Liver disease is set for its pivotal year

Nash, the one-time favourite therapy area for biopharma speculators, is back.

Spotlight

When Intercept kicked off the Nash craze back in 2014 it spawned numerous imitators. Next year could see all four of the leaders, including Intercept itself, deliver pivotal trial results showing once and for all whether a drug treating this elusive liver disease could become a commercial proposition (see table below).

The field has had its issues, with Gemphire and Shire delivering three Nash setbacks in recent days. But this does not appear to have dampened enthusiasm overall, with investor interest also piqued by mid-stage players, of which Conatus and Cymabay are also awaiting study readouts. 

Today Gemphire axed a paediatric fatty liver disease trial of its candidate, gemcabene, after seeing unexpected increases in liver fat. This is a huge setback as paediatric Nash had been seen as a less competitive space than adult disease, and the company opened off 60%.

And that was its second piece of bad news, the stock already having crashed 51% on Wednesday after Gemphire said the US FDA would not allow long-duration trials of gemcabene to take place until data from a sub-chronic toxicology study were generated. For now a small, investigator-initiated study in adults is ongoing.

Meanwhile, Shire last month quietly dropped development of its fast-tracked bile acid transporter volixibat without specifying a reason; the project had been in phase II. 

More positive developments have come from Galmed and Madrigal, whose respective candidates, Aramchol and MGL-3196, recently wowed the markets and prompted a resurgence in Nash interest. Notwithstanding questions over Aramchol’s inconsistent dose response and missed endpoints, both companies’ attention now turns to phase III design (Investors toast Galmed Nash results, but what will the FDA say?, June 12, 2018).

First to market

For the most advanced players, however, it is all about pivotal readouts. The race to launch the first ever Nash drug now looks to be between Intercept’s Ocaliva and Gilead’s selonsertib.

Next year their respective Regenerate and Stellar-3 trials should yield interim data, which the companies hope will be enough to file for accelerated US approval. For this a project likely must meet one of two surrogate endpoints: Nash resolution without fibrosis worsening or fibrosis improvement without Nash worsening.

It will also be important for Ocaliva to demonstrate safety, as deaths and severe liver injury have been problematic in its approved use, primary biliary cholangitis, and this will be closely watched especially at the high doses being used in Nash. Ocaliva’s failure in a Japanese Nash trial is providing investors with a second a cause for concern.

The most important distinction in pivotal trial design, however, is the timeframe in which changes in Nash score and fibrosis might be detected.

The importance of endpoints in phase III Nash trials
Project Study Primary endpoint(s) Timeframe
Ocaliva Regenerate Fibrosis improvement w/no Nash worsening 18 months
    Nash resolution w/no fibrosis worsening 18 months
    All-cause mortality 7 years
Selonsertib Stellar-3 Fibrosis improvement w/no Nash worsening 12 months
    Event-free survival 5 years
Elafibranor Resolve-It Nash resolution w/no fibrosis worsening 17 months
    All-cause mortality 4 years
Cenicriviroc Aurora Fibrosis improvement w/no Nash worsening 12 months
    Cirrhosis progression, all-cause mortality 5 years
Source: clinicaltrials.gov.

The timeframe is vitally important, considering the failure of Genfit’s elafibranor to hit 12-month fibrosis and Nash clearance endpoints in phase II. Elafibranor and cenicriviroc, which Allergan acquired with Tobira for $534m, are the other two phase III Nash assets, and are somewhat further behind Ocaliva and selonsertib.

After a timeline slippage, not unusual in Nash studies, Genfit was hoping to have recruited the first 1,000 subjects, necessary to yield primary elafibranor efficacy data, in the first quarter; but there has been no confirmation of this, the only news having been that an interim review in April recommended the study’s continuation.

Allergan’s cenicriviroc, meanwhile, stumbled in 2017 when two-year phase II results found no difference in fibrosis reduction with no worsening of Nash. The asset is in the phase III Aurora trial, testing the same endpoint at 12 months, and there has been some suggestion that design could be altered to focus on patients with a higher Nash score at baseline.

Intercept and Gilead are separately testing their respective assets in the Reverse and Stellar-4 studies in late-stage Nash/cirrhosis.

Earlier stage

That leaves two earlier-stage assets on which investors will be focused: Conatus’s emricasan and Cymabay’s seladelplar.

The former’s phase II trials are Encore-PH, in Nash and severe portal hypertension, Encore-NF (Nash fibrosis) and Encore-LF (decompensated Nash cirrhosis). The first should yield topline data in the second half, and if these are positive it could point the way towards approval in a less competitive space than Nash fibrosis.

Seladelpar, meanwhile, has already demonstrated potential in primary biliary cholangitis, and the larger indication of Nash is a logical next focus. As this is a PPAR agonist, however, it could face similar questions to those that have clouded development of elafibranor and gemcabene.

Beyond that, of course, broader questions remain about how big a market Nash could be; even if it is large an efficacious treatment could bring about a similarly self-destructive effect to that seen in hepatitis C, Bernstein analysts have suggested. For now, however, the key focus is on generating hard clinical data.

Key upcoming trial readouts in Nash
Project Company Mechanism Trial ID Readout
Phase III
Ocaliva Intercept Farnesoid X receptor agonist NCT02548351 Interim data H1 2019
Selonsertib Gilead Ask1 inhibitor NCT03053050 Interim data H1 2019
Cenicriviroc Allergan CCR type 2/5 dual antagonist NCT03028740 Possible interim readout 2019
Elafibranor Genfit PPAR alpha & delta agonist NCT02704403 Possible data late 2019
Phase II
Emricasan Conatus Caspase inhibitor NCT02960204 H2 2018
Seladelpar  Cymabay PPAR delta agonist NCT03551522 H2 2019
Gemcabene Gemphire PPAR alpha agonist* NCT03508687 2020
Note: *primary mechanism is inhibition of acetyl CoA carboxylase 1, apoC-III and CCR2/CCR5, but the FDA's partial clinical hold is caused by its PPAR agonist properties.

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