Abstract 3979: Targeting nicotinamide metabolism with NAMPT-inhibitor OT-82 potentiates venetoclax in preclinical models of pediatric and adult acute myeloid leukemia

Abstract This study evaluates whether targeting the heightened dependence of acute myeloid leukemia (AML) on nicotinamide metabolism can be therapeutically exploited to inhibit AML progression and mitigate venetoclax resistance. AML continues to have poor survival outcomes in children and adults. While the BCL-2 inhibitor venetoclax has revolutionised the treatment of adult AML, there are increasing reports of inherent and acquired resistance to venetoclax. Emerging evidence implicates metabolic reprogramming and increased dependence on the activity of nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme in the cellular nicotinamide biosynthesis pathway, in AML progression and venetoclax resistance. We evaluated the efficacy of the clinical-stage NAMPT inhibitor OT-82 alone and in combination with venetoclax against AML cell lines in vitro and primary AML bone marrow patient samples ex vivo by resazurin reduction-based viability, synergy, live/dead and apoptosis assays. Xenograft models derived from 7 pediatric and 9 adult AML patients were treated with OT-82 or venetoclax or their combination in a Single Mouse Trial design to assess therapeutic benefit across a diverse AML panel. PDXs encompassed KMT2A-rearranged, FLT3-mutant, TP53-deficient, and epigenetically altered subtypes, reflecting the heterogeneity of human AML and included venetoclax-refractory cases. OT-82 demonstrated potent single-agent activity against AML cell lines in vitro and primary patient samples from de novo and relapsed/refractory AML patients ex vivo with nanomolar IC50s. The drug induced apoptosis in leukemia cells while sparing normal progenitors. Strong synergy was observed between OT-82 and venetoclax. In vivo, OT-82 potentiated venetoclax and venetoclax/azacitidine in a venetoclax-resistant pediatric AML cell line xenograft model, significantly extending survival of mice treated with OT-82/venetoclax or OT-82/venetoclax/azacitidine in comparison to the single agents or venetoclax/azacitidine. Extending in vivo efficacy testing to 16 additional AML PDXs in Single Mouse Trial format demonstrated that OT-82 significantly delayed AML progression across the AML PDX panel (p=0.0051), as well as the individual adult and pediatric AML PDX panels (p=0.0185, p=0.0009, respectively). The OT-82 and venetoclax drug combination induced the most pronounced survival extensions, achieving maintained complete responses in 4/7 and 7/9 pediatric and adult AML PDXs, respectively, including high-risk cases and those with resistance to single agent venetoclax. In conclusion, this study establishes NAMPT inhibition by OT-82 as a promising metabolism-targeting strategy to overcome venetoclax resistance and supports clinical translation of OT-82 in combination with venetoclax in adult and pediatric AML. Citation Format: Michelle Haber, Mawar Karsa, Patrick Connerty, Ayu Karsa, Dayna Spurling, Giovanna Pomilio, Veronique Litalien, Jinhan Xie, Laurence C. Cheung, Rishi S. Kotecha, Olga Chernova, Andrei V. Gudkov, Richard B. Lock, Murray David Norris, Andrew H. Wei, Donia Moujalled, Klaartje Somers. Targeting nicotinamide metabolism with NAMPT-inhibitor OT-82 potentiates venetoclax in preclinical models of pediatric and adult acute myeloid leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3979.