For Doctors in a Hurry
- Clinicians lack targeted treatments for refractory immune thrombocytopenia that avoid broad immunosuppression while addressing the CD38-mediated metabolic pathways of platelet destruction.
- Researchers conducted a phase 1/2 trial involving 25 adults with steroid-refractory immune thrombocytopenia receiving 450 milligrams of oral nicotinamide mononucleotide twice daily.
- Five patients (20.0 percent) reached platelets of 50 x 10^9 per liter, and 60 percent exceeded 1.5 times their baseline count.
- The study identifies the CD38-nicotinamide adenine dinucleotide axis as a metabolic checkpoint that regulates macrophage-mediated platelet clearance without impairing humoral immunity.
- These findings support further investigation of oral nicotinamide mononucleotide as a non-depleting metabolic strategy for managing antibody-mediated autoimmune diseases.
Managing immune thrombocytopenia (ITP) often requires long-term, non-specific immunosuppression, forcing clinicians to balance therapeutic efficacy against the risk of opportunistic infections [1]. Recent evidence suggests that dysregulated homeostasis of nicotinamide adenine dinucleotide (NAD+, a coenzyme essential for cellular energy metabolism) is a common feature in several autoimmune conditions, driving aberrant immune cell activation [2, 3]. Specifically, the CD38 enzyme acts as a major consumer of NAD+, and its activity has been linked to the pro-inflammatory polarization of macrophages and the subsequent destruction of opsonized cells (platelets marked by antibodies for clearance) [1, 4]. While traditional therapies focus on depleting B cells or suppressing T cell responses, metabolic modulation offers a route to restore immune balance without compromising systemic host defenses [3]. In a recent phase 1/2 trial of 25 adults with steroid-refractory disease, low-dose oral nicotinamide mononucleotide (450 mg twice daily) induced a confirmed platelet response of at least 50 × 10⁹ per liter in 20% of participants within 14 days [5, 1]. These findings suggest that targeting the CD38-NAD+ axis provides a targeted metabolic strategy to manage antibody-mediated cytopenia while preserving stable immunoglobulin levels [5].
The CD38-NAD+ Mechanism of Platelet Destruction
The researchers identified the CD38 enzyme as a critical regulator of platelet survival, demonstrating that its activity directly influences the metabolic state of immune cells. In clinical observations of patients with refractory immune thrombocytopenia, the administration of an anti-CD38 antibody induced rapid platelet recovery within 3 days. This therapeutic effect was notably consistent even in complex clinical scenarios, as the antibody successfully induced platelet recovery after retreatment in relapsed cases. These findings suggest that the CD38 pathway is a primary driver of accelerated platelet clearance rather than a secondary or transient phenomenon.
The underlying pathophysiology involves a specific metabolic shift known as the CD38-NAD+ axis. The study found that CD38-mediated depletion of NAD+ drives M1-like macrophage polarization, a pro-inflammatory state that enhances the immune system's ability to clear target cells. This metabolic depletion further increases the expression of Fc gamma receptor I (FcγRI) on the surface of macrophages. Because this receptor binds tightly to antibodies, its upregulation directly promotes macrophage phagocytosis (the process of engulfing and destroying) of opsonized platelets. By linking metabolic exhaustion to increased receptor density, the researchers established that the loss of NAD+ effectively primes the immune system to aggressively destroy platelets marked by autoantibodies. For clinicians, this clarifies why standard immunosuppression sometimes fails: the underlying metabolic drive for phagocytosis remains active.
Preclinical Validation and Humoral Preservation
To validate the therapeutic potential of targeting the CD38-NAD+ axis, the researchers utilized murine models of immune-mediated platelet destruction. In these mice, CD38 inhibition or nicotinamide mononucleotide (NMN) supplementation successfully restored NAD+ levels, reversing the metabolic depletion that characterizes the disease state. This restoration of the intracellular metabolic environment led to a functional shift in immune cell behavior. Specifically, the researchers observed that CD38 inhibition or NMN supplementation reprograms macrophages and downregulates FcγRI, the high-affinity receptor responsible for clearing antibody-coated platelets. By reducing the density of these receptors on the macrophage surface, the treatment effectively interrupted the primary pathway of platelet destruction.
