BTK signalling as a novel target in hidradenitis suppurativa treatment

Treating hidradenitis suppurativa (HS) with the Bruton’s tyrosine kinase (BTK) inhibitor remibrutinib is a novel treatment approach that was examined in a phase 2 study. The results suggest that this new mode of treatment could be both safe and effective for HS.

Research on pathogenesis has identified that HS lesions contain B cells and plasma cells that are linked to immunoglobulin generation and complement activation [1,2]. Also, activation of BTK and spleen tyrosine kinase pathways are involved in central signal transduction.

Prof. Alexandra Kimball (Harvard Medical School, MA, USA) presented a study that investigated therapy with the selective BTK inhibitor remibrutinib for moderate-to-severe HS over 16 weeks [1]. The trial forms part of a phase 2b multicentre platform study with 5 cohorts (A to E) that assessed various agents for this indication. The rationale for cohort D, testing remibrutinib against placebo, stems from findings that point to a role of BTK activation in HS [1,2].

Cohort D included 77 participants; 33 participants were randomised to remibrutinib at either 25 mg or 100 mg twice daily over 16 weeks, 11 patients received a placebo; the pooled placebo group of all cohorts included 50 participants [1]. The primary endpoint was a simplified HS Clinical Response (HiSCR) that stands for a ≥50% reduction in abscess and nodule (AN) count with no increase in draining tunnels.

At week 16, the results revealed higher rates of participants on the BTK inhibitor achieving simplified HiSCR50 with 72.7% (25 mg) and 48.5% (100 mg) versus 34.7% (pooled placebo; see Figure). Remibrutinib in both doses was also superior to pooled placebo regarding higher HiSCR response rates: HiSCR75 was achieved by 42.4% (25 mg) and 27.3% (100 mg) versus 18.4% (pooled placebo), and HiSCR90 by 36.4% (25 mg) and 15.2% (100 mg) versus 8.2% (pooled placebo). Also, greater reductions were observed in draining tunnels and AN counts along with ameliorations in skin pain in favour of remibrutinib.

Figure: Primary study endpoint of simplified HiSCR at week 16 [1]         

NRI, non-responder imputation; sHiSCR, simplified Hidradenitis Suppurativa Clinical Response.

As for safety, remibrutinib was deemed well tolerated. One grade 4 adverse event occurred in each of the remibrutinib arms, but, overall, adverse events were mainly mild to moderate.

“We are very much looking forward to how this mode-of-action will perform in the future,” Prof. Kimball concluded. Due to the novel mode-of-action, it might be possible to combine BTK inhibitors with other biologics in this indication.

Relevant readings:

• Hidradenitis suppurativa treatment with secukinumab linked to low immunogenicity (AAD 2024)
• HS: Targeting IL-1 pathway potential option after anti-TNF failure (AAD 2024)

1. 
   
   1. Kimball AB. Efficacy and safety of the oral Bruton’s tyrosine kinase inhibitor, remibrutinib, in patients with moderate to severe hidradenitis suppurativa in a randomized, phase 2, double-blind, placebo-controlled platform study. LB1, 2024 AAD Annual Meeting, 8–12 March, San Diego, USA.
   2. Gudjonsson JE, et al. JCI Insight. 2020;5(19):e139930.

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Posted on 22 April, 20241 May, 2024