'Another swing, another miss' for Gilead as NASH combo flops in phase 2

Analysts expect Gilead to keep working on firsocostat and cilofexor but that it may look elsewhere for pipeline opportunities. (Gilead)

Gilead Sciences' nonalcoholic steatohepatitis (NASH) pipeline took another hit as a pair of treatments failed to move the needle on liver scarring in a phase 2 study, both on their own and in combination. The Big Pharma is digesting the data with regulators to figure out what’s next for the programs. 

The 392-patient ATLAS study tested firsocostat, an acetyl-CoA carboxylase (ACC) inhibitor, and cilofexor, a farnesoid X receptor (FXR) agonist, alone and in combination with each other as well as with selonsertib, Gilead’s ASK1 inhibitor that flunked two phase 3 studies earlier this year. 

None of the treatments reduced scarring in patients with advanced fibrosis without worsening of NASH, both of which are measured using liver biopsy. After 48 weeks, firsocostat and cilofexor each hit that goal in about 12% of patients. The combinations missed these goals, too, with selonsertib-firsocostat reducing scarring in 16% of patients and selonsertib-cilofexor and firsocostat-cilofexor doing so in 19% and 21% of patients, respectively. 

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The most common side effects in patients who received the most effective combo, firsocostat and cilofexor, were pruritis, or skin itching, headache, diarrhea and nausea. 

“NASH is a complex disease driven by multiple mechanisms. The results from the ATLAS study suggest the potential for a combination therapeutic approach for patients with advanced fibrosis by targeting different aspects of this disease,” said Gilead Chief Medical Officer Merdad Parsey, M.D., Ph.D., in a statement. “We continue to analyze the ATLAS data and will work with regulators to determine appropriate next steps for these therapies.”  

Though the study missed its biopsy-measured endpoints, Gilead emphasized that the firsocostat-cilofexor combo achieved statistically significant improvements in other measures of NASH, including noninvasive tests for liver enzyme levels and scarring. It also outshone placebo on the study’s secondary endpoints, such as steatosis, or liver fat buildup, inflammation, ballooning of liver cells and the NAFLD Activity Score, a measure of fatty liver disease activity. 

RELATED: Gilead’s selonsertib flunks another NASH phase 3 

The results fit a trend that Gilead has seen in its NASH studies. A postmortem of its phase 3 STELLAR studies of selonsertib found that patients whose post-treatment biopsy showed reduced scarring did not see improvements elsewhere. 

“In patients who had a histologic response, really all that changed were the features that are on the slide,” said Rob Myers, vice president and clinical fibrosis research lead at Gilead, in a previous interview. A patient whose disease improved after treatment was found to have less scarring based on what a pathologist saw in a tiny sliver of liver tissue. But they did not improve based on all the other tests “that are important to clinicians and patients.” 

RELATED: AASLD: Gilead wants to move the needle for fatty liver therapies

Analysts were split in what the data mean for Gilead, with Jefferies analyst Michael Yee offering a more hopeful outlook. Yee chalked up the study’s failure to achieve statistically significant results to “how small each cohort is.” Firsocostat and cilofexor were each tested in about 30 patients, with the combinations given to groups of about 70 patients each. 

“While the patient numbers in each cohort are indeed low, the combo cohorts, particularly the FIR (ACC inhibitor)/ CILO (FXR agonist) arm, look promising and justify a discussion with regulatory agencies on a potential path forward with the initiation of larger Phase IIb studies in F3 and/or F4 patients,” he wrote. 

JPMorgan analyst Cory Kasimov called the data “another swing, another miss” and a “2019 strikeout” for Gilead in NASH. He expects Gilead to keep plugging away at NASH, given it has multiple programs in the space, including a study combining firsocostat and cilofexor with Novo Nordisk’s GLP-1 med semaglutide. 

“Although we expect NASH to continue to be a focus for the co with many programs ongoing, this is a complex disease that, in our view, will take time to figure out,” Kasimov wrote. “Bigger picture, we think today’s results further increase the pressure on GILD for M&A/BD given the lack of near-term pipeline opportunities outside of [rheumatoid arthritis prospect] filgotinib.” 

SVB Leerink analyst Geoffrey Porges sees Gilead persevering with the firsocostat-cilofexor combo, but doesn't rule out the company directing funds to other areas such as oncology and fibrosis.

“We expect the company to initially persist in their development of this firsocostat/cilofexor combination; if the combination can be advanced into a single relatively small pivotal trial, with this study providing regulatory support to the application, Gilead may continue to invest in its development,” Porges wrote. "However, given the company’s greater interest in oncology than hepatology, it seems possible that further investments in NASH will be limited or small, with the available capital and expenses being part of an overall re-deployment into oncology and other areas such as fibrosis."