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 [...]

On Mar. 14th, 2024, resmetirom (REZDIFFRA™) became the first and only medicine approved by the FDA for the treatment of NASH (non-alcoholic steatohepatitis, aka MASH). Resmetirom, an oral, liver-targeting, once-daily THR-β-selective agonist originally discovered at Roche Nutley, was first highlighted as a Molecule of the Month in Dec. 2022. Now, with the FDA’s accelerated approval, this 2023 Molecule of the Year nominee reflects a historic milestone for liver drug discovery. This article reviews how the molecule works, how it was discovered, and why it’s a big deal.

LEO 134310 is a non-steroidal, selective glucocorticoid receptor (GR) agonist in Ph. I for plaque psoriasis. Glucocorticoid receptor modulators are widely used in tissue-restricted forms (think Flonase) for their acute effects, but prolonged engagement of GR is undesirable. Previously LEO Pharma described the identification of this topical [...]

Gamma-secretase is most well-known as a target for Alzheimer’s disease, though such programs have not been successful to date. Nirogacestat is a gamma-secretase inhibitor that Pfizer originally intended to treat AD, but found life at Springworks Therapeutics as a treatment as a first-in-class drug for rare and aggressive desmoid tumors (DTs). Nirogacestat received the first FDA approval for a treatment for desmoid tumors in Nov. 2023, and this article reviews how it was discovered, how the therapeutic hypothesis emerged after confusing assay disconnects, and lessons learned from the program.

MK-1454 (Merck) is an intratumoral stimulator of interferon (IFN) genes (STING) agonist that is being developed for treatment of advanced solid tumors and lymphomas. The molecule follows Aduro’s ADU-S100 , which was terminated after Ph. II due to a lack of substantial activity. Another chemotype of STING agonist, Eisai’s E7766 , has [...]