
Arnett, E. M. et al. (1965) “Solvent Effects in Organic Chemistry. V. Molecules, Ions, and Transition States in Aqueous Ethanol,” J. Am. Chem. Soc. 87(7)1541-1553. cited by applicant
Augustyns, K. et al. (2005) “Inhibitors of proline-specific dipeptidyl peptidases: DPP IV inhibitors as a novel approach for the treatment of Type 2 diabetes,” Expert Opin. Ther. Patents 15(10)1387-1407. cited by applicant
Barb et al. (2016) “Pharmacological management of nonalcoholic fatty liver disease” Metabolism Clinical and Experimental 65:1183-1195. cited by applicant
Berge, S. M. et al. (1977) “Pharmaceutical Salts,” J. Pharmaceutical Sciences 66(1):1-19. cited by applicant
Berger et al. (2005) “PPARs: Therapeutic targets for metabolic disease” TRENDS in Pharmacological Sciences 26(5): 244-251. cited by applicant
Beuers et al. (2015) “New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond,” Journal of Hepatology, 62(1): S25-S37. cited by applicant
Bharate, S. et al. (2010) “Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review.” J. Excipient and Food Chem. 1(3)3-26. cited by applicant
Boettcher, E. et al. (2012) “Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis,” Aliment. Pharmacol. Ther. 35(1)66-75. (Abstract Only, Retrieved from https://www.ncbi.nih.gov/pubmed/22050199). cited by applicant
Boulet, L-P. (2009) “Influence of Comorbid Conditions on Asthma” European Respiratory Journal 33:897-906. cited by applicant
Brenna, E. et al. (2009) “Enzyme-mediated synthesis of EEHP and EMHP, useful pharmaceutical intermediates of PPAR agonists” Tetrahedron: Asymmetry 20:2594-2599. cited by applicant
Bugianesi, E. et al. (2005) “Insulin Resistance: A Metabolic Pathway to Chronic Liver Disease,” Hepatology 42(5):987-1000. cited by applicant
Cairns, D. (editor) “Essentials of Pharmaceutical Chemistry, Fourth Edition” 2012, p. 14. cited by applicant
Chatila, W. M. et al. “Comorbidities in Chronic Obstructive Pulmonary Disease” Proc. Am. Thorac. Soc. (2008) vol. 5, pp. 549-555. cited by applicant
Chaumeil, J. C. “Micronization: A Method of Improving the Bioavailability of Poorly Soluble Drugs,” Meth. Find. Exp. Clin. Pharmacol. (1998) vol. 20, No. 3, pp. 211-215. cited by applicant
Cheung et al. (2015) “Time to make the change from ‘primary biliary cirrhosis’ to ‘primary biliary cholangitis’,” Can J Gastroenterol Hepatol, 29:293. cited by applicant
Choi, W. S. et al. (2004) “Amorphous ultrafine particle preparation for improvement of bioavailability of insoluble drugs: grinding characteristics of fine grinding mills,” Int. J. Miner. Process. 74S:S165-S172. cited by applicant
Chou et al. (2013) “Metrelepin: First Global Approval” Drugs 73:989-997. cited by applicant
Deeg et al. (2007) “Pioglitazone and Rosiglitazone Have Different Effects on Serum Lipoprotein Particle Concentrations and Sizes in Patients With Type 2 Diabetes and Dyslipidemia” Diabetes Care 30(10):2458-2464. cited by applicant
Demuth, H.-U. et al. (2005) “Type 2 diabetes—Therapy with dipeptidyl peptidase IV inhibitors,” Biochim. Biophys. Acta, 1751:33-44. cited by applicant
Duval et al. (2002) “The role of PPARs in atherosclerosis,” TRENDS in Molecular Medicine 8(9):422. cited by applicant
Fan, W. and Evans, R. (2015) “PPARs and ERRs: molecular mediators of mitochondrial metabolism” Curr. Opin. Cell Bio. 33:49-54. cited by applicant
FDA approves Ocaliva for rare, chronic liver disease, FDA Press Release, May 31, 2016, retrieved from: https://www.fda.gov/news-events/press-announcements/fda-approves-ocaliva-rare-chronic-liver-disease. cited by applicant
FDA News Release—FDA Approves Egrifta to treat Lipodystrophy in HIV Patients; downloaded from www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm233516.htm on Sep. 7, 2016 (2 pages). cited by applicant
