Bruton’s tyrosine kinase inhibition promising for pemphigus vulgaris

An open-label, phase 2 study with the oral and reversible Bruton’s tyrosine kinase inhibitor rilzabrutinib for pemphigus vulgaris patients resulted in substantial rates of disease control and less usage of corticosteroids.

“Bruton’s tyrosine kinase (BTK) has a broad role in the rapid innate as well as the delayed adaptive immune response in pemphigus. Rilzabrutinib is not simply a BTK inhibitor, but it is a potent oral and reversible BTK inhibitor,” said Prof. Dedee F. Murrell (St George Hospital, University of New South Wales, Australia), explaining the rationale for the presented phase 2, proof-of-concept BELIEVE study (NCT02704429) [1-3]. The trial investigated rilzabrutinib for the treatment of newly diagnosed or relapsing pemphigus vulgaris [1].

The open-label study included 27 patients with a median age of 51. Among them, 33% were newly diagnosed and 67% relapsing. Concerning disease severity, 41% suffered from moderate pemphigus and 59% from moderate-to-severe pemphigus. The mean time from diagnosis was 8.9 years. Oral rilzabrutinib was administered at a dose of 400–600­ mg twice daily while concomitant low-dose corticosteroids were allowed.

The primary endpoint was control of disease activity (CDA) after 4 weeks; secondary endpoints consisted of complete response rate, pemphigus disease area index (PDAI), decrease in steroid use, and quality of life. After 4 weeks, 52% of participants reached the primary CDA endpoint and this percentage increased to 70% after 12 weeks. After week 12, CDA was 67% in newly diagnosed and 72% in relapsing pemphigus patients. In moderate and moderate-to-severe grades at the same time point, CDA was 64% and 75%, respectively. “The CDA rates consistently improved over time, irrespective of pemphigus duration or the severity of pemphigus at onset,” Prof. Murrell elaborated.

Treatment with rilzabrutinib also improved PDAI scores significantly and reduced the extent of steroid use (see Figure). Overall, a clinically meaningful improvement in quality of life was found at week 12 compared with baseline, which stabilised during the post-treatment follow-up to week 24; the greatest effect was observed in the group of newly diagnosed patients.

Figure: Results for PDAI activity scores and use of corticosteroid in part A of the BELIEVE trial [1]



CS, corticosteroids; PDAI, pemphigus disease area index; SD, standard deviation.

“In terms of safety, we saw only transient and mild-to-moderate adverse events, giving an overall favourable risk-benefit profile,” said Prof. Murrell. Further results for rilzabrutinib will be seen in part B of BELIEVE and the ongoing phase 3 PEGASUS pivotal study (NCT03762265).

1. Murrell D. Treatment with rilzabrutinib results in rapid and significant decrease in steroid use and improved quality of life in patients with chronic Relapsing Pemphigus: BELIEVE Phase II Study. Session S033, AAD VMX 2021, 23-25 April.
2. Didona D, et al. Front Immunol. 2019;10:1418.
3. Bradshaw JM, et al. Nat Chem Biol. 2015;11(7):525-31.

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Posted on 7 June 20216 September 2023