A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability and Efficacy of Caveolin-1-Scaffolding-Protein-Derived Peptide (LTI-03) in Patients with Idiopathic Pulmonary Fibrosis (RENEW)

The primary objective of this study is to determine the safety and tolerability of inhaled LTI-03 in participants diagnosed with idiopathic pulmonary fibrosis within 5 years of screening who may be receiving standard of care antifibrotic therapy. This objective addresses the critical need to evaluate the clinical acceptability and adverse event profile of this caveolin-1-scaffolding-protein-derived peptide when administered via inhalation in patients with established disease, including those already on approved antifibrotic treatments.

The secondary objectives include:

• To determine the efficacy of inhaled LTI-03 in participants diagnosed with idiopathic pulmonary fibrosis within 5 years of screening who may be receiving standard of care antifibrotic therapy.

• To assess the effect of inhaled LTI-03 on patient-reported outcomes.

• To assess the effect of inhaled LTI-03 on the occurrence of respiratory hospitalizations.

• To evaluate the pharmacodynamic biomarkers of inhaled LTI-03.

The clinical trial enrolled a total of **92 participants** diagnosed with **Idiopathic Pulmonary Fibrosis**. The study population included both **male and female** individuals aged **40 years or older**. Participants were required to have received their IPF diagnosis within 5 years prior to screening, with confirmation through centrally reviewed high-resolution computed tomography of the chest demonstrating lung fibrosis involvement of at least 10% of the lung, exceeding any emphysema involvement. Eligible participants demonstrated a forced vital capacity percent predicted of at least 45% and a hemoglobin-corrected diffusion capacity of the lungs for carbon monoxide percent predicted of at least 30%. Those receiving standard of care **antifibrotic therapy**, including nintedanib, pirfenidone, or nerandomilast, were required to maintain a stable prescribed dose for a minimum of 12 weeks prior to randomization, while participants who had previously discontinued these treatments must have done so at least 8 weeks before enrollment. All participants were required to demonstrate the ability to adequately self-administer the investigational drug using the protocol-specified inhaler device.

This is a Phase 2, randomized, double-blind, placebo-controlled clinical trial evaluating the safety, tolerability, and efficacy of LTI-03, a caveolin-1-scaffolding-protein-derived peptide, in participants diagnosed with idiopathic pulmonary fibrosis. The investigational medicinal product LTI-03 is administered as an inhalation powder in hard capsule form using a Plastiape Monodose RS01 Model 7 Dry Powder Inhaler device, with a maximum daily dose of 10 mg. The placebo consists of InhaLac® 500, which is micronized lactose monohydrate. Participants may continue receiving standard of care antifibrotic therapy, including nintedanib, pirfenidone, or nerandomilast, provided they have been on a stable dose for at least 12 weeks prior to randomization.

The primary objective of this trial is to determine the safety and tolerability of inhaled LTI-03 in participants diagnosed with idiopathic pulmonary fibrosis within 5 years of screening who may be receiving standard of care antifibrotic therapy. The primary endpoint is the incidence of treatment-emergent adverse events from Day 1 through Week 24. Secondary endpoints include change from baseline through 24 weeks in forced vital capacity measured in milliliters, change in percent predicted forced vital capacity, and change in lung fibrosis measured by high resolution computed tomography. Exploratory endpoints assess changes in the Living with Pulmonary Fibrosis questionnaire dyspnea and cough domains, time to all-cause respiratory hospitalization, lung transplantation or death through 28 weeks, and biomarkers related to the pathophysiology of idiopathic pulmonary fibrosis.

Eligible participants include male or female individuals aged 40 years or older with a diagnosis of idiopathic pulmonary fibrosis within 5 years of screening, confirmed by centrally read high resolution computed tomography according to ATS/ERS/JRS/ALAT guidelines. Lung fibrosis involvement must be at least 10% of the lung and greater than emphysema involvement. Participants must have a forced vital capacity percent predicted of at least 45% and a hemoglobin-corrected diffusion capacity of the lungs for carbon monoxide percent predicted of at least 30% within 8 weeks prior to randomization. Participants must be able to adequately self-administer the study drug using the protocol-specified inhaler device. Those who previously received antifibrotic therapy must have discontinued treatment at least 8 weeks prior to randomization.

The treatment period extends for 24 weeks, with participant involvement continuing through Week 28 for follow-up assessment. The estimated recruitment start date is September 2025, with an estimated trial end date of August 2027. Participants undergo screening procedures to confirm eligibility, followed by randomization and initiation of treatment on Day 1. Study visits are scheduled at regular intervals throughout the 24-week treatment period to monitor safety, tolerability, and efficacy parameters. An end-of-study visit occurs at Week 28, four weeks after completion of the treatment period. Early termination from the study may occur based on safety concerns, participant withdrawal of consent, or other protocol-specified criteria affecting participant safety or data integrity.

The experimental medication **LTI-03** is a **caveolin-1-scaffolding-protein-derived peptide** administered as an **inhalation powder in hard capsule** form. The active substance is classified as a protein-based therapeutic agent. LTI-03 is delivered via the **Plastiape Monodose RS01 Model 7 Dry Powder Inhaler**, a CE-marked inhaler device specifically designed for administration of the investigational product. The route of administration is by **inhalation**. The maximum daily dose is **10 mg**, with a maximum total dose of **10 mg** per administration. The maximum treatment period is **24 weeks**. The dosing schedule and frequency of administration are implemented according to the study protocol to evaluate the safety, tolerability, and efficacy of the investigational product in participants with **idiopathic pulmonary fibrosis** diagnosed within 5 years of screening.

The **placebo** used in this study is **InhaLac® 500**, which consists of **micronized lactose monohydrate**. The placebo is administered to maintain the double-blind nature of the trial and serves as the control comparator against the active investigational product. Participants may continue to receive standard-of-care **antifibrotic therapy** during the course of the trial, allowing for the assessment of LTI-03 in combination with existing therapeutic regimens for idiopathic pulmonary fibrosis.

Efficacy will be assessed through multiple parameters over a 24-week treatment period in participants with **idiopathic pulmonary fibrosis**. The primary efficacy endpoint is the change from baseline through 24 weeks in **forced vital capacity (FVC)** measured in milliliters. Secondary efficacy endpoints include the change from baseline through 24 weeks in percent predicted forced vital capacity (ppFVC) and the change from baseline at 24 weeks in lung fibrosis measured by **high resolution computed tomography (HRCT)**. Exploratory endpoints encompass the change from baseline through 24 weeks in the Living with Pulmonary Fibrosis (L-PF) questionnaire dyspnea and cough domains, time to all-cause respiratory hospitalization, lung transplantation, or death through 28 weeks, and the change from baseline through 24 weeks for biomarkers related to the pathophysiology of idiopathic pulmonary fibrosis. The assessment of lung fibrosis by HRCT will be performed using central read methodology. Patient-reported outcomes will be evaluated using the validated L-PF questionnaire to assess symptom domains.