Emricasan (Conatus/Novartis) is a small molecule which inhibits pan-caspases. These enzymes are key modulators of apoptosis and inflammation, and chronically elevated apoptosis is often present in liver disease, which leads to the accumulation of apoptotic cells and the release of apoptotic bodies. These end products of apoptosis are engulfed by surrounding tissues which promote disease pathology and inflammation. Caspase-mediated apoptosis is mainly driven by caspase 3 and 7, which cleave cytokeratin-18 (CK18) to create the protein fragment, cleaved CK18 (cCK18). This is a mechanistic biomarker of apoptosis, and elevated levels have been associated with severity in NASH patients. Additionally, cCK18 has also been observed to increase with disease severity in patients with cirrhosis. Therefore, emricasan’s ability to inhibit caspases could reduce the loss of hepatocytes and production of apoptotic bodies that promote disease progression.
Prospects for emricasan look dim after it failed to meet the primary endpoint in all of its Phase IIb trials (ENCORE-NF, ENCORE-PH, and ENCORE-LF). Furthermore, results from the 24-week extension of the ENCORE-PH trial were negative and did not reach the predefined objectives. Novartis had recently planned a combination trial with tropifexor and emricasan, though it is likely that the company will reconsider this after evaluating the data. Thus, we expect that emricasan will likely be discontinued as a monotherapy treatment for non-alcoholic steatohepatitis (NASH).
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