Efficacy, Safety, and Pharmacodynamic Effects of the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib (GDC‐0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double‐Blind, Placebo‐Controlled Trial

Abstract

Objective Fenebrutinib (GDC‐0853) is a noncovalent, oral, and highly selective inhibitor of Bruton’s tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo‐controlled study. Methods Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI‐4) response at week 48. Results Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI‐4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group–based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK‐dependent plasmablast RNA signature, anti–double‐stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. Conclusion While fenebrutinib had an acceptable safety profile, the primary end point, SRI‐4 response, was not met despite evidence of strong pathway inhibition.

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

“…In RA patients with an inadequate response to methotrexate, fenebrutinib caused dose-dependent reductions in the rheumatoid factor with comparable efficacy to adalimumab [ 61 ]. A similar response was observed in a phase 2 study performed in SLE patients, where fenebrutinib caused dose-dependent reductions in anti-double-stranded DNA autoantibodies [ 62 ]. However, in moderate to severe SLE patients, no improvement was observed in the symptoms ( Table 2 ) [ 63 ].…”

“…Fenebrutinib was investigated in a phase 2, multicenter, randomized, placebo-controlled study in patients with moderately-to-severely active SLE. The study demonstrated significant reductions in CD19+ B cells and anti-dsDNA autoantibodies, but no significant clinical response was observed [ 62 ]. Treatment was well tolerated but the primary end point of the study, SLE Responder Index 4 (SRI-4) response at week 48, was not met.…”

Bruton's tyrosine kinase inhibition—An emerging therapeutic strategy in immune‐mediated dermatological conditions

“…The most common reason for discontinuation was lymphopenia (n = 1 and n = 3 in the 150 mg daily and 200 mg twice-daily arms, respectively; n = 0 in the placebo arm). 99 In addition to these two "front runners," other agents are in development for immune-mediated dermatological conditions.…”

The potential of pirtobrutinib in multiple B-cell malignancies

“… 13 Fenebrutinib is being studied in autoimmune indications; there are no current clinical trials testing it in hematologic malignancies. 14 Preliminary results from the phase 2 dose-expansion study of nemtabrutinib in B-cell malignancies were recently presented, which included 51 CLL/SLL patients of whom 43 (84.3%) had prior BTK inhibitor therapy. Nemtabrutinib demonstrated an overall response rate (ORR) of 57.9% for 38 efficacy-evaluable CLL/SLL patients, with grade ⩾ 3 treatment-emergent adverse effects in 68% of total participants (80 of 118).…”