Delving into the Latest Updates on Obeticholic acid with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(3α,5β,6α,7α)-6-ethyl-3,7-dihydroxycholan-24-oic acid, 6-Ethyl-CDCA, 6-ethyl-chenodeoxycholic-acid

+ [10]

Target

FXR

Mechanism

FXR agonists(Bile acid receptor FXR agonists)

Therapeutic Areas

Digestive System DisordersOther DiseasesCongenital Disorders

Active Indication

Primary Biliary CholangitisLiver Cirrhosis, BiliaryFibrosis, Liver+ [4]

Inactive Indication

Bile acid malabsorptionBile Acid Malabsorption, PrimaryCholangitis, Sclerosing+ [9]

Originator Organization

Intercept Pharmaceuticals, Inc.

Active Organization

Intercept Pharmaceuticals, Inc.

Hangzhou Minsheng Pharmaceutical Co., Ltd.

Advanz Pharma Corp. Ltd.

Inactive Organization

National Institute on Alcohol Abuse & Alcoholism

Sahlgrenska Universitetssjukhuset

Imperial College Healthcare NHS Trust

+ [1]

Drug Highest PhaseApproved

First Approval Date

US (27 May 2016),

Liver Cirrhosis, Biliary

RegulationPriority Review (US), Breakthrough Therapy (US), Fast Track (US), Accelerated Approval (US), Orphan Drug (US)

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Structure

Molecular FormulaC26H44O4

InChIKeyZXERDUOLZKYMJM-ZWECCWDJSA-N

CAS Registry459789-99-2

This study will evaluate the efficacy, safety and tolerability, as well as PK/PD of OCA in eligible pediatric participants with biliary atresia with successful hepatoportoenterostomy (HPE, also known as a Kasai portoenterostomy). The double-blind period comprises of 2 phases: dose titration phase and age expansion treatment phase.

Start Date01 Mar 2024

Sponsor / Collaborator

Intercept Pharmaceuticals, Inc.

CTR20233711 / RecruitingPhase 3

奥贝胆酸片治疗原发性胆汁性胆管炎的有效性和安全性研究

[Translation] Study on the efficacy and safety of obeticholic acid tablets in the treatment of primary biliary cholangitis

评价奥贝胆酸片治疗原发性胆汁性胆管炎（PBC）的有效性和安全性。

[Translation]

To evaluate the efficacy and safety of obeticholic acid tablets in the treatment of primary biliary cholangitis (PBC).

Start Date12 Jan 2024

Sponsor / Collaborator

Hangzhou Minsheng Pharmaceutical Co., Ltd.

NCT04939051 / RecruitingPhase 2IIT

Obeticholic Acid for Prevention in Barrett's Esophagus

This phase II trial studies the effect of obeticholic acid in treating patients with Barrett's esophagus. Bile acids present in duodenogastroesophageal reflux contribute to neoplastic progression in Barrett's esophagus. Obeticholic acid has shown anti-cholestatic, anti-inflammatory and anti-fibrotic effects mediated by FXR activation. It down regulates bile acid availability and decreases proinflammatory cytokine production including IL-1beta and TNFalpha in human enterocytes and immune cells. This chain of events reduces the bile acid exposure in esophagus tissue thereby limiting bile acid induced damage and dysplastic progression.

Start Date03 Jan 2024

Sponsor / Collaborator

National Cancer Institute

100 Clinical Results associated with Obeticholic acid

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100 Translational Medicine associated with Obeticholic acid

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100 Patents (Medical) associated with Obeticholic acid

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1,692

Literatures (Medical) associated with Obeticholic acid

01 Mar 2024·Medicinal research reviews

FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid

Review

Author: Wang, Kang ; Wang, Guangji ; Hao, Haiping ; Zhang, Yuecan ; Wang, Hong

Abstract:

Nonalcoholic fatty liver disease, also called metabolic dysfunction‐associated steatotic liver disease, is the most common liver disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on metabolic regulation, inflammation suppression, cell death prevention, and fibrogenesis inhibition, farnesoid X receptor (FXR) is widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or called metabolic dysfunction‐associated steatohepatitis (MASH). Many FXR agonists have been developed for NASH/MASH therapy. Obeticholic acid (OCA) is the pioneering frontrunner FXR agonist and the first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval as a NASH pharmacotherapy because its moderate benefits did not outweigh its safety risks, which may cast a shadow over FXR‐based drug development for NASH/MASH. This review summarizes the milestones in the development of OCA for NASH/MASH and discuss its limitations, including moderate hepatoprotection and the undesirable side effects of dyslipidemia, pruritus, cholelithiasis, and liver toxicity risk, in depth. More importantly, we provide perspectives on FXR‐based therapy for NASH/MASH, hoping to support a successful bench‐to‐clinic transition.

