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Home , Chenodeoxycholic acid, Cholic acid, Obeticholic acid, Ursodeoxycholic acid

Drugs DOI 10.1007/s40265-016-0616-x

ADIS DRUG EVALUATION

Obeticholic Acid: First Global Approval

1 1 A. Markham • Susan J. Keam

Ó Springer International Publishing Switzerland 2016

Abstract (OcalivaTM) is a farnesoid-X and intestine that is a key regulator of acid, inflam- receptor (FXR) agonist that is being developed by Intercept matory, fibrotic and metabolic pathways. Activation of Pharmaceuticals for the treatment of various diseases, FXR suppresses de novo synthesis of bile acids from and has recently been granted accelerated approval in the and increases the transport of bile acids out of USA for the treatment of primary biliary cholangitis in hepatocytes, thus reducing hepatic exposure to bile acids combination with in adults with an [1, 5]. FXR activation also promotes insulin sensitivity, inadequate response to ursodeoxycholic acid, or as decreases circulating triglycerides and reduces hepatic monotherapy in adults unable to tolerate ursodeoxycholic gluconeogenesis and glycogenolysis [2, 6]. acid. The drug is in preregistration for this indication in the Obeticholic acid was granted accelerated approval in the EU. This article summarizes the milestones in the devel- USA in May 2016 for the treatment of primary biliary opment of obeticholic acid leading to this first approval for cholangitis in combination with ursodeoxycholic acid in primary biliary cholangitis. adults with an inadequate response to ursodeoxycholic acid, or as monotherapy in adults unable to tolerate ursodeoxycholic acid [1, 5], and is awaiting approval in the 1 Introduction EU for the same indication [4]. Approval in the USA was based on improvements in (ALP) Obeticholic acid (OcalivaTM) is an orally bioavailable levels (as a surrogate marker of clinical benefit) seen in a farnesoid-X receptor (FXR) agonist [1]. It is semisynthetic phase III trial in patients with primary biliary cholangitis derivative of the primary human chenodeoxy- [5]. The recommended starting dosage of oral obeticholic , a natural FXR agonist [2]. The drug has been acid is 5 mg once daily. If adequate reduction in ALP and/ developed by Intercept Pharmaceuticals for the treatment or total bilirubin has not been achieved after 3 months’ of various liver diseases, including , primary treatment, and the patient is tolerating the drug, the dosage biliary cholangitis, non-alcoholic fatty , non- may be increased to 10 mg once daily [1]. alcoholic steatohepatitis, and primary sclerosing cholangi- Orphan drug designation for obeticholic acid in primary tis [3, 4]. FXR is a nuclear receptor expressed in the liver biliary cholangitis has been granted in the USA and EU; fast track designation in primary biliary cholangitis was granted in the USA in May 2014. In December 2014, a This profile has been extracted and modified from the AdisInsight rolling NDA submission for accelerated approval of database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and obeticholic acid in primary biliary cholangitis was initiated clinical studies to market launch and beyond. and the phase IIIb COBALT confirmatory clinical out- comes trial in patients with advanced disease commenced, & Susan J. Keam in accordance with FDA accelerated approval regulations. [email protected] Phase II and III trials of obeticholic acid in non-alcoholic 1 Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, steatohepatitis and phase II trials of the drug in alcoholic New Zealand A. Markham, S. J. Keam

Granted Orphan Drug status in the EU (Jan)

Granted priority review in the USA (Aug)

Granted Fast Track designation in the USA (May) Phase I clinical trials initiated (May) PDUFA action date extended Granted Orphan Drug status in the USA (Apr) by US FDA (Feb)

Phase II clinical trials initiated (Oct) Phase III clinical trials initiated (Jan) Approved in the USA (May)

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Jan 2012 Phase III POISE (NCT01473524) Est Jun 2018 Dec 2014 Phase III COBALT (NCT02308111) Est Apr 2023

