Efficacy and safety of subcutaneous efgartigimod with prednisone in moderate-to-severe pemphigus (ADDRESS): a global, phase III, randomised controlled, double-blind trial.

Abstract

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare, chronic, potentially life-threatening, immunoglobulin (Ig)G-mediated, autoimmune skin and/or mucosal blistering diseases. Efgartigimod, a human IgG1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing both healthy and pathogenic IgG autoantibody levels. To investigate the efficacy, safety and impact of subcutaneous efgartigimod PH20 (co-formulated with recombinant human hyaluronidase PH20) in conjunction with prednisone in the treatment of pemphigus. Adult participants with newly diagnosed or relapsing moderate-to-severe pemphigus were recruited in this phase III, prospective, multicentre, randomised, double-blinded, placebo-controlled study (NCT04598451). Participants were randomised (2 : 1) to weekly subcutaneous efgartigimod PH20 or placebo. Subcutaneous efgartigimod PH20 2000 mg was administered on days 1 and 8, followed by 1000 mg weekly until complete remission on minimal prednisone therapy (CRmin) (≤ 10 mg daily). All participants received concomitant prednisone starting at 0.5 mg kg-1 daily. The primary outcome was the proportion of participants with PV who achieved CRmin by week 30, while receiving minimal prednisone, for ≥ 8 weeks. Pharmacodynamics and safety were also assessed. Overall, 222 participants (PV: n = 190; PF: n = 32) were randomised (subcutaneous efgartigimod PH20: n = 147; placebo: n = 75). The proportions of participants with PV achieving CRmin within 30 weeks were comparable between the subcutaneous efgartigimod PH20 and placebo groups, with no statistically significant difference observed [44/124 (35.5%) vs. 20/66 (30.3%); P = 0.60; odds ratio 1.19 (95% confidence interval 0.60-2.41)]. Total prednisone consumption over time was comparable between groups. Subcutaneous efgartigimod PH20 resulted in rapid reductions from baseline in total IgG and anti--desmoglein-1 and anti-desmoglein-3 autoantibody levels, but these did not translate to improvements in Pemphigus Disease Area Index scores. The rates of adverse events (AEs) in the subcutaneous efgartigimod PH20 and placebo groups were 89.1% (n = 131/147) and 76.0% (n = 57/75), respectively; most were mild to moderate [serious AEs: 12.2% (n = 18/147) and 13.3% (n = 10/75), respectively]. No deaths occurred. Subcutaneous efgartigimod PH20 in combination with systemic corticosteroids did not demonstrate clinical benefit over systemic corticosteroids alone in patients with moderate-to-severe pemphigus at 30 weeks, but it was well tolerated in this patient population. Pemphigus (pronounced pem–fuh–guhs) is a group of rare skin conditions. These can cause painful blisters and sores. Pemphigus occurs when the body’s immune system mistakenly makes disease-causing antibodies. These antibodies attack proteins that bind skin cells together. Without treatment, pemphigus can be fatal. The ADDRESS trial included adults at 82 study sites across 20 countries. We tested a drug called efgartigimod for safety and efficacy in pemphigus. Efgartigimod is made from a piece of antibody, which binds to a protein called ‘FcRn’. FcRn helps maintain antibody levels. By binding FcRn, efgartigimod acts to reduce antibodies. This includes the antibodies that attack the body in pemphigus. Over 30 weeks, we examined how many people given efgartigimod had 8 weeks of no symptoms. We compared that number with the number of people who had been given a ‘placebo’ who had 8 weeks of no symptoms. The placebo looks like efgartigimod but does not affect antibody levels. Both groups were also given another drug called prednisone. We found that around one-third of people in each group had an 8-week symptom-free period. Around 9 in 10 people given efgartigimod experienced ‘adverse events’. This compares with 7.6 in 10 people given placebo. Most of these adverse events were mild or moderate and went away after a few days or were treated. About every eighth patient in each group had serious adverse events. These could be life-threatening, require long hospital stays or result in long-term disability. There were no deaths during the study. This study provides useful information for future clinical trials in these complicated conditions.