A Clinical Study of NAD in the Treatment of Immune Thrombocytopenia

A Prospective, One-arm and Open Clinical Study to Assess Safety and Efficacy of Nicotinamide Adenine Dinucleotide in the Treatment of Primary Immune Thrombocytopenia

To evaluate the safety and efficacy of nicotinamide adenine dinucleotide in the treatment of immune thrombocytopenia in patients who have not responded adequately or relapsed after first-line treatment and at least one second-line therapy including Anti-CD20 Antibody and/or TPO-RA.

Immune thrombocytopenia (ITP) is an organ-specific autoimmune disease, which is characterized by decreased platelet count and skin and mucosal bleeding. ITP is a kind of disease with increased platelet destruction and impaired platelet production caused by autoimmunity. Conventional treatment of adult ITP includes first-line glucocorticoid and immunoglobulin therapy, second line TPO and TPO receptor agonist, splenectomy and other immunosuppressive treatments (such as rituximab, vincristine, azathioprine, etc.). ITP is one of the most common hemorrhagic diseases. At present, the treatment response of ITP is not good, and a considerable number of patients need drug maintenance treatment, which seriously affects the quality of life of patients and increases the economic burden of patients. Therefore, there is still a lack of effective treatment for adult ITP, especially for recurrent and refractory ITP patients, which is one of the problems that have attracted more attention and need to be solved urgently.

The main pathogenesis of ITP is the loss of platelet autoantigen immune tolerance, which leads to abnormal activation of humoral and cellular immunity. It is characterized by antibody mediated platelet destruction and insufficient platelet production by megakaryocytes. The residual long-term autoreactive plasma cells may be a source of therapeutic resistance to autoimmune cytopenia. Antiplatelet specific plasma cells have been detected in the spleen of patients with rituximab refractory ITP. Therefore, the strategy of simply eliminating B cells may not work, because LLPC will continue to produce pathogenic antibodies. However, targeting LLPC becomes a new strategy to treat autoimmune diseases.

CM313, a kind of anti-CD38 antibody, is a new type of monoclonal antibody targeting CD38. It targets plasma cells and has carried out some clinical studies in multiple myeloma, with good therapeutic effects. We treated patients with refractory/relapsed ITP using CM313 and achieved good therapeutic outcomes, which may provide a new strategy for treating ITP. Current research shows that CD38, as a metabolic enzyme, can hydrolyze nicotinamide adenine dinucleotide (NAD+), leading to a decrease in intracellular NAD+. Additionally, during aging and inflammation, CD38 is highly expressed on macrophages, and the downregulation of NAD+ levels. Based on the current mechanistic studies of CD38 monoclonal antibody treatment for ITP, we found that macrophages in ITP patients exhibit a shift towards M1 polarization. We hypothesize that CD38 antibodies may reduce platelet destruction by macrophages by upregulating NAD+ levels, which in turn inhibits M1 polarization. Therefore, increasing NAD+ levels may have therapeutic potential for ITP. Since nicotinamide adenine dinucleotide (NAD+) has been used in clinical practice as an adjunctive treatment for leukopenia, coronary artery disease as well as myocarditis, and nicotinamide mononucleotide (NMN) has been explored in clinical trials, we will further investigate the therapeutic efficacy and safety of these compounds in ITP patients.

Therefore, the investigators designed this clinical trial to evaluate the safety and efficacy of Nicotinamide Adenine Dinucleotide (Coenzyme I for Injection, NAD+) and nicotinamide mononucleotide (NMN) in the treatment of primary immune thrombocytopenia in patients who are steroid-refractory or steroid-dependent, and fail to respond to at least one previous second-line therapy, including rituximab and/ or TPO agonist.

