Inhaled LTI-03 for Idiopathic Pulmonary Fibrosis: A Randomized Dose Escalation Study.

Rationale: LTI-03 is a novel inhaled therapeutic in development for idiopathic pulmonary fibrosis (IPF). LTI-03 has been shown to promote alveolar epithelial cell survival and reduce profibrotic protein expression in experimental models of lung disease. Objectives: To evaluate the safety and pharmacokinetics (PK) of LTI-03 and effects on disease biomarkers in patients with IPF. Methods: This Phase 1b, randomized, controlled, dose-escalation study randomized 24 participants, 3:1 into 2 sequential dose cohorts, to receive inhaled LTI-03 (5 or 10 mg/day) or placebo for 14 days. The primary endpoint was the incidence of treatment-related adverse events (TEAEs). Exploratory analyses included PK and change from baseline in fibrosis-related and epithelial integrity-related biomarkers in plasma, peripheral blood mononuclear cells (PBMCs), and deep bronchial brushings (DBB). Measurements and Main Results: Inhaled LTI-03 was well-tolerated, with no treatment-related AEs leading to treatment discontinuation. All TEAEs were mild or moderate in severity. Cough was the most common TEAE and the only treatment-related TEAE experienced by more than 1 participant. There was no evidence of airway obstruction by symptoms or spirometry. LTI-03 did not induce inflammation (phosphorylated AKT) in PBMCs. In DBB samples, LTI-03 significantly reduced the expression of interleukin-11, chemokine ligand 7, thymic stromal lymphopoietin, and galectin 7; dose-related reductions were also observed for collagen type 1 alpha chain 1 and plasma surfactant protein D. Conclusions: Inhaled LTI-03 exhibited a favorable safety and tolerability profile over 14 days. Exploratory biomarker analyses suggest a positive effect on epithelial homeostasis and corresponding antifibrotic effects. At A Glance: Scientific Knowledge on the Subject: Current standard of care therapies for IPF do not halt or reverse disease progression, and systemic side effects commonly result in discontinued use. LTI-03 is a caveolin scaffolding domain (CSD) peptide formulated as an excipient-free dry powder for the treatment of IPF. It has demonstrated anti-fibrotic and epithelial protective effects in animal models of fibrosis and in IPF precision cut lung slices via putative replenishment of endogenous Cav-1 signaling, which is lost in fibrotic diseases.What This Study Adds to the Field: The results of this study support the conclusion that LTI-03 was well tolerated in patients with IPF at doses of 5 and 10 mg/day. Exploratory biomarker analyses from deep bronchial brushings suggested that positive pharmacodynamic effects were achieved on target cell types. Taken together, these results support the initiation of a Phase 2 efficacy study in patients with IPF. Data sharing statement: Rein Therapeutics, Inc. ("Rein") understands and acknowledges the need to share clinical study data with the research community in an open and transparent manner and has provided de-identified patient data in the manuscript. Rein will not consider further requests pertaining to clinical data outside of what has been accepted and published by the journal. Any queries regarding clinical study data must be submitted in writing to https://info@reintx.com . A data supplement for this article is available via the Supplements tab at the top of the online article.