Oral rilzabrutinib, first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: phase II BELIEVE study

Pemphigus vulgaris (PV) is a potentially life-threatening B-cell-mediated autoimmune disease characterized by debilitating intraepithelial blisters and erosions on skin and mucous membranes. It results from IgG autoantibodies binding to the keratinocyte proteins desmoglein (Dsg)1 and Dsg3, inducing acantholysis. Both innate and adaptive immunological pathways can be rational therapeutic targets in PV.

First-line PV treatment includes either high-dose corticosteroids (CS) (≥1mg/kg) or intravenous rituximab plus moderate-to-high doses of CS (0.5-1 mg/kg) tapered over 3 months for moderate PV or 6 months for severe PV. Continued or maintenance therapy to manage relapses poses a significant risk of immunosuppression and possible adverse effects. Immune-mediated therapies that are more specifically targeted, fast acting and steroid sparing, and have safety profiles well suited for chronic administration are the need of the hour. Rilzabrutinib (PRN1008) is a potent, oral and reversible covalent Bruton tyrosine kinase (BTK) inhibitor developed to treat autoimmune diseases. Recently a study showing efficacy of rilzabrutinib in pemphigus was published in the British Journal of Dermatology.

BTK causes 'targeted immunosuppression' with no direct effects on T cells and plasma cells. Rilzabrutinib forms both noncovalent and covalent bonds with BTK for enhanced selectivity and extended inhibition. Rilzabrutinib exhibits minimal cross-reactivity with other kinases, and thus lower risk for off target drug-mediated effects. It intervenes in multiple immunological mechanisms including inhibiting B-cell receptor signalling, IgG-mediated Fc gamma receptor activation and phagocytosis, IgE-mediated Fc epsilon receptor activation and degranulation, and finally activation, adhesion, recruitment and oxidative burst in neutrophils, all without directly impacting T cells or depleting B cells. Oral rilzabrutinib has a large volume of distribution, a half-life of approximately 3–4 h, and > 90% BTK occupancy within 4 hours of dosing.

Patients and methods

This multicentre, single-arm, phase II 'BELIEVE' study was a open-label, proof-of-concept study to evaluate the efficacy and safety of rilzabrutinib, with or without concomitant low-dose CS, in patients with PV. Patients of 18–80 years of age with a clinical diagnosis of new-onset or relapsing, moderate-to-severe PV based on histopathological and immunohistological evaluation were included in the study. Disease severity was measured by Pemphigus Disease Area Index (PDAI) with scores of 8 to < 45 (moderate 8 to < 15, moderate to severe ≥ 15). Prednisone equivalent CS ≤ 0.5 mg/kg per day was permitted for 2 weeks prior to initiation of rilzabrutinib. Patients using recent or concomitant BTK inhibitors or immunological response modifiers, and needing ongoing CYP3A-sensitive drugs and/or proton pump inhibitors were excluded.

Treatment

Patients received an initial dose of oral rilzabrutinib 400 mg twice daily, with optional dose adjustment up to 600 mg twice daily, for 12 weeks, with an additional 12 weeks' off treatment follow-up. Concomitant CS doses were 0 to ≤ 0.5 mg/kg per day, unless higher 'rescue' doses were later needed. CS doses were tapered as per investigator's discretion after confirming control of disease activity (CDA) and continuing improvement at least 2 weeks later. Assessments were performed on days 1 and 2, and weeks 2, 4, 8, 12, 16, 20 and 24.

Outcomes

The primary efficacy endpoint was the proportion of patients achieving CDA within 4 weeks of starting rilzabrutinib with zero CS or a CS dose ≤ 0.5 mg/kg per day (defined as 'low-dose CS'). CDA was defined as the absence of new lesions and beginning of healing of existing lesions. The primary safety endpoint of treatment-emergent adverse events (TEAEs) was reported through 24 weeks (12 weeks on treatment, 12 weeks of off-treatment follow-up) and were graded per the National Cancer Institute's Common Terminology Criteria for Adverse Events. Secondary endpoints included time to CDA, CR and relapse post-rilzabrutinib; and CS usage. CR was defined as the absence of new lesions and all lesions healed. Additional and exploratory endpoints were changes from baseline in PDAI activity, quality-of-life score (Autoimmune Bullous Disease Quality of Life, ABQOL), appetite score (Simplified Nutritional Appetite Questionnaire, SNAQ), pharmacokinetics, BTK occupancy in peripheral blood mononuclear cells (PBMCs),10 and anti-Dsg1/3 autoantibody levels.

