Kevin R. Flaherty’s research while affiliated with Concordia University–Ann Arbor and other places

What is this summary about? This plain language summary shares results from a clinical study called INTEGRIS-IPF that was published in the American Journal of Respiratory and Critical Care Medicine in 2024. This study looked at a medicine called bexotegrast (beck-so-teh-grast) as a possible treatment for idiopathic pulmonary fibrosis (i-dee-uh-pa-thick pul-muh-ner-ee fie-bro-sis; IPF). Bexotegrast is an investigational medicine, which means that it is being studied and has not yet been approved by the US Food and Drug Administration (FDA), for people with IPF to take as a treatment. IPF is a chronic, progressive lung disease that makes it hard to breathe and gets worse over time. There is no cure for IPF, treatment includes symptom management and consideration for the use of nintedanib or pirfenidone, which may decrease the pace of disease progression. The study compared bexotegrast to a placebo (a treatment that looks identical to the medicine but has no medicinal effect) to look at how well it works and how safe it is in treating people with IPF. Most people in the study also took one of two medicines that are already approved by the FDA for IPF, pirfenidone or nintedanib.

Background Suspected Interstitial Lung Disease (ILD) patients may be referred to an ILD-specialist centre or non-ILD-specialist centre for diagnosis and treatment. Early referral and management of patients at ILD-specialist centres has been shown to improve survival and reduce hospitalisations. The COVID-19 pandemic has affected the ILD patient diagnostic pathway and prompted centres to adapt. Aims This study investigates and contrasts ILD patient pathways in ILD-specialist and non-ILD-specialist centres, focusing on referrals, caseloads, diagnostic tools, multi-disciplinary team (MDT) meeting practices, and resource accessibility. Methods Conducted as a cross-sectional study, a global self-selecting survey ran from September 2022 to January 2023. Participants included ILD specialists and healthcare professionals (HCPs) from ILD-specialist centres and non-ILD-specialist centres. Results Of 363 unique respondents from 64 countries, 259 were from ILD-specialist centres and 104 from non-ILD-specialist centres. ILD centres had better resource availability, exhibiting higher utilisation of diagnostic tests (median: 12 tests), than non-ILD centres (9 tests); and better access to specialist professions attending MDTs (median: 6 professions at meeting) in specialist centres than non-ILD centres (3 professions at meeting). Transitioning to virtual MDTs allowed HCPs from outside of centres to join meetings in nearly 90% of all centres, increasing regular participation in 60% of specialist centres and 72% of non-ILD centres. For treatment of patients, specialist centres had better access to antifibrotic drugs (91%) compared to non-ILD centres (60%). Conclusions Diagnostic pathways for ILD patients diverged between specialist centres and non-ILD centres. Disparities in resource and specialist availability existed between centres.

Background Acute exacerbations of fibrosing interstitial lung diseases (ILDs) are associated with high mortality. We used prospective data from the INBUILD trial to investigate risk factors for acute exacerbations and the impact of these events in patients with progressive pulmonary fibrosis. Methods Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF) were randomised to receive nintedanib or placebo. Associations between baseline characteristics and time to first acute exacerbation were assessed using pooled data from both treatment groups using Cox proportional hazard models, firstly univariable models and then a multivariable model using forward stepwise selection. The risk of death was estimated based on the Kaplan−Meier method. Results Over a median follow-up of approximately 19 months, acute exacerbations were reported in 58 (8.7%) of 663 patients. In the risk factor analysis, the final model included DLco % predicted, treatment and age. Lower DLco % predicted was associated with an increased risk of acute exacerbation with a hazard ratio (HR) of 1.56 (95% CI: 1.21, 2.02) per 10 units lower (p<0.001). Age ≥65 years was associated with a numerically increased risk (HR 1.55 [95% CI: 0.87, 2.77]; p=0.14). Treatment with nintedanib conferred a numerically reduced risk versus placebo (HR 0.60 [95% CI: 0.35, 1.02]; p=0.06). The estimated risks of death ≤30 days and ≤90 days after an acute exacerbation were 19.0% (95% CI: 8.9, 29.2) and 32.0% (95% CI: 19.7, 44.2). Conclusions Acute exacerbations of progressive pulmonary fibrosis may have similar risk factors and prognostic impact as acute exacerbations of IPF.

Rationale: Inhaled nitric oxide (iNO) has been shown to result in benefits in moderate to vigorous physical activity (MVPA) in patients with fibrotic interstitial lung disease (if-ILD) on supplemental oxygen in two independent trials. Objective: This phase 3 randomized double-blind placebo-controlled study sought to validate the benefit of ambulatory iNO in patients with f-ILD requiring supplemental oxygen. Methods: Patients with f-ILD on supplemental long-term oxygen were randomized in a 1:1 fashion to inhaled nitric oxide at 45 µg/kg ideal body weight/hour or placebo for 16 weeks. The primary outcome was the change from baseline to week 16 in MVPA assessed by accelerometry. Secondary outcomes included overall activity, six-minute walk distance and patient reported outcomes. Measurement and main results: 145 patients were enrolled; 75 were assigned to receive iNO and 70 to placebo. The change from baseline in MVPA at 16 weeks was -9.2 minute/day (SE 3.51) in the iNO45 group versus -3.7 (3.76) minute/day in the placebo group (difference, 5.5; P=0.265). No statistically significant differences between the two treatment arms were found for any of the secondary outcomes. A subgroup analysis of patients with intermediate or high probability of pulmonary hypertension on echocardiography did not demonstrate any benefit. The most common adverse events reported were respiratory tract infections, but the therapy was generally very well tolerated. Conclusions: There was no demonstrable benefit to iNO in patients with f-ILD on supplemental oxygen in daily physical activity assessed by actigraphy, a potential novel clinical trial endpoint. Clinical trial registration available at www. Clinicaltrials: gov, ID: NCT03267108.

Rationale: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. Objectives: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. Methods: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis (IPF) discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease (COPD) cohort. A proteomic-based measure of biological age was constructed and survival analysis performed assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. Results: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the IPF discovery cohort (n=874), with nineteen remaining significant mediators of this relationship in the ILD validation cohort (n=983) and one mediating this relationship in the COPD cohort. Latent transforming growth factor beta binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. Conclusions: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

Rationale Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).