Key milestones in the development of obeticholic acid for the treatment of primary biliary cholangitis. Est estimated date of completion, PDUFA User Fee Act hepatitis, primary sclerosing cholangitis, and biliary atresia 2 Scientific Summary are underway in several countries. 2.1 Pharmacodynamics 1.1 Company Agreements Obeticholic acid is a potent and selective agonist of FXR

Intercept Pharmaceuticals has granted Dainippon Sumit- (EC50 99 nmol/L). It is highly lipophilic, but has no omo Pharma an exclusive licence to obeticholic acid in intrinsic cholestatic activity [7]. In rat models of Japan, China and Korea for the treatment of chronic liver [7] and liver fibrosis [8, 9], obeticholic acid diseases. Dainippon will focus initially on primary biliary demonstrated anticholeretic activity (preventing impair- cholangitis and non-alcoholic steatohepatitis. Intercept will ment of bile flow) [7] and reversed fibrosis and receive from Dainippon an initial payment of $US15 mil- and decreased [8, 9]. lion and is eligible to receive approximately $US300 mil- lion milestone payment, plus a double-digit royalty on 2.2 Pharmacokinetics sales. Dainippon has an option to licence in other Asian countries, including Taiwan, and for additional indications. Multiple once daily oral 10 mg doses of obeticholic acid

Dainippon is responsible for the costs of developing and produced maximum plasma concentrations (Cmax) after commercialising the drug in its territory [3].

H 1.2 Patent Information O

Intercept Pharmaceuticals owns six US patents, four pending US patent applications and corresponding foreign H OH patents and patent applications. Foreign patents covering H H obeticholic acid are granted in the EU, Switzerland, Liechtenstein, Australia, Canada, China, Israel, Japan and Macao. The composition of matter patent is expected to H H expire in 2022. Intercept Pharmaceuticals has patent exclusivity for HO OH obeticholic acid, which is expected to expire through 2028. HHH The additional pending composition of matter patent is expected to expire in 2033. Chemical Structure of Obeticholic Acid Obeticholic Acid: First Global Approval

Features and properties of obeticholic acid Alternative names 6-ECDCA; 6a-ethyl ; DSP-1747; INT-747; OCA; Ocaliva Class Cholic acids; pentanoic acids; small molecules Mechanism of Farnesoid X-activated receptor agonists action Route of Oral administration

Pharmacodynamics EC(50) for FXR 99 nmol/L

Pharmacokinetics tmax 10 h, volume of distribution 618 L Adverse events Most frequent Pruritus, fatigue, abdominal pain and discomfort Occasional Rash, arthralgia, oropharyngeal pain Rare Eczema ATC codes WHO ATC code A05 (bile and liver therapy); A05A (bile therapy); A05A-A (bile acid preparations); A05B-A (liver therapy); A07E (intestinal anti-inflammatory agents); A10X (other drugs used in diabetes); C02K-X (other antihypertensives); C10A-C (bile acid sequestrants) EphMRA ATC A10X (other drugs used in diabetes); A5A (bile therapy and cholagogues); A5A2 (bile stone therapy) A5B (hepatic code protectors, lipotropics); A7E (intestinal anti-inflammatory agents); C10A9 (all other cholesterol/triglyceride regulators); C2A3 (antihypertensives plain, others) Chemical name (R)-4-[(R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-Ethyl-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-17-yl]pentanoic acid

