Description：IMPACT has discovered two series of novel PARP inhibitors with more than 60 novel compounds that are many folds more potent than AZD2281 (Olaparib) in multiple in vitro assays, and selected IMP4297 as a clinical candidate for development based on excellent pharmacological and safety profiles. Compared to AZD2281, IMP4297 is much more potent and more selective against BRCA mutation cells vs normal cells. In efficacy studies IMP4297 was 20-fold more potent than AZD2281 in a BRCA1 deficient MDA-MB-436 human breast cancer xenograft mouse model, as well as in a PDX (patient-derived xenograft) mouse model with BRCA1 mutated human triple negative breast cancer. Importantly, IMP4297 caused tumor regression with little body weight change (<5%), and was much more efficacious than AZD2281, consistent with the high in vitro selectivity of IMP4297. In comparison with AZD2281, IMP4297 is not only much more potent, but much more efficacious, with a large therapeutic window in vivo. IMP4297 has the potential to be developed as a ”best-in-class” PARP inhibitor for the treatment of cancers with defects in DNA repair mechanisms, such as with BRCA1 and BRCA2 mutations, including breast, ovarian and prostate cancers. IMP4297 is currently in Phase I dose escalation studies in Australia and in China. Long term (>3-9 months) stable disease has been observed in several patients. Significant decline in tumor biomarkers, as well as tumor size reduction has been observed at doses of 5-20 mg QD in patients with and without BRCA mutation. Only a few mild and transient drug-related hematological AEs were observed, and no drug-related SAE was reported so far. IMP4297 has demonstrated high oral bioavailability and dose-proportional increase of drug blood concentration, as well as much better oral absorption than Olaparib in PK studies. These clinical data suggests that IMP4297 is a potential best-in-class PARP inhibitor which could be highly efficacious and well tolerated in cancer patients.
IP： Five patent applications have been filed for these novel PARP inhibitors, and three patents in China and three patents in the US have been granted.
Status：IMP4297 is undergoing Phase I studies in Australia and in China.
Future Plan：We have developed a fast-to-market clinical development strategy for IMP4297 as a single agent in cancer patients with BRCA mutation.