The physiological impact of these metabolic changes was evident in the stabilization of blood counts, as the study demonstrated that CD38 inhibition or NMN supplementation prevents thrombocytopenia in these animal models. Beyond efficacy, the researchers addressed a critical safety concern regarding the potential for broad immunosuppression, which often complicates standard treatments for immune thrombocytopenia. Using an ovalbumin immunization model (a standard experimental method to assess the immune system's ability to mount a response to a specific foreign protein), the findings showed that NMN treatment does not impair antigen-specific antibody production. This preservation of the adaptive immune response suggests that NMN can modulate the destructive phase of autoimmunity while maintaining the patient's humoral immunity (the component of the immune system mediated by secreted antibodies). For practicing physicians, this implies a potential future where autoimmune cytopenias can be managed without leaving patients vulnerable to opportunistic infections.
Phase 1/2 Trial Safety and Tolerability
Building on the mechanistic insights from murine models, the researchers conducted a single-arm, open-label phase 1/2 trial to evaluate the clinical utility of metabolic intervention in humans. The study enrolled 25 adult patients diagnosed with either steroid-refractory or steroid-dependent immune thrombocytopenia, a population that typically requires aggressive second-line therapies. These participants received low-dose oral nicotinamide mononucleotide (NMN) at a dosage of 450 mg twice daily for a duration of 2 weeks. This specific dosing regimen was designed to assess whether oral supplementation could sufficiently modulate the CD38-NAD+ axis to restore platelet counts without the need for systemic immunosuppression.
The primary safety analysis indicated that the metabolic precursor was well tolerated by the cohort. No dose-limiting toxicities or treatment-related serious adverse events occurred among the 25 patients during the study period. The researchers reported that mild treatment-related adverse events occurred in 12% of patients, while non-severe infections (grade 1) were observed in 8% of patients. Crucially for clinicians concerned about the infectious risks associated with traditional therapies, immunoglobulin levels remained stable during NMN treatment. This stability is consistent with the preservation of humoral immunity, suggesting that the treatment does not compromise the patient's ability to maintain a baseline antibody-mediated defense. Further details regarding the longitudinal outcomes of this cohort can be found under the ClinicalTrials.gov identifier NCT06776510.
Clinical Response and Durability
The efficacy of oral NMN was evaluated using a primary platelet response endpoint, defined as achieving a platelet count of 50 × 10⁹ per liter or greater within the first 2 weeks of treatment. To ensure the validity of these results, the researchers required that this threshold be confirmed by two consecutive measurements taken one or more days apart. Furthermore, the protocol mandated that this response be achieved without the use of rescue therapy or any dose escalation of concurrent medications, such as thrombopoietin receptor agonists or corticosteroids. Among the 25 patients enrolled in the trial, five patients (20.0%) met this primary platelet-response endpoint, demonstrating that a subset of individuals with refractory immune thrombocytopenia can achieve clinically significant hemostatic levels through metabolic modulation alone.
Beyond the primary endpoint, exploratory analyses provided a broader view of the treatment's impact on platelet kinetics. The study found that 60% of patients achieved platelet counts more than 1.5 times their baseline levels during the treatment period, suggesting a biological effect even in those who did not reach the strict 50 × 10⁹ per liter threshold. The durability of these improvements was also notable for a short-term intervention; 52% of patients maintained their clinical responses through week 8, indicating a sustained effect after the initial 2-week dosing period. These findings identify the CD38-NAD+ axis as a critical immunometabolic checkpoint (a metabolic pathway that regulates the activation and function of immune cells) in immune thrombocytopenia. By targeting this checkpoint, clinicians may soon be able to utilize non-antibody-depleting metabolic strategies to manage antibody-mediated diseases, offering a safer alternative to broad immunosuppression.
References
1. Li H, Zhang L. Targeting the CD38-NAD⁺ axis alleviates antibody-driven cytopenia in autoimmune disorders without inducing broad immunosuppression. Blood. 2025. doi:10.1182/blood-2025-4793
2. Li J, Zhang C, Hu Y, Peng J, Feng Q, Hu X. Nicotinamide enhances Treg differentiation by promoting Foxp3 acetylation in immune thrombocytopenia.. British journal of haematology. 2024. doi:10.1111/bjh.19820
3. Mann R, Stavrou V, Dimeloe S. NAD + metabolism and function in innate and adaptive immune cells. Journal of Inflammation. 2025. doi:10.1186/s12950-025-00457-7
4. Xu Q, Liu X, Mohseni G, et al. Mechanism research and treatment progress of NAD pathway related molecules in tumor immune microenvironment. Cancer Cell International. 2022. doi:10.1186/s12935-022-02664-1
5. Li H, Xu Y, Chen Y, et al. Low-dose oral nicotinamide mononucleotide for immune thrombocytopenia: a phase 1/2 trial.. Nature medicine. 2026. doi:10.1038/s41591-026-04366-x