01 Feb 2024·Bioorganic chemistry

Discovery of LH10, a novel fexaramine-based FXR agonist for the treatment of liver disease

Article

Author: Jiao, Shixuan ; Wang, Wenxin ; Huang, Wanqiu ; Yang, Zhongcheng ; Chen, Ya ; Zhang, Luyong ; Cao, Zhijun ; Li, Zheng ; Chen, Siliang

Farnesoid X receptor (FXR) was considered as a promising drug target in the treatment of cholestasis, drug-induced liver injury, and non-alcoholic steatohepatitis (NASH). However, the existing FXR agonists have shown different degrees of side effects in clinical trials without clear interpretation. MET-409 in clinical phase Ⅲ, has been proven significantly fewer side effects than that of other FXR agonists. This may be due to the completely different structure of FEX and other non-steroidal FXR agonists. Herein, the structure-based drug design was carried out based on FEX, and the more active FXR agonist LH10 (FEX EC₅₀ = 0,3 μM; LH10 EC₅₀ = 0.14 μM)) was screened out by the comprehensive SAR studies. Furthermore, LH10 exhibited robust hepatoprotective activity on the ANIT-induced cholestatic model and APAP-induced acute liver injury model, which was even better than positive control OCA. In the nonalcoholic steatohepatitis (NASH) model, LH10 significantly improved the pathological characteristics of NASH by regulating several major pathways including lipid metabolism, inflammation, oxidative stress, and fibrosis. With the above attractive results, LH10 is worthy of further evaluation as a novel agent for the treatment of liver disorders.

01 Feb 2024·Experimental eye research

TYR mutation in a Chinese population with oculocutaneous albinism: Molecular characteristics and ophthalmic manifestations

Article

Author: Li, Jun ; Wang, Bingqi ; Chen, Chonglin ; Yu, Xinping ; Wang, Yinghuan

Oculocutaneous albinism (OCA) is a rare inherited disorder characterized by a partial or complete reduction of melanin biosynthesis that leads to hypopigmentation in the skin, hair and eyes. The OCA1 subtype is caused by mutations in TYR. The purpose of this study was to investigate the genetic and clinical ophthalmic characteristics of TYR mutations in patients with OCA. Herein, 51 probands with a clinical diagnosis of OCA were enrolled. Whole-exome sequencing and comprehensive ophthalmic examinations were performed. Overall, TYR mutations were detected in 37.3% (19/51) in the patients with OCA. Fifteen patients had compound heterozygous variants, and four cases had homozygous variants. Eleven different pathogenic variants in TYR were detected in these 19 patients, with missense, insertion, delins and nonsense in 71.1% (27/38), 15.8% (6/38), 2.6% (1/38), and 10.5% (4/38), respectively. Clinical examinations revealed that 84.2% (16/19) of patients were OCA1A, and 15.8% (3/19) were OCA1B. Most TYR probands (52.6%, 10/19) had moderate vision impairment, 15.8% (3/19) had severe visual impairment, 10.5% (2/19) exhibited blindness, only 5.3% (1/19) had mild visual impairment and 15.8% (3/19) were not available. Photophobia and nystagmus were found in 100% (19/19) of the patients. In addition, grade 4 foveal hypoplasia was detected in 100% (12/12) of the patients. In conclusion: The TYR patients exhibited severe ocular phenotypes: the majority (93.8%, 15/16) of them had a moderate vision impairment or worse, and 100% (12/12) had severe grade 4 foveal hypoplasia. These novel findings could provide insight into the understanding of OCA.

