Dual αvβ6 and αvβ1 Inhibition over 12 Weeks Reduces Active Type I Collagen Deposition in Individuals with Idiopathic Pulmonary Fibrosis: A Phase 2, Double-Blind, Placebo-controlled Clinical Trial

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of type I collagen. ⁶⁸Ga-CBP8, a type I collagen positron emission tomography probe, measures collagen accumulation and shows higher collagen deposition in patients with IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of α_vβ₆ and α_vβ₁ integrins under late-stage evaluation for treatment of IPF. Objectives: To evaluate changes in type I collagen in the lungs of participants with IPF after treatment with bexotegrast. Methods: In this phase 2 (NCT05621252), single-center, double-blind, placebo-controlled study, adults with IPF received bexotegrast 160 mg or placebo for 12 weeks. The primary endpoint was the change in whole-lung standardized uptake value of ⁶⁸Ga-CBP8 positron emission tomography. Changes in lung dynamic contrast-enhanced magnetic resonance imaging parameters, FVC, cough severity, and biomarkers of collagen synthesis and progressive disease were also assessed. Measurements and Main Results: Of 10 participants, 7 received bexotegrast and 3 received placebo. At Week 12, the mean change from baseline in the top quartile of ⁶⁸Ga-CBP8 whole-lung standardized uptake value was -1.2% with bexotegrast versus 6.6% with placebo; the greatest mean changes were observed in subpleural lung regions in both groups (bexotegrast, -3.7%; placebo, 10.3%). Dynamic contrast-enhanced magnetic resonance imaging showed numerically increased peak enhancement and faster contrast washout rate in bexotegrast-treated participants, suggesting improvements in lung microvasculature and decreased extravascular extracellular volume. Bexotegrast treatment resulted in numerical improvements in FVC, cough severity, and biomarkers. Conclusions: The reduced uptake of ⁶⁸Ga-CBP8 in the lungs of participants with IPF indicates an antifibrotic effect of bexotegrast, suggesting the potential for favorable lung remodeling. Clinical trial registered with www.clinicaltrials.gov (NCT05621252).

Keywords: bexotegrast; collagen type I; fibrotic disease; idiopathic pulmonary fibrosis; positron emission tomography imaging.

Figure 1.

Overview of (A) study design and (B) participant disposition.

Figure 2.

(A) Representative positron emission tomography images of total lung collagen at baseline and Week 12 and (B) absolute and (C) individual change from baseline in top quartile SUV of whole lung at Week 12. The length of the box represents the range between the 25th and 75th percentiles, the whiskers represent the maximum and minimum, and the horizontal line in the box represents the median. All individual data points are displayed. The nonadherent/COVID-19 participant in the bexotegrast group is indicated by the red circle. Baseline FVC and FVC percent predicted values for representative bexotegrast and placebo images were 2,400 ml and 66% and 1,700 ml and 49%, respectively. SUV = standardized uptake value.

Figure 3.

Absolute change from baseline in the top quartile SUV of (A) collective subpleural and central regions of the lung and (B) individual lung regions. The values for lower subpleural, middle subpleural, upper subpleural, lower central, middle central, and upper central are the average of the left and right values for each region. The length of the box represents the range between the 25th and 75th percentiles, the whiskers represent the maximum and minimum, and the horizontal line in the box represents the median. All individual data points are displayed. The nonadherent/COVID-19 participant in the bexotegrast group is indicated by the red circle. SUV = standardized uptake value.

Figure 4.

(A) Absolute and (B) individual changes from baseline in peak enhancement and (C) absolute and (D) individual changes from baseline in washout rate (k_washout) in whole lung at Week 12. (E) Representative parametric maps of peak enhancement and k_washout at baseline and Week 12. The length of the box represents the range between the 25th and 75th percentiles, the whiskers represent the maximum and minimum, and the horizontal line in the box represents the median. All individual data points are displayed. The nonadherent/COVID-19 participant in the bexotegrast group is indicated by the red circle. Baseline FVC and FVC percent predicted values for the representative bexotegrast and placebo images were 4,500 ml and 92% and 2,640 ml and 69%, respectively.

Figure 5.

LS mean (SE) change from baseline in (A) FVC, (B) FVCpp, and (C) mean (SE) change from baseline in cough severity at Week 12. *One placebo-treated participant did not have acceptable quality spirometry after baseline. FVCpp = percent predicted FVC; LS = least squares; VAS = visual analog scale.

Figure 6.

LS mean (SE) change from baseline in (A) PRO-C3 and (B) ITGB6 at Week 12. ITGB6 = integrin-β6; LS = least squares; PRO-C3 = type III collagen synthesis neoepitope.