Cathelicidin / LL-37: how it got to PCAC

Origin

LL-37 is the 37-residue C-terminal antimicrobial peptide cleaved from the precursor protein hCAP-18, the only cathelicidin found in humans. The 2015 review by Bandurska and colleagues in Biofactors characterized LL-37 as the sole human cathelicidin and described its broad antimicrobial, wound-healing, and immunomodulatory activities reported across the cell-biology and infection-model literature PMID 26434733. The peptide is catalogued in PubChem under CID 16133745 (PubChem 16133745).

Research history

The 2016 review by Fabisiak, Murawska, and Fichna at the Medical University of Lodz, published in Pharmacological Reports, summarized LL-37’s pleiotropic activities — antimicrobial action against bacteria, fungi, and certain viruses, as well as roles in chemotaxis, angiogenesis, and modulation of inflammatory signaling PMID 27117377. The authors noted that LL-37’s clinical translation has been complicated by short systemic half-life, susceptibility to proteolytic degradation, and reports that the peptide can be either protective or pro-inflammatory depending on context, dose, and tissue. Bandurska et al. observed that cathelicidin-related peptides have served as templates for the design of synthetic antimicrobial candidates rather than as direct therapeutic agents.

Most published LL-37 work is laboratory-based — biochemical characterization, antimicrobial-activity panels, and disease-model studies in animals and in vitro systems. Indexed peer-reviewed efficacy data from large-scale randomized controlled trials of LL-37 itself in humans are limited, although shorter LL-37-derived analogues have been the subject of small clinical investigations in topical wound and ulcer settings.

Regulatory journey

LL-37 has no FDA-approved drug application. Compounding pharmacies that wish to use LL-37 as a bulk drug substance must rely on the section 503A framework, which permits compounding from bulk substances that appear on FDA’s 503A bulks list or that are the subject of an approved drug application. The agency’s program page describes the bulks-list workflow and the interim three-category framework: Category 1 (eligible pending rulemaking), Category 2 (significant safety concerns, not eligible pending further evaluation), and Category 3 (insufficient information) (FDA — Bulk Drug Substances Used in Compounding).

A range of peptide nominations, including LL-37-related substances, were placed in Category 2 pending advisory-committee review under FDA’s “may present significant safety risks” notice (FDA Category 2 notice). The agency has flagged peptide nominations generally for concerns related to immunogenicity, peptide-related impurities arising from solid-phase synthesis, and active-pharmaceutical-ingredient characterization.

FDA scheduled LL-37 for the Pharmacy Compounding Advisory Committee meeting at the end of February 2027. PCAC’s role is advisory: the committee reviews the nomination materials, the agency’s safety analysis, and public comment, and recommends whether the substance should be added to the 503A bulks list. FDA is not required to follow the committee’s recommendation but the committee record is generally regarded as the central public-record analysis.

What’s at stake

A favorable PCAC recommendation, followed by FDA agreement and final rulemaking, would clear the path for traditional 503A compounders to prepare LL-37 under individual prescriptions. An unfavorable recommendation would leave LL-37 in Category 2 and outside the routine 503A safe harbor, with continued enforcement discretion against bulk-substance use. Because LL-37 sits at the intersection of antimicrobial-peptide drug development and a broader set of unapproved-peptide compounding nominations, the PCAC briefing document is expected to address the agency’s general concerns about peptide impurities and immunogenicity in addition to LL-37-specific evidence. This page will be updated when the February 2027 briefing materials are released.