Four companies are within striking distance of filing NASH drugs for approval, but the competitive landscape is more nuanced than simply crossing the finish line first.

NASH, or non-alcoholic steatohepatitis, has no approved treatments. Estimates hold that about 30 million people in the U.S. have the fatty liver disease, representing a $35 billion market opportunity by some of the more bullish forecasts. Leaders in the space think there's more than enough room for multiple marketed therapies. How battle lines will be drawn is something they have yet to work out.

Investors got an early taste of what's to come this week at the J.P. Morgan Healthcare Conference in San Francisco. With late-stage readouts looming for Gilead Sciences, GenFit and Intercept Pharmaceuticals, 2019 is poised to be big year for the therapeutic area.

A stream of data

Earliest on the readout calendar are selonsertib and obeticholic acid.

Selonsertib is an ASK-1 inhibitor from Gilead, under investigation in two late-stage studies that should have results in the first and second quarters. Wall Street isn't terribly confident in the drug's chances of success, but Gilead remains optimistic. The biotech said positive data from its STELLAR 3 and STELLAR 4 studies would warrant a regulatory submission in the back half of this year and a potential approval in 2020.

Obeticholic acid, meanwhile, is the active ingredient in Intercept's Ocaliva, which the Food and Drug Administration cleared in 2016 for a liver illness called primary biliary cholangitis. Intercept hopes to expand the drug's label into NASH, and at JPM narrowed the timeline for Phase 3 data on the drug from the first half of this year to the first quarter.

French biotech GenFit also anticipates Phase 3 data for its candidate elafibranor to come in 2019, but likely near the tail end. Allergan ​rounds out the list of late-stage NASH drugs with cenicriviroc, a small molecule that inhibits a receptor involved in cell signaling. The Phase 3 AURORA trial assessing cenicriviroc has a primary completion date of Sept. 16, 2020, according to the federal database clinicaltrials.gov.

The Phase 3 NASH trials are similar in structure. But a differentiator — and sticking point — are their main objectives. STELLAR 3, STELLAR 4 and AURORA have primary endpoints of fibrosis improvement without worsening of NASH, whereas Genfit's RESOLVE-IT study is the opposite. Intercept's REGENERATE study has fibrosis improvement and NASH resolution as co-primary endpoints.

The FDA recently signaled in a guidance document that success on either NASH resolution, fibrosis improvement or the combination of the two are acceptable endpoints for potential approval of a NASH therapy. Still, there's been debate about which endpoint, and really which drugs, will prove most useful in the field's early days.

Allergan sees the greatest need for treatment among patients with advanced liver fibrosis, hence the design for AURORA.

"You want to reduce fibrosis to reduce cirrhosis. And we think that the payers will absolutely want reduction in fibrosis for later-stage disease," said David Nicholson, Allergan's chief medical officer, in an interview with BioPharma Dive.

GenFit, meanwhile, argues that if it's NASH driving the liver fibrosis, then having a drug that delivers NASH resolution is useful across the entire population.

"The advantage of starting with drugs that are able to resolve NASH is that you have the choice of whether to use an anti-neoplastic drug as a monotherapy, or you may decide to combine that with an antifibrotic drug," Dean Hum, the company's chief operating officer, told BioPharma Dive.

NASH and fibrosis progress slowly, meaning longer-term data may be needed to show the true impact of NASH resolution on liver scarring. However, Allergan, GenFit and other NASH developers generally agree that different therapies will be needed to address such a large patient population with varying degrees of disease severity.

On a broader level, drugmakers are also trying to remedy some of the more problematic aspects of clinical NASH investigations. Diagnosing the disease currently requires an invasive liver biopsy, which has been a deterrent to enrollment.

NASH is largely asymptomatic until late, too, making the potential side effects from investigational therapies a tough pill to swallow for patients. Nicholson notes this challenge doesn't just affect NASH, but rather all "silent" illnesses. Glaucoma, for which there are FDA-approved therapies, is one such example.

"Glaucoma is the second leading cause of blindness, but people don't wander around feeling like, 'Oh, my intraocular pressure is too high,'" he said. "So it's not unique to NASH ... these silent diseases are more difficult to recruit."

'Waves of approval'

While JPM didn't bring data updates for the later-stage NASH pipeline, drugmakers did give more color on their mindset heading into such a pivotal year.

John McHutchison, Gilead's head of R&D, told investors at JPM he anticipates "waves of approval," with the first being highly potent treatments for patients who have more advanced fibrosis, and then subsequent waves that work on less severe NASH and have better safety profiles.

In that way, he suspects the NASH market will evolve similarly to that of another prominent liver disease: hepatitis C. Gilead's drugs Sovaldi and Harvoni effectively cured hep C — though that has paradoxically caused many of the revenue problems the company continues to grapple with.

"We know there are a number of different targets, a number of different biologically plausible mechanisms, [but] we don't know how to combine them to lead to the ultimate best efficacy for patients with NASH. That's what we're trying to explore," McHutchison said during the conference.

Gilead's already testing selonsertib combined with drugs that regulate fatty acid metabolism or bile acid synthesis.

Combo therapies are popular among its main NASH rivals as well. Allergan and Novartis teamed up in 2017 to research the pairing of cenicriviroc​ and an FXR agonist, while GenFit's Hum said his company expects to use elafibranor as a first-line monotherapy and later as a backbone for combo treatments.

And at JPM, Intercept announced a licensing agreement for Aralez Pharmaceuticals' bezafibrate, with plans to use the drug plus obeticholic acid for the treatment of primary biliary cholangitis and other liver diseases.

Less advanced candidates are also attracting investor attention. Phase 2 successes for Madrigal Pharmaceuticals' hormone receptor agonist MGL-3196 and Viking Therapeutics' thyroid beta agonist VK2809 led to big stock surges for both biotechs last year — though the share price for each has since trickled back down.

M&A ripples

The chatter surrounding NASH has at times turned into deal talks. The past year alone saw Roche snap up Jecure, AstraZeneca acquire an investigational therapy from Ionis, and Novartis and Pfizer combine forces on research efforts. Some analysts believe there's more to come.

Gilead, for instance, has a war chest of around $30 billion. Chief Financial Officer Robin Washington said during JPM that M&A is the biotech's top focus this year from a capital allocation standpoint.

Given analyst concerns over its NASH pipeline, another deal there wouldn't be too surprising — particularly because Gilead recently entered two deals for preclinical NASH drugs. One of those deals, inked with a Korean drugmaker, Yuhan Corp., came the day before JPM started.

"We continue to think Gilead is lacking a good mid- or late-stage cardiometabolic NASH drug," Raymond James analyst Steven Seedhouse wrote in a Jan. 7 investor note.

That's not to say Gilead's existing NASH pipeline isn't valuable.

In fact, Seedhouse wrote in a Jan. 3 note following Bristol-Myers Squibb's bid for Celgene that Gilead's NASH drugs would be a main negotiating point should a potential suitor come knocking. Raymond James doesn't believe there is such a buyer, though, seeing as they'd have to shell out close to $135 billion by the investment bank's estimates.