Inhibition of Bruton’s tyrosine kinase: a new way of approaching SLE?

In a dose-finding study, orelabrutinib demonstrated promising results as a future treatment option in systemic lupus erythematosus (SLE). Good overall tolerability and greater response rates were observed compared with placebo.

Orelabrutinib is an oral drug that selectively inhibits Bruton’s tyrosine kinase (BTK). It already has approval for the treatment of B-cell cancer in China and is currently under investigation for several other indications [1,2]. Prof. Zangou Li (Peking University People’s Hospital, China) presented data of a phase 1b/2a, randomised, double-blind, placebo-controlled, dose-finding study (NCT04305197) on orelabrutinib in adult patients with an SLE Disease Activity Index 2000 (SLEDAI-2K) ≥5 and positive testing for autoantibodies [1]. Besides safety and tolerability results that were the trial's primary objectives, the researchers were also interested in the pharmacokinetics, pharmacodynamics, and preliminary efficacy.

All 60 randomised participants had been on a stable standard-of-care therapy at least 3 months before the trial started. Within 4 study groups, the participants were assigned to either placebo or 1 of 3 different dosages of the study drug: daily orelabrutinib 50 mg, 80 mg, and 100 mg over 12 weeks. Due to the study phase and design, there was no possibility of formal hypothesis testing.

“Based on the clinical features and the laboratory parameters, there was not much difference between the groups,” Prof. Li pointed out regarding the baseline characteristics. The mean age at baseline was 33.7 years, and 96.7% were women. In the different study arms, between 85.7% and 93.3% had a background treatment of corticosteroids, 80% to 86.7% took hydroxychloroquine, and 57.1% to 80% immunosuppressive agents. All doses of orelabrutinib induced a BTK occupancy that was nearly 100% over 24 hours. The drug demonstrated a half-life of 4 hours and an increasing plasma exposure according to dosage.

Prof. Li stated that the safety data was mostly similar between the groups. Overall, adverse events were mainly mild to moderate. Serious treatment-emergent adverse events only happened in the 80 mg and 100 mg study drug arms in 26.7% and 12.5% of participants, respectively. Furthermore, a decrease in lymphocytes was also more frequent in these arms: 40.0% and 31.3% versus 7.1% (placebo) and 13.3% (50 mg dosage), respectively.

As for clinical results, orelabrutinib led to numerical higher response rates in the SLE Responder Index (SRI) 4, compared with placebo: 35.7% (placebo), 46.7% (50 mg), 53.3% (80 mg) and 56.3% (100 mg). In participants with severe disease (SLEDAI-2K ≥8), the differences in SRI4 response rates were more pronounced and amounted to 24.5% and 33.6% between placebo and orelabrutinib groups. Trends were also observed for improvement of proteinuria, anti-dsDNA and IgG production, total B-cell count reduction, and complement increase (C4).

“In conclusion, orelabrutinib is generally safe and well-tolerated in patients with SLE, and preliminary results also suggest trending efficacy supporting further studies in larger and longer-term trials in SLE,” Prof. Li closed.

1. Li R, et al. Orelabrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), for the treatment of systemic lupus erythematosus (SLE): results of a randomized, double-blind, placebo-controlled, phase IB/IIA dose-finding study. LB0005, EULAR 2022 Congress, 1–4 June, Copenhagen, Denmark.
2. Dhillon S. Drugs. 2021;81:503–507.

Posted on 21 July 202217 May 2024