When Gilead conceded failure in its high-profile Phase III study for top late-stage NASH drug selonsertib, CSO John McHutchison pointed disappointed investors to a combination approach being tested in a mid-stage trial. Those data are not ready just yet, but today the big biotech unveiled some early numbers to bolster their case for a cocktail.
On display today at the International Liver Congress are topline results from a proof-of-concept study testing cilofexor (nonsteroidal farnesoid X receptor or FXR agonist) and firsocostat (acetyl-CoA carboxylase or ACC inhibitor). Out of 20 patients who were treated with the oral regimen once daily for 12 weeks, 74% experienced “a significant decline of at least 30 percent in hepatic fat” — a hallmark of the disease.
Researchers also documented improvements in other biomarkers, including “serum ALT (median relative reduction, -37%; p<0.001) and GGT (-32%; p<0.001), along with markers of reduced bile acid synthesis.”
Cilofexor and firsocostat are also part of a triplet combo with the ASK1 inhibitor selonsertib, at the center of the Phase II ATLAS study that McHutchison highlighted. In general, FXR activation is thought to fight liver fibrosis, ACC inhibitors block fatty acid synthesis, while ASK1 inhibitor also helps reduce inflammation.
“NASH is a complex disease with multiple biological pathways that influence its progression. Combination therapeutic approaches which target these pathways, are likely to be needed to effectively treat patients living with NASH, particularly those with advanced fibrosis who have the greatest unmet need,” said McHutchison in a statement.
Gilead took a hit when selonsertib flopped in its closely-watched STELLAR-4, outperformed by the placebo at the low dose, though analysts acknowledged that fibrosis was a tough target to tackle.
With a flock of smaller players — including Intercept, Genfit, Madrigal and NGM Bio, which is partnered with Merck — contending for the still vacant NASH throne, Gilead has been picking up early-stage assets in pursuit of a sustaining franchise. In fact, cilofexor came from the buyout of Phenex Pharma and you might remember firsocostat as GS-0976, which Gilead paid Nimbus $600 million for.
It won’t be easy. But the pull is strong: NASH, which is typically associated with obesity and diabetes, is set to eclipse hepatitis C as the leading reason for liver transplants by 2020.
At the conference, Gilead also presented screening data in support of non-invasive tests to identify NASH patients with advanced fibrosis. Reducing the need for the costly and risky liver biopsies typically needed for the diagnosis can pave a smoother path for patients toward treatment — ultimately when they get approved.
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