Ulixertinib (BVD-523): A Comprehensive Monograph on a First-in-Class ERK1/2 Inhibitor

Executive Summary

Ulixertinib (also known as BVD-523) is an investigational, orally available, small molecule drug representing a first-in-class, highly selective, and potent inhibitor of the extracellular signal-regulated kinases 1 and 2 (ERK1/2). As a reversible, ATP-competitive inhibitor, Ulixertinib targets the terminal node of the mitogen-activated protein kinase (MAPK) signaling cascade, a pathway frequently hyperactivated in over a third of human cancers due to oncogenic mutations in genes such as BRAF and RAS. This mechanism provides a strong therapeutic rationale for its use in tumors driven by this pathway, and critically, offers a strategy to overcome acquired resistance to upstream MAPK inhibitors (e.g., BRAF and MEK inhibitors), which often involves the reactivation of ERK signaling.

Clinical development, led by BioMed Valley Discoveries, has established a recommended Phase II dose (RP2D) of 600 mg twice daily in adults, based on a foundational Phase I dose-escalation and expansion study (NCT01781429). This trial demonstrated preliminary but meaningful clinical activity, including durable partial responses in patients with advanced solid tumors harboring NRAS mutations, as well as both V600 and non-V600 BRAF mutations. Notably, responses were observed in patients who had previously progressed on BRAF and/or MEK inhibitor therapy, validating its core strategic application. However, the drug's efficacy is context-dependent, as a Phase II trial in metastatic uveal melanoma (NCT03417739), a disease driven by GNAQ/GNA11 mutations, failed to show objective responses.