Overview of ongoing and upcoming clinical trials in autoimmune blistering diseases: pemphigus uulgaris and pemphigus foliaceus (ADDRESS and ADDRESS+) and bullous pemphigoid

Background: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) belong to the heterogenous group of autoimmune diseases and are clinically characterized by mucosal erosions and/or cutaneous blisters and erosions. IgG autoantibodies primarily target desmoglein (Dsg)‐3 in PV and both Dsg‐1 and Dsg‐3 in the mucocutaneous variant of PV, while PF is attributed exclusively to autoimmunity against Dsg‐1. Bullous pemphigoid (BP) is an autoimmune blistering disease, characterized by subepidermal blisters and mediated by IgG autoantibodies against BP180 (type XVII collagen) and BP230 structural proteins of the dermal‐epidermal junction. The neonatal Fc receptor (FcRn) rescues IgG from lysosomal degradation, thereby increasing availability of circulating IgGs. Efgartigimod is a human IgG Fc fragment engineered to block FcRn, reducing the serum level of circulating IgGs, including pathogenic IgG autoantibodies. In a recent Phase 2 trial, efgartigimod decreased serum concentrations of anti‐Dsg‐3 and anti‐ Dsg‐1 IgG autoantibodies in 34 patients with mild to moderate PV or PF (Goebeler M, et al. Br J Dermatol. 2021.). Total IgG and anti‐desmoglein autoantibody reductions were associated with improved Pemphigus Disease Area Index (PDAI) scores. Disease control (DC) was achieved by 28/31 (90%) patients receiving efgartigimod either as monotherapy or as add‐on to prednisone after a median of 17 days. Complete clinical remission (CR) was achieved by 14/22 (64%) patients receiving combined treatment of efgartigimod and prednisone 0.1‐0.5 mg/kg/day. Efgartigimod was well tolerated, and most adverse events were mild. Based on these results, a Phase 3 trial of efgartigimod was launched in patients with PV and PF. ADDRESS is a multicenter, randomized, doubleblind, placebo‐controlled trial evaluating efficacy and safety of efgartigimod in patients with PV or PF (ClinicalTrials.gov; NCT04598451). ADDRESS+ is an open‐label extension trial designed to evaluate long‐term safety and efficacy of efgartigimod in patients who participated in the ADDRESS trial (ClinicalTrials.gov; NCT04598477). Here we provide an overview of the ADDRESS and ADDRESS+ trials and bring awareness to an upcoming phase 2/3 trial of efgartigimod in patients with BP. Methods: ADDRESS and ADDRESS+ eligibility criteria include clinical diagnosis with PV or PF, age >18 years, and PDAI score >15. A total of 150 patients (126 PV and 24 PF) are undergoing randomization (2:1) to receive subcutaneous efgartigimod co‐formulated with PH20 or placebo/ PH20 on top of oral prednisone (or equivalent). Primary endpoint is the proportion of patients with PV who achieve complete remission on minimal therapy (CRmin) within 30 weeks. Secondary endpoints include: proportion of patients with PV or PF achieving CRmin within 30 weeks, time to CR, and time to DC. In ADDRESS+, treatment continuation will be based on clinical status at time of rollover: no efgartigimod if CRmin has been achieved, weekly efgartigimod PH20 SC if CRmin has not been achieved, new treatment cycle in case of treatment failure or flare after CRmin. Safety and long‐term remission will be studied in ADDRESS+. Results: More details on ADDRESS and ADDRESS+ are available on ClinicalTrials. gov (ADDRESS: NCT04598451; ADDRESS+: NCT04598477). More details on the Phase 2/3 trial in BP will be available soon.