Inhaled peptide LTI-03 passes early safety testing, but efficacy in pulmonary fibrosis awaits longer-term trials

Idiopathic pulmonary fibrosis causes repeated injury and scarring in the alveoli, gradually robbing patients of their ability to breathe. Existing drugs can slow the decline in lung function but struggle to halt disease progression, so researchers are attempting to deliver drugs directly to the lungs. A newly published Phase 1b trial in *Nature Communications* found that short-term use of the inhaled candidate peptide LTI-03 had a generally acceptable safety profile and also produced preliminary signs of drug activity in lung tissue.

This randomized, double-blind, placebo-controlled, dose-escalation study enrolled 24 recently diagnosed patients who had not received antifibrotic treatment and was conducted at six centers in the United States, the United Kingdom, Germany, and Australia. In both sequential cohorts, participants were assigned in a 3-to-1 ratio to inhale 5 mg or 10 mg of LTI-03 daily, or placebo, for 14 days; an additional safety review was conducted before the second cohort began.

All participants completed the study. There were no treatment-emergent adverse events of grade 3 or higher, and no participant discontinued treatment because of a treatment-related event. Cough was the most common adverse event, occurring in 33.3% and 55.6% of participants in the two LTI-03 groups, respectively, compared with 33.3% in the placebo group. Two patients experienced moderate drug-related cough, both of which resolved the same day. Another patient developed a fever after bronchoscopy and was hospitalized for observation; the researchers determined that this was unrelated to the drug.

LTI-03 consists of seven naturally occurring amino acids and was designed from the scaffolding domain of caveolin-1, with the aim of supporting alveolar epithelial cell survival while suppressing profibrotic signaling. Deep bronchial brush samples collected after treatment showed that both doses reduced interleukin-11 and thymic stromal lymphopoietin. Levels of collagen type I alpha 1 chain, CXCL7, and galectin-7 were also lower in the 10 mg daily group than in the placebo group. These molecules are involved, respectively, in fibrotic deposition, inflammation, and epithelial injury responses, providing clues that the drug reached its intended site of action.

However, reductions in biomarkers cannot be directly equated with clinical benefit. The study included only 24 participants, treatment lasted 14 days, and its primary objective was safety. It also lacked sufficient size or duration to assess lung function, symptoms, acute exacerbations, or disease progression. Some exploratory analyses used one-tailed statistical tests based on a prespecified assumption that the markers would decline. The reduction in plasma surfactant protein D also did not reach statistical significance, while the other markers tested showed no clear changes.

The study was fully funded by Rein Therapeutics, the developer of LTI-03. The findings are sufficient to support follow-up trials with longer treatment durations and larger populations, but the real threshold will be whether LTI-03 can produce reproducible improvements in lung function or disease course when patients are receiving the current standard of care, while maintaining the tolerability required for long-term inhaled treatment.