Date: 2016-05-31
Type of information: Halting of the trial
phase: 2
Announcement: halting of the trial
Company: Cymabay Therapeutics (USA - CA)
Product: MBX-8025 (2-[4-[[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]acetic acid (1:1) lysine dihydrate)
Action
mechanism: PPAR agonist. MBX-8025 is a potent and selective agonist of peroxisome proliferator-activated receptor delta (PPAR?) agonist, a nuclear receptor important for lipid transport, storage and metabolism in liver and muscle.
Disease: primary biliary cholangitis
Therapeutic area: Rare diseases - Hepatic diseases - Liver diseases
Country: Canada, USA
Trial
details: The trial is an 8-week, dose ranging, open label, randomized, Phase 2 study with an 18-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA). (NCT02955602)
Latest
news: * On May 31, 2016, CymaBay Therapeutics announced that it has discontinued its current Phase 2 study of MBX-8025 in patients with Primary Biliary Cholangitis (PBC) after determining that the study met its objective of establishing proof-of-concept for MBX-8025 by showing marked improvements in biochemical markers of cholestasis. The study also identified a treatment emergent signal of transaminase elevations. Subsequent studies will investigate lower doses to optimize risk benefit. The study was a placebo controlled, double blind, dose ranging study of 12 weeks duration in patients who had an inadequate response to ursodiol, as characterized by a persistent elevation in ALP. The study planned to enroll approximately 75 patients who were randomized to receive placebo, 50 or 200 mg doses of MBX-8025. The goal of the study was to assess whether the improvements in biochemical markers of cholestasis observed previously for MBX-8025 in other patient populations would be observed in patients with PBC. The primary endpoint was the percent change in alkaline phosphatase (ALP). A secondary endpoint was the responder rate for patients achieving the composite criteria of serum ALP values less than 1.67xULN with a decrease of at least 15% and normal levels of total bilirubin (TBIL). ALP values were blinded to everyone involved in the study. Additional secondary endpoints were changes in gamma glutamyl transferase (GGT), TBIL and 5’-nucleotidase, other recognized biochemical markers of cholestasis. As these markers were part of the safety surveillance, they were only blinded with respect to the dosing group. It became apparent early in the study that many patients were showing pronounced decreases in these secondary efficacy endpoints, even greater decreases than those observed in earlier clinical studies, suggesting that MBX-8025 was exhibiting a potent anti-cholestatic effect. During the study, three cases of asymptomatic increases in transaminases were observed (two in the 200 mg and one in the 50 mg cohorts). All three were reversible on cessation of treatment and were not accompanied by elevation of TBIL. No transaminase signal was observed in prior Phase 2 studies in which over 120 patients were treated with MBX-8025 at doses between 50 and 200 mg. Since the study had already shown a clear efficacy signal, the company made the decision to discontinue the study, with the knowledge that additional studies at lower doses would be needed. After the study was unblinded, changes in the primary endpoint ALP were analyzed using data available for the 26 subjects enrolled in the study and completing at least two weeks of treatment. According to the original statistical plan, changes in ALP were calculated using the last observation carried forward (LOCF). While additional data may become available as patients complete ongoing study termination visits, this is not expected to affect the results appreciably. The mean decreases from baseline in ALP for the 50 and 200 mg dose groups were 57% and 62%, respectively, vs. 0.37% for placebo (p < 0.0001 for both). The responder rates for the placebo, 50 and 200 mg groups were 10%, 67% and 100%, respectively. The p-values comparing the responder rates for the 50 and 200 mg groups vs. placebo were 0.020 and 0.0004 (Fisher’s Exact Test), respectively. Thus, MBX-8025 exhibits a rapid and potent anti-cholestatic effect in patients with PBC. The lack of a dose response suggests that lower doses could be effective as well. Patients receiving study drug also demonstrated improvements in metabolic parameters, including reductions of LDL-C of 16 and 26% for the 50 and 200 mg dose groups, respectively, vs. 0.8% for placebo after two weeks of dosing. It is also noteworthy that, despite the potent anti-cholestatic effect, no adverse events of pruritus were reported on treatment. A recently completed preclinical study with MBX-8025 show that the main route of elimination of the drug is through bile and that the drug is concentrated in bile. Since patients with PBC have impaired bile flow, we believe that the exposure of the drug to the liver in patients with PBC could have been higher than in prior clinical studies in subjects with normal liver function, explaining both the more potent anti-cholestatic effect and the transaminase signal. * On November 10, 2015, CymaBay Therapeutics announced the initiation of a Phase 2 study of MBX-8025 in patients with primary biliary cholangitis. In this study, patients who have had an inadequate response to ursodiol will be enrolled and randomized to receive either placebo or MBX-8025 (either 50 mg or 200 mg) for 12 weeks. The primary endpoint will be the change in alkaline phosphatase, a parameter that has been used in prior clinical studies with PBC and which is believed to reflect the status of the disease. A variety of secondary outcomes will also be studied. The study is designed to enroll approximately 75 patients in the U.S., U.K., Canada, Germany and Poland and is expected to be completed around the end of 2016.