Statistical analysis

Quantitative results were summarized using descriptive statistics. Efficacy and time-to-event results, including two-sided 95% confidence intervals (CIs), were evaluated by the exact Clopper–Pearson method and Kaplan–Meier estimates.

Results

Fifty two patients were screened from 13 sites in Australia, Croatia, France, Greece and Israel; 27 patients were enrolled. Their median age was 51 years, 56% were female and 81% were white. Nine patients (33%) had newly diagnosed and 18 (67%) had relapsing PV. The mean baseline PDAI score overall was 19.1 (SD-10.7); it was 21.2 (SD, 11.5) for newly diagnosed and 18.0 (SD, 10.4) for relapsing disease. Overall, 11 patients (41%) had moderate disease with mean baseline PDAI score 10.0 (SD,1.2), and 16 patients (59%) had moderate-to-severe disease with mean baseline PDAI score 25.3 (SD, 9.7). PV was confirmed in all patients based on histopathology and immunohistological evaluations. Baseline anti-Dsg antibody profiles were n = 13 anti-Dsg3+ only, n = 3 anti-Dsg1+ only, n = 10 anti-Dsg1+/Dsg3+ and n = 1 double negative.

Six patients entered the study without any CS treatment; four patients (one newly diagnosed; three chronic relapsing cases with durations of PV prior to study initiation of 3.4, 3.5 and 8.2 years respectively received rilzabrutinib only (no CS) for the first 12 weeks. The starting low CS dose (≤ 0.5 mg/kg per day) was determined by clinical need and screening period dose. The dose of rilzabrutinib dose was even increased to 600 mg wice daily in few patients. BTK occupancy levels just prior to dose escalations were below the 70% target for the three patients (66%, 43% and 23%, respectively) in whom dose was escalated.

The mean duration of rilzabrutinib exposure was 80 days (SD, 21). Three patients achieved CDA on rilzabrutinib alone (no CS) by 2 weeks; two patients relapsed off rilzabrutinib at week 20 and received low-dose CS. The other 24 patients (89%) received concomitant low-dose CS at some time during the first 12 weeks, including 11 (46%) who tapered to minimal CS of < 10 mg per day. CS doses were stable during screening, indicated by similar mean screening and baseline CS doses: screening 20 mg per day (SD, 13.0) for newly diagnosed and 10.9 mg per day (SD, 15.9) for relapsing patients; and at baseline: 20 mg per day (SD, 9.7) for newly diagnosed and 10.3 mg per day (SD, 10.6) for relapsing patients.

Pharmacokinetic and BTK occupancy indicated rapid rilzabrutinib absorption and clearance from plasma, with high levels of durable BTK inhibition (target threshold of ≥ 70%) observed 2 h after the first rilzabrutinib dose and maintained throughout the dosing interval, reflecting the slow dissociation rate of rilzabrutinib from BTK.

Efficacy

The primary endpoint of CDA with zero-to-low-dose CS at or prior to week 4 was achieved in 14 of 27 patients (52%, 95% CI), including three patients not initially taking CS. In 14 patients achieving CDA, the primary endpoint response was accompanied by low CS doses compared with guideline recommendations for medium-to-high-dose CS. CDA was achieved rapidly, with a median time to first CDA of 33 days (95% CI ) of rilzabrutinib based on Kaplan– Meier estimates. The CDA rate improved over time: 19 (70%) by week 12, and 23 (85%) after an additional 12 weeks off rilzabrutinib. The median time to relapse per Kaplan–Meier estimates in patients achieving CDA and after treatment completion or discontinuation was 96 days. The CR endpoint was met in six of 27 patients (22%) by week 24. Four patients (15%) achieved CR by week 12 and an additional two by week 20 without increased doses of CS. The mean CS dose at the time of CR was 7.2 mg per day (range 1–20). Three patients maintained CR for ≥ 80 days, and three for between 23 and 60 days.

Disease severity, measured by PDAI scores, improved more rapidly, and from a higher starting point, in newly diagnosed patients than in relapsing patients. PDAI score reduction was evident as early as the week 2 visit in both groups. Overall CS use decreased more over time in newly diagnosed than relapsing patients. The mean CS dose in newly diagnosed patients fell from 20.0 mg per day (SD, 9.7) at baseline to 11.8 mg per day (SD, 8.9) at 12 weeks. In relapsing patients, the mean CS dose was reduced from 10.3 mg per day (SD, 10.6) at baseline to 7.8 mg per day (SD, 7.7) at 12 weeks. For all patients over 12 weeks of rilzabrutinib, the mean dose of CS was 13 mg per day. During follow-up off rilzabrutinib, four patients required increased rescue doses of CS (> 0.5 mg/kg per day) to control flare-ups.

