MRTX1133: The First Clinical KRAS(G12D) Inhibitor is Discontinued

The clinical success of ibrutinib (Imbruvica®) validated BTK inhibition as a therapeutic strategy for B cell malignancies while challenging the prevailing assumption that covalent kinase inhibitors would be too promiscuous for clinical use. Despite its off-target kinase activity and associated toxicities, ibrutinib established a blueprint for rationally designed covalent inhibitors and launched a new generation of BTK-targeted therapies that have since expanded beyond oncology into immunology and neurological diseases.

Camlipixant is a highly selective P2X3 receptor antagonist discontinued for chronic cough after mixed results in the Ph. 3 CALM study program. In the Ph. 2b SOOTHE trial, 50 mg BID significantly reduced 24-hour cough frequency versus placebo, but while the same dose met the primary endpoint in CALM-1, it failed to achieve significance in the CALM-2 study. GSK is now evaluating camlipixant in the Ph. 2b BALANCE trial for IBS-associated abdominal pain, where it could provide clinical validation of P2X3 antagonism in a new indication.

Gedatolisib (Revtorpyk®) is an IV-dosed, ATP-competitive, multi-target inhibitor of the PI3K/AKT/mTOR pathway that blocks all four class I PI3K isoforms plus mTOR, providing broader pathway suppression and potentially limiting compensatory feedback compared with single-node inhibitors. Discovered at Wyeth and subsequently developed by Pfizer and Celcuity, gedatolisib was FDA approved in July 2026 in combination with fulvestrant, with or without palbociclib, for adults with HR+/HER2– breast cancer without a detected PIK3CA mutation in the second-line, metastatic setting.

Zilurgisertib (Atebrioz®) received FDA approval as the first ALK2 inhibitor for the treatment of FOP patients 12 and older on the strength of Ph. 2 PROGRESS study data, demonstrating a 99.9% reduction in new heterotopic ossification lesion volume. Discovered by Novartis, developed by Incyte, and licensed to Mirum Pharmaceuticals, the molecule’s discovery story was shared by Thomas Ullrich at the EFMC Medicinal Chemistry 2026 First Time Disclosures session and detailed mitigation of a phototoxicity liability and the validation of a compound exposure correlation between blood and saliva.

NVP-KFA115 is Novartis’ second-generation CRBN-mediated molecular glue degrader of the IKZF2 and IKZF4 transcription factors that advanced to Ph. 1 for advanced tumors. Clinical cardiac and peripheral neuropathy findings with the first-generation agent, NVP-DKY709, prompted development of an improved molecule. As revealed at ACS Fall 2026, a serendipitous synthetic side product mitigated the predecessor’s cardiac liabilities, and subsequent optimization of permeability and degradation potency delivered NVP-KFA115.