(median) &1.5 h (tmax). The median tmax for two active The pharmacokinetic properties of obeticholic acid are metabolites, glyco- and tauro-obeticholic acid, was 10 h. not expected to be altered according to age, gender, eth- Absorption of obeticholic acid was not affected by con- nicity or renal function based on population pharmacoki- comitant administration with food [1]. netic analyses [1]. Hepatic impairment increases plasma Systemic exposure to the drug increased in a dose pro- exposure to obeticholic acid and its active metabolites, and portional manner after administration of obeticholic acid 5, dosage adjustment is recommended in patients with mod- 10 and 25 mg once daily (2.5 times the highest recom- erate to severe (Child–Pugh Classes B and C), but not mild mended dosage) for 14 days. Exposure to the glyco- and (Child–Pugh Class A), hepatic impairment [1]. tauro-obeticholic acid metabolites and total obeticholic acid (obeticholic acid plus the two active metabolites), 2.3 Drug Interactions however, increased more than dose proportionally; after daily administration of obeticholic acid the metabolite-to- Obeticholic acid absorption, systemic exposure and effi- parent ratios of - and -obeticholic acid were cacy may be reduced by the coadministration of bile acid 13.8 and 12.3, respectively. Human plasma protein binding binding resins (e.g. cholestyramine, colestipol, or cole- of obeticholic acid and its conjugates is [99 % and the sevelam), which reduce bile acid absorption. On this basis volume of distribution is 618 L [1]. it is recommended that obeticholic acid is taken C4h Obeticholic acid is conjugated with glycine or taurine in before or 4 h after a bile acid binding resin, or at as great an the liver to form glyco- and tauro-obeticholic acid, which interval as possible [1]. are secreted into bile. These metabolites may be absorbed Concomitant administration of obeticholic acid and in the small intestine, leading to enterohepatic recircula- warfarin decreases the International Normalised Ratio tion. Furthermore, microorganisms in the ileum and colon (INR); monitoring of the INR, and warfarin dosage can deconjugate glyco- and tauro-obeticholic acid, con- adjustment to maintain the target INR range, is required verting them into the parent drug, which may then be when these drugs are coadministered. Obeticholic acid may reabsorbed or excreted in faeces. The latter is the primary increase exposure to drugs that are CYP1A2 substrates route of elimination, accounting for &87 % of a radiola- when coadministered; therapeutic monitoring of CYP1A2 belled dose of the drug [1]. substrates that have a narrow therapeutic index (e.g. A. Markham, S. J. Keam

Key clinical trials of obeticholic acid Drugs(s) Sponsor/ Indication Phase Status Location(s) Identifier initiator

Obeticholic acid, placebo Investigator Nonalcoholic II Completed US NCT01265498 steatohepatitis Obeticholic acid, placebo Investigator Lipodystrophy II Planned (not yet US NCT02430077 recruiting) Obeticholic acid, placebo Intercept Nonalcoholic III Recruiting Multinational NCT02548351 steatohepatitis Obeticholic acid Investigator Bile acid diarrhoea II Completed UK NCT01585025 Obeticholic acid, placebo Investigator Alcoholic hepatitis II Recruiting US NCT02039219 Obeticholic acid, placebo Investigator Bariatric and II Recruiting Sweden NCT01625026 disease Obeticholic acid, atorvastatin, Intercept Nonalcoholic II Recruiting US NCT02633956 placebo steatohepatitis Obeticholic acid, placebo Intercept Primary biliary III Recruiting Multinational NCT02308111 cholangitis Obeticholic acid Intercept Effects on lipoprotein II Ongoing US NCT01865812 metabolism Obeticholic acid, placebo Intercept Primary biliary III Ongoing Multinational NCT01473524 cholangitis Obeticholic acid, placebo Intercept Primary sclerosing II Recruiting US, Italy NCT02177136 cholangitis Obeticholic acid, ursodeoxycholic Intercept Primary biliary II Completed Multinational NCT00550862 acid, placebo cholangitis theophylline and tizanidine) is recommended during con- 0.0001) reduced from baseline versus placebo in the comitant treatment [1]. obeticholic acid titration and obeticholic acid 10 mg/day groups, as were bilirubin levels (p\0.005) [10]. Following 2.4 Therapeutic Trials the double-blind phase, 193 patients entered a long term extension part of the trial; all received obeticholic acid at 2.4.1 Primary Biliary Cholangitis an initial dose of 5 mg/day with the option to increase this to 10 mg/day after 3 months based on response and toler- 2.4.1.1 Phase III Treatment with obeticholic acid pro- ability. After an additional 18 months of treatment, duced a durable improvement in hepatic biochemistry in improvements in ALP, GGT, ALT and AST levels seen in patients with primary biliary cholangitis who had not the obeticholic titration and obeticholic acid 10 mg/day responded adequately to, or were not able to tolerate, groups at the end of the 12-month double-blind phase were ursodeoxycholic acid, in the phase III POISE trial maintained and mean bilirubin levels did not increase [11]. (NCT01473524). 217 patients were initially randomised to 12 months’ treatment with once daily obeticholic acid 2.4.1.2 Phase II Treatment with obeticholic acid in 5–10 mg (dose titrated after 6 months based on response), combination with ursodeoxycholic acid significantly obeticholic acid 10 mg once daily or placebo. The primary reduced ALP, GGT and ALT levels compared to placebo in efficacy endpoint was achieving the Global Primary Biliary a double-blind phase II study (NCT00550862) in patients Cirrhosis Study Group (GPBCSG) ALP/bilirubin goal of with primary biliary cholangitis who had not responded ALP levels \1.67 9 ULN and normal bilirubin levels and adequately to treatment with ursodeoxycholic acid alone. an ALP reduction of C15 % at 12 months [10]. At the end The mean change in ALP levels from baseline was 24, 25, of this phase of the study, significantly more patients in the 21 and 3 % after up to 3 months’ treatment with obeticholic acid titration and obeticholic acid 10 mg/day ursodeoxycholic acid (mean daily dose at entry groups were responders (i.e. achieved the GPBCSG 15.6–16.3 mg/kg) plus obeticholic acid 10 (n = 38), 25 ALP/bilirubin goal and ALP reduction of C15 %) com- (n = 47) or 50 (n = 39) mg/day, or placebo (n = 37; pared with placebo recipients (46 and 47 vs 10 %; both p\ p \ 0.0001 vs all obeticholic acid doses). These reductions 0.0001). ALP, gamma-glutamyl transferase (GGT) and in ALP were maintained after C12 months’ follow up in 78 aspartate transaminase (AST) levels were significantly (p\ patients who enrolled in an open-label follow-up study [12]. Obeticholic Acid: First Global Approval

