Abstract C152: Preclinical and emerging Phase 1 study data indicates that novel deuterated MET kinase inhibitor DO-2 mitigates the side effects seen with current approved MET kinase inhibitors: Preventing deleterious ‘de-hinging’ to improve tolerability
Authors: Perera Timothy P.S. , Mevellec Laurence , Prenen Hans , Dekeyser Bernd , Robbrecht Debbie , Bins Sander , Sikkema Barend , de Bruijn Peter , Machiels Jean-Pascal , Galot Rachel , Briol Damien , Knight Richard , Loryan Irena , Hu Yang , Wastelin Florence , Verweij Jaap 
Published: December 2023

Introduction. MNNG HOS transforming gene (MET) kinase inhibitors have demonstrated clinical activity in patients with non-small cell lung cancer (NSCLC) harboring exon14 (METex14) skipping mutations, validating this as an actionable drug target. High daily doses (500-800mg daily) are needed to reach sufficient plasma exposure of active drug to achieve sufficient target engagement to drive efficacy. However, these high doses are associated with toxicities that frequently lead to dose interruptions and reductions which negatively impact efficacy.

Background. The 2nd generation of selective Type 1b MET inhibitors (capmatinib, tepotinib, savolitinib), with more soluble metabolites than the 1st generation inhibitors (SGX-523, JNJ-38877605, PF-04217903), have shown efficacy in the clinic. However, they still carry the metabolic liability of the 1st generation agents translating into high levels of circulating metabolites that are not active against the MET kinase, necessitating high daily doses to achieve sufficient active drug exposures. These inactive ‘de-hinged’ metabolites (which are unable to interact with a key recognition site located in the ‘hinge region’ of the MET kinase) remain in the circulation, leading to ‘off-target’ toxicities which are not linked to efficacy, but often necessitates dose reductions and/or-interruptions.

Experimental procedures. Based on a detailed understanding of the metabolic liabilities of type 1b MET kinase inhibitors and using site specific deuteration of the key metabolic hotspot, we have used the Kinetic Deuterium Isotope Effect (KDIE) to overcome a metabolic liability that negatively impacts current agents.

Summary of the new, unpublished data. The resulting deuterated compound DO-2, is well tolerated and highly potent in pre-clinical xenograft studies (MED ~0.2mg/kg: MTD &gt;50mg/kg), brain penetrant (Kp, uu, brain ; 0.3 in rats), with low once daily doses (3mg/kg) causing complete and sustained cures of all animals (8/8) carrying well established ~300mm3 MET exon14 xenografts.  IND enabling toxicology studies in rabbit (most relevant species for metabolism) have shown that the renal effects of the predecessor JNJ-38877605 were no longer apparent with DO-2 at efficacious exposure levels. Based on the pre-clinical efficacy and toxicology data, DO-2 has entered the clinic in a Phase 1 study (NCT05752552), where early data indicates that the improved preclinical profile translates into the clinic with increased active drug exposure when compared to the non-deuterated JNJ-38877605.

Conclusion. Preclinical data and emerging clinical data from highly MET inhibitor sensitive MET exon14 tumours as well as in other less sensitive MET driven tumors indicate that DO-2 has the potential to mitigate the side effects seen with current approved MET kinase inhibitors, leading to better tolerability and lower inactive metabolite levels and at lower daily dose levels. Supporting preclinical data and emerging clinical data will be presented.

Citation Format: Timothy P.S. Perera, Laurence Mevellec, Hans Prenen, Bernd Dekeyser, Debbie Robbrecht, Sander Bins, Barend Sikkema, Peter de Bruijn, Jean-Pascal Machiels, Rachel Galot, Damien Briol, Richard Knight, Irena Loryan, Yang Hu, Florence Wastelin, Jaap Verweij. Preclinical and emerging Phase 1 study data indicates that novel deuterated MET kinase inhibitor DO-2 mitigates the side effects seen with current approved MET kinase inhibitors: Preventing deleterious ‘de-hinging’ to improve tolerability [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C152.