Low-dose oral nicotinamide mononucleotide for immune thrombocytopenia: a phase 1/2 trial.

Abstract

Autoimmunity remains challenging to treat without broad immunosuppression. We previously showed that anti-CD38 antibody can rapidly elevate platelet counts in refractory immune thrombocytopenia (ITP), but the underlying mechanism was unclear. Here we report that anti-CD38 antibody induces platelet recovery within 3 days, including after retreatment in relapsed cases. Mechanistically, CD38-mediated nicotinamide adenine dinucleotide (NAD⁺) depletion drives M1-like macrophage polarization with increased Fc gamma receptor I (FcγRI) expression, thereby promoting macrophage phagocytosis of opsonized platelets. In mice, CD38 inhibition or nicotinamide mononucleotide (NMN) supplementation restores NAD⁺, reprograms macrophages, downregulates FcγRI and prevents thrombocytopenia. In an ovalbumin immunization model, NMN treatment does not impair antigen-specific antibody production, supporting preservation of humoral responses. Based on these findings, we conducted a single-arm, open-label phase 1/2 trial of low-dose oral NMN (450 mg twice daily for 2 weeks) in adults with steroid-refractory or steroid-dependent ITP. Primary endpoints were safety/tolerability and platelet response (≥50 × 10⁹ per liter within 2 weeks, confirmed by two consecutive measurements one or more days apart, without rescue therapy or dose escalation of thrombopoietin receptor agonists or corticosteroids). Among 25 enrolled patients, no dose-limiting toxicities or treatment-related serious adverse events occurred; NMN was well tolerated, with only mild treatment-related adverse events in 12% and non-severe infections (grade 1) in 8% of patients while immunoglobulin levels remained stable, consistent with preserved humoral immunity. Five patients (20.0%) met the primary platelet-response endpoint. In exploratory analyses, overall, 60% of patients achieved platelet counts more than 1.5× baseline during treatment, and 52% maintained responses through week 8. Together, these data identify the CD38-NAD⁺ axis as an immunometabolic checkpoint in ITP and support further exploration of NMN as a non-antibody-depleting metabolic strategy for antibody-mediated disease. ClinicalTrials.gov identifier: NCT06776510 .