In a double-blind, placebo-controlled phase II study 10.8 % (p = 0.076) after treatment with obeticholic acid (NCT00570765 [201]) in patients with primary biliary 25 or 50 mg once daily, respectively, compared with a cholangitis, 12 weeks’ treatment with obeticholic acid 10 5.4 % decrease in placebo recipients [2]. or 50 mg/day as monotherapy reduced ALP levels by 39–45 %. In the 28 patients who completed the double- 2.4.3 Chronic Bile Acid Diarrhoea blind phase and were enrolled in an open-label long-term extension trial, obeticholic acid was given either at the In the investigator-initiated phase II OBADIAH1 trial dosage received during the double-blind phase, or at a dose (NCT01585025) treatment with obeticholic acid increased of 10 mg/day with the option to titrate up to a maximum levels of FGF19 and reduced bile acid synthesis in patients dose of 50 mg/day; treatment with ursodeoxycholic acid with primary bile acid diarrhoea (n = 10). Median stool could also be added. After C 4.5 years’ follow up, mean frequency, stool form and diarrhoea index were reduced by ALP levels were reduced by 244 U/L (p = 0.003 vs 24, 14 and 34 %, respectively (p B 0.05 for each), after 2 baseline) in all 19 patients who remained enrolled, and by weeks treatment with obeticholic acid 25 mg/day. Bile 182 U/L in 11 patients who continued to receive obeti- acids reduced from 1.5 to 0.9 lmol/L (p = 0.13; fasting) cholic acid without concomitant ursodeoxycholic acid and 34.5 to 20.9 lmol/L (p = 0.02; 6 h response AUC). (p = 0.01 vs baseline). GGT levels were reduced by Bile acids (6 hour response AUC) decreased from 32 to 317 U/L (p = 0.002 vs baseline) and 235 U/L (p = 0.02 22 lmol/L (p = 0.04) in a second group of patients with vs baseline) respectively, ALT by 37 U/L (p = 0.001 vs secondary bile acid diarrhoea (n = 10), however, fasting baseline) and 32 U/L (p = 0.005) respectively, and AST FGF19 and C4 levels were not significantly improved [14]. by 22 U/L (p = 0.005 vs baseline) and 17 U/L (p = 0.02 vs baseline), respectively [13]. 2.5 Adverse Events

