Deep modality-agnostic pipeline to shut down the RAS/MAPK pathway

Therapeutic Programs

Our lead product candidates are naporafenib (ERAS-254, our oral pan-RAF inhibitor), ERAS-007 (our oral ERK1/2 inhibitor), and ERAS-801 (our CNS-penetrant EGFR inhibitor). These programs are examples of our innovative strategy to target key upstream and downstream MAPK nodes. We are also advancing multiple other programs targeting key oncogenic drivers in the RAS/MAPK pathway.

Naporafenib: our PAN-RAF inhibitor

Naporafenib is a potential first-in-class pan-RAF kinase inhibitor (with high potency and selectivity against BRAF and CRAF), and has been studied in over 500 patients to date. We are planning to evaluate the molecule in indications where it has already shown promising clinical proof of concept – namely, NRASm melanoma and pan-RAS Q61X tissue agnostic solid tumors, as well as explore various combinations with other programs in our pipeline to target other RAS/MAPK pathway-driven tumors.

ERAS-0015 AND ERAS-4001: OUR RAS-TARGETING FRANCHISE

Our RAS-targeting franchise is advancing molecules that potently and selectively bind oncogenic RAS alterations (e.g., G12X, G13X +/- Q61X) and block activation of wildtype RAS isoforms that mediate tumor resistance. These molecules prevent RAS-mediated signaling either by preventing RAS from binding to downstream effector proteins by forming a RAS-Cyclophilin A protein complex (as in the case of ERAS-0015) or by locking KRAS in the inactive GDP-bound state (as in the case of ERAS-4001). In preclinical studies that included contemporaneous side-by-side comparisons, ERAS-0015 demonstrated 5- to 10-fold greater in vitro and in vivo potency and favorable absorption, distribution, metabolism, and excretion (ADME) properties and pharmacokinetic (PK) performance in animal species over another pan-RAS molecular glue in development. ERAS-4001 is a potent and selective inhibitor of KRAS that has the potential to provide an improved therapeutic window over RAS inhibitors and prevent KRAS wildtype-mediated resistance over mutant-selective approaches. We plan to advance ERAS-0015 and ERAS-4001 into the clinic to treat patients with (K)RASm solid tumors.

ERAS-801: our CNS-penetrant EGFR inhibitor

EGFR-mediated signaling plays a key role in the growth of many tumor types. Targeting of wildtype EGFR (wtEGFR) and mutant variants of EGFR (EGFRm) by small molecules and antibodies has resulted in improved patient outcomes in NSCLC, CRC, and HNSCC. However, the ability of these agents to effectively target wtEGFR and EGFRm in the CNS remains an unmet medical need. The lack of clinical activity is likely multifactorial, but we believe there are two primary reasons why approved EGFR inhibitors are not effective: (1) the molecules do not penetrate the CNS well, and (2) the molecules are weak inhibitors of the EGFRvIII mutant protein as homodimers or heterodimers that include wildtype EGFR. ERAS-801 is designed to be a potent, selective, reversible, and orally available small molecule with both: (1) highly enhanced CNS penetration (3.7:1 brain:plasma ratio in mice) and (2) the ability to target both EGFR alterations such as EGFRvIII, the most common mutant form of EGFR found in GBM, and wtEGFR, which heterodimerizes with EGFRvIII.

ERAS-007: our ERK 1/2 inhibitor

ERAS-007 is the most potent ERK inhibitor in development and has the longest target residence time among ERK inhibitors that we are aware of. ERAS-007 has been evaluated as a single agent in a Phase 1 trial in patients with advanced solid tumors. Multiple objective responses were observed in patients with various tumor types, all of which harbor alterations (BRAF, HRAS, and NRAS) in the RAS/MAPK pathway, including melanoma, salivary gland cancer, NSCLC, and thyroid cancer. The adverse event profle was reversible, manageable, and consistent with ERK inhibition. These findings support the development of ERAS-007 as a monotherapy or in combination in diverse, biomarker-selected tumor types.

ERAS-601: our SHP2 inhibitor

ERAS-601 is a potent, selective oral inhibitor of SHP2, a convergent node for upstream RTK signaling and a critical “on/off switch” that activates GTP-bound RAS signaling. SHP2 also drives tumor cell proliferation and development of resistance. Our SHP2 inhibitor is designed to block oncogenic signal transduction and delay the onset of resistance—thereby potentially serving as a backbone of combination therapy.

ERAS-12: our EGFR D2/D3 bispecific antibody program

Inhibition of wildtype EGFR signaling mediated by overexpression of EGFR has shown promise in treating various tumors, including HNSCC and CRC. In tumors where overexpression of EGFR is thought to be the primary driver of EGFR signaling, an antibody-based approach is the most effective way to target the receptor, and approved antibodies have demonstrated good tolerability as well as activity by inhibiting EGFR activation and mediating antibody-dependent cellular cytotoxicity (ADCC), a process by which the antibody alerts the immune system to attack the bound tumor cell. However, all approved anti-EGFR antibodies target domain III (D3) only, which is the inactive conformation of wildtype EGFR, and no approved antibodies target domain II (D2), which is the active, ligand binding, conformation of wildtype EGFR. Antibodies targeting D2 are expected to be more effective when epidermal growth factor (EGF) or other members of the EGF family are overexpressed. We are developing a bispecific antibody that is active against both the inactive and active conformations of wildtype EGFR.