MBX-8025 yields ‘striking’ efficacy results but new safety signal in primary biliary cholangitis

The investigational peroxisome proliferator–activated receptor delta agonist MBX-8025 exhibited a “striking anticholestatic effect” without causing pruritus in a phase II trial of 35 patients with primary biliary cholangitis.

But three patients developed grade 3 increases in serum transaminase levels that reversed when they stopped treatment, David Jones, MD, of the University of Newcastle (United Kingdom) and his associates will report at the annual meeting of the American Association of Liver Diseases. The effect seemed dose related, so future studies should explore whether MBX-8025 is effective at lower doses, they concluded in a late-breaking abstract released in advance of the meeting.

Primary biliary cholangitis, an important cause of end-stage liver disease, is initially associated with fatigue and pruritus and often responds inadequately to first-line treatment with ursodeoxycholic acid. MBX-8025 selectively activates the peroxisome proliferator–activated receptor delta, a nuclear receptor that regulates genes involved in lipid storage and transport. In prior studies, MBX-8025 decreased serum alkaline phosphatase (ALP) levels and seemed well tolerated in healthy volunteers and patients with dyslipidemia, the investigators noted.

As a next step, they randomly assigned patients with primary biliary cholangitis whose ALP levels remained at least 1.67 times the upper limit of normal, despite at least 12 months of ursodeoxycholic acid therapy, to receive either placebo or 50 or 200 mg MBX-8026 for 12 weeks. The primary outcome was percent change in ALP levels, which, at baseline, averaged 233 U/L in the placebo group, 312 U/L in the 50 mg group, and 248 U/L in the 200-mg group.

At the end of treatment, ALP levels had dropped by an average of 63% in the 200-mg MBX-8025 group, 53% in the 50-mg group, and 2% in the placebo group (P less than .0001 for each dose effect versus placebo). Percent decreases in gamma-glutamyl transferase averaged 43% for both dose groups and 3% in the placebo group. Median levels of 7-alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, fell by 77% in the 200-mg group and by 55% in the 50-mg group, but rose by 29% in the placebo group. Both the 50-mg and the 200-mg doses yielded statistically similar effects on all three cholestatic markers.

Although MBX-8025 did not appear to cause or worsen pruritus, 3 of the 35 patients developed rapid, asymptomatic, grade 3 increases in serum levels of alanine aminotransferase, the researchers reported. Two patients were taking 200 mg MBX-8025, and one was taking 50 mg. The effect fully reversed after patients stopped treatment, and was not associated with hyperbilirubinemia. Another patient in the 200-mg group stopped treatment because of what the investigators called “a muscle adverse event [that we] considered drug-related.”

The trial was halted halfway through recruitment, having established proof of concept, the investigators concluded. Because MBX-8025 is primarily excreted in bile, and primary biliary cholangitis obstructs bile flow, affected patients might have had more hepatic exposure to the agent than did those in previous trials, and this might explain the new safety signal, they noted.

CymaBay Therapeutics makes MBX-8025 and funded the trial. Dr. Jones disclosed ties to Intercept, GlaxoSmithKline, Novartis, and Falk. Eight coinvestigators disclosed employment with or other ties to CymaBay Therapeutics. The other three coinvestigators had no relevant disclosures.

The investigational peroxisome proliferator–activated receptor delta agonist MBX-8025 exhibited a “striking anticholestatic effect” without causing pruritus in a phase II trial of 35 patients with primary biliary cholangitis.

But three patients developed grade 3 increases in serum transaminase levels that reversed when they stopped treatment, David Jones, MD, of the University of Newcastle (United Kingdom) and his associates will report at the annual meeting of the American Association of Liver Diseases. The effect seemed dose related, so future studies should explore whether MBX-8025 is effective at lower doses, they concluded in a late-breaking abstract released in advance of the meeting.

Primary biliary cholangitis, an important cause of end-stage liver disease, is initially associated with fatigue and pruritus and often responds inadequately to first-line treatment with ursodeoxycholic acid. MBX-8025 selectively activates the peroxisome proliferator–activated receptor delta, a nuclear receptor that regulates genes involved in lipid storage and transport. In prior studies, MBX-8025 decreased serum alkaline phosphatase (ALP) levels and seemed well tolerated in healthy volunteers and patients with dyslipidemia, the investigators noted.

As a next step, they randomly assigned patients with primary biliary cholangitis whose ALP levels remained at least 1.67 times the upper limit of normal, despite at least 12 months of ursodeoxycholic acid therapy, to receive either placebo or 50 or 200 mg MBX-8026 for 12 weeks. The primary outcome was percent change in ALP levels, which, at baseline, averaged 233 U/L in the placebo group, 312 U/L in the 50 mg group, and 248 U/L in the 200-mg group.

