PO.6.131 A randomized, double-blind, placebo controlled study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALPN-303, a potent dual baff/april inhibitor, in adult healthy volunteers

BackgroundTherapeutic agents targeting the B-cell cytokines B-cell activating factor of the TNF family (BAFF) and/or a proliferation-inducing ligand (APRIL), including the monoclonal antibody belimumab and the wild-type (WT) TACI-Fc fusion proteins atacicept and telitacicept, have demonstrated promising clinical potential in rheumatic diseases like systemic lupus erythematosus (SLE) and/or other B-cell-related diseases such as autoantibody-related nephritides. 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.1,2 ALPN-303 may therefore significantly improve clinical outcomes in SLE and other B-cell-related diseases.PurposeTo evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of ALPN-303 in adult healthy volunteers (HV).MethodsIn this first-in-human study (NCT05034484), adult HVs are enrolled in single ascending dose cohorts of intravenously (IV) or subcutaneously (SC) administered ALPN-303. For each IV cohort, the first 2 subjects are randomized 1:1 to receive ALPN-303 or placebo, followed by the remaining 4 subjects randomized 3:1 to receive ALPN-303 or placebo. For each SC cohort, HVs are randomized 4:2 to receive a single SC dose of ALPN-303 or placebo. All subjects are followed to assess safety and PK of ALPN-303, to measure levels of circulating immunoglobulins (Ig), and to characterize leukocyte populations in peripheral blood by flow cytometry.ResultsALPN-303 has been well tolerated in all IV and SC cohorts evaluated to date, and overall exhibits dose-related PK and expected PD effects on circulating Ig levels, including reductions in serum Ig (Figure 1). To date there have been no treatment-related serious adverse events, no infusion-related reactions, and no adverse trends in safety laboratory parameters reported in any of the dosed cohorts. The remainder of dose escalation is expected to be completed by the time of the meeting; the presentation will include all available safety, PK, and PD (circulating Ig and B-cell population) data.Abstract PO.6.131 Figure 1Single dose ALPN-303 preliminarily reduces serum Ig in a dose-dependent manner in adult healthy volunteersConclusionIn this first-in-human study, ALPN-303 to date demonstrates acceptable preliminary safety and tolerability, and