Trial of combo therapy for MASH-related cirrhosis to start this year
Denifanstat-resmetirom combo targets liver scarring
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Sagimet Biosciences said it expects a clinical trial testing a combination therapy in people with cirrhosis, or irreversible liver scarring, due to metabolic dysfunction-associated steatohepatitis (MASH), a severe form of steatotic liver disease, to start in the second half of this year.
The proof-of-concept Phase 2 trial will evaluate Sagimet’s experimental oral therapy denifanstat in combination with Madrigal Pharmaceuticals’ resmetirom, the active ingredient in Rezdiffra, a therapy approved for people with non-cirrhotic MASH.
The trial plan follows positive data from a Phase 1 clinical trial (NCT07216313) that evaluated the combo’s safety, tolerability, pharmacokinetics (movement into, through, and out of the body), and drug interactions in healthy adults.
“We completed our Phase 1 [pharmacokinetics] clinical trial of denifanstat and resmetirom combination and anticipate advancing the combination into a proof-of-concept Phase 2 clinical trial in [MASH-related cirrhosis], for which there are currently no approved treatments, in the second half of the year,” David Happel, CEO of Sagimet, said in a company press release.
MASH, formerly known as nonalcoholic steatohepatitis, is marked by the buildup of fat in the liver that leads to inflammation and scarring (fibrosis). In some cases, this can progress to cirrhosis, where fibrosis becomes irreversible and interferes with liver function.
Conditional approval, breakthrough therapy
Rezdiffra is an oral medication taken once daily that activates thyroid hormone receptor beta, a protein involved in processes linked to liver fibrosis in MASH. It is conditionally approved both in the U.S. and Europe to treat adults with MASH and moderate to advanced liver fibrosis who have not developed cirrhosis. Conditional approvals allow treatments to be made available based on early clinical evidence indicating potential benefits while additional studies are conducted to confirm their effectiveness.
Denifanstat is an experimental oral therapy that works by suppressing fatty acid synthase, a protein responsible for producing fat in the liver. It is therefore expected to reduce fat accumulation associated with MASH. It holds U.S. breakthrough therapy designation, a status intended to accelerate its development and regulatory review, for people with MASH and moderate to advanced fibrosis without cirrhosis.
Results from a Phase 2b clinical trial (NCT04906421) showed denifanstat was more effective than a placebo at resolving MASH without worsening liver fibrosis in adults with biopsy-confirmed disease and moderate to severe liver fibrosis. Positive effects were also reported among those with severe liver fibrosis.
Sagimet initially planned to move denifanstat into Phase 3 testing, but later adjusted its development strategy to evaluate whether combining denifanstat with resmetirom could benefit MASH patients with cirrhosis.
Preclinical data have supported this hypothesis, showing greater reductions in liver disease markers with the therapy than with either individual therapy in two mouse models of MASH.
The Phase 1 trial, which started dosing last fall, tested single and multiple doses of the denifanstat-resmetirom combination in 40 healthy volunteers. According to Sagimet, the combination therapy was generally well tolerated, without safety concerns. There were no reports of serious adverse events, clinically significant laboratory abnormalities, or treatment discontinuations.
These results will inform the design of the upcoming proof-of-concept Phase 2 trial in MASH patients with cirrhosis, including the optimal dose of each therapy. The trial’s start date will depend on discussions with regulators.
