Discontinued Healing & Recovery

Pexiganan

also known as: Locilex, MSI-78, Pexiganan acetate

A Xenopus-magainin-derived antimicrobial peptide (Locilex; Dipexium Pharmaceuticals / later acquired by PLx Pharma) developed for topical treatment of mildly infected diabetic foot ulcers. Twice rejected by the FDA — once in 1999 (Magainin Pharmaceuticals) and again in 2017 (Dipexium) after the OneStep-1 and OneStep-2 Phase 3 trials failed to show superiority over placebo cream. Instructive regulatory case study in antimicrobial peptide drug development.

A 22-residue synthetic cationic antimicrobial peptide analog of magainin-2, originally isolated from the skin of the African clawed frog Xenopus laevis in 1987 by Michael Zasloff. Developed by Magainin Pharmaceuticals as a 1% cream (Locilex) for topical treatment of mildly infected diabetic foot ulcers. The FDA's Anti-Infective Drugs Advisory Committee voted against approval in March 1999 despite the drug meeting non-inferiority endpoints versus oral ofloxacin, on grounds that non-inferiority to an oral antibiotic did not constitute evidence of clinical effectiveness. Dipexium Pharmaceuticals acquired the asset, conducted two additional placebo-controlled Phase 3 trials (OneStep-1 and OneStep-2) in 2016, both of which failed to show superiority of pexiganan cream over placebo cream. The company terminated development in October 2016 after the second Phase 3 failure. Stands as one of the most thoroughly tested antimicrobial peptides in human trials and an instructive case study for AMP drug development — particularly for the challenge of demonstrating clinical efficacy in mildly infected wounds where the placebo-response rate (driven by standard wound care) is high.

Mechanism of action

Forms amphipathic α-helix on contact with bacterial membranes. Cationic charge (seven lysines, zero aspartates or glutamates) drives electrostatic attraction to negatively charged bacterial outer-membrane lipopolysaccharide and inner-membrane phosphatidylglycerol / cardiolipin. Membrane permeabilization occurs via a toroidal-pore mechanism at threshold concentrations, causing rapid bactericidal activity against both Gram-positive and Gram-negative bacteria, including many antibiotic-resistant strains. Selectivity for bacterial over mammalian membranes is moderate — sufficient for topical use but not for systemic administration.

Primary uses

Mildly infected diabetic foot ulcer — proposed topical treatment (not FDA-approved; Phase 3 failure)
Antimicrobial peptide drug-development case study

Typical dosing

1% cream, applied twice daily twice daily (topical)

Dose regimen used in OneStep Phase 3 trials. Not an approved product; the dosing information is for research reference only.

Regulatory status

Not FDA-approved. Received a non-approvable letter from the FDA in 1999 (Magainin Pharmaceuticals). The OneStep-1 and OneStep-2 Phase 3 trials (Dipexium Pharmaceuticals, 2016) both failed to show superiority over placebo; development was terminated in October 2016. Represents one of the most fully-developed and tested antimicrobial peptides in Phase 3 clinical trials, making its ultimate failure a defining case in antimicrobial peptide drug development.

References

[pubmed] Lipsky BA, et al. "Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized, controlled, double-blinded, multicenter trial of pexiganan cream." Clin Infect Dis, 2008;47:1537-1545 (pivotal Phase 3 versus ofloxacin).
[news-release] Dipexium Pharmaceuticals. "Dipexium Pharmaceuticals Announces Top-Line Results from Phase 3 OneStep-1 and OneStep-2 Clinical Studies of Locilex." October 24, 2016.
[review] Gottler LM, Ramamoorthy A. "Structure, membrane orientation, mechanism, and function of pexiganan - a highly potent antimicrobial peptide designed from magainin." Biochim Biophys Acta, 2009;1788:1680-1686.

Related peptides

LL-37

The only human cathelicidin — an antimicrobial peptide with direct activity against bacteria, fungi, viruses, and biofilms, with additional roles in wound healing and immune signaling.

Omiganan

An indolicidin-derived cationic antimicrobial peptide (Micrologix / BioWest / Cutanea Life Sciences / Cellect Biotechnology / Maruho) developed across roughly two decades for several dermatologic and catheter-prevention indications. Failed its pivotal Phase 3 for central venous catheter exit-site infection prevention (2002), then pivoted to rosacea where it also failed Phase 3 (2015). Not FDA-approved.

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.