Gennaro et al. “Remington's Pharmaceutical Sciences, 19th Edition” (1995) Mack Publishing, pp. 1380-1383. cited by applicant
Ghonem et al., “Fibrates and Cholestasis,” Hepatology, 62:635-643 (2015). cited by applicant
Giri et al. “Efficacy of Saroglitazar, a Novel PPAR Agonist in a Mouse Model of Non-Alcoholic Steatohepatitis” Poster No. 2011, Keystone Symposia Conference, Mar. 22-27, 2015 at Whistler, British Colombia, Canada. cited by applicant
Hadigan, C. et al. (2004) “Metabolic Effects of Rosiglitazone in HIV Lipodystrophy: A Randomized, Controlled Trial,” Ann. Internal Med. 140(10):788-794. (Abstract Only). cited by applicant
Herrine, S. K. “Nonalcoholic Steatohepatitis (NASH)” Merck Manual (Revised May 2016) Retrieved on Sep. 13, 2017 from http://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/approach-to-the-patient-with-liver-disease/nonalcoholic-steatohepatitis-nash. (3 pages). cited by applicant
Hirschfield et al. (2015) “Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid,” Gastroenterology 148(4):751-761). cited by applicant
Honda et al. (2013) “Anticholestatic effects of Bezafibrate in Patients with Primary Biliary Cirrhosis Treated With Ursodeoxycholic Acid,” Hepatology, 57:1931-1941. cited by applicant
Hosonuma et al. (2015) “A Prospective Randomized Controlled Study of Long-Term Combination Therapy Using Ursodeoxycholic Acid and Bezafibrate in Patients With Primary Biliary Cirrhosis and Dyslipidemia,” Am J Gastroenterol 110:423-431. cited by applicant
Ikegami et al. (2008) “Ursodeoxycholic acid: Mechanism of action and novel clinical applications,” Hepatology Research 38:123-131. cited by applicant
IND Committee: “Minutes of IND Committee Meeting Held on Jul. 19, 2012” Retrieved on Oct. 15, 2013 from the Internet from URL: http://www.docstoc.com/docs/145152750/IND-Minutes-draft-19-07-12 (2 pages). cited by applicant
International Preliminary Report on Patentability dated Aug. 15, 2013 for International Application No. PCT/IN2012/000069 (5 pages). cited by applicant
International Preliminary Reporton Patentability dated Dec. 1, 2015 for International Patent Application No. PCT/IN2014/000367 (9 pages). cited by applicant
International Preliminary Report on Patentability dated Jul. 9, 2015 for International Application No. PCT/IN2013/000391 (9 pages). cited by applicant
International Preliminary Report on Patentability dated Mar. 1, 2016 for Application No. PCT/IN2014/000551 (7 pages). cited by applicant
International Preliminary Report on Patentability dated Mar. 8, 2016 for International Patent Application No. PCT/IN2014/000584 (10 pages). cited by applicant
International Preliminary Report on Patentability dated Oct. 6, 2015 for International Patent Application No. PCT/IN2014/000445 (7 pages). cited by applicant
International Preliminary Report on Patentability dated Oct. 9, 2015 for International Application No. PCT/IN2014/000489 (7 pages). cited by applicant
International Search Report and Written Opinion dated Dec. 19, 2014 for Application No. PCT/IN2014/000551 (11 pages). cited by applicant
International Search Report and Written Opinion dated Dec. 23, 2014 for International Patent Application No. PCT/IN2014/000445 (10 pages). cited by applicant
International Search Report and Written Opinion dated Feb. 2, 2015 for International Patent Application No. PCT/IN2014/000367 (14 pages). cited by applicant
International Search Report and Written Opinion dated Mar. 23, 2015 for Application No. PCT/IN2014/000584 (14 pages). cited by applicant
International Search Report and Written Opinion dated Nov. 20, 2013 for International Application No. PCT/IN2013/000391 (13 pages). cited by applicant
International Search Report and Written Opinion dated Nov. 20, 2014 for International Application No. PCT/IN2014/000489 (10 pages). cited by applicant
