Gilead's FXR drug posts positive phase 2 data in rare liver condition

Gilead unveiled phase 2 data at The Liver Meeting showing its FXR agonist improved liver biochemistry and cholestasis—in which bile flow from the liver stops or slows down—in patients with primary sclerosing cholangitis: a rare, chronic liver condition that has no approved treatments. 

Primary sclerosing cholangitis (PSC) leads to the scarring and inflammation of the ducts that drain bile from the liver. Over time, progressive damage to the bile ducts can cause cirrhosis, liver failure and cancer of the bile ducts, called cholangiocarcinoma. According to the National Institute of Diabetes and Digestive and Kidney Diseases, doctors cannot cure PSC or delay its progression. Treatment is limited to opening blocked bile ducts. 

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Gilead’s drug, dubbed GS-9674, is an agonist of farnesoid X receptor (FXR) originally developed at Phenex Pharmaceuticals. The company picked up GS-9674 in its $470 million acquisition of Phenex’s FXR programs in 2015. 

The reported phase 2 data came from a 52-patient trial of patients who had PSC without cirrhosis. Twenty-two patients received a daily 100mg dose of GS-9674, 20 received a lower dose of 30mg and 10 received placebo.

After 12 weeks of treatment, patients on the highest dose showed “significant improvements in liver biochemistry tests.” The drug outperformed placebo in decreasing levels of the liver enzymes serum alkaline phosphatase, gamma-glutamyl transferase, alanine aminotransferase and aspartate aminotransferase. Both treatment groups had lower levels of C4, an intermediate product in the synthesis of bile acids. 

“Patients living with PSC urgently need effective and tolerable treatment options,” said Michael Trauner, M.D., presenting author and Head of the Division of Gastroenterology and Hepatology at the Medical University of Vienna, Austria. “These Phase 2 results are encouraging in terms of beneficial changes in liver biochemistry, markers of bile acid homeostasis, and patient-reported outcome measures. We look forward to further determining the safety and efficacy of this investigational agent.”  

The investigators stopped dosing three patients on the 100mg dose, as well as one patient on placebo due to adverse events. One of the patients had pruritus, or skin itch, which is not uncommon in patients with liver disease. Still, the data are a win for the company. 

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“Gilead is committed to applying our research expertise in liver disease to address this debilitating condition, which may lead to serious liver-related complications for PSC patients,” said John McHutchison, AO, M.D., chief scientific officer and head of research and development at Gilead Sciences. “These latest results from our Phase 2 program of GS-9674 are a positive step forward in the search for effective therapy.”  

Since acquiring GS-9674, Gilead has forked over $400 million for Nimbus Therapeutics’ Acetyl-CoA Carboxylase (ACC) inhibitor program for nonalcoholic steatohepatitis (NASH). The company paid Nimbus a $200 million milestone payment in 2016 and could end up handing over as much as $800 million in development milestones.