139

News (Medical) associated with Obeticholic acid

25 Jun 2024

·www.echemi.com

Emerging PBC Treatments: The Fourth Novel Therapy Set to Lead the Market

In recent years, the treatment of primary biliary cholangitis (PBC) has seen remarkable progress, with the continuous introduction of new drugs bringing good news to PBC patients worldwide. According to reports from authoritative institutions, the global PBC treatment market is thriving and is expected to experience explosive growth in the coming years. However, despite the fact that three PBC treatment drugs have already been approved, the market still has a significant unmet need, and the industry's expectations for new therapeutic drugs are becoming increasingly urgent. First, let's understand the three PBC treatment drugs currently on the market. Ursodeoxycholic acid (UDCA) is the recognized first-line treatment drug and has been widely used in clinical practice for many years. However, it is regrettable that about 40% of patients do not respond well to this treatment, leaving them in urgent need of more effective treatment options. Against this backdrop, Ocaliva and Elafibranor emerged, being approved as second-line treatment options for PBC in 2016 and 2021, respectively. The introduction of these two drugs has undoubtedly brought new hope to PBC patients. However, market competition has not stopped. Industry insiders generally believe that Seladelpar has the potential to become the fourth novel PBC drug approved globally. Seladelpar is an oral, potent, and selective PPARδ agonist, and its unique mechanism of action gives it significant advantages in regulating bile acid synthesis, inflammation, fibrosis, and lipid metabolism. Based on preclinical and clinical data, Seladelpar has demonstrated good efficacy and safety in the treatment of PBC. Currently, the drug is undergoing priority review in the United States and is expected to receive approval for marketing in August 2024. At that time, it is expected to bring a safer and more effective treatment option to PBC patients worldwide. In addition to Seladelpar, the industry is also paying attention to other PBC drug candidates in development. For example, Setanaxib is a new drug that targets NOX4 and NOX1, and it has unique potential in the field of PBC treatment. Furthermore, domestic pharmaceutical companies are also actively engaged in the development of PBC drug research, such as the dual-target peptide drug TB001 developed by a well-known pharmaceutical company. The successive launch of these candidate drugs will bring new development opportunities to the PBC treatment market. It is worth mentioning that with the advancement of technology and the depth of research, the PBC treatment field is facing unprecedented development opportunities. More and more new drugs and new technologies are emerging, bringing more treatment options to PBC patients. At the same time, as global medical standards improve and medical resources are optimized, the treatment experience of PBC patients will also be significantly improved. We have reason to believe that in the near future, PBC patients will be able to enjoy safer, more effective, and more convenient treatment services.

Priority ReviewDrug Approval

11 Jun 2024

·www.fiercepharma.com

Ipsen, Genfit gain FDA approval for Iqirvo in liver disorder, teeing up Intercept showdown

Three years after Ispen licensed elafibranor from Genfit, it has gained FDA approval to treat the rare liver disorder primary biliary cholangitis (PBC). Once hyped as a potential blockbuster medicine for metabolic-associated steatohepatitis (MASH), Ipsen and Genfit’s elafibranor has found its calling as a treatment for a lower-profile liver disorder. The FDA has approved Iqirvo for primary biliary cholangitis (PBC), a chronic autoimmune condition which affects approximately 100,000 people in the U.S., most of them women between the ages of 30 and 60. PBC causes a buildup of bile and toxins, leading to inflammation and fibrosis of the liver. Over time, patients become increasingly fatigued and develop a debilitating itch (pruritis). In the absence of treatment, the condition can require a liver transplant or lead to premature death. Ipsen will charge $11,500 for a month’s supply of the first-in-class peroxisome proliferator-activated receptor (PPAR) agonist. After weak data eliminated elafibranor as a potential candidate for MASH, Ipsen in-licensed it from Genfit in 2021 as a treatment for PBC for 480 million euros ($515 million). The FDA endorsement is an accelerated nod, based on data showing that an 80 mg tablet of elafibranor reduces the rate of production of the alkaline phosphatase (ALP) enzyme—a key biomarker indicating the extent of liver damage. Achievement of a full approval will depend on success in confirmatory trials determining whether Iqirvo can improve survival and prevent abdominal swelling or gastrointestinal bleeding. The approval sets the two French companies up to compete with Intercept Pharmaceuticals’ Ocaliva, which has been on the market for eight years. Before Intercept was acquired by Italian private company Alfasigma last year, it expected sales of Ocaliva in 2023 to reach between $320 million and $340 million. Analysts estimate (PDF) sales of Iqirvo to reach 193 million euros ($207 million) in 2027. Peak sales have been tabbed at 400 million euros ($429 million). Alfasigma made its buyout of New Jersey-based Intercept shortly after the FDA rejected a bid for approval of Ocaliva in MASH for the second time in three years. Both Iqirvo and Ocaliva are approved for PBC in combination with ursodecxycholic acid (UDCA) or as a monotherapy in patients that can not take UDCA. Analysts at ODDO BHF said that the approval for Ipsen “marks a success story in the active business development policy since the appointment of current CEO David Loew in 2020,” and raises hopes for other partnerships. In regard to Iqirvo, however, one warning ODDO BHF had for investors is the lack of a reduction in pruritis on the label. The characteristic has “been seen as a weakness of Iqirvo,” the analysts wrote, especially in comparison to another drug expected to be approved in the indication in August—CymaBay Therapeutics’ seladelpar. In February of this year, Gilead gained the asset with a $4.3 billion buyout of CymaBay.

