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. 2023 Feb 3;207(8):1089–1091. doi: 10.1164/rccm.202206-1035RR

New Frontiers in Therapeutics for Interstitial Lung Diseases

Nathan Mesfin 1, Ruchika Sangani 1, Divya A Shankar 1,✉, Christine Reardon 1
PMCID: PMC10112432  PMID: 36735934
Am J Respir Crit Care Med. 2023 Feb 3;207(8):1089–1091.

Martinez FJ, et al.; CleanUP-IPF Investigators of the Pulmonary Trials Cooperative. Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults with Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial. JAMA (1)

Recommended Reading from the Pulmonary Center, Boston University School of Medicine Fellows; Christine Reardon, M.D., Program Director

Martinez FJ, et al.; CleanUP-IPF Investigators of the Pulmonary Trials Cooperative. Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults with Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial. JAMA (1)

Reviewed by Nathan Mesfin

Chronic antimicrobial therapy is well established in the management of certain lung diseases such as chronic obstructive pulmonary disease (2, 3). However, extrapolating these benefits to other lung diseases such as idiopathic pulmonary fibrosis (IPF) remains an open question. This question becomes more salient in light of the fact that perturbed lung microbiomes are implicated in both the progression and acute exacerbations of IPF (4–6). Prior studies have shown conflicting results regarding antibiotics in IPF, suggesting that the nonmicrobial properties of antibiotics are important considerations (7–9).

This randomized, nonblinded pragmatic clinical trial evaluated the role of two antimicrobial agents in patients with IPF across 35 U.S. sites from August 2017 to June 2019. The study was terminated early because of futility. Patients (n = 513) were randomized to receive either co-trimoxazole or doxycycline (n = 254) versus no therapy (n = 259). Participants were patients clinically diagnosed with IPF by the enrolling investigator. Exclusion criteria were pregnancy, recent antibiotic use, allergy to investigational antibiotics, immunosuppressive therapy use, or participation in another study. The primary composite endpoint time-to-first nonelective respiratory hospitalization or all-cause mortality was not different between the intervention and control groups (hazard ratio, 1.04; 95% confidence interval, 0.71–1.53), with a total of 52 and 56 events, respectively, over a 13-month follow-up period. There was no significant effect with respect to the specific antimicrobial agent on the primary endpoint. There were also no significant differences in change in FVC, diffusion capacity, or patient-reported outcomes between the intervention and control groups. There were more serious respiratory and gastrointestinal adverse events in the intervention group than in the control group.

The rise of pragmatic trials has accelerated the implications of trial outcomes to real-world clinical practice (10). This trial’s high recruitment rate (513 out of 522 eligible patients), simple design, and patient-centered primary outcome make its results broadly applicable. This study needs to be interpreted in the context of its limitations, including lack of blinding or placebo control, establishment of IPF diagnoses in a noncentralized fashion, and the absence of microbiological data (BAL or sputum) to guide patient selection. The imbalance of smoking status across the groups may have also masked treatment effects. Although the study provides evidence that there is no clinical benefit of antimicrobial therapy to IPF patients in general, the question as to whether a subset of IPF patients with significant lung microbiome dysbiosis would benefit from targeted antimicrobial therapy remains unanswered.

References

  • 1. Martinez FJ, Yow E, Flaherty KR, Snyder LD, Durheim MT, Wisniewski SR, et al. CleanUP-IPF Investigators of the Pulmonary Trials Cooperative Effect of antimicrobial therapy on respiratory hospitalization or death in adults with idiopathic pulmonary fibrosis: the CleanUP-IPF randomized clinical trial. JAMA . 2021;325:1841–1851. doi: 10.1001/jama.2021.4956. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Am J Respir Crit Care Med. 2023 Feb 3;207(8):1089–1091.

Hirani N, et al.; Target Inhibition of Galectin-3 by Inhaled TD139 in Patients with Idiopathic Pulmonary Fibrosis. Eur Respir J (11)

Hirani N, et al.; Target Inhibition of Galectin-3 by Inhaled TD139 in Patients with Idiopathic Pulmonary Fibrosis. Eur Respir J (11)

Reviewed by Ruchika Sangani

Galectin (Gal)-3 is a β-galactoside–binding lectin that has been implicated in fibrinogenesis. Studies have shown that the expression of Gal-3 is upregulated in BAL fluid and the serum of IPF patients, and murine models have shown that global deficiency of Gal-3 attenuates fibrosis (12). Accordingly, the authors conducted a phase-1/2a study of inhaled TD139, a potent inhibitor of Gal-3, to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug (11). Lung-targeted delivery through inhalation could offer advantages because of rapid absorption and the elimination of first-pass metabolism, which may reduce the likelihood of adverse effects that currently limit the use of oral therapies for IPF (13).

This randomized, double-blind, multicenter, placebo-controlled, dose-escalation study was conducted in two parts. In part 1, healthy participants (n = 36), all of whom were male, were randomized to receive a single dose of TD139 (0.15, 1.5, 3, 10, 20, or 50 mg) or placebo by means of dry powder inhaler followed by outpatient visits for safety and pharmacokinetics assessments. Part 2 involved randomizing patients (n = 24), of which 95.8% were male, with definite or probable IPF to receive TD139 (0.3, 3, or 10 mg) or placebo once daily by means of dry powder inhaler for 14 days. Patients who received oral corticosteroids or any approved or investigational antifibrotic therapies within 4 weeks of screening were excluded.

