Bruton’s tyrosine kinase inhibition: a novel treatment option for Sjögren’s syndrome?

In a phase 2 study, remibrutinib significantly reduced objective disease parameters in patients with Sjögren's syndrome (SS). The agent also lowered immunoglobulins and disease-related autoantibodies, and was relatively well tolerated.

Today, SS is considered a B-cell-driven disease, resulting from abnormal responses to autoantigens causing chronic inflammation of the exocrine glands [1]. Clinical symptoms commonly include oral and ocular dryness, fatigue, and joint pain [1]. Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell receptor signalling. Inhibition of BTK has therefore emerged as a potential therapeutic option for selective immune modulation in a wide spectrum of diseases and has already been shown to be efficacious in chronic urticaria [2].

The LOUiSSE study (NCT04035668) is a phase 2 clinical trial to evaluate the safety and efficacy of the novel BTK inhibitor remibrutinib in patients with moderate-to-severe SS [3].

Included were 72 patients with SS classified according to the 2016 ACR/EULAR SS criteria, who were treated with 2 doses of remibrutinib or placebo. “Only patients with a residual unstimulated salivary flow rate of >0 ml/min were included,” said Prof. Thomas Dörner (Charité University Hospital, Germany). The primary efficacy endpoint was a change from baseline in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 24. Changes in patient-reported outcomes, such as the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), were secondary endpoints. “Very importantly, the study also compared twice versus once-daily dosing,” Prof. Dörner said.

Baseline demographics were similar between groups. “Owing to the similar results between twice and once-daily dosing, we combined the 2 dosing arms and compared them with placebo,” Prof. Dörner explained. The study was positive for the primary endpoint: ESSDAI was significantly reduced by -2.86 (P=0.003) in the remibrutinib arm compared with the placebo arm.

No treatment effect was seen on the ESSPRI score compared with placebo, including the 3 ESSPRI subdomains (dryness, pain, and fatigue). However, remibrutinib showed a trend towards improved unstimulated salivary flow.

Remibrutinib decreased the cytokine CXCL13 levels early on, whereas, in the placebo group, levels of this biomarker remained elevated. In addition, the BTK inhibitor modulated IgG and IgM as signatures of disease activity, with the strongest effects on IgM levels. The reduction of these immunoglobulins correlated with the decrease of anti-SSB and anti-SSA antibodies in the remibrutinib arm from baseline to week 24.

The agent had a favourable safety profile and was well tolerated in patients with SS over 24 weeks. Prof. Dörner concluded that remibrutinib is a potentially effective oral disease-modifying therapy for SS, which will be established in longer-term studies. The lack of effect on patient-reported outcomes may result from the relatively short treatment duration (24 weeks).

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   1. Brito-Zeron P, et al. Nat Rev Dis Primers. 2016;2:16047.
   2. Maurer M, et al. J Allergy Clin Immunol. 2022;S0091-6749(22)01181-2.
   3. Dörner T. Remibrutinib (LOU064) in Sjögren’s Syndrome: safety and efficacy results from a 24-week placebo-controlled proof-of-concept study. 1113, ACR Convergence 2022, 10–14 November, Philadelphia, USA.

 

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Tags: Sjögren’s Syndrome; remibrutinib; Bruton's tyrosine kinase inhibitor; BTK inhibitor



Posted on 1 December, 20226 September, 2023