Drug ApprovalAcquisitionExecutive Change

11 Jun 2024

·www.biopharmadive.com

Ipsen drug for rare liver disease approved by FDA

Dive Brief:The Food and Drug Administration on Monday cleared a new treatment option for the rare liver disease primary biliary cholangitis, granting an accelerated approval to Ipsens drug Iqirvo.The agencys OK was based on clinical trial data showing treatment with Iqirvo improved certain biochemical markers for cholestasis, or the accumulation in the liver of bile and toxins. In people with primary biliary cholangitis, or PBC, this build-up and its associated inflammation causes scarring and damages bile ducts.Iqirvos place on the market is contingent on Ipsen proving in follow-up testing that changes in cholestasis markers lead to improved survival or prevent liver decompensation.Dive Insight:Iqirvos approval gives people with PBC another treatment option beyond Intercept Pharmaceuticals Ocaliva, which was approved in 2016 as the first new drug for the disease in two decades.The other approved medicine, ursodeoxycholic acid or UDCA, is effective in some patients, but others dont respond well or are unable to tolerate the drugs side effects. The FDAs approvals for Ocaliva in 2016 and for Iqirvo Monday specify use in combination with UDCA for adults who have an inadequate response to that medicine, or as monotherapy in those people who cant take UDCA.Intercept, which last year agreed to sell to the Italian company Alfasigma, is seeking to confirm Ocalivas 2016 approval with follow-up data from post-marketing studies and real-world use. An FDA decision on full approval is expected by Oct. 15.Iqirvo and Ocaliva work differently, but both were cleared based on their ability to reduce levels of an enzyme called ALP in the blood. Data from the trial supporting Iqirvos approval showed that 51% of treated study participants met the main goal of a biochemical response, compared to only 4% of those given a placebo. ALP levels were normalized in 15% of people who received Iqirvo, versus none in the placebo group.Iqirvos labeling warns of a wide range of side effects, including muscle pain, myopathy, rhabdomyolysis, fractures and drug-induced liver injury. Based on animal data, the label also cautions of the potential for fetal harm in people who are pregnant.Ocaliva also comes with significant cautions, including a black box warning for hepatic decompensation and failure in people with PBC thats led to cirrhosis.The two drugs may soon be joined by another therapy from CymaBay Therapeutics, which was recently acquired by Gilead Sciences in a $4.3 billion deal. That medicine is currently under FDA review, with a decision set for mid-August.PBC is thought to affect about 100,000 people in the U.S. It causes progressive damage and typically is associated with severe fatigue and intense itching.Ipsen licensed Iqirvo three years ago from Genfit, which is owed about 50 million euros in a milestone payment timed to the drugs first commercial sale. '

AcquisitionDrug ApprovalAccelerated Approval

100 Deals associated with Obeticholic acid

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External Link

KEGG	Wiki	ATC	Drug Bank
D09360	Obeticholic acid	A05AA04	DB05990

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Primary Biliary Cholangitis	EU	Advanz Pharma Corp. Ltd.	12 Dec 2016
Primary Biliary Cholangitis	IS	Advanz Pharma Corp. Ltd.	12 Dec 2016
Primary Biliary Cholangitis	LI	Advanz Pharma Corp. Ltd.	12 Dec 2016
Primary Biliary Cholangitis	NO	Advanz Pharma Corp. Ltd.	12 Dec 2016
Liver Cirrhosis, Biliary	US	Intercept Pharmaceuticals, Inc.	27 May 2016

