Background Povetacicept (ALPN-303) is an Fc fusion protein of a variant, engineered TACI domain, which mediates significantly more potent inhibitory activity than WT TACI-Fc or BAFF- or APRIL-specific monoclonal antibodies, with enhanced pharmacokinetic (PK) and immunomodulatory properties versus WT TACI-Fc in preclinical studies. Povetacicept may therefore significantly improve clinical outcomes in systemic lupus erythematosus (SLE) and other B-cell-related diseases. This study was designed to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of povetacicept in adult healthy volunteers (HV).
Methods In this first-in-human study (NCT05034484), 66 adult HV were randomized 4:2 into single ascending dose cohorts of intravenous (IV) or subcutaneous (SC) povetacicept or placebo. Participants were followed to assess safety and PK, circulating immunoglobulins (Ig), and circulating leukocyte populations.
Results Povetacicept has been well tolerated in all cohorts evaluated as single IV or SC doses of up to 960 mg. Overall, it exhibits dose-related PK and expected PD effects, including dose-related reductions in serum IgA, IgM, IgG (figure 1), and in circulating antibody-secreting cells (plasmablasts and plasma cells). These PD effects appear greater than those reported for WT TACI-Fc molecules in HV and appear to be saturated at doses ≥80 mg. Coverage of free APRIL was maintained for 2–3 weeks with 80 mg and ≥4 weeks with 240 mg, respectively. The most frequent adverse event (AE) has been mild headache. To date, there have been no imbalances of infections between the placebo and dosed groups, no treatment-related serious AEs, no administration-related reactions other than mild injection site pain, and no adverse trends in safety laboratories (table 1).
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