International Search Report dated May 9, 2012 for International Application No. PCT/IN2012/000069 (3 pages). cited by applicant
Jackson, K. “No Benefit from Ezetimibe in NASH” In Medpage Today (Jun. 2015). cited by applicant
Jain et al. (2015) “Saroglitazar, a novel PPARα/γ agonist with predominant PPARα activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models,” Pharmacol Res Perspect.; 3(3):e00136. cited by applicant
Jain et al. (2018) “Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models,” Liver Int. 38(6):1084-1094. cited by applicant
Jain et al. “Saroglitazar Shows Therapeutic Benefits in Mouse Model of Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)” Poster No. 1957-P, 75th Scientific Session—ADA, Jun. 5-9, 2015, Boston, MA, USA. cited by applicant
Jain et al. (2017) “Saroglitazar, a novel first in class drug discovered & developed in India for management of diabetic dyslipidemia and related metabolic conditions,” “Pharmacologists of India Their Contribution” published by Vallabh Prakashan: book chapter 30, p. 246-261. cited by applicant
Jani, R. H. et al. (2013) “Pharmacokinetics, Safety, and Tolerability of Saroglitazar (ZYH1), a Predominantly PPARα Agonist with Moderate PPARγ Agonist Activity in Healthy Human Subjects” Clin. Drug Investig. 33:809-816. cited by applicant
Jani, R. H. et al. (2009) “A Prospective Randomized, Double Blind, Placebo Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ZYH1 Following Once a Day (OD) Oral Administrations up to 10 Days in Healthy Volunteers,” Diabetes (2009) 58(No. Suppl. 1):A569. cited by applicant
Jani, R. H. et al. (2014) “A Multicenter, Prospective, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Saroglitazar 2 and 4 mg Compared with Placebo in Type 2 Diabetes Mellitus Patients Having Hypertriglyceridemia Not Controlled with Atorvastatin Therapy (PRESS VI),” Diabetes Technology & Therapeutics, 16(2):63-71. cited by applicant
Kandel et al. (2016) “Genomewide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARα in primary human hepatocytes,” Biochimica et Biophysica Acta (BBA)—Gene Regulatory Mechanisms, 1859(9):1218-1227. cited by applicant
Kaplan et al. (2005) “Primary Biliary Cirrhosis,” N Engl J Med 353:1261-1273. cited by applicant
Kurihara et al. (2000) Effect of Bezafibrate in the Treatment of Primary Biliary Cirrhosis, Current Therapeutic Research, 61 (2):74-82. cited by applicant
LaBrecque, D. et al. (2012) “World Gastroenterology Organisation, Global Guidelines: Nonalcoholic Fatty Liver disease and Nonalcoholic Steatohepatitis (long version)” World Gastroenterology Organisation 29 pages. cited by applicant
Lemoine, M. et al. “Steatohepatitis (fatty liver) Is Associated With Increased Hepatic Expression of SREBP-1 in HIV-Infected Patients With Antiretroviral Therapy-Linked Lipodystrophy,” Abstract from 55th Annual Meeting of the American Association for the Study of Liver Diseases, Oct. 29 to Nov. 2, 2004; Printed from http://www.natap.org/2004/AASLD/aasld_10.htm. (8 pages). cited by applicant
Leuschner et al. (1999) “Oral Budesonide and Ursodeoxycholic Acid for Treatment of Primary Biliary Cirrhosis: Results of a Prospective Double-Blind Trial,” Gastroenterology 117:918-925. cited by applicant
Lieberman, et al. (1989) “Pharmaceutical Dosage Forms: Tablets, vol. 1, 2nd Edition” Marcel Dekker Inc., pp. 111-114. cited by applicant
Macallan, D. C. et al. (2008) “Treatment of Altered Body Composition in HIV Associated Lipodystrophy: Comparison of Rosiglitazone, Pravastatin, and Recombinant Human Growth Hormone,” HIV Clinical Trials, 9(Issue 4):254-268. (Abstract Only). cited by applicant
Package Insert for ACTOS (pioglitazone) tablets for oral use (2013). cited by applicant
Package Insert for AVANDIA (rosiglitazone maleate) Tablets (2008). cited by applicant
