• FMC-220 is a first-in-class covalent activator of p53^Y220C designed to address potency and tolerability challenges of non-covalent approaches

• In preclinical studies, FMC-220 demonstrated unprecedented potency and durable anti-tumor activity in vitro and in vivo at low doses. IND anticipated in 2H 2025

• Frontier’s pipeline of precision medicines continues to progress rapidly, with interim clinical data for FMC-376, an ON+OFF KRAS^G12C inhibitor currently in the Phase 1/2 PROSPER trial, expected 2H 2025 

BOSTON and SOUTH SAN FRANCISCO, Calif., January 9, 2024/ — Frontier Medicines Corporation, a clinical-stage precision medicine company seeking to unlock the proteome to advance transformational therapies, today announced the selection of FMC-220, the first covalent p53^Y220C activator designed to overcome the limitations of potency and durability seen in non-covalent approaches. FMC-220 represents a groundbreaking advancement, with the potential to provide transformative benefits for patients with tumors harboring an important mutant of p53. Preclinical studies demonstrate that FMC-220 delivers unprecedented potency and durable anti-tumor activity both in vitro and in vivo, achieving pronounced tumor regression at low doses. This innovative drug candidate leverages a covalent design to deliver prolonged target engagement, driving durable activation of p53 function inducing tumor cell senescence and importantly, cell death.

“This is an exciting and transformational year for Frontier Medicines as we look forward to interim clinical data for FMC-376, our novel dual KRAS^G12C inhibitor, and move our second development candidate, FMC-220, a first-in-class covalent p53^Y220C activator, closer to the clinic,” said Chris Varma, Ph.D., chairman, CEO, and co-founder of Frontier Medicines. “FMC-220 exemplifies the unique advantages of our proprietary Frontier™ Platform, which unlocked Y220C for covalent targeting, shattering the potency barrier that limits non-covalent molecules. This critical mutation is a significant unmet medical need, and we anticipate filing the IND for FMC-220 later this year.”

FMC-220 is a highly selective, covalent small molecule activator designed to provide prolonged target residence time and persistent pharmacodynamic effects. These properties irreversibly block tumor progression by driving senescence and tumor cell death. IND-enabling studies to support the clinical evaluation of FMC-220 in patients with solid tumors and other cancers are ongoing, with a planned Investigational New Drug (IND) application submission to the U.S. Food and Drug Administration (FDA) in the second half of 2025.

About p53^Y220C 

p53 is often referred to as the “guardian of the genome” due to its critical role in maintaining genomic stability, but it can be altered in cancer with mutations such as Y220C. The Y220C mutation destabilizes the p53 protein, impairing its tumor-suppressive functions and contributing to cancer progression. It is estimated to occur in approximately 1-2% of all cancers, with a significant presence in solid tumors such as lung, breast, and colorectal cancers, as well as other cancer types.

About Frontier Medicines

Frontier Medicines is a clinical stage precision medicine company pioneering groundbreaking medicines to transform treatment for genetically-defined patient populations, starting with oncology and immunology. Our proprietary chemoproteomics powered drug discovery engine, the Frontier™ Platform, leverages covalent chemistry and machine learning to unlock hard-to-treat disease causing proteins for drug development. Today, we are advancing a diversified pipeline of wholly-owned precision medicines against the most important drivers of cancer and high-value immunology programs. Our lead candidate, FMC-376, is a dual inhibitor of ON+OFF KRAS^G12C. FMC-376 is a potential best-in-class therapy designed to completely block both forms of the KRAS mutation to overcome the lack of response and resistance seen with single-acting KRAS^G12C inhibitors. For more information, please visit www.frontiermeds.com.  Follow Frontier on LinkedIn.