Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study*

Summary

Background

Bruton tyrosine kinase (BTK) inhibition targets B‐cell and other non‐T‐cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti‐desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus.

Objectives

To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof‐of‐concept, phase II trial.

Methods

Patients with Pemphigus Disease Area Index severity scores 8–45 received 12 weeks of oral rilzabrutinib 400–600 mg twice daily and 12 weeks of follow‐up. Patients initially received between 0 and ≤ 0·5 mg kg ⁻¹ prednisone‐equivalent corticosteroid (CS; i.e. ‘low dose’), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero‐to‐low‐dose CS and safety.

Results

In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32–71): 11 using low‐dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment‐related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis.

Conclusions

Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.

Abstract

What is already known about this topic?

• Standard pemphigus treatment relies on systemic high‐dose corticosteroids (CS), rituximab and/or immunosuppressives, which are limited by delayed onset of action and potential toxicities.

• Immune‐mediated mechanisms that are fast acting on both the innate and adaptive immune systems, are steroid sparing, and have safety profiles well suited for chronic administration are greatly needed for patients with pemphigus.

What does this study add?

• Rilzabrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor targeting B‐cell and other non‐T‐cell immune cells implicated in pemphigus pathophysiology.

• Treatment with rilzabrutinib (with or without low‐dose CS) demonstrated rapid disease control and a well‐tolerated safety profile in patients with newly diagnosed and relapsing pemphigus vulgaris.

• BELIEVE provides evidence for a promising treatment strategy via BTK inhibition, supporting further investigation of rilzabrutinib in other immune‐mediated diseases.

Linked Comment:  A.M. Drucker and N.H. Shear. Br J Dermatol 2021; 185:691–692 .

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