NEV-801, a new tumor-targeting and highly selective HIF-1 inhibitor, utilizes a potent camptothecin derivative tethered with a potent podophyllotoxin derivative as antitumor payload. Simultaneous use of two individual topoisomerase I and II inhibitor drugs has been attempted before but the efficacy has been limited by two combined toxicity. In both pre-clinical models and first-in-human trials in advanced, aggressive, drug-resistant tumors NEV-801 demonstrates extremely low toxicity and significantly high efficacy trending with dose escalation.
In pre-clinical studies, NEV-801 demonstrated very strong monotherapy activity, inducing 37.5% complete regressions in imatinib-resistant tumor model CML562 xenograft bearing mice, and 98% tumor growth inhibition in human colon cancer xenograft bearing mice as well as 100% complete response in ovarian TC1 mice model when used in combination with PD-1 and CTLA-4.
Furthermore, NEV-801 was well-tolerated in non-human primate (NHP) toxicology studies and maximum tolerated dose (MTD) was not able to be obtained at very high doses, indicating that its MTD could be at least 10 time higher than that of irinotecan or imatinib.
In phase 1(a) dose escalation human clinical trials NEV-801 demonstrates trending efficacy with dose with 65% disease stabilization across all doses and 12% long term (>9 months) stable disease at higher doses..Additionally,12% of patients reevaluated after four cycles experienced tumor shrinkage of between 10 and 28%.. >250 cycles of drug have been administered to 27 patients. MTD is > 400mg/m2 with no SAEs attributable to drug.
In summary, our data show NEV-801 is a compelling therapeutic candidate for advanced, aggressive, drug-resistant solid tumors and leukemia. The strong anti-tumor activity and superior tolerance suggest NEV-801 has a very wide therapeutic window. Furthermore, the distinct mechanism of drug action and non-overlapping toxicity profile offers the great potential to combine NEV-801 with other therapies for enhanced benefit/risk.