Pulmonary Fibrosis Research: Advances, Setbacks, What’s Ahead

Patients with pulmonary fibrosis (PF) have limited treatment options. But with all the research currently being done around PF, “there remains a lot of enthusiasm and hope in this disease space,” according to Joyce Lee, MD, senior medical advisor of research and health care quality at the Pulmonary Fibrosis Foundation.

September is Pulmonary Fibrosis Awareness Month. This interstitial lung disease —which is characterized by progressive irreversible lung scarring, breathing difficulty, and persistent coughing — currently affects approximately 250,000 Americans, with an estimated 50,000 new cases diagnosed annually.¹ Given the lack of curative therapies and treatment options for this patient population, Pulmonary Fibrosis Awareness Month aims to raise the visibility of this difficult disease, as well as to highlight promising PF research developments and increase knowledge of the disease state.²

At present, ongoing and planned studies in PF “span the breadth of administration, from inhaled to oral therapies, as well as novel mechanisms of action and genotype-driven patient identification,” Dr Lee noted.

“Efforts like these will move us closer to the goal of personalized medicine for patients living with PF,” said Dr Lee, who is also director of the Interstitial Lung Disease Program at the University of Colorado School of Medicine in Aurora.

Progress and Setbacks

“With increasing incidence of pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), significant strides have been made in the understanding of the underlying pathobiology of IPF,” said Tejaswini Kulkarni, MD, director of the Interstitial Lung Disease Program at the University of Alabama at Birmingham and Vice-Chair of the Interstitial Lung Disease Section with the American College of Chest Physicians.

“New knowledge in the disease mechanisms, from inflammation to fibrosis in non-IPF interstitial lung diseases (ILDs), including differences and commonalities with IPF, have recently emerged, leading to the development of promising drugs not only for IPF but also patients with progressive pulmonary fibrosis (PPF).”

PF researchers are continuing to explore novel therapies for PF treatment after disappointing results in several recent trials. As reported in May 2023, for example, the novel autotaxin inhibitor ziritaxestat failed to demonstrate efficacy as a treatment for IPF in 2 identically designed phase 3 trials (ISABELA 1 and ISABELA 2; ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444).⁷

Additionally, in findings announced in June and August 2023, respectively, the humanized monoclonal antibody pamrevlumab failed to reduce the rate of decline in forced vital capacity (FVC) in the phase 3 ZEPHYRUS-1 trial (ClinicalTrials.gov Identifier: NCT03955146), and the novel galectin-3 inhibitor GB0139 failed to reduce the rate of decline in FVC in IPF in the phase 2b GALACTIC-1 trial (ClinicalTrials.gov Identifier: NCT03832946).^8,9

“Despite these recent failures, we have learned important lessons to consider when designing PF clinical trials,” Dr Kulkarni noted. “Aside from several drugs in early-phase clinical trials, at least 3 drug candidates are being evaluated in phase 3 studies of patients with IPF and PPF,” including inhaled Treprostinil (ClinicalTrials.gov Identifier: NCT04708782), BI 1015550 (ClinicalTrials.gov Identifier: NCT05321069), and BMS 986278 (ClinicalTrials.gov Identifier: NCT04308681).¹⁰

Other Recent Research

The PRECISIONS trial (ClinicalTrials.gov Identifier: NCT04300920), which is currently underway, is investigating use of N-acetylcysteine (NAC), “an inexpensive and well-tolerated agent for treatment of lung and other organ diseases, as a potential treatment for IPF, said Dr Lee.⁵ The study is the first pharmacogenomic study in IPF patients to be sponsored by the NIH, Dr Lee noted, with additional support from the Pulmonary Fibrosis Foundation (PFF) and the Three Lakes Foundation.

An initial paper on the study was published in December 2022 by the PRECISIONS team and the PFF, said Dr Lee, who further explained that “The study is investigating whether NAC provides clinical benefit in the quarter of patients with IPF that carry a specific genetic variant, the TOLLIP rs3750920 TT genotype.” 

Other notable research from the past year explored associations between disease outcomes in ILD and exposure to particulate matter 2.5 μm or less in diameter (PM_2.5).⁶ The study, by Goobie et al, analyzed satellite-based pollution data and as well as medical data from 3 patient cohorts with 6388 patients, including 1870 patients from the PFF Registry.

Results showed that increased PM_2.5 exposure was linked to worse baseline lung function and higher transplant and mortality rates only in the cohort with the highest exposure to sulfate, ammonium, and black carbon, which are PM_2.5 constituents associated with industrial and traffic-related emissions. Increased PM_2.5 exposure was also associated with worse baseline lung function and higher transplant and mortality rates in a meta-analysis by Goobie et al combining all 3 cohorts.⁶

Such findings underscore the need for more stringent regulation and reduction of human-derived emissions, the study authors wrote.

Expanding Trial Participation

Efforts are being made to expand the pool of patients participating in PFF clinical trials, which has been an ongoing challenge, said Dr. Lee.

“Including more patients in the development of clinical trials is critical, and involvement of patients from the start of the drug discovery process can be very meaningful for those developing potential therapies,” Dr Lee noted.

“We are working to increase marketing efforts to recruit from a wider pool of geographic locations and conducting outreach through community organizations and foundations to engage more patients in clinical trials,” Dr Lee said. The PFF Clinical Trial Finder provides a comprehensive list of trials that patients can search to identify “relevant and feasible” opportunities to participate in PF studies.

Dr Kulkarni urged pulmonologists in various clinical settings to remain aware of PF trials and discuss the possibility of clinical trial participation with every patient with PF.

Yet even patients who are eager to participate in PF clinical trials may face significant barriers to participation, Dr Kulkarni acknowledged.

Travel difficulties represents a major factor affecting patient enrollment in clinical trials, said Dr. Lee. Such difficulties include challenges with coordinating oxygen during travel and the need to drive long distances to participate in trials conducted at academic centers.

PF trial criteria for inclusion and exclusion may also preclude some interested patients from participating in trials. “Although these criteria have evolved over time and are now broader, very few trials will allow inclusion of patients with advanced disease,” noted Dr Kulkarni. “Thus, careful consideration of these factors by industry and investigators when designing clinical trials may improve trial efficiency.”

“Patient and caregiver empowerment and incorporation of patient-centric endpoints may overcome some of these barriers to clinical trial enrollment in PF,” Dr Kulkarni added.

PFF Community Registry

Continuing growth in the PFF Community Registry – which now has more than 2,000 participants³ – will help to expand to the pool of research participants, and is an advance to be celebrated, said Dr Lee.³

“This unique and decentralized registry study relies on self-reported information from patients and lung transplant recipients who have been diagnosed with PF or ILD, as well as their caregivers and biological family members,” said Dr Lee.

“The Community Registry complements the PFF Patient Registry, which began in 2016 and includes patient data provided by clinicians.”⁴ The combined data from these registries provide a comprehensive and multifaceted resource for PF research, said Dr Lee.

An Emerging Research Priority

One emerging priority in PF research is the identification of early PF and related treatment implications, noted Dr Lee. “Work has been done that identifies ‘high-risk’ individuals, which not only includes those with a family history of PF, but also those with underlying conditions, such as rheumatoid arthritis,” she stated. “Many investigators are interested in these early forms of PF, and future work will focus on determining if early identification and subsequent intervention has an impact on long-term disease outcomes,” said Dr Lee.