Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

Abstract

Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

“…The reversible Btk-inhibitor fenebrutinib does not inhibit the Btk homologous kinase Tec [37] that is a critical back-up pathway for maintaining physiologic hemostasis under Btk inhibition [14]. Indeed, in line with the absence of a bleeding phenotype of XLA patients, a recent clinical study detected no increased bleeding risk in fenebrutinibtreated patients [40]. The latter is also consistent with the observation that high fenebrutinib concentrations did not increase platelet-dependent bleeding time in vitro [13].…”

“…Fenebrutinib inhibited FcγRIIA-stimulated platelet aggregation in blood in vitro at a low IC50 (10 nM), and complete inhibition was observed with 50 nM [13]. A clinical study in patients with rheumatoid arthritis treated with a single daily dose of 50 mg fenebrutinib for 3 months detected no adverse effects as compared to placebo, notably no infections [40]. Plasma concentrations of IgM (−8.8%) but not of IgG were significantly lowered.…”

“…Plasma concentrations of IgM (−8.8%) but not of IgG were significantly lowered. However, higher doses of fenebrutinib (1x150 mg/day, and 2 × 200 mg/day) that were needed for clinical efficacy were associated with adverse events notably upper respiratory tract infections [40]. Perhaps the higher Btk-expression of autoreactive B-cells or the necessity to reach sessile B-cells in lymph nodes requires higher drug concentrations.…”

Targeted Therapy for Chronıc Spontaneous Urtıcarıa: Ratıonale and Recent Progress

“…Bruton tyrosine kinase (BTK) is a tyrosine kinase expressed in various hematopoietic cells including macrophages, mast cells, and basophils. In addition to playing a major role in B-cell development and functions, BTK is also a part of the FcεR activation and signaling in mast cells [96,97]. BTK inhibitors are used to treat different malignancies of B-cell origin [98].…”

Marine-Derived Biologically Active Compounds for the Potential Treatment of Rheumatoid Arthritis

“…It exhibits less toxicity profile and produces effects when used in combination with MTX. The common adverse effects include latent reactions, skin reactions, and cardiac arrest [ 48 ]. Etanercept is a hybrid protein consisting of human TNF receptors and immunoglobulin backbone.…”