Cirius believes the results of a Phase IIb study could portend future clinical success for its next-generation insulin sensitizer to treat NASH, despite the compound’s failure to reach statistical significance in the trial’s primary analysis. But the privately held company still isn’t saying whether investors will sign on to fund further study of the compound.
CEO Bob Baltera told BioCentury the company believes the totality of the trial’s data -- including measures of MSDC-0602K’s effects on glucose metabolism and liver enzymes as well as an exploratory post hoc analysis of liver biopsy results -- suggests that the compound could show both a cardiovascular benefit and effects on liver outcomes in a fully powered Phase III study to treat non-alcoholic steatohepatitis.
Data presented Friday from the Phase IIb EMMINENCE trial showed MDSC-0602K led to a trend toward improvement in non-alcoholic fatty liver disease activity score (NAS), but the results were not significant. The top dose of three led to an improvement of at least 2 points in NAS in 39.5% of patients vs. 29.7% for placebo (p=0.158). Cirius will present the results on Monday at the American Association for the Study of Liver Disease meeting in Boston.
Baltera said the primary analysis plan in EMMINENCE was designed to remove the potential for bias by using a “scrambled” re-read of baseline characteristics. Cirius conducted a post hoc analysis that used qualifying baseline readings and re-interpreted certain missing data as treatment failures; in that analysis, the top dose led to a 42.6% response rate vs. 27.7% for placebo (p=0.029).
Coupled with significant improvements in insulin resistance, glucose metabolism and liver enzyme levels, Cirius believes those results suggest enough likelihood of Phase III success to move forward with a pivotal study of the mTOT inhibitor.
As Cirius maps out a clinical plan, it may also need to raise cash; it sought to go public this year but has yet to do so. An amended IPO prospectus filed in February said Cirius had $20.2 million remaining in its till, and had raised $66.6 million since its 2015 inception. A subsequent filing in May said Cirius had raised another $7.5 million in equity funding. Baltera declined to discuss the company’s funding situation or financial goals.
Baltera said Cirius intends to meet with FDA to discuss a plan for a pivotal trial. The company believes one study could satisfy regulators’ benchmark for conditional approval based on liver biopsy data and show a longer-term cardiovascular outcomes benefit.
Biomarkers and other non-invasive endpoints have begun to upstage biopsy-derived endpoints in NASH, although they are still far from registrational (see "NASH: How Non-Invasive Biomarkers Promise to Displace Biopsies").
Cirius has not yet chosen a dose for the Phase III study; Baltera said it may test more than one.
MSDC-0602K is a next-generation therapy in the thiazolidinedione (TZD) class that is designed to act on the mitochondrial pyruvate carrier complex while avoiding activation of PPARγ, which can lead to edema. Baltera said edema rates for MDSC-0602K and placebo were “identical” in the Phase IIb trial (see “Cirius Safety”).
TZDs are often prescribed for Type II diabetes. Baltera said that by blunting the effects of overeating and caloric intake on downstream metabolic issues, drugs in that class can affect fibrosis in NASH patients while also showing a CV benefit.
Cirius’ private investors include Frazier Healthcare Ventures, Novo A/S, Adams Street Partners, Renaissance Venture Capital Fund and Hopen Life Science Ventures (see “More NASH Cash”).
Targets: mTOT - Mitochondrial target of thiazolidinedione; PPARγ - Peroxisome proliferation activated receptor γ