Background/Purpose: Fenebrutinib (GDC-0853, FEN) is an oral, non-covalent, and highly selective inhibitor of Bruton’s tyrosine kinase (BTK) in clinical development for autoimmune diseases. The efficacy, safety, and pharmacodynamic effects of fenebrutinib in patients with moderate-to-severe systemic lupus erythematosus (SLE) activity were assessed in this Phase 2, randomized, placebo-controlled, multi-center study.

Methods: Patients who met SLICC or revised ACR SLE criteria, had ≥1 serologic marker of SLE (ANA, anti-dsDNA, or anti-Smith), SLEDAI ≥6 (later amended to ≥8) at screening, and were on ≥1 standard of care (SOC) therapy (corticosteroid, antimalarial, and/or immunosuppressive) were included; patients with renal or CNS involvement, recent exposure to B cell depleting therapy, or who were receiving a calcineurin inhibitor were excluded. Enrolled patients were randomized to placebo, FEN 150 mg QD, or FEN 200 mg BID, for 48 weeks of therapy. Corticosteroid taper was recommended, with burst and taper permitted from week 0 to week 12 (W0 to W12) and W24 to W36. SRI-4 at W48 was the primary endpoint, comparing the FEN arms with placebo using a sample size of 240 patients targeted for 88% power. BICLA response at W48 was a secondary endpoint.

Results: This study enrolled 260 patients from 44 sites in 12 countries, with the majority of patients recruited in Latin America, USA, and Western Europe. At week 48, the SRI-4 response rates for FEN 150 mg QD and FEN 200 mg BID were 51% (95% CI: -8.5, 21.2) and 52% (95% CI: -7.3, 22.4), respectively, compared to 44% for the placebo arm (Table 1). The week 48 BICLA response rates for FEN 150 mg QD and FEN 200 mg BID were 53% (95% CI: -3.4, 26.8) and 42% (95% CI: -14.2, 16.1), respectively, compared to 41% for the placebo arm (Table 1). Safety results were similar between FEN and placebo, although more serious adverse events were observed in the FEN 200 mg BID arm (Table 1). Treatment with both doses of FEN significantly reduced levels of CD19+ B cells, anti-dsDNA autoantibodies, IgG, and a BTK-dependent RNA signature highly expressed in plasmablasts by week 48 compared to placebo; C4 levels modestly improved with FEN versus placebo (Table 2).

Conclusion: The primary endpoint of SRI-4 for FEN was not met despite evidence of strong BTK target and pathway inhibition. FEN had an acceptable safety profile.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-safety-and-pharmacodynamic-effects-of-the-brutons-tyrosine-kinase-inhibitor-fenebrutinib-gdc-0853-in-moderate-to-severe-systemic-lupus-erythematosus-results-of-a-phase-2-rando/