At the end of treatment, ALP levels had dropped by an average of 63% in the 200-mg MBX-8025 group, 53% in the 50-mg group, and 2% in the placebo group (P less than .0001 for each dose effect versus placebo). Percent decreases in gamma-glutamyl transferase averaged 43% for both dose groups and 3% in the placebo group. Median levels of 7-alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, fell by 77% in the 200-mg group and by 55% in the 50-mg group, but rose by 29% in the placebo group. Both the 50-mg and the 200-mg doses yielded statistically similar effects on all three cholestatic markers.

Although MBX-8025 did not appear to cause or worsen pruritus, 3 of the 35 patients developed rapid, asymptomatic, grade 3 increases in serum levels of alanine aminotransferase, the researchers reported. Two patients were taking 200 mg MBX-8025, and one was taking 50 mg. The effect fully reversed after patients stopped treatment, and was not associated with hyperbilirubinemia. Another patient in the 200-mg group stopped treatment because of what the investigators called “a muscle adverse event [that we] considered drug-related.”

The trial was halted halfway through recruitment, having established proof of concept, the investigators concluded. Because MBX-8025 is primarily excreted in bile, and primary biliary cholangitis obstructs bile flow, affected patients might have had more hepatic exposure to the agent than did those in previous trials, and this might explain the new safety signal, they noted.

CymaBay Therapeutics makes MBX-8025 and funded the trial. Dr. Jones disclosed ties to Intercept, GlaxoSmithKline, Novartis, and Falk. Eight coinvestigators disclosed employment with or other ties to CymaBay Therapeutics. The other three coinvestigators had no relevant disclosures.

The investigational peroxisome proliferator–activated receptor delta agonist MBX-8025 exhibited a “striking anticholestatic effect” without causing pruritus in a phase II trial of 35 patients with primary biliary cholangitis.

But three patients developed grade 3 increases in serum transaminase levels that reversed when they stopped treatment, David Jones, MD, of the University of Newcastle (United Kingdom) and his associates will report at the annual meeting of the American Association of Liver Diseases. The effect seemed dose related, so future studies should explore whether MBX-8025 is effective at lower doses, they concluded in a late-breaking abstract released in advance of the meeting.

Primary biliary cholangitis, an important cause of end-stage liver disease, is initially associated with fatigue and pruritus and often responds inadequately to first-line treatment with ursodeoxycholic acid. MBX-8025 selectively activates the peroxisome proliferator–activated receptor delta, a nuclear receptor that regulates genes involved in lipid storage and transport. In prior studies, MBX-8025 decreased serum alkaline phosphatase (ALP) levels and seemed well tolerated in healthy volunteers and patients with dyslipidemia, the investigators noted.

As a next step, they randomly assigned patients with primary biliary cholangitis whose ALP levels remained at least 1.67 times the upper limit of normal, despite at least 12 months of ursodeoxycholic acid therapy, to receive either placebo or 50 or 200 mg MBX-8026 for 12 weeks. The primary outcome was percent change in ALP levels, which, at baseline, averaged 233 U/L in the placebo group, 312 U/L in the 50 mg group, and 248 U/L in the 200-mg group.

At the end of treatment, ALP levels had dropped by an average of 63% in the 200-mg MBX-8025 group, 53% in the 50-mg group, and 2% in the placebo group (P less than .0001 for each dose effect versus placebo). Percent decreases in gamma-glutamyl transferase averaged 43% for both dose groups and 3% in the placebo group. Median levels of 7-alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis, fell by 77% in the 200-mg group and by 55% in the 50-mg group, but rose by 29% in the placebo group. Both the 50-mg and the 200-mg doses yielded statistically similar effects on all three cholestatic markers.

Although MBX-8025 did not appear to cause or worsen pruritus, 3 of the 35 patients developed rapid, asymptomatic, grade 3 increases in serum levels of alanine aminotransferase, the researchers reported. Two patients were taking 200 mg MBX-8025, and one was taking 50 mg. The effect fully reversed after patients stopped treatment, and was not associated with hyperbilirubinemia. Another patient in the 200-mg group stopped treatment because of what the investigators called “a muscle adverse event [that we] considered drug-related.”

The trial was halted halfway through recruitment, having established proof of concept, the investigators concluded. Because MBX-8025 is primarily excreted in bile, and primary biliary cholangitis obstructs bile flow, affected patients might have had more hepatic exposure to the agent than did those in previous trials, and this might explain the new safety signal, they noted.

CymaBay Therapeutics makes MBX-8025 and funded the trial. Dr. Jones disclosed ties to Intercept, GlaxoSmithKline, Novartis, and Falk. Eight coinvestigators disclosed employment with or other ties to CymaBay Therapeutics. The other three coinvestigators had no relevant disclosures.