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NASH Drugs: A Comprehensive Review Of Current Clinical Trials

Summary

NASH has no FDA-approved therapy and could represent a $35 billion market by 2025, prompting many biotechs to race for the approval of the first NASH-targeted drugs.

The most advanced product candidates are Genfit's and Intercept's Phase 3 compounds, with many other biotechs currently conducting Phase 2 trials.

This article aims to provide an updated and fairly comprehensive review of the current status and prospects of all major contenders in the NASH field.

Non-alcoholic steatohepatitis, or NASH, is a form of chronic liver disease caused by a build-up of fat in the liver (progressive fatty liver disease) affecting at least 2 to 5% of Americans, with some estimates going as high as a 17% prevalence rate in the U.S. population. There is currently no FDA-approved therapy for NASH, even though the disease can progress to cirrhosis and ultimately lead to hepatocellular carcinoma (liver cancer), which makes it one of the major unmet medical needs of the 21st century - NASH is now the second most common cause for liver transplantation in the U.S., and it is anticipated to become the leading cause by 2020.

Treating NASH is therefore a pressing matter of public health and the development of targeted therapies has been strongly supported by the FDA and EMA alike in the past years. The market for NASH drugs is currently estimated to reach $35 to $40 billion by 2025, a huge, mostly untapped market that could support several blockbuster drugs in the years to come.

NASH problems

Several companies are currently developing NASH-targeted drugs. Those with the most serious prospects include Genfit (OTCPK:GNFTF), Intercept (NASDAQ:ICPT), Gilead (NASDAQ:GILD), Novo Nordisk (NYSE:NVO), Tobira (NASDAQ:TBRA) and Galmed (NASDAQ:GLMD). Some other companies, such as Conatus (NASDAQ:CNAT), Galectin (NASDAQ:GALT) and MediciNova (NASDAQ:MNOV) have been granted Fast Track designations and are starting to explore the field. However, until now, only Intercept and Genfit have launched Phase 3 trials based on histological evidence (the current gold standard assessment of NASH) that their compounds are able to reverse or reduce NASH symptoms in randomized controlled trials.

This article aims to provide an updated and fairly comprehensive review of the current status and projections of all major contenders in the NASH field.

Genfit - Phase 3 ongoing, first patients enrolled and pipeline expanded

Genfit is developing Elafibranor, a dual PPARα/δ agonist, for the treatment of NASH patients (NAS≥4) with moderate to severe fibrosis (F2-F3) and an exploratory subset of patients with mild fibrosis (F1) - Genfit has been granted a Fast Track designation for this indication.

In recent developments, the biotech announced the enrollment of the first patients in its ongoing RESOLVE-IT Phase 3 trial. Genfit just held an analysts event in New York in which the biotech's management gave interesting information about its strategy to advance and expand its NASH prospects, including specific details on a projected timeline for its Phase 3 trial. Based on current enrollment rates, Genfit is projecting to have enrolled the first 1,000 patients by Q1-2017, which would allow the company to file pivotal data with the FDA and EMA after 72 weeks, on track for a potential H2-2019 "Subpart-H" product launch, as shown on the slide below (see additional details in this article).

Genfit also took the opportunity to reiterate that its flagship drug, Elafibranor, has a strong potential for first-line treatment of high-risk NASH patients (NAS≥4, F2-F3) owing to the drug's consistent efficacy results (see this article for details about Phase 2b published data), its excellent safety profile (with demonstrated cardioprotective effects) and a potential first-to-market status.

(Source: Genfit's analysts presentation, March 31, 2016)

While stressing the absolute need for the broad adoption of NASH therapies to have access to reliable non-invasive diagnostic tools, Genfit's management also confirmed the continued development of its NASH-specific biomarker program with the intention of reaching commercial stage by the time its drug, Elafibranor, also reaches the market - a smart and probably unavoidable strategy since the lack of alternative to liver biopsies for the diagnostic of NASH patients would curb any rapid growth of this market.

Expanding on the NASH pipeline, Genfit also announced that it would start later this year two new Phase 2 trials with Elafibranor in NASH pediatric and cirrhotic patients, and explore potential combination therapies with other compounds. See Genfit's full pipeline below.

(Source: Genfit's analysts presentation, March 31, 2016)

As a side note, Genfit surprised many analysts with the announcement that it would launch a Phase 2 trial of Elafibranor in primary biliary cholangitis, or PBC, just a few days before the scheduled advisory panel (April 7) discussing Intercept's application to market OCA for this indication. While insisting that the decision to develop Elafibranor in PBC was based on solid clinical data from previous Phase 2 trials (effects observed on ALP and other relevant endpoints) and a strong scientific rationale, Genfit's management could not avoid evoking OCA's pruritus side effect - a tangible problem for PBC patients who already tend to suffer from pruritus caused by their condition.

Even though Intercept insists that pruritus severity scores were globally similar in PBC patients taking OCA or placebo, OCA did increase the absolute number of pruritus-related adverse events (56% OCA vs. 38% placebo). Hence, Genfit appears to be betting on Elafibranor's excellent safety record to show efficacy in PBC and a more favorable safety profile than placebo, hoping to capture some of OCA's potential market, should Intercept's drug be approved later this year.

In terms of finances, Genfit recently raised ~$54 million in a private placement with U.S. investors and currently estimates to be able to fund all operations to YE 2019 with the current cash reserve (~$125 million). While the biotech's management confirmed that plans for a U.S. IPO are still very much alive pending better market conditions, this latest private placement was also the opportunity for Genfit to show that it is still able to raise enough money to complete its Phase 3 trial when it needs to, and that financing issues should not worry investors in the short term.

Intercept - Phase 3 started but enrollment status unclear

Intercept is developing OCA (obeticholic acid), a semi-synthetic FXR agonist, for the treatment of NASH patients with fibrosis (similar to Genfit's target population) - OCA was designated as a Breakthrough Therapy for this indication. The biotech officially announced the launch of its pivotal REGENERATE Phase 3 trial in September 2015. However, when asked directly about the status of Intercept's Phase 3 enrollment in a February 23 conference call (six months after the trial's official start), Mark Pruzanski, Intercept's CEO, declined to give any specific details about the company's enrollment status with the following answer (emphasis added):

We'd like to remind you that the screening process for any trial in NASH with a biopsy endpoint is fairly lengthy (...) it's simply too early in the study to have sufficient visibility on enrollment at this time.
(...) so I'll say that we are very hard at work on getting sites up and running in the U.S. and other countries. I alluded in my prepared comments, prepared remarks on two of the investigator meetings we've been having in the U.S. and in Europe. These have been extremely well attended with universal enthusiasm. And again, not surprising, that this is the first ever Phase 3 NASH registration trial and there's really a lot of interest around the world in participating." - Source: February 23 Conference Call

Hence, while Genfit did confirm that some of its Phase 3 centers were actually enrolling patients, Intercept has not...


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