Pexiganan
A frog-skin-derived antimicrobial peptide developed as a topical cream for infected diabetic foot ulcers, rejected twice by the FDA because it never beat existing treatment.
Also known as pexiganan acetate, magainin analogue, MSI-78, Locilex (proposed), MSI-78
Human RCT — Randomised controlled trials in humans, but not an approved product for this use.
Pexiganan has been through more than one phase 3 programme and failed each time. The 1990s trials showed roughly 90% clinical cure or improvement with 1% cream, statistically comparable to oral ofloxacin, and the FDA declined approval in 1999 because comparable is not enough. The repeat OneStep-1 and OneStep-2 trials completed in 2016 again failed to show superiority over vehicle plus standard care. It is one of the best-documented cautionary tales about antimicrobial peptides looking excellent in vitro and doing nothing extra in a real wound.
How it works
Pexiganan is an optimised analogue of magainin 2, first isolated from the skin of the African clawed frog Xenopus laevis. Its 22 residues fold into an amphipathic alpha-helix on contact with a membrane, with a cationic face that binds the anionic phospholipids and lipopolysaccharide enriched in bacterial membranes and a hydrophobic face that inserts into the bilayer. At threshold concentration the peptides self-assemble into toroidal pores that dissipate the membrane potential and cause rapid lysis. Because the target is the membrane's physical chemistry rather than a protein, resistance selection is slow — in vitro passage studies found no meaningful MIC drift, and pexiganan retained activity against MRSA, VRE and ESBL producers. Selectivity for bacteria over human cells comes from the outer leaflet of mammalian membranes being zwitterionic and cholesterol-rich rather than anionic. The interesting biology never translated into a clinical advantage.
Targets: Bacterial cytoplasmic membrane, Anionic phospholipids, Lipopolysaccharide
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| Trial regimen for mildly infected diabetic foot ulcerApplied to the debrided ulcer bed and covered with a dressing. | — | twice daily | topical |
- · 1% pexiganan acetate cream applied twice daily for 14-28 days alongside standard wound care and offloading. This is the regimen from the phase 3 programme; the product has never been marketed, so there is no approved dosing.
Cycling
Trial courses ran 14 to 28 days. There is no marketed product and therefore no real-world protocol.
Pharmacology
- Half-life
- Not established — designed for topical use with minimal systemic absorption, and systemic pharmacokinetics were never a development focus.
- Onset
- Bactericidal in vitro within minutes to hours; clinical wound endpoints in the trials were assessed over 14 to 28 days.
- Routes
- topical
- Molecule
- Synthetic 22-amino-acid cationic alpha-helical peptide, analogue of magainin 2
- Sequence length
- 22 amino acids
- Molecular weight
- 2477.2 Da
Handling
- Diluent
- Not applicable - formulated as a topical cream in the clinical programme
- Lyophilised
- Freezer, -20°C, for research peptide.
- Reconstituted
- Refrigerated and used quickly; cationic peptides adsorb to plastic and lose potency in dilute solution.
Mixing
Research-grade lyophilised pexiganan is soluble in water; it was never developed as an injectable and systemic use is not supported by any safety data.
Side effects
- commonLocal irritation or stinging at the application site— The dominant finding in trials; systemic adverse effects were essentially absent.
- uncommonContact dermatitis
- rareHaemolysis at high concentration— A property of cationic membrane-lytic peptides generally, and a reason systemic use was never pursued.
Do not use if
- Not for systemic or injected use — no human systemic safety data exist.
- Not a substitute for debridement, offloading and systemic antibiotics in a moderately or severely infected diabetic foot ulcer, where delaying proper care risks amputation.
- Known hypersensitivity to the peptide or cream base.
Combining it
- redundantsystemic antibiotics — In the phase 3 trials pexiganan cream was compared against oral ofloxacin and neither beat the other; a topical peptide does not treat deep or systemic infection.
- cautionanionic wound dressings — Cationic peptides bind avidly to anionic materials and to wound exudate proteins, which can strip active drug out of the wound bed. This inactivation is a plausible contributor to the disappointing trial results.
What to monitor
- · Wound size, depth and probe-to-bone at each dressing change.
- · Signs of spreading infection that would demand systemic antibiotics.
- · No systemic laboratory monitoring is applicable.
Legal status
Not approved anywhere. Available only as a research peptide.
References
- Lipsky et al. 2008, topical pexiganan cream versus oral ofloxacin in mildly infected diabetic foot ulcers (trial)
- Gottler & Ramamoorthy 2009, structure and mechanism of pexiganan (MSI-78) (review)
- Dipexium OneStep-1 and OneStep-2 phase 3 results reporting failure to meet endpoints (trial)
Mechanism in depth
A synthetic analogue of magainin, the antimicrobial peptide from frog skin, formulated as a topical cream for infected diabetic foot ulcers. Membrane-disruptive and broad-spectrum in vitro.
What usually goes wrong
Pexiganan is the clearest example of the antimicrobial-peptide translation gap: it went through phase 3 twice, decades apart, and both times failed to demonstrate superiority over existing therapy. The FDA declined it. Excellent in vitro activity did not become clinical benefit, and that pattern - not any individual failure - is the reason this whole compound class has produced so few drugs.
Pharmacokinetics
- Crosses blood-brain barrier
- no
Receptor targets
- Bacterial membrane — Cationic amphipathic
Membrane disruption
What to expect, and when
Topical.
Genuinely uncertain
- Whether the failures reflect the molecule, the indication, or the trial design remains argued.