Fenebrutinib disappoints in systemic lupus erythematosus

The noncovalent, highly selective inhibitor of Bruton’s tyrosine kinase (BTK) fenebrutinib is safe in patients with systemic lupus erythematosus (SLE) but falls short of improving disease activity, according to the results of a phase II trial.

A total of 260 patients with moderate-to-severely active SLE receiving background standard of care therapy participated in the trial. They were enrolled from 44 sites in 12 countries, with the most coming from Latin America, the US, and Western Europe.

The patients were randomized to treatment with placebo or fenebrutinib at 150 mg once daily (QD) or 200 mg twice daily (BID). They were advised to taper corticosteroid use from weeks 0 to 12 and weeks 24 to 36.

At week 48, the primary endpoint of SLE Responder Index 4 (SRI-4) was 44 percent with placebo, 51 percent with fenebrutinib 150 mg QD, and 52 percent with 200 mg BID. The differences noted with active treatment vs placebo were not significant (p=0.37 and p=0.34, respectively) for fenebrutinib 200 mg BID, and 44 percent for placebo.

Likewise, the British Isles Lupus Assessment Group (BILAG)-based combined lupus assessment (BICLA) response rates at week 48 did not differ across the treatment arms: 41 percent with placebo, 53 percent with fenebrutinib 150 mg QD (p=0.086), and 42 percent with 200 mg BID  (p=0.879).

Safety results were comparable, even though serious adverse events occurred more frequently in the 200 mg BID arm.

Compared with those on placebo, patients who received fenebrutinib exhibited lower levels of a BTK-dependent plasmablast RNA signature, anti-dsDNA autoantibodies, total IgG, and IgM, as well as increased complement C4 by week 48.