Erasca (ERAS) R&D Update summary

RAS-targeting franchise progress

• ERAS-0015 demonstrated 8-20x higher binding affinity to cyclophilin A and 5-10x greater in vivo potency than RMC-6236, with favorable ADME, PK, and tumor distribution properties.

• ERAS-4001, a pan-KRAS inhibitor, showed potent inhibition of KRAS in both GTP- and GDP-bound states, achieving tumor stasis and regression in multiple KRAS mutant models.

• Both ERAS-0015 and ERAS-4001 show best-in-class or first-in-class potential with strong preclinical potency and favorable pharmacokinetics.

• GLP toxicology studies for ERAS-0015 are complete and for ERAS-4001 are near completion, supporting IND filings in H1 2025 and Q1 2025, respectively.

• CMC activities for both molecules are advancing per plan, with drug substance and product development ongoing.

Naporafenib clinical development and SEACRAFT trials

• SEACRAFT-1 trial in RAS Q61X solid tumors showed a 23% response rate and 71% disease control rate, but did not meet the threshold for a tissue-agnostic indication.

• In NRAS mutant melanoma, SEACRAFT-1 showed a 40% response rate (4/10), with three confirmed and one unconfirmed partial response, and 70% of patients remained on treatment at data cutoff.

• Mandatory rash prophylaxis reduced grade ≥3 dermatologic toxicities from ~30% to ~12% and drug discontinuations from ~20% to <10%, while increasing dose intensity to nearly 99% for naporafenib and 100% for trametinib.

• Median progression-free survival for naporafenib plus trametinib is ~5 months, and median overall survival is 13-14 months, both superior to historical controls.

• Naporafenib plus trametinib received Fast Track Designation from the FDA for NRASm melanoma.

Clinical progress and regulatory alignment

• Positive Phase 1b SEACRAFT-1 data for naporafenib plus trametinib support the ongoing Phase 3 SEACRAFT-2 trial.

• Regulatory alignment with US and European agencies paves the way for potential tissue-specific approval in melanoma; Stage 1 randomized data from SEACRAFT-2 expected in 2025.

• SEACRAFT-2, a pivotal trial in NRAS-mutant melanoma, is ongoing with high investigator enthusiasm and on-track site activation.