In an exploratory analysis, mean anti-Dsg3 antibody levels decreased from 404 units/mL (SD, 462) at baseline to 289 units/mL (SD, 384) after 12 weeks of rilzabrutinib (with or without low-dose CS). In 16 patients with high baseline anti- Dsg3 autoantibodies (≥ 100 units mL_1), mean anti-Dsg3 levels decreased from 552 (SD, 486) to 342 (SD, 416) after 12 weeks of rilzabrutinib, with a trending further reduction during 12 weeks off-treatment [week 24: mean, 295 units mL_1 (SD, 346). By week 4, CDA rates were 55% in moderate and 50% in moderate-to-severe pemphigus, 56% for newly diagnosed and 50% for relapsing and chronic patients, and 43% and 55% for patients with baseline total anti-Dsg antibody titres < 100 and ≥ 100 units/mL respectively.

Safety

TEAEs independent of causality occurred in 20 (74%) patients; the most common were nausea (22%) and headache (15%). Twelve of 27 patients (44%) experienced a treatment-related TEAE, with the most common being nausea (15%) and upper abdominal pain (11%); all others occurred in no more than two patients. The majority of treatment related TEAEs were grade 1/2 and transient. Three patients experienced serious adverse event which were grade 3 cellulitis on day 26, pneumonitis on day 9 and pancreatic pseudocyst discovered on day 29 who withdrew from the study for elective surgery. The investigator regarded this as not related to rilzabrutinib.

Quality-of-life and appetite scores

Mean ABQOL scores decreased slightly from 19.3 at baseline to 14.8 at 12 weeks: mean alteration 3.7 (SD, 7.0). In newly diagnosed and relapsing patients, mean ABQOL scores at baseline to 12 weeks decreased from 20.1 to 12.6 (mean change 6.6) and from 18.9 to 15.8 (mean change 2.5). The SNAQ score22 increased slightly after 12 weeks of treatment indicating that appetite was not suppressed.

The BELIEVE study is the first trial to demonstrate clinical activity of BTK inhibition in human autoimmune skin disease. Rilzabrutinib showed rapid and clinically meaningful efficacy, with most patients achieving CDA by 4 weeks on the background of zero-to-low-dose CS. Excitingly, the rapid achievement of CDA (median 33 days) by patients without moderate-to-high CS doses suggests the possibility of a CS-free rilzabrutinib acute control regimen for future patients or at least one with a rapid CS taper to minimize CS-related adverse effects.

A high proportion of patients achieved CDA, despite limited, initial anti-Dsg3 reduction, suggests a faster effect of rilzabrutinib on the innate immune system. Delayed anti-Dsg3 reductions were likely due to rilzabrutinib's indirect depletion of short-lived plasma cells due to B-lymphocyte inhibition. This is consistent with BTK-mediated inhibition of multiple non-T-cell immune cells, rather than delayed adaptive immune suppression, reflected better by later changes in PDAI score and partial reductions in autoantibody formation. The rapidity of onset of response, coupled with the fact that rilzabrutinib has no direct effect on plasma cells, suggests that its early efficacy in pemphigus is partly due to its effects on the innate immune system.

The safety results indicated a favourable risk-to-benefit profile for rilzabrutinib. Additionally, rilzabrutinib enabled reduced initial CS doses and facilitated rapid tapering, a major goal in pemphigus therapies. Another advantage of rilzabrutinib is rapid clearance and reversible pharmacodynamic effects after stopping treatment.

In conclusion, this study confirms rilzabrutinib as the first BTK inhibitor showing a favourable risk-to-benefit profile in PV and can be effectively and safely combined with zero or low-dose CS for a rapid response.

Source- Murrell DF, Patsatsi A, Stavropoulos P, Baum S, Zeeli T, Kern JS, Roussaki-Schulze AV, Sinclair R, Bassukas ID, Thomas D, Neale A, Arora P, Caux F, Werth VP, Gourlay SG, Joly P; BELIEVE trial investigators. Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study. Br J Dermatol. 2021 Oct;185(4):745-755. doi: 10.1111/bjd.20431.