As it stands now, only two FDA-approved drugs—ursodeoxycholic acid (UDCA) and ocaliva—are available to delay the progression of mild PBC and manage its symptoms, so there is a need beyond these non-curative options for patients with PBC. While there is no approved treatment for PSC, however, the FDA did recently grant orphan status for potential treatment of the disease to GS-9674, which became part of Gilead's lineup with the company’s 2015 acquisition of Phenex Pharmaceuticals AG.

 

“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 Dr. John McHutchison, chief scientific officer and head of research and development for Gilead. “These latest results from our Phase 2 program of GS-9674 are a positive step forward in the search for effective therapy.”

 

In the Phase 2, double-blind, placebo-controlled trial, 52 non-cirrhotic patients with PSC were randomized to receive GS-9674 100 mg (n=22), GS-9674 30 mg (n=20), or placebo (n=10) orally once daily for 12 weeks. After 12 weeks of treatment, patients receiving GS-9674 100 mg demonstrated significant improvements in liver biochemistry tests, with a median reduction in serum alkaline phosphatase (ALP) of 20.5 percent vs. an increase of 3.4 percent with placebo (p=0.029), and median reduction in gamma-glutamyl transferase (GGT) of 30.3 percent vs. an increase of 1.1 percent with placebo (p<0.001). Patients also saw a median reduction in alanine aminotransferase (ALT) of 49.4 percent vs. 12.9 percent with placebo (p=0.009), and a median reduction in aspartate aminotransferase (AST) of 42.3 percent vs. 10.8 percent with placebo (p=0.019). In both groups treated with GS-9674, reduced serum levels of C4 (an intermediate in the synthesis of bile acids) were observed compared with placebo (-23.2 percent in the 100 mg group, p=0.21; and -30.5 percent in the 30 mg group, p=0.024). Reductions in serum bile acids were greatest with the 100 mg dose.

 

GS-9674 was well tolerated, and the incidence of Grade 2 or 3 pruritus (itching) was numerically lower with GS-9674 100 mg: (13.6 percent) and 30 mg (20 percent) compared with placebo (40 percent). There were no elevations in serum lipids. Treatment was discontinued due to adverse events in three patients treated with GS-9674 100 mg (14 percent), including one discontinuation due to pruritus and one patient with placebo (10 percent).

 

“Patients living with PSC urgently need effective and tolerable treatment options,” commented Dr. Michael Trauner, presenting author of the research during The Liver Meeting 2018 and head of the Division of Gastroenterology and Hepatology at the Medical University of Vienna in 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.”

 

FXR is the primary regulator of bile acid synthesis and plays important roles in glucose and lipid metabolism. GS-9674 is being investigated for the treatment of PSC, primary biliary cholangitis (PBC) and advanced fibrosis due to nonalcoholic steatohepatitis (NASH).

 

As the website Seeking Alpha noted in October of Gilead’s efforts in this disease area, “The once-dormant clinical research and development of therapies for non-viral liver diseases is now characterized by intense competition and ongoing scientific advance. By expanding its clinical portfolio into cholestatic liver diseases, Gilead Sciences ... is strategically planning an offset to decreasing sale revenues originating from viral liver diseases therapeutics.”