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However, their clinical utility can often be limited by incomplete and\/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN\u2010303; TACI vTD\u2010Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild\u2010type TACI\u2010Fc or BAFF\u2010 or APRIL\u2010specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first\u2010in\u2010human study in healthy adults, povetacicept was well\u2010tolerated as single ascending doses of up to 960\u2009mg administered intravenously or subcutaneously. Dose\u2010dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2\u20133\u2009weeks and \u22654\u2009weeks after doses of 80\u2009mg and \u2265240\u2009mg, respectively. Maximal pharmacodynamic effects were observed at dose levels \u226580\u2009mg for a single dose, associated with on\u2010target reductions in antibody\u2010secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease\u2010related biomarker galactose\u2010deficient\u2010immunoglobulin A1 (Gd\u2010IgA1), and were superior to results reported for wild\u2010type TACI\u2010Fc. These data strongly support further development of povetacicept for the treatment of B\u2010cell\u2010mediated automimmune diseases.<\/jats:p>","DOI":"10.1111\/cts.70055","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T11:15:01Z","timestamp":1730718901000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A first\u2010in\u2010human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF\/APRIL antagonist, in healthy adults"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3297-1285","authenticated-orcid":false,"given":"Rupert","family":"Davies","sequence":"first","affiliation":[{"name":"Alpine Immune Sciences, a Vertex Company  Seattle Washington 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