Non-alcoholic steatohepatitis, or NASH, is a liver disease characterized by excess liver fat, inflammation and fibrosis. In 2015, there were an estimated 17 million people in the United States with NASH, which is expected to increase to an estimated 27 million people by 2030. Left untreated, patients’ disease may progress to liver failure, which is life-threatening without a successful liver transplant. NASH is expected to become the leading cause for liver transplants in the United States. Additionally, patients with NASH often present with metabolic disease and other co-morbidities, which is likely to require combination therapy.
Currently, there are no approved therapies for NASH. Diet and lifestyle modifications for weight loss are encouraged; however, adherence by patients is low. Medications are used to address common comorbidities of NASH, such as diabetes, but the effectiveness of this approach to treat or control NASH has been inconclusive.
FXR agonism has been investigated in large-scale clinical trials and has shown clinically relevant improvements in NASH. We believe that potency, sustained exposure and continuous target engagement are key to optimizing therapeutic benefit with an FXR targeted therapy. MET409 and MET642 were purposefully designed to be differentiated treatments for NASH as potent, sustained FXR agonists, with the ability to be dosed orally once daily.
Our most advanced product candidate, MET409, has been investigated in a Phase 1b proof-of-concept clinical trial in NASH patients, in which it demonstrated notable improvements in NASH biomarkers after 12 weeks of treatment. To evaluate the potential of our FXR program as the backbone of combination therapy in NASH, we are evaluating MET409 in a Phase 2a combination trial with empagliflozin (Jardiance®),a sodium-glucose cotransport-2 (SGLT2) inhibitor, in patients with both type 2 diabetes mellitus (T2DM) and NASH.
In addition to MET409, we are evaluating a second FXR candidate, MET642, which originates from the same base chemotype as MET409, and has shown comparable FXR target engagement and pharmacology in preclinical studies, as well as increased potency and differentiated pharmaceutical properties. We completed a Phase 1 clinical trial of MET642 in healthy volunteers, and are now evaluating MET642 in a Phase 2a, 16-week, randomized, placebo-controlled trial in patients with NASH. We anticipate selecting a candidate of MET409 or MET642 for a Phase 2b monotherapy biopsy trial in NASH as early as in the second half of 2021 and beginning that trial as early as the end of 2021 if the candidate is MET409 or the first half of 2022 if the candidate is MET642.