JAK kinases are now well-established targets in immunology, but the class has always had safety concerns hanging over it. The safety issues were exacerbated by a recent FDA decision to expand the black box warnings for the class for major cardiovascular events. Inhaled, lung-restricted JAK inhibitors have been of interest because they could [...]

PF-05221304 is a liver targeted inhibitor of acetyl-CoA carboxylase (ACC). ACC is a key regulator of lipid metabolism, and there has been significant interest in ACC inhibitors for the treatment of multiple indications including NASH and diabetes. Pfizer previously took a systemic ACC inhibitor into the clinic (PF-05175157), which was found [...]

Bexotegrast is a dual-selective αvβ6-αvβ1 integrin inhibitor with surprising efficacy and safety data from a Ph. II trial in idiopathic pulmonary fibrosis (IPF). The αv integrins have been studied for decades in indications such as cancer and IPF. Both small molecule and antibody-based integrin inhibitors have demonstrated preclinical toxicities in non-human primates. This article highlights the unmet need for effective therapies for IPF and related conditions, a comparison of bexotegrast with other integrin binders, and possible reasons why bexotegrast is different in terms of safety.

DS-3801b is a non-macrolide GPR38 agonist and a Ph. I clinical candidate for treatment of chronic constipation (SAD 1-100 mg PO). GPR38 is the receptor for the GI hormone motilin, which as the name suggests, regulates GI motility. Agonism of GPR38 is expected to reduce constipation by activating GI tract smooth muscle cells to move things [...]

Resmetirom is an oral, liver-targeting, once-daily THRβ-selective agonist, which in December 2022 became the first drug to meet its primary endpoints in Ph. III for NASH, demonstrating both NASH resolution and no worsening of fibrosis by biopsy over placebo in 316 test patients. Madrigal will file an NDA for resmetirom in 2023, allowing it to [...]