NRX-0305, an orally bioavailable, CNS penetrant pan-mutant BRAF degrader demonstrates robust efficacy in intracranial models of melanoma brain metastasis and primary glioma

Mutations in BRAF , a key component of the MAPK pathway, drive constitutive pathway activation and oncogenic transformation across multiple tumor types. BRAF V600 mutations occur in approximately 40-50% of cutaneous melanomas, of which 30-50% develop brain metastases during disease. CNS progression is common following acquired resistance to BRAF inhibitor and MEK inhibitor combination therapy, with 40-60% of patients experiencing intracranial relapse despite initial systemic response. BRAF mutations are also detected in ~5-8% of primary gliomas, predominantly in pediatric and epithelioid subtypes. Although approved BRAF inhibitors provide meaningful benefit to patients with Class 1 mutations, there is a high unmet need for patients with brain involvement due to limited CNS activity of existing therapies.We developed NRX-0305, a CNS-penetrant, pan-mutant BRAF degrader designed to selectively degrade mutant BRAF across Class 1/2/3 mutant tumors while sparing wildtype BRAF. Pharmacokinetic and pharmacodynamic studies following oral dosing confirmed brain exposure, robust BRAF degradation, and pathway inhibition. Daily oral administration of NRX-0305 demonstrated potent single-agent efficacy in multiple intracranial models of BRAF-mutant melanoma and glioma. In a BRAF inhibitor-resistant melanoma brain metastasis PDX model, NRX-0305 achieved dose-dependent efficacy and significantly improved survival relative to vehicle and dabrafenib treatment, demonstrating superiority to clinically approved BRAF inhibitors.These findings establish pan-mutant BRAF degradation as a promising therapeutic strategy for BRAF-mutant CNS malignancies and highlight NRX-0305's potential to overcome the limited CNS activity and treatment-emergent resistance associated with BRAF targeted therapies.