Debiopharm and Repare Therapeutics Inc. announced that the first patient has been dosed in Module 4 of the ongoing Phase 1/1b MYTHIC (NCT04855656) clinical trial, investigating the combination of Debio 0123 and lunresertib. In this trial, Debiopharm and Repare seek to assess the safety, pharmacokinetics, pharmacodynamics and preliminary clinical activity of this PKMYT1 and WEE1 inhibitor combination. In early January, De biopharm and Repare announced a collaboration to evaluate the clinical combination of Debio 0123, an oral, brain-penetrant, highly selective WEE1 kinase inhibitor and lunresertib, a first-in-class, selective and potent oral small molecule inhibitor of PKMYT1.

This collaboration is based on preclinical in vivo data and other data showing rapid, remarkable tumor regressions and high predicted clinical tolerability and represents the first clinical-stage approach to inhibiting both PKMYT1 and Wee1. WEE1 is a key regulator of the G2/M and S phase checkpoints, activated in response to DNA damage and replication stress, allowing cells to repair their DNA before resuming their cell cycle. WEE1 inhibition, particularly in combination with DNA damaging agents, induces an accumulation of DNA damage and pushes the cells through cell cycle without DNA repair, promoting mitotic catastrophe and induction of apoptosis in cancer cells.

Debiopharm is currently being investigated in clinical trials in patients with solid tumors as a monotherapy and in combination. Debiopharm is being developed to address high unmet needs of patients living with the burden of difficult-to-treat cancers. Lunresertib (RP-6306) is a first-in- class, selective and potent oral small molecules inhibitor of PKMYT1, a cancer target Repare discovered and identified as synthetic lethal with CCNE1 amplification, FBXW7 and PPP2R1A alterations in solid tumors.

Lunresertib is currently the sole PKMYT1 inhibitor known to be in clinical trials and is being evaluated alone and in combinations across several studies in the US, UK/EU4 and Canada. Repare has presented positive initial Phase 1 data from its ongoing Phase 1 MYTHIC trial (NCT04855656), demonstrating proof of concept for lunresertib alone and in combination. In addition to being well tolerated and having a compelling safety profile, Repare presented anti-tumor activity for lunresertib in combination with camonsertib, an ATR inhibitor developed by Repare, expanded clinical studies for which are ongoing.