Our lead product candidate, milademetan, is a small molecule, oral inhibitor of MDM2 and is being developed in patients with MDM2-dependent cancers. Historically, MDM2 inhibition has presented treatment challenges due to dose-limiting, on-target hematologic toxicities. We believe an MDM2-targeted therapy must possess certain pharmacological characteristics related to potency, pharmacokinetics and drug accumulation to allow for the design of an optimized dosing schedule. An optimized dosing schedule is intended to improve peak drug exposure leading to apoptosis and cell cycle arrest during the dosing period, while permitting hematopoietic precursor cell recovery during the dosing break, thereby minimizing hematologic toxicity.
Precision oncology underlies Rain’s developmental philosophy across all its pipeline programs. Each program targets aberrant genetic or cell signaling networks in cancers with an appropriate clinical development strategy employing diagnostic assays to identify biomarkers predictive of efficacy. We've learned from the past to prioritize pairing drug and patient. The precision strategy is aimed squarely at improving historical rates for program success by maximizing patient benefit.
Our approach leverages currently available tumor genetic testing strategies to enroll and treat patients with advanced cancer. We anticipate employing companion diagnostics and partnerships with industry-leading assay developers to identify patients based on molecular biomarkers indicating oncogene addiction and dependency on specific cellular signaling networks.
Cancers with homologous recombination deficiencies (HRD+) are typically identified due to a loss of functional BRCA1/2, which is the most reliable and preferred repair mechanism in cells. HRD+ cancers have several alternative pathways to rely upon if the BRCA-based homologous recombination (HR) route is non-functional.
Normal cells rely primarily upon the BRCA1/2 pathway for double stranded DNA break repair through HR. PARP inhibitors prevent timely repair of single-stranded DNA breaks, which leads to double-stranded DNA breaks that cannot be repaired in HRD cancers. This mechanism explains the utility of PARP inhibitors in HRD+ cancers.
RAD52 facilitates DNA repair and plays a critical role in pathways alternative to both the BRCA1/2 HR and the non-homologous end joining pathway for which PARP is a major constituent. Therefore, in cells resistant to PARP therapy that may already be deficient in BRCA1/2, multiple alternative DNA repair routes that rely upon RAD52 may be required. RAD52 inhibition is anticipated to lead to disruption of DNA repair in HRD+ cancers leading to cancer cell apoptosis.