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Research Articles

Preclinical models of nicotinamide phosphoribosyltransferase inhibitor-mediated hematotoxicity and mitigation by co-treatment with nicotinic acid

Jacqueline M. TarrantDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA, Correspondence[email protected]

Preeti DhawanDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Jatinder SinghDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA, ;Retrophin Inc., Cambridge, MA, USA,

Tanja S. ZabkaDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Emer ClarkeReachBio, Seattle, WA, USA,

Garry DosSantosReachBio, Seattle, WA, USA,

Peter S. DragovichDepartment of Discovery Chemistry and

Deepak SampathDepartment of Translational Oncology, Genentech Inc., South San Francisco, CA, USA, and

Tori LinDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Bobbi McCrayDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Nghi LaDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Trung NguyenDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Ariel KaussDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Donna DambachDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Dinah L. MisnerDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Dolores DiazDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA,

Hirdesh UppalDepartment of Safety Assessment, Genentech Inc., South San Francisco, CA, USA, ;Medivation, San Francisco, CA, USA

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Abstract

Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in glycolysis and is a key molecule involved in maintaining cellular energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of an important salvage pathway in which nicotinamide is recycled into NAD. NAMPT is up-regulated in many types of cancer and NAMPT inhibitors (NAMPTi) have potential therapeutic benefit in cancer by impairing tumor metabolism. Clinical trials with NAMPTi APO-866 and GMX-1778, however, failed to reach projected efficacious exposures due to dose-limiting thrombocytopenia. We evaluated preclinical models for thrombocytopenia that could be used in candidate drug selection and risk mitigation strategies for NAMPTi-related toxicity. Rats treated with a suite of structurally diverse and potent NAMPTi at maximum tolerated doses had decreased reticulocyte and lymphocyte counts, but no thrombocytopenia. We therefore evaluated and qualified a human colony forming unit-megakaryocyte (CFU-MK) as in vitro predictive model of NAMPTi-induced MK toxicity and thrombocytopenia. We further demonstrate that the MK toxicity is on-target based on the evidence that nicotinic acid (NA), which is converted to NAD via a NAMPT-independent pathway, can mitigate NAMPTi toxicity to human CFU-MK in vitro and was also protective for the hematotoxicity in rats in vivo. Finally, assessment of CFU-MK and human platelet bioenergetics and function show that NAMPTi was toxic to MK and not platelets, which is consistent with the clinically observed time-course of thrombocytopenia.

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Acknowledgements

The authors would like to thank Bianca Liederer for her input on the evaluation of the rat toxicity studies.

Declaration of interest

During the conduct of this work, authors were employees of either Genentech or ReachBio. All work was funded by Genentech, Inc.

Supplementary material available online

Supplementary Figures 1, 2, 3 and 4.

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Preclinical models of nicotinamide phosphoribosyltransferase inhibitor-mediated hematotoxicity and mitigation by co-treatment with nicotinic acid

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Preclinical models of nicotinamide phosphoribosyltransferase inhibitor-mediated hematotoxicity and mitigation by co-treatment with nicotinic acid

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