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
“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-hour half-life and is suitable for once-daily dosing, according to Perlmutter.
Perlmutter said Eikon presented data at the American Society of Clinical Oncology meeting on EIK1003 combined with full-dose paclitaxel in heavily pretreated ovarian and breast cancer populations. He said more than 90% of enrolled patients had previously received a taxane and that the majority had either responses or stable disease. The hematologic toxicity observed in the combination was consistent with what would be expected from paclitaxel, he said, while emphasizing that the data remain early.
The company is also studying EIK1003 with carboplatin and paclitaxel in a first-line ovarian cancer setting and has evaluated a combination with abiraterone in prostate cancer. Perlmutter said Eikon expects to present EIK1003-abiraterone data at the European Society for Medical Oncology congress, along with additional EIK1004 results.
Yap said combinations should be supported by a clear scientific rationale, evidence that each component contributes to efficacy and an acceptable therapeutic index. He highlighted combinations of PARP1 inhibitors with topoisomerase I payload antibody-drug conjugates as a potentially rational avenue. PARP1 helps remove topoisomerase I complexes from damaged DNA, he said, suggesting that PARP1 inhibition could help sustain the DNA damage caused by those therapies.
For EIK1004, Perlmutter said brain penetration could be important as more breast cancer patients experience central nervous system metastases after systemic treatment. The company is enrolling patients with such disease in early studies, he said. Yap added that systemic therapies able to address both brain metastases and extracranial disease represent an unmet need.
Werner Helicase Program
Eikon also discussed EIK1005, an oral Werner helicase inhibitor developed using the company’s microscopy-based drug discovery platform. Perlmutter said the drug was designed by screening compounds that altered the motion characteristics of Werner helicase.
Werner helicase inhibition is being investigated particularly in tumors with microsatellite instability. Perlmutter said EIK1005 has a preclinical profile that supported initial testing in healthy volunteers and has a half-life of more than nine days, enabling potential once-weekly dosing. The company is now evaluating activity in patients with microsatellite instability and in other patients who may potentially respond, with initial data planned for presentation at ESMO.
Yap said early data reported for Werner helicase inhibitors from other companies have shown modest objective response rates but potentially durable disease control. He characterized the class as promising, citing the duration patients have remained on treatment in early trials and the reported absence of myelosuppression in those programs.
About Eikon Therapeutics (NASDAQ:EIKN)
We are a late-stage clinical biopharmaceutical company dedicated to building a global, fully-integrated organization developing important, innovative medicines to address serious unmet medical needs. We are led by world-renowned drug developers Dr. Roger M. Perlmutter, M.D., Ph.D., and Dr. Roy Baynes, M.D., Ph.D. Our vision is to become a generational leader, by purposefully integrating traditional biology research with advanced engineering to develop better medicines faster. Our initial focus is oncology, where we are advancing a pipeline of drug candidates targeting areas of high unmet need in large indications.
