The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

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In pemphigus foliaceus (PF) and pemphigus vulgaris (PV) IgG autoantibodies to desmogleins (Dsg) 1 and 3 lead to acantholysis, causing painful cutaneous and/or mucosal lesions. The neonatal crystallizable fragment receptor (FcRn) binds to IgG and circulating immune complexes (CIC) at acid pH to regulate their half-life and inflammatory activity. SYNT001 is a humanized IgG4 monoclonal antibody optimized to inhibit FcRn function at low pH. SYNT001-103 (NCT03075904) is an ongoing, open-label phase 1b study evaluating safety and clinical effect of SYNT001 in PV or PF. Up to 3 cohorts (N¼8 subjects each) assessing 5 weekly doses 45 mg/kg SYNT001 IV are planned. Primary objective is safety; secondary objectives include pharmacodynamics and clinical response. Follow-up is through Day 112. The study is approved by each sites IRB; all subjects provide written informed consent. As of 12/31/2017, 3 subjects (2 PV, 1 PF) were enrolled in Cohort 1 (10 mg/kg). All completed 5 doses of SYNT001 and were in varying stages of follow-up. Two subjects had treatmentrelated mild-to-moderate headache after Dose 1 only. The 3rd subject had a transient urticarial infusion reaction after doses 4 and 5 responsive to diphenhydramine. By wDay 30 1 PV subject had decreases of 48% in total IgG, 63% CIC, 30% anti-Dsg1 titer and 40% anti-Dsg3. Pemphigus Disease Area Index (PDAI) was 47 at baseline, 38 on Day 14 and a low of 15 on Day 28. By wDay 30 the other PV subject had decreases of 59% in IgG, 48% CIC, 64% anti-Dsg1 and 61% anti-Dsg3. PDAI was 19 at baseline, 12 on Day 7 and a low of 9 on Day 33. By wDay 30, the PF subject had decreases of 65% in IgG, 47% CIC and 32% anti-Dsg1; Dsg3 was negative. PDAI was 9 at baseline and a low of 7 on Day 21. These interim data show SYNT001 is well tolerated in PV and PF. This first-in-human study in pemphigus provides initial proof-of-concept for anti-FcRn treatment with SYNT001 in this disorder. Patient-Oriented Eczema Measure (POEM) is the preferred patient-reported outcome (PRO) measure to assess atopic dermatitis (AD) symptoms. Dermatology Life Quality Index (DLQI) is a commonly used PRO to assess the burden of skin disease. Previous severity strata were developed for POEM and DLQI in clinical cohorts, which may be biased toward more severe disease. Severity strata were not previously examined in population-based cohorts. Patient-Oriented Scoring AD (PO-SCORAD) is another commonly used PRO for assessing the symptoms of AD, yet severity strata are not established. We sought to confirm previously developed strata for POEM and DLQI, and develop strata for the PO-SCORAD in a population-based cohort of adults with AD. A cross-sectional, population-based study of 8,217 adults was performed using a structured questionnaire. A diagnosis of AD was determined using modified UK Diagnostic Criteria for AD (N¼602). AD severity was assessed using self-reported global AD severity (anchoring question), POEM, PO-SCORAD, and DLQI. Strata were selected using an anchoring approach based on patient-reported disease severit...