Jazz Pharmaceuticals plc (NASDAQ:JAZZ) and collaboration partner Redx Pharma (AIM: REDX) today presented data showing the pan-RAF kinase inhibitor, JZP815, was active in multiple RAF- and RAS-mutant tumor pre-clinical models, with a pharmacokinetic profile that may provide drug exposure required for target engagement in humans.
“As a precision pan-RAF inhibitor with a differentiated mechanism of action, JZP815 is a promising drug candidate for several types of difficult-to-treat solid tumors, including colorectal cancer, non-small cell lung cancer, melanoma and ovarian cancer,” said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. “By not inducing paradoxical pathway activation, which can stimulate the growth of certain cancers, JZP815 may offer a significant advancement in the pan-RAF inhibitor class with the potential to address unmet patient need. We look forward to submitting the investigational new drug application for JZP815 this year.”
JZP815 targets specific components of the mitogen-activated protein kinase (MAPK) pathway, namely all three RAF proteins – ARAF, BRAF and CRAF – that when activated by oncogenic mutations, can be a frequent driver of human cancer.
Pre-clinical data of JZP815 administered orally as both a monotherapy and in combination with mitogen-activated protein kinase (MAPK) pathway inhibitors were presented at the American Association for Cancer Research 2022 Annual Meeting (AACR). Key findings of several pre-clinical models include1:
- JZP815 inhibited all 3 RAF kinase family members (ARAF, BRAF, CRAF) at low-to-sub nanomolar potencies in biochemical assays.
- JZP815 did not induce significant paradoxical pathway activation, observed with approved first generation BRAF-selective inhibitors, while demonstrating equivalent cellular potencies for MAPK pathway inhibition driven by either mutant RAF monomers or dimers or mutant RAS-induced RAF dimers in tumor cells.
- JZP815 significantly inhibited tumor growth, including inducing tumor regression, as a single agent in multiple mouse xenograft solid tumor models harboring RAS and/or BRAF mutations.
- JZP815’s pharmacokinetic profile sustained on-target pathway pharmacodynamic responses in a predictable dose and time dependent manner.
- JZP815 demonstrated enhanced activity when combined with inhibitors of other MAPK pathway components including MEK1/2, SOS1, SHP2 and EGFR inhibitors in both class 2 and class 3 mutant BRAF patient-derived tumor cells ex vivo, and KRAS mutant NSCLC and colorectal cancer xenografts in vivo.
The full Jazz presentation abstract, titled, “JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models” is available at https://www.abstractsonline.com/pp8/#!/10517/presentation/15283.
Jazz acquired JZP815 from Redx Pharma, and the two companies are collaborating on this pre-clinical research. Jazz plans to submit an IND for JZP815 this year.
