"The next hepatitis C."
That's what another liver disease, non-alcoholic steatohepatitis (NASH), has been called. The global market for NASH drugs could be $40 billion annually -- and there are no approved treatments for the disease. Gilead Sciences (NASDAQ:GILD) is sorely in need of something beyond hepatitis C, with sliding sales of its hep-C drugs Harvoni and Sovaldi.
Gilead has high expectations for its late-stage NASH candidate GS-4997. But should the big biotech be worried that Allergan (NYSE:AGN) could dominate NASH like Gilead has dominated hepatitis C and HIV?
Like Gilead, Allergan has its eyes on the potentially lucrative NASH market. The Ireland-based drugmaker acquired Tobira Therapeutics last year, picking up two experimental NASH drugs -- cenicriviroc (CVC) and evogliptin.
Evogliptin is only in an early stage study for the NASH indication, so Gilead probably isn't too concerned at this point about how it might threaten prospects for GS-4997. However, CVC is in a late-stage study. Allergan expects to complete final data collection for the primary outcome of fibrosis improvement in July 2019. That's earlier than Gilead's projected January 2020 date for completing its late-stage study of the primary outcome measure for GS-4997.
A couple of other companies also have late-stage NASH candidates with similar head starts over Gilead. Intercept Pharmaceuticals (NASDAQ:ICPT) expects to report results from its phase 3 study of obeticholic acid (OCA) in treating NASH in 2019. French drugmaker Genfit (OTC:GNFTF) should be on track to also announce late-stage results for its experimental NASH treatment, elafibranor, around the same time.
Combinations could be key
Some experts think that one drug by itself might not be enough to most effectively treat NASH. I spoke with Genfit's COO and chief scientific officer, Dean Hume, several months ago. He thought it was likely that NASH treatment will ultimately involve combination therapies.
Allergan seems to agree. The company recently announced a collaboration with Novartis (NYSE:NVS) to conduct a phase 2b study of its CVC and Novartis' FXR agonist in treating NASH. Allergan's chief research and development officer, David Nicholson, said that the deal with Novartis allows both companies "to focus on multi-therapy treatment, which is expected to be the most likely approach based on the multi-factorial aspects" of NASH.
Does the Novartis collaboration potentially give Allergan a leg up over Gilead? Probably not. Gilead has its own phase 2 study evaluating a combination of GS-4997, FXR agonist GS-9674, and ACC inhibitor GS-0976 underway. The study is expected to wrap up later this year.
It's difficult to compare all of these late-stage experimental drugs right now. We do know a few things based on earlier clinical results, though.
In Gilead's phase 2 study of GS-4997, 43% of patients taking an 18 mg dose of the drug experienced significant fibrosis improvement of at least one stage from baseline. There weren't any serious adverse events, with the most common side effects being headache, nausea and sinusitis.
Prior to its acquisition by Allergan, Tobira reported results from a phase 2 study showing that 20% of patients taking CVC for one year saw an improvement in fibrosis by at least one stage without worsening of NASH. However, the study didn't meet the primary endpoint of a two-point reduction in the NAFLD activity score, a measure developed to numerically quantify progression of NASH. The most common adverse events were fatigue and diarrhea.
As for Intercept, phase 2 results for OCA in treating NASH showed 38% of patients taking the highest dosage (40 mg) of the drug experienced a two-point reduction in the NAFLD activity score. However, the improvement was only statistically significant by a small margin. Intercept also reported a relatively high number of patient discontinuations because of pruritis (itchiness).
Genfit's elafibranor didn't meet the primary outcome of NASH resolution without worsening fibrosis in a phase 2 study. But the company saw a very high placebo effect, especially in patients with early cases of NASH. Patients with more advanced NASH conditions at baseline experienced much better results from taking elafibranor. There were no serious adverse events, with the most common side effects being relatively mild gastrointestinal issues.
Could you argue that Gilead's GS-4997 had the best overall phase 2 results? Perhaps, but looking at all of these studies is like comparing apples and oranges. Genfit is the only drugmaker to show NASH resolution, but its results come with an asterisk due to the high number of patients on placebo also experiencing NASH resolution.
Up for grabs
So should Gilead Sciences worry about Allergan? Yes and no.
The big biotech would certainly prefer to be first to market with the most effective NASH treatment of all. If all goes well with their late-stage studies, Intercept, Genfit, and Allergan will probably beat Gilead to market. From that standpoint, Gilead needs to be at least somewhat concerned about all three rivals.
However, the first to market might not be the biggest winner in NASH. It will come down to efficacy and safety. Allergan's CVC could prove better than Gilead's drug on both fronts, but it might not.
There probably will be plenty of room for multiple drugs to become huge winners. As is the case with rheumatoid arthritis, the potential size of the NASH market is large enough to accommodate several blockbuster drugs. And the likelihood that combo therapies will prove to be most effective provides even more room for multiple companies to succeed.
And if a real reason for Gilead to worry emerges, there's a simple solution. Gilead could always just buy its primary rival -- whoever that might be.