dm+d

34000511000001101

Lactation Safety Information

Yes
Ursodeoxycholic acid
No published evidence of safety
Low levels anticipated in milk due to very high protein binding
Low side effect profile in normal adult use
13 July 2017

New Medicines

Zektayos-HepjuvoNon-alcoholic steatohepatitis (NASH) with stage 2 or 3 liver fibrosis

Information

Zektayos-Hepjuvo
New formulation
Advanz Pharma
Intercept

Development and Regulatory status

Phase III Clinical Trials
Filing withdrawn
Not approved
Sep 22Despite the PIII REVERSE trial in patients with compensated cirrhosis failing to meet its primary outcome, Intercept expects to re-file in the US for its lead indication of liver fibrosis due to NASH by the end of the year. It will be supported a second analysis of data from the PIII REGENERATE study and is unaffected by the efficacy results of REVERSE [27].
May 22Intercept has licensed the rights to obeticholic acid outside of the US to Advanz Pharma. Intercept will continue to manufacture Ocaliva for use outside the US and Advanz will take over the responsibilities for its packaging, distribution and commercialisation [25].
Dec 21Intercept had been hoping to extend the review period in the EU to allow time for results from an ongoing to PIII trial, due Q1 22. It is in the process of generating additional efficacy and safety data from REGENERATE, including a full reread of month 18 biopsies using a new consensus biopsy reading approach, to support a potential refiling in the US. It will take a decision on refiling in Europe only after that new data comes in [24].
Dec 21Intercept withdraw EU filing [24].
Jul 21UK launch is delayed. Company has asked NICE to delay the start of its appraisal (until late April 2022) to allow them to prepare facilitate a suitably comprehensive and robust submission [23].
Aug 20Intercept Pharmaceuticals announces intention to re-submit to FDA for approval for NASH in 2021 [22].
Jun 20US FDA issues a complete response letter (CRL) to Intercept Pharmaceuticals regarding the NDA of obeticholic acid (OCA) for the treatment of fibrosis due to NASH. The agency has determined that predicted benefit of OCA based on a surrogate histopathologic endpoint remains uncertain and does not sufficiently outweigh the potential risks to support accelerated approval for the treatment of patients with liver fibrosis due to NASH. US FDA has recommended additional post-interim analysis efficacy and safety data from the ongoing REGENERATE study to support potential accelerated approval [22].
May 20FDA review of obeticholic acid delayed to June 26 2020 to accommodate review of additional data requested by the FDA that the company (Intercept) plans to submit next week [21].
Dec 19Filed In EU [20]
Nov 19FDA accept NDA with priority review for treatment of liver fibrosis due to NASH
Feb 19Filing for approval is expected in US and Europe by the end of 2019 [16].
Feb 18Intercept announced the initiation of the phase III REVERSE trial evaluating the efficacy and safety of obeticholic acid in subjects with compensated cirrhosis due to nonalcoholic steatohepatitis (NCT03439254. The company intends to file for the treatment of NASH patients with compendated cirrhosis, based on the results of this study, which is due to complete in October 2022 [14, 15].
Dec 17PIII REGENERATE study ongoing, with an estimated primary completion date of October 2021.
May 15Intercept announces enrolment will start in Q3 2015 in a PIII study in 2,500 pts with stage 2 or 3 liver fibrosis, designed to secure accelerated approval. The study´s primary goals are improving fibrosis by at least one stage without worsening NASH scores and resolving NASH symptoms without exacerbating scarring. Intercept has scheduled a 72-week interim analysis in which investigators will take a look at tissue samples from about 1,400 patients to chart how well OCA is doing against its primary endpoints, and Intercept expects that data to fuel its FDA and international regulatory filings [7].
Jan 15Granted breakthrough therapy designation for NASH by the US FDA [4].
Nov 14Intercept Pharmaceuticals expects to commence a PIII programme for obeticholic acid in patients with NASH in H1 2015, after discussing regulatory and clinical requirements with the US FDA and EMA [6].
Mar 11The US PII/III FLINT study started [1].

Category

First-in-class farnesoid X receptor (FXR) agonist derived from chenodeoxycholic acid
Non-alcoholic fatty liver disease (NAFLD) is accumulation of fat in the liver, which is not due to alcohol. When inflammation is present, it becomes non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. In Europe, prevalence of NAFLD is estimated at 20-30% in the general population and 2.6-10% in the paediatric population. Prevalence of NASH is approximately 5%. Fatty liver develops in up to 94% of obese individuals [3].
Non-alcoholic steatohepatitis (NASH) with stage 2 or 3 liver fibrosis
Oral