2.4.2 Non-Alcoholic Steatohepatitis The most common adverse events in patients with primary biliary cholangitis treated with obeticholic acid in the phase Treatment with obeticholic acid 25 mg once daily III POISE trial were pruritus (70, 56 and 38 % in obeti- improved the histological features of non-alcoholic cholic acid 10 mg/day [n = 73], obeticholic acid titrated steatohepatitis compared to placebo in the National Insti- [n = 70] and placebo [n = 73] recipients, respectively), tute of Diabetes and Digestive and Kidney Diseases fatigue (25, 19 and 15 %) and abdominal pain and dis- (NIDDK)-sponsored phase II FLINT trial [6]. After 72 comfort (10, 19 and 14 %). Other adverse events included weeks’ treatment, 50 of 110 (45 %) obeticholic acid rash (10, 7 and 8 %), arthralgia (10, 6 and 4 %), oropha- recipients had improved centrally-scored liver histology ryngeal pain (8, 7 and 1 %), dizziness (7, 7 and 5 %), (C2-point decrease in non-alcoholic constipation (7, 7 and 5 %), peripheral oedema (7, 3 and activity score, without worsening of fibrosis) compared 3 %) palpitations (7, 3 and 1 %), pyrexia (7, 0 and 1 %), with 23 of 109 (21 %) recipients in the placebo group thyroid function abnormality (4, 6 and 3 %) and eczema (3, (p = 0.0002). Resolution of definite non-alcoholic steato- 6 and 0 %) [1]. hepatitis was observed in 22 of 102 (22 %) obeticholic acid Severe pruritus—defined as intense or widespread - and 13 of 98 (13 %) placebo recipients who had biopsy ing, interfering with activities of daily living, or causing specimens taken at baseline and 72 weeks [6]. severe sleep disturbance, or intolerable discomfort, and typically requiring medical intervention—occurred in 23, 2.4.2.1 In Patients with Type 2 Diabetes Six weeks’ 19 and 7 % of obeticholic acid 10 mg/day, obeticholic acid treatment with obeticholic acid increased insulin sensitivity titrated and placebo recipients, respectively [1]. and reduced markers of liver inflammation and fibrosis in Serious or otherwise clinically significant liver-related patients with type 2 diabetes and nonalcoholic fatty liver adverse events included ascites in one patient in the disease in a placebo-controlled phase II trial obeticholic acid 10 mg/day group, two episodes of ascites (NCT00501592) [2]. All patients underwent a two-step and four episodes of hepatic encephalopathy in one patient (low and high dose) hyperinsulinaemic-euglycaemic clamp in the obeticholic acid titrated group and variceal bleeding procedure before the first and after the last dose of obeti- in one patient in the placebo group [1]. cholic acid or placebo. With low dose insulin, the glucose infusion rate (insulin sensitivity) increased by 28 % 2.6 Ongoing Clinical Trials (p = 0.19) and 20.1 % (p = 0.06) with obeticholic acid 25 or 50 mg once daily, respectively, compared with a 5.5 % Phase III studies are underway to further investigate the reduction in placebo recipients. With high dose insulin, safety and efficacy of obeticholic acid in patients with insulin sensitivity increased by 18.3 % (p = 0.036) and primary biliary cirrhosis (COBALT [NCT02308111]) and A. Markham, S. J. Keam non-alcoholic steatohepatitis (REGENERATE obeticholic acid for the treatment of primary biliary cirrhosis [NCT02548351]) [15]. [media release]. Jun 29 2015. http://ir.interceptpharma.com/ releasedetail.cfm?releaseid=919926. Phase II studies are under way to investigate the effects 5. US Food and Drug Administration. FDA approves Ocaliva for of combined obeticholic acid and atorvastatin in patients rare, chronic liver disease [media release]. May 31 2016. http:// with nonalcoholic steatohepatitis (CONTROL www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ [NCT02633956]), the efficacy and safety of obeticholic ucm503964.htm. 6. