Design: phase III, multicentre, randomised, double-blind, placebo-controlled trial, 2:1 allocation
Population: 222 adults with newly diagnosed or relapsing moderate-to-severe pemphigus — 190 pemphigus vulgaris, 32 pemphigus foliaceus — all on prednisone 0.5 mg/kg daily
Primary outcome: complete remission on minimal prednisone (≤10 mg daily) by week 30, sustained ≥8 weeks, in pemphigus vulgaris
Effect: 35.5% (44/124) with efgartigimod vs 30.3% (20/66) with placebo; odds ratio 1.19 (95% CI 0.60–2.41), P = 0.60

Efgartigimod blocks the neonatal Fc receptor, so immunoglobulin G is no longer recycled and circulating IgG — including pathogenic autoantibody — falls. In pemphigus, where anti-desmoglein antibodies are the accepted mechanism, that ought to work. ADDRESS, a global phase III double-blind trial, tested it in 222 adults with moderate-to-severe pemphigus (190 pemphigus vulgaris, 32 pemphigus foliaceus), randomised 2:1 to weekly subcutaneous efgartigimod or placebo, all on prednisone from 0.5 mg/kg daily.

The pharmacodynamics worked and the clinical outcome did not. Total IgG and both anti-desmoglein-1 and anti-desmoglein-3 levels fell rapidly. Complete remission on minimal prednisone by week 30, sustained for at least eight weeks, was reached by 44 of 124 patients with pemphigus vulgaris on efgartigimod (35.5%) against 20 of 66 on placebo (30.3%) — P = 0.60, odds ratio 1.19 (95% confidence interval 0.60 to 2.41). Total prednisone consumption was no lower. Pemphigus Disease Area Index scores did not improve with the antibody reduction. Adverse events were more frequent on efgartigimod (89.1% vs 76.0%) but mostly mild to moderate, serious events were similar, and nobody died.

For practice today this changes nothing about what you prescribe — rituximab with corticosteroid remains the standard for moderate-to-severe pemphigus. What it changes is the reasoning. Autoantibody titre is a monitoring tool and a mechanism, not a treatment target in itself, and a drug that moves the titre convincingly has now failed to move the disease.

Continue current practice: corticosteroid with rituximab remains the standard for moderate-to-severe pemphigus.
Do not read a falling desmoglein titre on any therapy as proof the skin is following.
Assess pemphigus response clinically — lesion count, new blister formation, Pemphigus Disease Area Index — not serologically alone.
Note that about a third of patients reached remission on prednisone alone in this trial; that is the comparator any new agent has to beat.
Tolerability was acceptable, so the failure here is efficacy, not safety.

Why it matters

It separates the biomarker from the disease: the autoantibody fell exactly as designed and the blisters did not care.

The statistics, in plain English

An odds ratio of 1.19 with a confidence interval from 0.60 to 2.41 straddles 1.0 comfortably: the data are equally consistent with modest benefit and with modest harm, and a P of 0.60 means there is nothing here to interpret as a trend. This is a properly powered phase III comparison, so the reading is not 'too small to tell' — it is a negative trial. The placebo remission rate of 30.3% is the number worth remembering, because it shows how much of pemphigus improvement in a trial comes from the corticosteroid backbone.