Further information

Yes

Trial or other data

Jul 22Intercept announces results from a new analysis of the PIII REGENERATE trial showing Ocaliva, given once-daily at 25 mg, helped 22.4% of patients with advanced fibrotic NASH achieve at least one stage of liver fibrosis improvement with no worsening of NASH at Month 18. That was significantly higher than the 9.6% recorded in the placebo arm. The trial has therefore met one of its primary endpoints agreed upon with the FDA. The new analysis is different from the previous one in that it uses a central consensus reading of liver biopsies by three pathologists, whereas the original analysis was based on each individual expert interpretation. In that old readout, the responses were 23.1% versus 11.9% for Ocaliva and placebo, respectively. However, Ocaliva again failed to show a statistically significant benefit fo resolution of NASH - 6.5% in the Ocaliva 25mg group had resolution of NASH with no fibrosis worsening after 18 months, vs. 3.5% for the placebo group. In addition, Ocaliva at a lower 10mg dosing strength did not show significant benefits on either endpoint. In its currently FDA-approved primary biliary cholangitis indication, Ocaliva is allowed at 10mg once daily maximum, and it already carries a black box warning against more frequent dosing [26].
Dec 19Interim analysis from PIII REGENERATE study (NCT02548351) published in The Lancet. Oeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity. Fibrosis improvement was achieved in only 12% in placebo group vs. 23% in obeticholic acid group (p=0.0002) [19].
Apr 19Intercept is using post-hoc analysis to demonstrate benefit from obetacholic acid in non-alcoholic steatohepatitis patients. A dose of 25mg achieve a 2-stage or greater liver fibrosis improvement in 13.3% of patients, compared to 4.5% achieved by placebo [17].
Feb 19Intercept has reported that its PIII trial REGENERATE has published that it has met its primary endpoint of improving liver fibrosiswithout any worsening of NASH following 18 months of treatment. The study included 931 patients with NASH. It is reported that the highest dose of obeticholic acid improved liver fibrosis with no worsening of NASH at 23.1% compared to a rate of 11.9% for placebo patients. The secondary efficacy endpoint of NASH resolution with no worsening of liver fibrosis showed a numerical change in favour of obeticholic acid, but was not statistically significant. Serious ADEs were 11% for placebo, 11% for obeticholic acid 10mg and 14% for obeticholic acid 25mg. Two placebo arm patients died, and one obeticholic acid 25mg patient died (none were considered treatment related). Severe pruritus occurred in 5% of obeticholic acid 25mg patients, and hepatobiliary events occurred in 3% of these patients. The company plans to file for approval in the US and in Europe by the end of 2019 [16].
Feb 17Following discussion with the FDA and EMA, the primary endpoint for the REGENERATE trial has been amended to proportion of patients achieving improvement in fibrosis OR resolution in NASH compared to placebo - previously, the primary endpoint required achieving both outcomes and the change will increase the likelihood of trial success [12].
Aug 16Phase 3 REGENERATE trial enrollment completion for interim analysis expected in 1Q 2017 [11]
Nov 15REGENERATE trial also recruiting from EU and Australasia [10].
Oct 15PIII REGENERATE (NCT02548351) study is currently recruiting 2000 pts from sites in the US [9].
Oct 15Intercept announce that in a trial testing three doses of obeticholic acid against placebo in 200 patients, obeticholic acid failed to meet the primary outcome of at least a 2-point improvement in NASH symptoms, with only the highest doses, 20 mg and 40 mg achieving significance. The drug also failed to reach statistical significance on secondary endpoints including liver fat, inflammation, ballooning and resolution of NASH symptoms. Intercept´s share price fell about 14% on concerns that OCAmay struggle to replicate its earlier PII success as its 2,000-patient PIII trial gets underway. In Sep 15, Intercept began enrolment in a global study testing 10 mg and 25 mg of OCA versus placebo with primary endpoints of improving NASH symptoms, reducing liver scarring, and preventing death and end-stage liver disease. Final data won´t be ready until 2021, but an interim analysis will evaluate how well OCA is doing at resolving NASH and reducing scars in about 1,400 patients. Intercept plans to submit those results to the FDA for early approval [8].
Mar 15PIII FLINT study published in The Lancet. Obeticholic acid improved histological features of non-alcoholic steatohepatitis vs. placebo (45% in the obeticholic acid group vs. 21% in the placebo group (RR 1.9, 95% CI 1.3 to 2.8; p=0.0002) at 72 weeks [5].
Aug 14In a PIIb 283-patient study, obeticholic acid met its primary endpoint of improving fatty-liver disease symptoms without worsening scarring, with 46% of those in the treatment arm showing meaningful improvement vs. 21% on placebo. Obeticholic acid also met its secondary endpoints of broadly reducing disease scores and significantly improving liver scarring, with 35% of OCA patients reporting a reduction in fibrosis vs. 19% on placebo. Intercept planning to start enrollment in the PIII study in 1H 2015 [2].
Mar 11US PII/III FLINT trial (NCT01265498) of obeticholic acid, 25 mg/day in 280 patients with biopsy-proven non-alcoholic steatohepatitis patients has started. The primary endpoint is hepatic histological improvement in non-alcoholic fatty liver disease (NAFLD) activity score at 72 weeks. The trial is being conducted by the National Institute of Diabetes and Digestive and Kidney [1]

Zektayos-HepjuvoNon-alcoholic steatohepatitis (NASH) with stage 4 liver fibrosis (cirrhosis)

Information

Zektayos-Hepjuvo
Licence extension / variation
Advanz Pharma
Intercept

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

First-in-class farnesoid X receptor (FXR) agonist derived from chenodeoxycholic acid
NASH is a serious liver disease resulting from metabolic dysfunction that is associated with steatosis (fat within the liver), inflammation and fibrosis, which may progress to cirrhosis. NASH-related cirrhosis is expected to become the leading indication for liver transplantation by 2020 [1].
Non-alcoholic steatohepatitis (NASH) with stage 4 liver fibrosis (cirrhosis)
Oral