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Clinical effectiveness of fenebrutinib in RA patients with methotrexate or TNFi failure

Presented by
Dr Stanley Cohen, Metroplex Clinical Research Center, Dallas, USA
EULAR 2019
A phase 2 study demonstrated that fenebrutinib had higher efficacy than placebo for ACR50 at week 12 in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate or TNF inhibitors. Furthermore, fenebrutinib was similar to adalimumab in methotrexate-refractory patients. The safety profile of fenebrutinib was acceptable.

Fenebrutinib is an orally available highly selective inhibitor of Bruton's tyrosine kinase (BTK) with potential anti-rheumatic activity. Dr Stanley Cohen (Metroplex Clinical Research Center, Dallas, USA) et al. evaluated the efficacy and safety of fenebrutinib compared with placebo and adalimumab, in combination with low-dose methotrexate, in patients with RA [1].

This multicentre, randomised, double-blind phase 2 trial included patients with moderate-to-severe active RA with an inadequate response to methotrexate or other DMARDs (MTX-IR, cohort 1) or TNF inhibitors (TNF-IR, cohort 2). Patients from the first cohort were randomly assigned to receive fenebrutinib 50 mg/day (n=40), 150 mg/day (n=109), or 200 mg (n=110) twice a day, adalimumab 40 mg every 2 weeks (n=111), or placebo (n=110). Patients from the second cohort were randomly assigned to receive fenebrutinib 200 mg (n=48) twice a day or placebo (n=50). Demographics and disease characteristics were balanced and an estimated 90% of patients per arm completed the study. Efficacy endpoints evaluated the proportion of patients with ACR50 response at week 12, comparing fenebrutinib doses to placebo (both cohorts) and to adalimumab (cohort 1).

The results showed that in cohort 1, ACR50 responses, the primary outcome, at week 12 increased with increasing fenebrutinib dose (18%, 28%, and 35% for fenebrutinib 50 mg, 150 mg, and 200 mg, respectively). Fenebrutinib 150 mg (28%, P=0.0164) and fenebrutinib 200 mg (35%, P=0.0003) were superior to placebo (15%), and similar to adalimumab (36%). In cohort 2, fenebrutinib again proved superior to placebo with ACR50 responses achieved by 25% and 12% respectively at week 12. A similar significant benefit with fenebrutinib over placebo was seen for the secondary endpoints of ACR20 response at fenebrutinib 200 mg (59% vs 36% for placebo), ACR70 response at all doses, and change in DAS28-CRP at all doses.
Finally, most adverse events (AEs) were balanced across cohort 1; there were 9 serious AEs in 7 patients and 1 death (myocardial infarct) in the fenebrutinib group receiving 200 mg. In cohort 2, more patients in the placebo arm reported mild to moderate AEs and no serious AEs were reported. Dr Cohen also mentioned that in contrast to other kinase inhibitors, there were no changes in haemoglobin/haematocrit, white blood cells, platelets, neutrophils, or monocytes, and there were minimal dose-dependent increases in serum creatinine levels, with no cases of renal insufficiency.

This trial provides clinical evidence to support the rationale for evaluation of BTK inhibition in patients with active RA. Further efficacy and safety profiles are needed, especially in patients with biologic DMARD refractory RA. Rheumatologists may be aware that BTK inhibition for some types of lymphoma is well established in the haematological malignancy arena with robust efficacy and safety data with new generation agents also under development with the intention of reducing toxicities [2].

  1. Cohen S, et al. Abstract OP0025. EULAR 2019
  2. Mato AR, et al. 58th ASH Annual Meeting; Blood 2016;128:3222.

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