Pexiganan

Pexiganan is an all-L-amino acid synthetic derivative of magainin-2 with enhanced cationic charge and optimized amphipathicity. It disrupts bacterial membranes through the carpet-model mechanism at low concentrations and toroidal pore formation at higher concentrations, identical to the parent magainin mechanism. The optimized sequence was selected for maximum broad-spectrum activity with minimal mammalian cell toxicity. Unlike systemic AMPs, topical application concentrations far exceed systemic MIC values, minimizing resistance selection pressure.

In vitro serial passage studies demonstrated markedly slower resistance development to pexiganan versus standard antibiotics. The fundamental membrane-targeting mechanism means bacteria cannot develop simple target mutations, resistance requires wholesale changes in membrane lipid composition, which carries significant fitness costs. Reduced propensity for resistance is a key claimed advantage for AMPs in wound care settings.

Two Phase 3 trials (n=835 total) comparing 0.8% pexiganan cream to placebo vehicle in mildly infected diabetic foot ulcers showed clinical cure rates of ~76% for pexiganan versus ~71% for vehicle. The FDA advisory committee (1999) voted 11-2 that the trials did not demonstrate superiority over vehicle, noting high vehicle response rates and questioning whether the trial design adequately differentiated drug effect from standard wound care. The trials compared pexiganan to vehicle rather than to an active antibiotic comparator, which the FDA considered a design flaw.

Dipexium Pharmaceuticals acquired pexiganan rights and redesigned Phase 3 trials comparing pexiganan cream to oral linezolid for mildly infected diabetic foot ulcers. The active comparator design addresses the FDA concerns from the 1999 rejection. New trials aim to demonstrate non-inferiority to linezolid, which could support FDA approval under a different evidentiary standard. Phase 3 results are expected to inform whether topical AMPs can achieve regulatory approval.