Created for the Challenge
Nuvalent’s novel drug candidates solve for the dual challenges of kinase resistance and selectivity, with the goal of enabling durable responses for patients with cancer.
(X = N, S, or T)
ROS1 fusions are an oncogenic driver alteration found in up to 3% of patients with non-small cell lung cancer (NSCLC). The clinical utility of approved therapies for ROS1-driven NSCLC is limited by emergent resistance mutations as well as central nervous system (CNS) disease.
NVL-520 is a novel brain-penetrant ROS1-selective inhibitor created to overcome several limitations observed with currently available therapies. NVL-520 is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with the prevalent G2032R “solvent front” resistance mutation and those with the S1986Y/F, L2026M, or D2033N resistance mutations.
We optimized NVL-520 for brain penetrance to potentially improve treatment options for patients with brain metastases. Importantly, we observed that NVL-520 selectively inhibits ROS1 over the structurally related tropomyosin receptor kinase (“TRK”) family to potentially avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients with ROS1-mutant variants. NVL-520 is planned to enter the clinic in the second half of 2021.
ALK fusions are an oncogenic driver alteration found in up to 5% of patients with non-small cell lung cancer (NSCLC). The clinical utility of approved therapies for ALK-driven NSCLC is limited by emergent resistance mutations as well as central nervous system (CNS) disease.
NVL-655 is a novel brain-penetrant ALK-selective inhibitor created to overcome several limitations observed with currently available therapies. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with the solvent front G1202R mutation or compound mutations G1202R / L1196M (“GRLM”), G1202R / G1269A (“GRGA”), or G1202R/L1198F (“GRLF”).
NVL-655 has been optimized for CNS penetrance to improve treatment options for patients with CNS metastases. ALK-selectivity is emphasized to minimize CNS adverse events related to off-target inhibition of the structurally-related tropomyosin receptor kinase (TRK) family. NVL-655 is planned to enter the clinic in the first half of 2022.
The ALK I1171X (X = N, S, or T) / D1203N (“IXDN”) compound mutations are emerging mutations that confer resistance to all available ALK inhibitor therapies for NSCLC. There are no approved therapies for the treatment of NSCLC with IXDN compound mutations.
We are advancing toward a novel, selective, brain-penetrant ALK inhibitor designed to remain active in tumors harboring IXDN compound resistance mutations. We expect to nominate a product candidate in 2022.
HER2 Exon 20 insertions
Mutations in human epidermal growth factor receptor 2 (“HER2” or “ERBB2”) occur in up to 4% of metastatic NSCLCs, with in-frame deletions, insertions, or duplications in exon 20 accounting for 90% of cases (collectively “HER2 Exon 20 Insertions”). Approximately 20% of patients with HER2 mutant NSCLC present with brain metastases, with the percentage increasing upon treatment. There are no approved targeted therapies for NSCLC patients with HER2 Exon 20 Insertions.
We are advancing toward a novel, selective, brain-penetrant HER2 inhibitor to treat patients with HER2 Exon 20 Insertions, including those with brain metastases, and to minimize adverse events and dose-limiting toxicities related to off-target inhibition of epidermal growth factor receptor (“EGFR” or “ERBB1”), a HER2 family member. We expect to nominate a product candidate in 2022.
At Nuvalent we are combining our close partnerships with physician-scientists, rigorous target selection, and disciplined program advancement to explore a robust pipeline of discovery programs with a focus on addressing the limitations of existing therapies for clinically proven kinase targets in oncology.
Our team combines clinical insights with deep expertise in structure-based drug design and oncology drug development to create new programs where we are able to rapidly advance molecules that are designed to precisely target driver kinases and spare off-targets. This molecular optimization and precise targeting, sometimes by avoiding highly similar off-targets, affords therapies designed to improve the lives of patients with cancer.