S276: povetacicept (alpn-303), a potent dual baff/april antagonist, for the treatment of autoimmune cytopenias and other antibody-related diseases

Background: BAFF and APRIL are cytokines that bind transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA), and/or BAFF receptor (BAFF-R) on B cells and together support B-cell development, survival, and differentiation into antibody-secreting cells (ASC). BAFF and APRIL have been strongly implicated in the pathogenesis of autoimmune cytopenias due to their importance in ASC survival and antibody production. Elevated levels of BAFF and APRIL, as well as polymorphisms in BAFF and TACI, have been described in patients with these diseases. Belimumab, an anti-BAFF antibody, has demonstrated encouraging efficacy in the treatment of immune thrombocytopenia (ITP) associated with systemic lupus erythematosus (SLE) and in combination with rituximab in patients with ITP. Currently, there are no BAFF and/or APRIL inhibitors approved to treat autoimmune hemolytic anemia (AIHA) or ITP. Povetacicept (ALPN-303) is an Fc fusion protein of an engineered TACI domain which mediates significantly more potent dual inhibition of APRIL and BAFF than WT TACI-Fc (e.g., atacicept, telitacicept) and has shown promise in preclinical models for the treatment of autoantibody (autoAb)-related diseases, such as SLE and autoAb-related glomerulonephritides. Aims: To evaluate povetacicept in a preclinical model of autoimmune cytopenia (AIHA) and to assess its initial safety, pharmacokinetics (PK), and pharmacodynamics (PD) in adult healthy volunteers (HV) in preparation for clinical trials in patients with autoimmune cytopenias. Methods: HEL-OVA-Duffy (HOD) mice express an RBC-restricted triple fusion protein of hen egg lysozyme (HEL), a portion of ovalbumin (OVA), and human blood group molecule Duffy. HOD mice bred to OTII transgenic mice that express an OVA-specific T cell receptor represent a preclinical AIHA model system that recapitulates clinical features and pathogenesis observed in AIHA patients. HOD+OTII+ mice treated to accelerate disease onset were randomized to 2 groups based on HOD autoAb titers and treated intraperitoneally (IP) with 10 mg/kg povetacicept or a molar-matched dose of Fc control 2x/wk for 3.5 wks (Fig 1). At study termination, mice were assessed for circulating RBC autoAbs, hematocrit, and immuno-phenotyping in spleen and bone marrow. In a Phase 1 randomized placebo-controlled trial (NCT05034484), adult HV were studied in single ascending dose cohorts of intravenous (IV) or subcutaneous (SC) povetacicept or placebo. Safety, PK, and PD including circulating immunoglobulins (Ig), and circulating leukocyte populations, including ASCs, were assessed. Results: In the AIHA mouse model, povetacicept treatment significantly reduced numbers of ASC, suppressed autoAb generation, and increased hematocrit (Fig 1). In HV, povetacicept has been well tolerated in all cohorts evaluated to date and exhibits dose-dependent PK and expected PD effects, including dose-dependent reductions in circulating ASC and in serum Ig (Fig 2). There have been no imbalances of infections between placebo and povetacicept groups, no serious adverse events, no infusion-related or injection site reactions other than grade 1 injection-site pain, and no adverse trends in safety laboratories. Summary/Conclusion: Povetacicept demonstrates promising efficacy in a preclinical AIHA model. In adult HV, it has demonstrated dose-dependent PK, acceptable safety and tolerability, and exhibits expected PD, including reductions in ASC and Ig. These findings support future clinical development of povetacicept in patients with antibody-related diseases, including autoimmune cytopenias.Keywords: BAFF, Autoantibody, Autoimmune hemolytic anemia (AIHA), Phase I