POS0881 EFFICACY AND SAFETY OF SUBCUTANEOUS BRODALUMAB, A FULLY HUMAN ANTI–IL-17RA MONOCLONAL ANTIBODY, FOR SYSTEMIC SCLEROSIS WITH MODERATE-TO-SEVERE SKIN THICKENING: A MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND PHASE 3 STUDY

Abstract

BackgroundSystemic sclerosis (SSc) is a rare chronic connective tissue disease of unknown cause characterized by autoimmunity, vasculopathy, and fibrosis of the skin and various internal organs. It is considered to constitute an area of high unmet medical needed due to limited treatment options and no sufficiently effective treatments. Our previous study (the single-arm, open-label, phase 1 study) indicated that brodalumab, a fully human anti-IL-17RA monoclonal antibody, had a potential to improve skin sclerosis in SSc patients, which could be attributed to its direct effects on fibroblasts and indirect effects via impacts on both B cell and T cell subsets (NCT04368403).ObjectivesTo evaluate the efficacy and safety of brodalumab for SSc patients with moderate-to-severe skin thickening in a phase 3, multicenter, randomized, placebo-controlled, double-blind study.MethodsEligible patients (modified Rodnan skin score (mRSS):10-29, present with the first symptoms of SSc other than Raynaud’s phenomenon within 60 months at enrolment) were randomized (1:1) to receive subcutaneous brodalumab 210 mg every 2 weeks (Q2W) or placebo during the 52-week placebo-controlled period. Primary endpoint was change from baseline of mRSS at week 24. Patients with an increase in mRSS of ≥5 points and ≥20% from baseline at or after week 24 were permitted to receive open-label treatment with brodalumab.ResultsA total of 100 patients was randomized to the brodalumab group (n=50) or the placebo group (n=50). Forty-six and 45 patients had diffuse cutaneous SSc in the brodalumab and placebo groups, respectively. In both groups, 47 patients completed the 24-week follow-up. Forty-four and 43 patients in the brodalumab and placebo groups completed the 52-week follow-up, respectively. At or after week 24, 38 patients (placebo, n=37; brodalumab, n=1) were switched to the active drug. Brodalumab achieved the primary endpoint (treatment difference of least square mean: −21.2 [95% CI -23.9, 18.5]; P<0.0001), and demonstrated a rapid, sustained reduction in mRSS over 52 weeks. Brodalumab also elevated the composite response index in SSc (CRISS) score, suppressed new development of digital ulcers, deterioration of respiratory function, and progression of lung lesions. Moreover, treatment of brodalumab improved the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) score, global assessment by physician (CGA) and patient (PGA), the Japanese version of the health assessment questionnaire-disability index (J-HAQ-DI) score, and the functional assessment of chronic illness therapy-fatigue (FACIT-Fatigue) score. The safety profile did not differ from that previously observed in other diseases such as psoriasis and ankylosing spondylitis and non-radiographic axial spondyloarthritis.ConclusionBrodalumab demonstrated a rapid, sustained, and significant decrease in skin sclerosis. Moreover, the outcome of brodalumab treatment suggested its therapeutic effects on lung/respiratory functions, digital ulcers, the symptoms of gastroesophageal reflux disease, and QOL without any noteworthy safety concerns.ReferencesNone.Figure 1.mRSS over the 24-week follow up. (Mean +/- SD)Table 1.Secondary endpoints at week 24BrodalumabPlacebomeanSDmeanSDDifference95% CIP valueMedian CRISS score1NA0NANANA<0.0001Cumulative new digital ulcer count0.10.285.06.5-4.9[-6.8, -3.0]<0.0001Percent predicted FVC*, %0.194.43-5.047.395.23[2.73, 7.72]<0.0001Percent predicted DLCO*, %-0.596.808-5.966.7735.38[2.60, 8.16]0.00022FSSG score*-2.35.9910.111.16-12.4[-16.1, -8.7]<0.0001PGA*, mm-6.821.9426.124.17-32.9[-42.3, -23.4]<0.0001CGA*, mm-34.014.6913.823.05-63.4[-71.9, -54.9]<0.0001J-HAQ-DI*-0.0450.2340.6980.7065-0.743[-0.958, -0.527]<0.0001FACIT-Fatigue subscale score*2.2346.869-9.40414.765811.638[6.920, 16.356]<0.0001*Change from baselineAcknowledgementsWe gratefully acknowledge the patients and their families for their participation in this trial. We thank all the investigators who had a part in this study for their contribution.Disclosure of InterestsTakemichi Fukasawa: None declared, Ayumi Yoshizaki: None declared, Hisashi Kagebayashi Employee of: Kyowa Kirin Co., Ltd., Shinichi Sato Consultant of: Kyowa Kirin Co., Ltd.