High-dose Gilead/Nimbus NASH drug hits liver fat

Gilead is hoping to get in on a market potentially worth $35 billion at its peak.(Nonalcoholic steatohepatitis (Michael Bonert/CC BY-SA 3.0)

In new phase 2 data published today, Gilead says a higher dose of its NASH drug saw statistically significant reductions in liver fat, although a lower dose missed the mark.

The midstage test looked at 126 patients who were either given Gilead’s drug GS-0976 at a 20mg dose, a 5mg dose, or a placebo every day for 12 weeks.

All patients in the study were diagnosed with NASH and liver fibrosis, stages F1 through F3 based on biopsy.

The good news for the Big Biotech: Patients on the high dose showed significant decreases in liver fat content compared to a dummy treatment after three months, while there was also a “significant decrease in TIMP-1,” a biomarker used for liver fibrosis. The lower 5mg dose, however, did not beat out placebo.

In other measures, including liver stiffness by FibroScan, liver stiffness by MRE, serum ALT and PIII-NP, a serum marker of fibrogenesis, Gilead found that “no statistically significant differences were observed between the treatment and placebo arms of the study.”

NASH is a form of chronic liver disease caused by a buildup of fat in the liver and is thought to affect around 15 million Americans. If left untreated, it can cause scarring, or fibrosis, in the liver, which can eventually lead to liver failure or cancer.

Some experts predict it could replace alcoholism and viral hepatitis as the leading cause of liver transplants by the next decade, generating a market for NASH-targeted medicines that could reach a whopping $35 billion at its peak. A number of other companies alongside Gilead—including Bristol-Myers Squibb, Allergan, Shire, Genfit and Intercept—are all looking to get into this lucrative market.

RELATED: Bristol-Myers NASH drug hits primary endpoint in phase 2

GS-0976 is an allosteric acetyl-CoA carboxylase inhibitor, an emerging class of drug candidates for NASH and other liver diseases.

It's one of three liver fibrosis programs at Gilead alongside FXR agonist GS-9674—originally developed by Phenex and also in phase 2 testing—as well as ASK1 inhibitor selonsertib that is in two phase 3 trials involving NASH patients with fibrosis (STELLAR 3) and cirrhosis (STELLAR 4). Gilead pulled the plug on another NASH hopeful LOXL2 inhibitor simtuzumab last year.

In April, Gilead posted the first clinical data on GS-0976, which it acquired from Nimbus Therapeutics in a $1.2 billion deal penned last year. Nimbus has already pocketed around half that figure in upfront and milestone payments.

That data was the first indication that Gilead's investment is on course in the fiercely contested race to bring NASH drugs to market, although the results—presented at the International Liver Congress in Amsterdam—were very preliminary.

That trial was small and open label—involving just 10 patients—and revealed that GS-0976 was able to block the formation of new fat in the liver (de novo lipogenesis) by 29% over the 12-week study period. The drug also achieved a sizable 43% reduction in liver fat by the end of the trial, although the data on liver fibrosis (scarring) was marginal. Using a biomarker for fibrosis (liver stiffness), patients on GS-0976 showed a decline from 3.4 to 3.1 kPa at week 12, which was just barely statistically significant.

Fibrosis will likely prove to be a major factor in NASH when the medications do come to the market, alongside reducing liver fat (which will not always lead to scarring and inflammation), as liver fat can also be reduced in some patients in its early stages with diet and exercise.

But excess fat in the liver is seen by biotechs as a precipitating event that drives inflammation and cellular damage in the liver, which in turn drives fibrosis and can ultimately cause cirrhosis.

Questions abound, however, over the future of NASH treatments in general at this early stage, and analysts at Bernstein said about the condition earlier this year: “We see commercialization [of NASH drugs] as highly challenging. Diagnosis is currently tied to liver biopsy; there are no 'easy' measures of treatment effectiveness (like HbA1c, total cholesterol or blood pressure). Broad acceptance of less invasive disease markers is still years away.”

The firm added that “treatment benefit for most patients is questionable,” and that the “disease will remain asymptomatic in the vast majority of patients.” It sees the “success case” for the market as being around $7 billion in global sales by 2025.