After being encouraged by some early readouts, Gilead Sciences and Novo Nordisk are doubling down on their fatty liver R&D pact by kick-starting a midstage nonalcoholic steatohepatitis (NASH) combo trial later this year.
Two years ago, Gilead revealed new midstage data about its combo of FXR agonist cilofexor and investigational ACC inhibitor firsocostat (which came out of biotech buys Phenex and Nimbus, respectively) that showed in 20 patients it could reduce liver fat by 74%, albeit with several grade 3 adverse events.
Gilead then teamed up with Novo in the hope that adding semaglutide (aka Ozempic), which has an FDA approval in Type 2 diabetes and works as a GLP-1 treatment that stimulates insulin production, could boost the efficacy of its two drugs.
Late last year, this combo had some middling data out of a phase 2a trial, but now the pair want to take that into a phase 2b test and drill down into its potential efficacy. This will look at Ozempic alone and in combo with Gilead’s experimental meds in patients with late-stage, compensated cirrhosis (liver scarring) due to NASH, or fatty liver disease.
The four-arm study will recruit 440 patients and assess its impact on liver fibrosis improvement and NASH resolution; the test is slated to begin recruitment in the second half of 2021.
The smaller phase 2a test of just over 100 people with NASH and mild to moderate fibrosis met its primary endpoint in November, showing all regimens were well tolerated over 24 weeks. But on efficacy terms, things weren’t as positive: Liver stiffness and the Enhanced Liver Fibrosis score declined in all groups, but this failed to be statistically significant.
It did, however, show statistically significant improvements in hepatic steatosis and liver injury, although these were “post-hoc analyses of exploratory efficacy endpoints,” something that makes trial observers twitch. The larger phase 2b will likely be a better proving ground for the cocktail.
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“NASH is a disease with a high unmet medical need, as no drugs are currently approved to treat this potentially life-threatening condition,” said Martin Holst Lange, executive vice president and head of development at Novo Nordisk.
“Building on the positive results from our proof-of-concept trial, we hope together with Gilead to demonstrate the potential for semaglutide with cilofexor and firsocostat to help people living with NASH.”
Patients with Type 2 diabetes are more prone to NASH, which is caused by a buildup of fat in the liver and can cause scarring as well as eventually (in a minority of cases) severe liver damage and cirrhosis. It’s tipped to become the biggest reason for liver transplants in the coming decade, outpacing alcoholism and hepatitis C.
A number of single agents against NASH, said by the more bullish analysts to be a $40 billion-a-year market at peak, have suffered setbacks in the clinic from a number of biopharmas, including Intercept Pharmaceuticals, Gilead itself, Genfit and others. Gilead will hope combinations can be new a way forward and help clear more fat from the liver to reduce the risk of further damage.