Eikon Therapeutics Eyes Safer PARP1 Cancer Treatments With EIK1003, EIK1004

Eikon is advancing highly selective PARP1 inhibitors EIK1003 and EIK1004, designed to preserve anticancer activity while potentially reducing the anemia, neutropenia and thrombocytopenia associated with dual PARP1/2 inhibitors.

EIK1004 is brain-penetrant for potential use in patients with central nervous system metastases.

EIK1003 is being tested in combinations including paclitaxel, carboplatin/paclitaxel and abiraterone.

Early paclitaxel data showed responses or stable disease in most heavily pretreated patients, though the company emphasized that results remain preliminary and that dose adjustments addressed a heart-rate-related off-target effect.

Eikon’s oral Werner helicase inhibitor EIK1005 is entering patient testing, particularly in microsatellite-instability tumors. Its more-than-nine-day half-life could support once-weekly dosing, while early industry data suggest the drug class may provide durable disease control without significant myelosuppression.

Eikon Therapeutics NASDAQ: EIKN outlined its development strategy for selective PARP1 inhibitors and its Werner helicase inhibitor during a discussion hosted by Cantor biotech analyst Imogen Mansfield. President, Chief Executive Officer and Board Chair Roger Perlmutter and MD Anderson Cancer Center’s Vice President and Head of Clinical Development Tim Yap discussed the rationale for improving on earlier PARP inhibitor therapies, which commonly inhibit both PARP1 and PARP2.

PARP inhibitors are used in cancers with defects in homologous recombination DNA repair, including tumors with BRCA1 or BRCA2 alterations. Yap described synthetic lethality as the approach of targeting a remaining DNA-repair pathway in tumor cells that have already lost another critical repair mechanism. While normal cells retain enough repair capacity to survive, tumor cells may undergo cell death when PARP activity is inhibited, he said.

Focus on PARP1 Selectivity Yap said the clinical rationale for PARP1-selective drugs centers on reducing the hematologic toxicity associated with PARP2 inhibition. PARP2 plays a role in erythropoiesis, and inhibition may contribute to anemia, neutropenia and thrombocytopenia, he said. The hope is that selectively targeting PARP1 could permit higher drug exposure, fewer dose interruptions and better combination options than first-generation dual PARP1/2 inhibitors.

“What we are really targeting is homologous recombination deficiency,” Yap said, noting that BRCA1 and BRCA2 are among several genetic alterations that can serve as markers of that condition. He also cited PALB2, RAD51C, RAD51D, FANCA, CHEK1, CHEK2 and ATM alterations as potentially relevant.

Perlmutter said the company’s EIK1003 and EIK1004 were identified through a partnership with China-based Impact Therapeutics. EIK1003 is not designed to penetrate the brain, while EIK1004 is brain-penetrant. He said the molecules show between 650-fold and 800-fold enzymatic selectivity for PARP1. Both speakers cautioned that selective PARP1 inhibition may not eliminate myelosuppression entirely. Yap said PARP1 inhibition itself could still cause some bone marrow suppression, but dialing out PARP2 inhibition could produce a meaningful difference relative to dual inhibitors.

Combination Development Strategy Eikon is evaluating whether the tolerability profile of EIK1003 can support use in combination with other cancer therapies. Perlmutter said the company has explored doses from 10 milligrams to 160 milligrams for EIK1003 and identified an off-target phosphodiesterase effect that can increase heart rate. He said the company monitored the effect and adjusted dosing accordingly. EIK1003 has an approximately 24...