Pai, V. et al. (2014) “A Multicenter, Prospective, Randomized, Double-blind Study to Evaluate the Safety and Efficacy of Saroglitazar 2 and 4 mg Compared to Pioglitazone 45 mg in Diabetic Dyslipidemia (PRESS V).” J. Diabetes Sci. Technol. 8(1):132-141. cited by applicant
Palomer et al. (2016) “PPARβ/δ and lipid metabolism in the heart” Biochemica et Biophysica Acta 1861:1569-1578. cited by applicant
Pharmatrans Sanaq AG “LubriSanaq” Dated Feb. 5, 2008. (2 pages). cited by applicant
Pivovarova et al. (2011) “All signs of the metabolic syndrome in hypertensive ISIAH rats are associated with increased activity of the transcription factors PPAR, LXR, PXR, and CAR in the liver,” Biochem. Moscow Suppl. Ser. B (5):29-36. cited by applicant
Poupon (2003) “Autoimmune overlapping syndromes,” Clin Liver Dis 7:865-878. cited by applicant
Prescribing Information for Zetia® (ezetimibe; year 2012). cited by applicant
Pubchem CID 31401 Ursodiol [online Retrieved from the internet, [Retrieved on Oct. 26, 2018], (Year: 2006). cited by applicant
Pubchem CID 60151560 Saroglitazar [online] Retrieved from the internet, [Retrieved on Oct. 26, 2018], (Year: 2012). cited by applicant
Rabahi et al. (2010) “Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone,” Gastroenterol Clin. Biol. 34:283-287. cited by applicant
Rakoski, M. et al. (2010) “Meta-analysis: Insulin Sensitizers for the Treatment of Non-alcoholic Steatohepatitis” Aliment. Pharmacol. Ther. 32:1211-1221. cited by applicant
Ramirez, T. et al. (2012) “Structural Correlates of PPAR Agonist Rescue of Experimental Chronic Alcohol-Induced Steatohepatitis,” J. Clin. Exper. Pathology 2(4):1-9. cited by applicant
Response to Written Opinion filed on May 21, 2015 for International Application No. PCT/IN2014/000489 (6 pages). cited by applicant
Seo, Y. S. et al. (2008) “PPAR agonists treatment is effective in a nonalcoholic fatty liver disease animal model by modulating fatty-acid metabolic enzymes” J. Gatroenterology Hepatology (2008) 23(1)102-109. cited by applicant
Sui et al. (2010) “Deficiency of PXR decreases atherosclerosis in apoE deficient mice,” J. Lipid Res. 51:1652-1659. cited by applicant
TAIwalkar et al. (2005) “Mycophenolate Mofetil for the Treatment of Primary Biliary Cirrhosis in Patients With an Incomplete Response to Ursodeoxycholic Acid,” J Clin Gastroenterol 39(2):168-171. cited by applicant
Tungsiripat, M. et al. (2010) “Rosiglitazone improves lipoatrophy in patients receiving thymidine-sparing regimens,” AIDS 24:1291-1298. cited by applicant
USPTO Trademark Database Entry for AEROSIL. cited by applicant
Van Wijk, J. P. H. et al. (2005) “Comparison of Rosiglitazone and Metformin for Treating HIV Lipodystrophy: A Randomized Trial,” Ann. Internal Med. 143(5)337-346. cited by applicant
Vleggaar et al. (2001) “Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant,” Gut 49:276-281. cited by applicant
Wallace et al. (2010) “The PXR is a drug target for chronic inflammatory liver disease,” Journal of Steroid Biochemistry & Molecular Biology 120:137-148. cited by applicant
Written Opinion of the International Searching Authority dated May 9, 2012 for International Application No. PCT/IN2012/000069 (4 pages). cited by applicant
Yessoufou et al. (2010) “Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels” Swiss Medical Weekly 140:w13071. cited by applicant
Yin et al. (2015) “Systematic review and meta-analysis: bezafibrate in patients with primary biliary cirrhosis,” Drug Design, Development and Therapy 9:5407-5419. cited by applicant
U.S. Appl. No. 16/919,404, Treatment for Primary Biliary Cholangitis, filed Jul. 2, 2020, Pending. cited by applicant
Cuperus et al. (2014) “Fibrate treatment for primary biliary cirrhosis,” Curr Opin Gastroenterol 30(3):279-286. cited by applicant

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