Bruton’s tyrosine kinase inhibitor highly effective in pemphigus vulgaris

An oral inhibitor of Bruton’s tyrosine kinase (BTK) together with very low-dose prednisone induces control of disease activity in patients with pemphigus at 12 weeks. This was the shown in the phase 2 Believe-PV proof of concept study [1].

The current standard of care is high-dose corticosteroids with prednisone-equivalent doses of ≥1 mg/kg with high toxicity and/or rituximab plus moderate-to-high initial doses of corticosteroids (≥0.5-1mg/kg).

“Despite the recent FDA approval of rituximab for moderate-to-severe pemphigus, there remains an unmet need for a quick-acting, steroid-sparing, anti-inflammatory treatment for this rare disease,” said Prof. Dedee Murrell (University of New South Wales, Australia). BTK inhibition interrupts multiple signalling pathways in immune cells, but not in T cells. In this way, B cell function can be impaired without reducing B cells directly. The agent proved also to be effective in naturally occurring pemphigus in dogs, even without corticosteroids.

The presented study included 27 patients with mild-to-severe pemphigus with an average duration of 6 years. Of these, 18 patients had relapsing disease and the remainder had newly diagnosed pemphigus. A majority (16 patients) had severe disease, as assessed by the standardised Pemphigus Disease Activity Index (PDAI) corresponding to a score of ≥15. Only 1 patient was negative for anti-desmoglein antibodies.

The mean corticosteroids dose at baseline was 14 mg/day, although that ranged from no steroids to 30 mg/day. The study consisted of a 12-week treatment phase and a 12-week follow-up phase. The primary endpoint was control of disease activity at day 29 as evidenced by no new lesions while on ≤0.5 mg/kg/day of corticosteroids. Secondary endpoints were complete remission, minimisation of prednisone usage, change in anti-desmoglein autoantibody levels, and clinical assessments including the PDAI and the Autoimmune Bullous Skin Disorder Intensity Score.

By the end of week 4, 54% of patients had achieved the primary endpoint, and 73% of patients reached the primary endpoint by the end of week 12 (see Figure). During this period, the mean prednisone dose was 12 mg/day. In addition, therapy was associated with up to a 65% median reduction in autoantibody levels at week 12. The agent demonstrated a favourable tolerability and risk/benefit profile.

“Obviously, the agent has the potential to eliminate or at least significantly reduce the need of corticosteroids in pemphigus patients that have very few treatment options,” concluded Prof. Murrell. The clinical efficacy demonstrated in the Believe-PV trial in combination with a favourable safety profile supports the further development of the molecule. Currently the company is recruiting patients for a phase 3 trial.

Figure: The Bruton’s tyrosine kinase inhibitor achieves control of disease activity in patients with pemphigus within a treatment period of 4 weeks [1]



SD, standard deviation. Primary endpoint: CDA within 4 weeks on low dose corticosteroids (low dose equals less than 0.5 mg/kg/day). mITT used to report CDA rates, excluding 1 patient who dropped out due to treatment-emergent adverse events. Figure kindly provided by Dr Murrell.

1. Murrell D. Abstract 10086, AAD Annual Meeting, 1-5 March 2019, Washington DC, USA.



Posted on 19 April 20196 September 2023