Overall, TD139 was well tolerated without any withdrawals or clinically significant safety concerns. One patient randomized to 10 mg/d was diagnosed with an acute IPF exacerbation. TD139 resulted in dose-dependent levels of the drug in plasma and BAL macrophages. Absorption was nonlinear, increasing with dose and exposure time. IPF patients had lower retainment of the drug in their lungs compared with healthy participants with greater accumulation in plasma and higher systemic exposure with increasing doses. Gal-3 levels were inhibited in a drug-concentration–dependent manner in BAL macrophages, and the highest dose of TD139 reduced both Gal-3 levels and several fibrosis-related biomarkers in the serum, including four with in vitro prognostic significance for IPF.

In conclusion, this study shows encouraging evidence regarding the safety and tolerability of TD139 and its ability to interact with Gal-3 to reduce both its expression and that of fibrosis-related biomarkers. The study was limited by its small sample size, which was predominantly male with mild disease, and short duration of drug exposure. Longer and larger studies are currently underway, which will additionally evaluate for clinical efficacy.

References

  • 11. Hirani N, MacKinnon AC, Nicol L, Ford P, Schambye H, Pedersen A, et al. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J . 2021;57:2002559. doi: 10.1183/13993003.02559-2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Am J Respir Crit Care Med. 2023 Feb 3;207(8):1089–1091.

Behr J, et al.; RELIEF investigators. Pirfenidone in Patients with Progressive Fibrotic Interstitial Lung Diseases Other Than Idiopathic Pulmonary Fibrosis (RELIEF): A Double-blind, Randomised, Placebo-controlled, Phase 2b Trial. Lancet Respir Med (14)

Behr J, et al.; RELIEF investigators. Pirfenidone in Patients with Progressive Fibrotic Interstitial Lung Diseases Other Than Idiopathic Pulmonary Fibrosis (RELIEF): A Double-blind, Randomised, Placebo-controlled, Phase 2b Trial. Lancet Respir Med (14)

Reviewed by Divya Shankar

Some non-IPF interstitial lung diseases (ILDs) are known to have progressive fibrotic phenotypes; these include connective tissue disease–associated ILDs, fibrotic nonspecific interstitial pneumonia, chronic hypersensitivity pneumonitis, and asbestos-induced fibrosis (15–17). Whereas the antifibrotic nintedanib has been approved for these conditions (17), the utility of the antifibrotic pirfenidone remains unclear (18, 19). Thus, Behr and colleagues sought to investigate the safety and efficacy of pirfenidone in non-IPF fibrotic ILDs (14).

This randomized, multicenter, double-blind placebo-controlled, parallel phase–2b trial enrolled 127 patients with non-IPF progressive fibrotic ILDs at 17 ILD centers in Germany from April 2016 to October 2018. Patients were randomized to either oral pirfenidone or placebo. The primary outcome was change in FVC percentage predicted at week 48. Key secondary outcomes were progression-free survival, 6-minute-walk distance, quality of life, and safety.

The study was terminated early due to slow recruitment; only 34% of the intended sample size was enrolled. There was no observed treatment effect in the per-protocol analysis, but rank analysis of covariance with imputation showed a significantly lower decline in FVC percentage predicted in the pirfenidone group (P = 0.043). No significant difference was found in progression-free survival, 6-minute-walk distance, or quality of life. There were numerically more serious adverse events in the placebo group than in the pirfenidone group.

This study was underpowered because of its early termination. Bearing this in mind, in the imputed dataset, there was a signal toward slower FVC decline after 48 weeks of treatment in patients randomized to pirfenidone. There were also numerically fewer deaths and adverse events in the pirfenidone group. These findings must be interpreted with caution, however, given the marginal statistical significance of the main result, imbalance among some baseline characteristics (age, sex, supplemental O2, and steroid monotherapy), and possible residual confounding (e.g., smoking status was not controlled for).

This study adds to the body of evidence that patients with progressive, non-IPF fibrotic ILDs respond to antifibrotics (17, 20). Nevertheless, as this study was underpowered, it will be important to monitor the outcomes of ongoing trials in the fibrotic ILD population. One such trial is investigating whether a lysophosphatidic acid antagonist may be beneficial for fibrotic ILDs in addition to antifibrotic and/or immunosuppressive therapies (21). Until more data are available, however, the work by Behr and colleagues suggests that the already available antifibrotic pirfenidone is safe, tolerable, and likely efficacious in a non-IPF fibrotic ILD population.

References

  • 14. Behr J, Prasse A, Kreuter M, Johow J, Rabe KF, Bonella F, et al. RELIEF investigators Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med . 2021;9:476–486. doi: 10.1016/S2213-2600(20)30554-3. [DOI] [PubMed] [Google Scholar]
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Articles from American Journal of Respiratory and Critical Care Medicine are provided here courtesy of American Thoracic Society

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