Erasca Gains IND Clearance for Pan-KRAS Inhibitor ERAS-4001

Erasca, Inc., a precision oncology company focused on developing treatments for cancers driven by the RAS/MAPK pathway, announced that the U.S. FDA has cleared its IND application for ERAS-4001. This potential first-in-class and best-in-class pan-KRAS inhibitor is designed to treat patients with KRAS-mutant (KRASm) solid tumors. The company has also received IND clearance for ERAS-0015, a promising pan-RAS molecular glue, both ahead of the company's expected timeline. Initial Phase 1 monotherapy data for these RAS-targeting programs are anticipated in 2026.

Jonathan E. Lim, M.D., CEO and co-founder of Erasca, expressed enthusiasm about the advancement of their RAS-targeting franchise. With the IND clearance for ERAS-4001, Erasca is set to move forward with clinical trials. ERAS-4001 targets various KRAS mutations and KRAS wildtype while sparing HRAS and NRAS, potentially offering a superior therapeutic window compared to other pan-RAS inhibitors. This innovative approach could address the 2.2 million people diagnosed globally each year with KRASm tumors by overcoming treatment resistance seen in current therapies.

The BOREALIS-1 Phase 1 trial will assess ERAS-4001’s safety, tolerability, pharmacokinetics, pharmacodynamics, and initial effectiveness in patients with KRASm solid tumors. Concurrently, ERAS-0015 is being tested in the AURORAS-1 Phase 1 trial, targeting patients with RAS-mutant solid tumors.

ERAS-0015 is an oral, highly potent pan-RAS molecular glue designed to inhibit RAS signaling with a potential best-in-class profile. Preclinical studies reveal that ERAS-0015 exhibits significantly higher binding affinity to cyclophilin A (CypA) compared to the leading pan-RAS molecular glue in development. It also shows greater potency in inhibiting RAS and superior in vivo antitumor activity, evidenced by comparable or improved tumor growth inhibition or regression at much lower doses than its competitors. ERAS-0015 aims to prevent resistance against mutant-selective inhibitors by inhibiting RAS wildtype variants, and it has demonstrated favorable ADME and PK properties in various animal models.

In parallel, ERAS-4001 is an oral, potent, and selective pan-KRAS inhibitor designed to potentially be both first-in-class and best-in-class. ERAS-4001 has shown strong preclinical in vitro efficacy against KRAS G12X mutations and KRAS wildtype amplifications, which may help reduce treatment resistance via KRAS wildtype activation. The inhibitor was inactive against HRAS and NRAS wildtype proteins, suggesting that it may offer a better therapeutic window than pan-RAS inhibitors. ERAS-4001 effectively targets both active and inactive states of KRAS with single-digit nanomolar IC50s and has induced tumor regression in multiple KRASm models in vivo. Preclinical studies indicated encouraging ADME and PK properties for ERAS-4001.

Erasca's mission centers on erasing cancer through precision oncology, focusing specifically on the RAS/MAPK pathway. The company, founded by leaders in oncology and RAS targeting, aims to develop innovative therapies and combination regimens to shut down this pathway effectively. Erasca's expertise, combined with guidance from a scientific advisory board of leading RAS/MAPK pathway experts, positions it to pursue its bold goal of eliminating cancer.