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis, Liver	NDA/BLA	US	Intercept Pharmaceuticals, Inc.	20 Jan 2023
Nonalcoholic Steatohepatitis	NDA/BLA	US	Intercept Pharmaceuticals, Inc.	20 Sep 2019
Biliary Atresia	Phase 3	-	Intercept Pharmaceuticals, Inc.	01 Mar 2024
Compensated cirrhosis	Phase 3	US	Intercept Pharmaceuticals, Inc.	30 Aug 2017
Compensated cirrhosis	Phase 3	AU	Intercept Pharmaceuticals, Inc.	30 Aug 2017
Compensated cirrhosis	Phase 3	CA	Intercept Pharmaceuticals, Inc.	30 Aug 2017
Compensated cirrhosis	Phase 3	FR	Intercept Pharmaceuticals, Inc.	30 Aug 2017
Compensated cirrhosis	Phase 3	DE	Intercept Pharmaceuticals, Inc.	30 Aug 2017
Compensated cirrhosis	Phase 3	HU	Intercept Pharmaceuticals, Inc.	30 Aug 2017
Compensated cirrhosis	Phase 3	NZ	Intercept Pharmaceuticals, Inc.	30 Aug 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04594694 (747-213, GlobeNewswire) Manual	Phase 2	Primary Biliary Cholangitis	75	bezafibrate 400 mg SR + OCA 5 mg titrated to 10 mg at week 4	dqtsgvxpqz(lerilfivms) = geatrnlaqb lvexhnzoqs (jxeuqnmqkw ) View more	Positive	18 May 2024
				bezafibrate 200 mg IR + OCA 5 mg titrated to 10 mg at week 4	dqtsgvxpqz(lerilfivms) = hyagrfmjrm lvexhnzoqs (jxeuqnmqkw ) View more
NCT02430077 (CTgov)	Phase 2	Lipodystrophy, Familial Partial	10	Obeticholic Acid	rrypmchxrs(vsahmabasx) = dbltmxpvfx bmecobovqp (kwlhfomouz, ztgjhryeql - adkfterwao) View more	-	13 Dec 2023
REVERSE (AASLD2023)	Phase 3	Nonalcoholic Steatohepatitis \| Compensated cirrhosis	919	Placebo	gdyomiqaks(euiqcnehhw) = OCA resulted in reduced ALT levels vs placebo kbmrbamqfo (ubvvrbyyrf ) View more	-	10 Nov 2023
				OCA 10 mg
NCT03439254 (CTgov)	Phase 3	Fibrosis \| Nonalcoholic Steatohepatitis \| Compensated cirrhosis	919	placebo (DB: Placebo)	fxblbyyors(vjmshridqy) = epjiobbqlo dzohetcdtb (oyicubwgpr, qzarywedla - ihuyupewpj) View more	-	23 Oct 2023
				OCA (DB: OCA 10 Milligrams (mg))	fxblbyyors(vjmshridqy) = mizxloqwzs dzohetcdtb (oyicubwgpr, usqqfvfwzj - prigezrrmj) View more
NCT02548351 (REGENERATE, EASL2023)	Phase 3	Nonalcoholic Steatohepatitis	2,477	Placebo	deobvjdavt(uvesueymgg) = zehffifmpx koiztqlcha (jmnlhcmwvz, 17, 174)	-	21 Jun 2023
				OCA 10 mg	deobvjdavt(uvesueymgg) = vvmdfxizcr koiztqlcha (jmnlhcmwvz, 23, 154)
NCT02308111 (COBALT, CTgov)	Phase 4	Primary Biliary Cholangitis	334	Placebo	swrfrlmkdl(ipowrkhhpp) = xpqhntktwr deskmkilon (afggenkpjc, poruuycbua - irjnnotczl) View more	-	09 Mar 2023
NCT02548351 (REGENERATE, NASH_TAG2023)	Phase 3	Nonalcoholic Steatohepatitis \| Fibrosis	-	Placebo	ktjxepxnqa(agjlppmanf) = zypwgbvxvl cbxniaewht (kaqjmqnlbd )	Positive	05 Jan 2023
				OCA 25 mg	ktjxepxnqa(agjlppmanf) = weiungwmfl cbxniaewht (kaqjmqnlbd )
NASH_TAG2023	Phase 3	Nonalcoholic Steatohepatitis	931	Obeticholic acid 25 mg	wrsudiksqn(nrvqxhnkyj) = Pruritus was the most common TEAE pmixhzcura (keszmfxeyh ) View more	Positive	05 Jan 2023
				Placebo
NCT02308111 (COBALT, Corporate Publications) Manual	Phase 4	Primary Biliary Cholangitis	-	Obeticholic acid	xromsiezjc(qzpvahpjsc) = vioyygceoq bzrunheifs (qwtxefahtd ) View more	Positive	06 Nov 2022
				Placebo	xromsiezjc(qzpvahpjsc) = mwcvhswolu bzrunheifs (qwtxefahtd ) View more
NCT03633227 (CTgov)	Phase 4	Primary Biliary Cholangitis	22	Placebo (Placebo)	rymtcznnns(akqetgooxn) = tzsqfjtwot ctfdkgotyx (aajdayhmlw, qsnrmxwxnz - uqtzthvyfx) View more	-	06 Sep 2022
				Obeticholic Acid (OCA) (Obeticholic Acid (OCA))	rymtcznnns(akqetgooxn) = ewuwnxhdkn ctfdkgotyx (aajdayhmlw, xzsnptltzq - joapmyrwtk) View more