BACKGROUND:Fenebrutinib (GDC-0853, FEN) is a non-covalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of FEN were assessed in this randomized, placebo-controlled, multi-center phase II study. METHODS:Patients with moderate-to-severely active systemic lupus erythematosus on background standard of care therapy were randomized to placebo, FEN 150 mg QD, or FEN 200 mg BID arms. Corticosteroid taper was recommended from weeks 0 to 12 (W0-W12) and W24-W36. The primary endpoint was SRI-4 at W48. RESULTS: Patients (N=260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, USA, and Western Europe. The SRI-4 response rates at W48 were 51% (p=0.37, versus placebo) for FEN 150 mg QD, 52% (p=0.34, versus placebo) for FEN 200 mg BID, and 44% for placebo. BICLA response rates at W48 were 53% (p=0.086, versus placebo) for FEN 150 mg QD, 42% (p=0.879, versus placebo) for FEN 200 mg BID, and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with FEN 200 mg BID. By W48, patients treated with FEN had reduced levels of a BTK-dependent plasmablast RNA signature, anti-dsDNA autoantibodies, total IgG, and IgM, as well as increased complement C4, all relative to placebo. CONCLUSIONS: While FEN had an acceptable safety profile, the primary endpoint, SRI-4, was not met despite evidence of strong pathway inhibition. This article is protected by copyright. All rights reserved.
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BACKGROUND:Fenebrutinib (GDC-0853, FEN) is a non-covalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of FEN were assessed in this randomized, placebo-controlled, multi-center phase II study. METHODS:Patients with moderate-to-severely active systemic lupus erythematosus on background standard of care therapy were randomized to placebo, FEN 150 mg QD, or FEN 200 mg BID arms. Corticosteroid taper was recommended from weeks 0 to 12 (W0-W12) and W24-W36. The primary endpoint was SRI-4 at W48. RESULTS:Patients (N=260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, USA, and Western Europe. The SRI-4 response rates at W48 were 51% (p=0.37, versus placebo) for FEN 150 mg QD, 52% (p=0.34, versus placebo) for FEN 200 mg BID, and 44% for placebo. BICLA response rates at W48 were 53% (p=0.086, versus placebo) for FEN 150 mg QD, 42% (p=0.879, versus placebo) for FEN 200 mg BID, and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with FEN 200 mg BID. By W48, patients treated with FEN had reduced levels of a BTK-dependent plasmablast RNA signature, anti-dsDNA autoantibodies, total IgG, and IgM, as well as increased complement C4, all relative to placebo. CONCLUSIONS: While FEN had an acceptable safety profile, the primary endpoint, SRI-4, was not met despite evidence of strong pathway inhibition. This article is protected by copyright. All rights reserved.
Authors: Pedro Mendes-Bastos; Ana Brasileiro; Pavel Kolkhir; Stefan Frischbutter; Jörg Scheffel; Sherezade Moñino-Romero; Marcus Maurer Journal: Allergy Date: 2022-02-28 Impact factor: 14.710