PB2554: DESIGN OF A PHASE 1B OPEN-LABEL STUDY TO ASSESS THE SAFETY, EFFICACY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF POVETACICEPT (ALPN-303) IN SUBJECTS WITH AUTOIMMUNE CYTOPENIAS (RUBY-4)

Topic: 28. Enzymopathies, membranopathies and other anemias Background: B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) play key roles in B cell development, survival, and differentiation into antibody-secreting cells (ASC). Given their importance in ASC survival and antibody production, inhibition of BAFF and/or APRIL (particularly in combination), is a promising approach for the treatment of a variety of autoimmune or autoantibody-related diseases including autoimmune cytopenias. Significantly higher levels of both BAFF and APRIL have been observed in the serum of patients with autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) compared to healthy subjects.1,2 An inhibitor of BAFF, belimumab, has demonstrated encouraging efficacy in the treatment of ITP associated with systemic lupus erythematosus and in combination with rituximab in patients with ITP.3-5 Currently, there are no BAFF and/or APRIL inhibitors approved to treat AIHA or ITP. Povetacicept (ALPN-303) is an engineered dual BAFF/APRIL antagonist with the potential to improve outcomes for patients with autoimmune cytopenias. In a mouse AIHA model, povetacicept treatment suppressed anti-erythrocyte antibodies and increased hematocrit. Povetacicept has been well tolerated in adult healthy volunteers and exhibits dose-dependent pharmacokinetic (PK) and pharmacodynamic (PD) effects corresponding to reductions in circulating ASC and immunoglobulins. We present here the design of a Phase 1b clinical trial of povetacicept in adults with autoimmune cytopenias. Aims: This is an open-label, group-sequential study to evaluate the safety, efficacy, PK, and PD of povetacicept in subjects with ITP, warm AIHA (wAIHA), or cold agglutinin disease (CAD). Methods: Subjects must have primary cytopenia for at least 12 weeks duration, confirmation of sustained thrombocytopenia (ITP, platelet count <30 × 109/L) or symptomatic anemia (AIHA, Hb ≤10 g/dL) on 2 occasions during the screening, and a history of failure or relapse to at least 2 prior treatment regimens. Subjects are allowed to use some background treatments including corticosteroids if the doses are stable for the durations specified by the protocol. Exclusion criteria include secondary autoimmune cytopenias, Evans syndrome, rituximab or splenectomy within 12 weeks. The study will include 3 parallel cohorts of subjects grouped by diagnosis (ITP, wAIHA, CAD). Seven to 14 subjects will be enrolled in each cohort and begin subcutaneous once every 4 weeks week dosing of povetacicept for 6 cycles (24 weeks). When the first 7 subjects in each cohort have been enrolled and treated with povetacicept for 12 weeks, an interim analysis will be conducted to determine if the disease cohort should stop enrolment for futility or lack of efficacy. Subjects who are experiencing treatment benefit at week 24 may continue with study treatment. Upon completion of their last treatment cycle, all subjects will be followed for safety for 8 weeks (Figure 1). The efficacy endpoints will be disease specific response criteria for platelet counts or Hb levels. Other endpoints will include safety, PK/PD, and immunogenicity. References: 1. Blair HA, Duggan ST. Drugs. 2018;78(3):355-366. 2. Mahevas M, Azzaoui I, Crickx E, et al. Haematologica. 2021;106(9):2449-2457. 3. Gu D, Ge J, Du W, et al. Autoimmunity. 2009;42(8):692-8. 4. Emmerich F, Bal G, Barakat A, et al. Br J Haematol. 2007;136(2):309-14. 5. Xu Z, Zhao B, Xiong H, et al. Int J Hematol. 2015;102(4):394-400. Results: NA Summary/Conclusion: NAKeywords: BAFF, Immune thrombocytopenia (ITP), Autoimmune hemolytic anemia (AIHA), Autoantibody

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