Inclusion Criteria:

• Age 18 and above, male or female;
• Conform to the diagnostic criteria of immune Thrombocytopenia (ITP) ≥3 months;
• Failure to achieve response or relapse after corticosteroid therapy, and failure to achieve response or relapse after previous second-line treatments such as TPO/TPORAs therapy, or are unable to afford the cost of the treatment;
• The platelet count of <30 X 10^9/L measured within 2 days prior to inclusion (During the screening visit and/or before receiving the study drug, platelet counts must be less than 30×10^9/L on at least two consecutive occasions, with a minimum interval of 1 day between the two tests.);
• ECOG physical state score ≤ 2 points;
• Subjects on stable dose maintenance therapy are allowed to be included (concomitant medications may include corticosteroids (≤0.5 mg/kg of prednisone or equivalent steroids) or TPO receptor agonists, etc.), but at the time of enrollment, only one concomitant medication with a stable dose is permitted. The concomitant medication must have been on a stable dose for at least 4 weeks prior to the first dose of the study drug;
• For female patients of childbearing potential, a negative pregnancy test result is required. Both female patients of childbearing potential and male patients must use highly effective contraception during the study and for 4 months/6 months after discontinuing treatment;
• Signed and dated written informed consent

Exclusion Criteria:

• Those who are allergic to Nicotinamide adenine dinucleotide or excipients, or who have previously received CD38 monoclonal antibody treatment with no efficacy.
• Those with autoimmune hemolytic anemia, or various types of secondary and genetic thrombocytopenia, such as leukemia, lymphoma, multiple myeloma, aplastic anemia, myelodysplastic syndrome, Evans syndrome, common variable immunodeficiency, systemic lupus erythematosus, cirrhosis, antiphospholipid antibody syndrome, pseudo-thrombocytopenia, drug-induced thrombocytopenia (e.g., quinine, heparin, antimicrobial drugs, anticonvulsants, etc.).
• A history of any thrombosis or embolism events within 12 months prior to the first dose, or the presence of extensive and severe bleeding, such as hemoptysis, upper gastrointestinal bleeding, intracranial hemorrhage, sepsis, or other irregular bleeding.
• Participation in any other clinical trial involving investigational drugs (including vaccine studies) or exposure to other investigational drugs within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose.
• Use of anticoagulants or any drugs with antiplatelet effects (e.g., aspirin) within 2 weeks prior to the first dose.
• Receiving emergency treatment for ITP within 2 weeks prior to the first dose (e.g., methylprednisolone, platelet transfusion, intravenous immunoglobulin, or TPO receptor agonist treatment).
• Receiving azathioprine, danazol, cyclosporine A, tacrolimus, sirolimus, or similar drugs within 4 weeks prior to the first dose; receiving CD20 monoclonal antibodies such as rituximab, cyclophosphamide, vincristine, or similar drugs within 3 months prior to the first dose.
• Splenectomy within 6 months prior to the first dose.
• Receiving a live vaccine within 4 weeks prior to the first dose, or planning to receive any live vaccine during the study period.
• A history of undergoing allogeneic stem cell transplantation or organ transplantation.
• A history of clinically significant diseases that, in the investigator's opinion, may pose a risk to the subject's safety or affect the assessment of safety or efficacy during the study if the disease/condition worsens.
• Subjects who have had malignant tumors within the past 5 years prior to screening (excluding completely cured carcinoma in situ of the cervix and non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin).
• Exhibiting clinically significant laboratory abnormalities at screening: a) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ the upper limit of normal (ULN); b) Total bilirubin ≥ 1.2 times ULN. ;c) Creatinine or blood urea nitrogen (BUN) ≥ ULN.
• Positive for HIV antibodies or syphilis antibodies.
• Positive for hepatitis B surface antigen (HBsAg) at screening, or positive for hepatitis B core antibody with a positive HBV-DNA result by polymerase chain reaction (PCR) testing, or positive for hepatitis C virus (HCV) antibodies.
• Women who are pregnant or breastfeeding, or planning to become pregnant or breastfeed during the study; and men whose partners are planning to become pregnant during the study.
• Subjects with mental disorders who are unable to provide informed consent or participate in the trial and follow-up properly.
• Subjects with unresolved toxicity symptoms caused by prior treatments before participating in the trial.
• Any other conditions deemed unsuitable for participation in this study as assessed by the investigator.