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid acid in patients with primary sclerosing cholangitis X nuclear receptor ligand obeticholic acid for non-cirrhotic, non- (AESOP, [NCT02177136]) and the effects of obeticholic alcoholic steatohepatitis (FLINT): a multicentre, randomised, acid in paediatric patients with biliary atresia (EudraCT placebo-controlled trial. Lancet. 2015;385:956–65. number 2014-004693-42). 7. Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-chen- odeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45(17):3569–72. 3 Current Status 8. Albanis E, Alvarez CE, Pruzansky M, et al. INT-747, a novel FXR activator, reverses hepatic fibrosis and cirrhosis in thioac- etamide-induced liver injury in rats [abstract no. 1040]. Hepa- Obeticholic acid received its first global approval on the tology. 2005;42(Suppl 1):605–6. 27th of May 2016 in the USA for primary biliary 9. Verbeke LD, Mannaerts I, Schierwagen R, et al. Obeticholic acid, cholangitis. an FXR agonist, reduces hepatic fibrosis in a rat model of toxic cirrhosis [abstract no. P0445]. J Hepatol. 2015;62(Suppl 2):S479. Compliance with ethical standards 10. Nevens F, Andreone P, Mazzella G, et al. An international phase 3 study of the FXR agonist obeticholic acid in PBC patients: Conflict of interest The preparation of this review was not supported effects on markers of cholestasis associated with clinical out- by any external funding. During the peer review process the manu- comes and hepatocellular damage [abstract no. 295]. Hepatology. facturer of the agent under review was offered an opportunity to 2014;60(Suppl 4):347A–8A. comment on the article. Changes resulting from any comments 11. Trauner MH, Nevens F, Andreone P, et al. Durable response in received were made by the authors on the basis of scientific com- the markers of cholestasis through 18 months of open-label long pleteness and accuracy. A. Markham is a contracted employee of term safety extension study of obeticholic acid in primary biliary Adis, Springer SBM. Susan J. Keam is a salaried employee of Adis, cirrhosis [abstract no. Sa1579]. Gastroenterology. 2016;150(4 Springer SBM. Suppl 1):S1073–4. 12. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeti- cholic acid in patients with primary biliary cirrhosis and inade- quate response to ursodeoxycholic acid. Gastroenterology. References 2015;148(4):751–61. 13. Kowdley KV, Shah H, Mason A, et al. Long-term safety and 1. Intercept Pharmaceuticals. OCALIVA (obeticholic acid) US efficacy of obeticholic acid treatment in primary biliary cirrhosis Prescribing Information. 2016. http://www.interconnectsupport. after more than 4 years of treatment [abstract no. 628]. Hepa- com/ocaliva_pi.pdf. Accessed 31 May 2016. tology. 2015;62(Suppl 1):521A–2A. 2. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of 14. Walters JR, Johnston IM, Nolan JD, et al. The response of the agonist obeticholic acid in patients with patients with bile acid diarrhoea to the farnesoid X receptor type 2 diabetes and nonalcoholic fatty liver disease. Gastroen- agonist obeticholic acid. Aliment Pharmacol Ther. terology. 2013;145(3):574–82. 2015;41(1):54–64. 3. Dainippon Sumitomo Pharma Co L, Intercept Pharmaceuticals I. 15. Ratziu V, Sanyal AJ, MacConell L, et al. Regenerate: a phase 3, Dainippon Sumitomo Pharma and Intercept Pharmaceuticals double-blind, randomized, placebo-controlled multicenter study announce agreement to develop and commercialize obeticholic of obeticholic acid therapy for nonalcoholic steatohepatitis [ab- acid (INT-747) for chronic liver disease [media release]. 30 Mar stract no. THU-488]. J Hepatol. 2016;64(Suppl 2):S294–5. 2011. http://www.interceptpharma.com. 4. Intercept Pharmaceuticals Inc. Intercept Pharmaceuticals submits applications in the U.S. and Europe for marketing approval of