Efgartigimod with prednisone fails to beat prednisone alone in pemphigus

Design

Phase 3, randomised 2:1, double-blind, placebo-controlled

Population

222 adults with moderate-to-severe pemphigus vulgaris or foliaceus

Primary outcome

Complete remission on minimal prednisone by week 30 (vulgaris)

Effect

35.5% vs 30.3%; OR 1.19 (0.60-2.41), P = 0.60

ADDRESS was a global phase 3, double-blind, placebo-controlled trial. It randomised 222 adults with newly diagnosed or relapsing moderate-to-severe pemphigus (190 vulgaris, 32 foliaceus) 2:1 to weekly subcutaneous efgartigimod, a neonatal Fc receptor blocker, or placebo. Everyone started prednisone at 0.5 mg/kg a day.

In pemphigus vulgaris, complete remission on 10 mg prednisone or less, sustained for at least eight weeks by week 30, was reached by 35.5% on efgartigimod and 30.3% on placebo (OR 1.19, 0.60 to 2.41; P = 0.60). Total and anti-desmoglein antibodies fell quickly, but disease activity scores and cumulative prednisone did not improve. Adverse events were more frequent with efgartigimod (89% vs 76%), with similar serious events (12% vs 13%).

Lowering antibody levels was not enough to change the clinical course here, which is a useful caution against judging pemphigus drugs by serology alone. For practice, nothing changes: rituximab-based regimens with corticosteroids remain the established first-line approach for moderate-to-severe disease, and this trial gives no reason to add an FcRn blocker.

• Do not add efgartigimod to steroids for pemphigus outside a trial; it showed no benefit at 30 weeks.
• Continue to use rituximab-based regimens for moderate-to-severe pemphigus where accessible.
• Judge response by clinical disease activity, not by falling desmoglein antibody titres alone.
• Plan bone protection and infection screening for every patient starting high-dose prednisone.

Why it matters

A drug that lowers the pathogenic antibody still failed to change the disease, which tempers enthusiasm for the whole class here.

Don't overread it

The trial tested this dose and schedule over 30 weeks; it does not rule out benefit in other settings or longer use.

The statistics, in plain English

An odds ratio of 1.19 with an interval from 0.60 to 2.41 means the data fit anything from substantially worse to about twice as good, so no benefit was shown. A trial this size could miss a small effect, but not a large one.

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