NASH Drugs At A Crossroads…

Non-alcoholic steatohepatitis, or NASH, which refers to liver inflammation due to fat buildup in the liver, is said to affect an estimated 16 million Americans. NASH is a more severe form of nonalcoholic fatty liver disease, or NAFLD. The incidence of NASH is on the rise, and even worrying is the fact that there are no approved treatments for the disease, yet.

2018 was a mixed bag for the NASH drug trials.

On February 14, 2018, Galmed Pharmaceuticals Ltd. (GLMD) reported disappointing results from ARRIVE, a proof-of-concept phase IIa clinical trial of Aramchol in patients with HIV-associated Non-alcoholic fatty liver disease (NAFLD) and lipodystrophy. The study did not meet the primary endpoint of improvement of liver fat at 12 weeks, as measured by MRI-PDFF. The announcement of the results sent the stock plunging 42.39% to $5.45 that day.

But in 4 months, Galmed turned the tables when it reported encouraging top-line, 52-week results from its study dubbed ARREST, on June 12, 2018, sending its shares up as much as 286% to $27.06.

ARREST was a phase IIb clinical trial of Aramchol in patients with biopsy-proven non-alcoholic steatohepatitis who were overweight or obese, and who were pre-diabetic or type-II-diabetic.

Another NASH trial failure of 2018 was that of Conatus Pharmaceuticals Inc. (CNAT). On December 5, 2018, the Company announced that its phase IIb clinical trial of Emricasan in patients with NASH Cirrhosis and severe portal hypertension, dubbed ENCORE-PH, did not meet the primary endpoint. Following the news, the stock shed nearly 57% of its value to $1.94.

Shifting gears to 2019 – it has been a disappointing start to the year for NASH drug development.

Yesterday, Gilead Sciences Inc. (GILD) announced that its phase III study of Selonsertib in patients with compensated cirrhosis due to NASH, dubbed STELLAR 4, did not meet the pre-specified week 48 primary endpoint.

However, Gilead has not thrown in the towel on Selonsertib. A phase III trial of Selonsertib in patients with bridging fibrosis (F3) due to NASH, dubbed STELLAR-3, and a phase II combination trial of Selonsertib, Cilofexor (GS-9674) and Firsocostat (GS-0976) in patients with advanced fibrosis due to NASH, dubbed ATLAS are underway, with data expected later this year.

Gilead is one of the four companies whose NASH drug candidates are in phase III development, and the other three being Allergan (AGN), Genfit SA (GNFTF.OB) and Intercept Pharmaceuticals Inc. (ICPT).

Allergan plc (AGN) is evaluating Cenicriviroc, a once-daily, oral drug candidate, in a phase III trial, dubbed AURORA, in NASH patients with stage 2 to 3 liver fibrosis. Initially, the top-line results from the study were expected in July 2019. But now, as per the updated database, the results are expected only by September 2020.

Genfit SA (GNFTF.OB) is evaluating Elafibranor, an oral once-daily treatment, in a phase III trial, dubbed RESOLVE-IT, in patients with NASH and fibrosis. The RESOLVE-IT study was initiated in March 2016, and is expected to enroll 2,000 patients, with interim results expected by the end of 2019.

Intercept Pharmaceuticals Inc. (ICPT) is evaluating once-daily, orally-administered Ocaliva as a potential treatment for non-cirrhotic NASH patients with advanced liver fibrosis in a phase III trial, dubbed REGENERATE. Top-line data from an interim analysis of REGENERATE is expected in the first quarter of 2019.

A phase III trial of Ocaliva in patients with a biopsy-confirmed diagnosis of cirrhosis due to NASH, dubbed REVERSE, is underway, with initial results expected in July 2020.

Closing Thoughts:

With the first phase III NASH trial having flopped, the focus is now on the other three late-stage trials, whose interim results are expected this year.

Besides the above-mentioned phase III NASH drug candidates, there are also a number of investigational NASH therapies in phase II and early stage of development.

Who will make it to the finish line and who will abandon the race to find a treatment for NAFLD/NASH? Only time will tell.

Related Reading:

The Race To Find A Treatment For NASH

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