M4112 / EMD Serono - LARVOL DELTA

Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors. (PubMed, J Immunother Cancer) - P1 | "There were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration number NCT03306420."

Journal • P1 data • Dermatitis • Dermatology • Fatigue • Immune Modulation • Immunology • Inflammation • Oncology • Solid Tumor

First-in-Human Study of MS201408-0005A as Single Agent and in Combinations (clinicaltrials.gov) - P1; N=15; Terminated; Sponsor: EMD Serono Research & Development Institute, Inc.; Completed ➔ Terminated; The study was terminated early due to lackluster pharmacodynamic data that showed no significant reduction of plasma kynurenine at steady state of M4112.

Clinical • Trial termination

Preclinical development of M4112, an IDO1/TDO2 dual selective and orally bioavailable small molecule inhibitor, and combination with avelumab, for treatment of solid tumors (SITC 2019) - "The dual-selective IDO1/TDO2 inhibitor, M4112, in combination with avelumab enhanced antitumor activity in mouse and human tumor models and normalized systemic Kyn/Trp levels. Thus, M4112 represents a promising therapeutic agent targeting both the IDO1 and TDO2 immunosuppressive pathways."

IO Biomarker • PD(L)-1 Biomarker • Preclinical

BcXyl, a β-xylosidase Isolated from Brunfelsia Calycina Flowers with Anthocyanin-β-glycosidase Activity. (PubMed, Int J Mol Sci) - "...MK411219) was obtained and the deduced protein sequence shared conserved domains with two anthocyanin-β-glycosidases (Bgln and BadGluc, characterized in fungi)...Similar to BcPrx01, an anthocyanin-degradation-related Peroxidase (POD), BcXyl was dramatically activated at the stage at which the rapid anthocyanin degradation occurred. Taken together, we suggest that BcXyl may be the first anthocyanin-β-glycosidase identified in higher plants."

Journal

First-in-human Phase I study of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase-1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid malignancies (AACR 2019) - "M4112 was generally well tolerated, with stable disease as best response. M4112 achieved >90% IDO1 inhibition in ex vivo stimulated blood assay. Unlike IDO1 specific inhibitors, ex vivo IDO1 inhibition did not translate into plasma Kyn reduction following M4112 treatment."

Clinical • IO Biomarker • P1 data • PD(L)-1 Biomarker