Povetacicept (ALPN-303)

Dual BAFF/APRIL B cell cytokine antagonist with best-in-class potential

Povetacicept is a dual B cell cytokine antagonist being developed for multiple autoimmune and inflammatory diseases.

ALPN-303, or povetacicept, is a dual antagonist of the B cell activating factor, or BAFF, and a proliferation inducing ligand, or APRIL, cytokines, which play key roles in the pathogenesis of multiple autoimmune diseases via their contribution to the activation, differentiation and/or survival of B cells, particularly antibody-secreting cells, as well as T cells and innate immune cells. Based upon an engineered transmembrane activator and CAML interactor, or TACI, domain, povetacicept has exhibited greater potency in preclinical in vitro studies versus wild-type TACI-based comparators, as well as other inhibitors of BAFF and/or APRIL alone and B cell depletion. In addition, povetacicept has been well-tolerated in preclinical in vivo models and exhibited superior pharmacokinetics and pharmacodynamics over wild-type TACI-Fc counterparts, including superior serum exposure, suppression of T-dependent antibody production, and/or serum immunoglobulins in mice and/or cynomolgus monkeys. In a randomized, placebo-controlled, first-in-human, Phase 1 study in adult healthy volunteers (NCT05034484), povetacicept was well tolerated at doses up to 960 mg, with dose-dependent pharmacokinetics and reductions in circulating immunoglobulins and antibody-secreting cells, supporting a convenient once every four-weeks dose regimen for subsequent studies. Broad development of povetacicept is planned across multiple autoimmune diseases, including IgA nephropathy, or IgAN, and other autoimmune kidney diseases, systemic lupus erythematosus, or SLE, and autoimmune cytopenias.

We believe povetacicept has the potential to become a development pipeline within a single product candidate, with significant market opportunity across multiple therapeutic areas including, but not limited to, nephrology, connective tissue diseases, such as lupus, hematology, neurology, and dermatology. Based on our encouraging clinical and nonclinical data, we have initiated a broad development plan with multiple clinical studies, including RUBY-3, an openlabel, dose-ranging basket study in autoimmune glomerulonephritis including IgAN, lupus nephritis, renal ANCA-associated vasculitis, and primary membranous nephropathy; and RUBY-4, an open-label basket study in autoimmune cytopenias including immune thrombocytopenia, warm autoimmune hemolytic anemia, and cold agglutinin disease. Each of the indications in these basket studies has strong scientific rationale for povetacicept based on the importance of specific autoantibodies in disease pathogenesis, as well as high medical need.

Clinical data from RUBY-3 presented as a late breaking poster at the World Congress of Nephrology, or WCN, 2024 demonstrate that both povetacicept 80 mg and 240 mg administered once every four-weeks have been well tolerated and in IgAN both doses demonstrate highly encouraging improvements in urine protein-creatinine ratio, or UPCR, and disease biomarkers, with early evidence suggesting potential for disease remission, as defined as UPCR < 0.5 g/g, and ≥ 50% reduction in UPCR from baseline with stable renal function (≤ 25% reduction in eGFR, or estimated glomerular filtration rate, from baseline). Based on such data, we have completed a successful end of phase 2 meeting with the Food and Drug Administration, or FDA, supporting advancement to a registrational, placebo-controlled phase 3 study of povetacicept in IgA nephropathy, targeted in the second half of 2024. In addition, we plan to initiate DENALI, a phase 2 study of povetacicept in SLE.

For more information on the data presented at WCN please see here.

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