Enhancing Patient Care in Progressive Pulmonary Fibrosis: Strategies for Addressing Unmet Needs and Optimizing Treatment Approaches

Anna-Maria Hoffmann-Vold, M.D., Ph.D., of Oslo University Hospital in Oslo, Norway, discussed the symptoms, diagnosis, treatment, unmet needs, emerging treatment and future of treatment in a Managed Healthcare Executive K-Cast video series.

Defining progressive pulmonary fibrosis

Progressive fibrosing interstitial lung disease is not a disease, it’s a phenotype, explained Hoffmann-Vold. The definition of progressive pulmonary fibrosis (PPF) should integrate a combination of deteriorating lung function, worsening in appearance on high-resolution CT scan, and patient-
reported symptoms. The definition is based on at least two out of three domains with a worsening within 12 months, so either worsening of respiratory symptoms in combination with physiological evidence of disease progression, which includes a decline of forced vital capacity (FVC) of more than 5% and a decline in diffusing capacity of the lungs for carbon monoxide of more than 10%, and/or radiological evidence of disease progression.

It is important to understand that different underlying diagnoses can lead to PPF, noted Hoffmann-Vold. As a rheumatologist, the conditions that she sees that develop into PPF are systemic sclerosis, rheumatoid arthritis, myositis, mixed connective tissue disease and Sjögren syndrome.

There isn’t one risk factor across all the different diagnoses, but certain risk factors for specific diagnoses, according to Hoffmann-Vold. For example, patients with systemic sclerosis with a short disease duration, diffuse skin disease or inflammatory markers are more likely to develop PPF.

Symptoms and the quality of life

Typically patients with PPF have varying episodes. A patient who has PPF over a one-year period can have a stable disease in the following year. Very few patients have rapidly progressive disease with worsening of all of the components of the disease every single year, notes Hoffmann-Vold.

Very often, it takes quite a while before patients become symptomatic, according to Hoffmann-Vold, and some patients with very severe disease may be asymptomatic. But once patients develop symptoms, such as dyspnea and cough, those symptoms have an impact on quality of life, and patients have higher morbidity and mortality, she said. With every PPF event, a patient’s lungs become more damaged. If patients experience enough damage in the lungs, they will also start desaturating when they exercise and, even worse, desaturating at rest, which requires oxygen therapy. “This, again, is really impacting the patient’s quality of life over time,” Hoffmann-Vold said. Patients might not be able to keep the same work habits as before or exercise in the same way. Those changes can impact the caregivers and the entire family of the patient as they need to adapt to the patient’s situation, which can be rather
challenging, said Hoffmann-Vold.

Diagnosis

PPF is not a diagnosis but a disease behavior and a clinical phenotype, Hoffmann-Vold stressed. “To really see this clinical phenotype, we need to monitor lung function [and] lung structure, assessed on HRCT [high-resolution computed technology] and by mapping respiratory symptoms over time. Only by doing this in a structured way we will identify patients with progressive pulmonary fibrosis,” said Hoffmann-Vold.

A monitoring approach that is individually tailored to patients with interstitial lung disease is important, Hoffmann-Vold noted, because without it, early identification of PPF is hampered.

Although it is not included in the criteria for PPF,Hoffmann-Vold suggested that conducting a 6-minute walking test or any exercise test with assessment of desaturation. For the patients at high risk of PPF, she recommended that this should be done more often in clinical practice.

Hoffmann-Vold emphasized the importance of early diagnosis and intervention and how they can improve patient outcomes. Interstitial lung disease is associated with reduced survival, but once a patient develops PPF, survival is further reduced, she said. These survival facts make identifying patients at risk of PPF important, she said. “If we can prevent a patient from developing PPF, we can prevent end-stage lung disease, which is associated with hospitalization, lung transplants and oxygen therapy, which all have a high healthcare cost,” said Hoffmann-Vold.

Treatment

A number of treatment guidelines have been updated or are about to be. The American Thoracic Society, a specialty group, issued an update of the idiopathic pulmonary fibrosis guidelines in 2022 that also included a guideline for how to treat patients with PPF, she noted. There also have been new guidelines issued that cover specific diseases associated interstitial lung disease. Early in 2025, the European Respiratory Society and the European Alliance of Associations for Rheumatology are expected to issue a joint guideline that will cover interstitial lung disease in rheumatic diseases and also PPF.

The 2022 guidelines conditionally recommended using nintedanib (Ofev), which was tested in the INBUILD trial, and that helped lead to the approval of nintedanib in different countries around the world for the treatment of PPF, Hoffmann-Vold said. For pirfenidone (Esbriet), the guidelines only recommended further research and not implementation in clinical practice yet.

Clinicians have several different treatment options for varying underlying diseases, such as systemic sclerosis, including a number of immunosuppressive treatment options, Hoffmann-Vold said. Nintedanib is recommended in patients with systemic sclerosis who have developed PPF. These patients can also be treated with a combination of nintedanib and mycophenolate. Hoffmann-Vold pointed out, despite having results from randomized clinical trials, the evidence is often rated as low — even very low — in these guidelines.

Clinicians need to keep nonpharmacological options in mind, Hoffmann-Vold noted, although those options often do not make it into guidelines. She said she strongly recommends pulmonary rehabilitation and oxygen initiation for lung transplant evaluation and also for palliative care.

Unmet needs

Consideration of the unmet needs of people with PPF needs to consider the entire management of the disease, not only the therapy, Hoffmann-Vold said. She mentioned novel ways of identifying at-risk patients, which include noninvasive tests of blood biomarkers and analysis of exhaled breath. Monitoring currently depends on patients coming into a clinic for tests. At-home monitoring could identify PPF earlier, she said.

There are also unmet needs in treatment, Hoffmann-Vold said: “We don’t have the perfect treatment yet.” Researchers need to conduct trials that test combination therapies and at therapy in patients with rheumatic disease and interstitial lung disease, who are often much younger. Another gap, said Hoffmann-Vold, is the understanding of strategies to taper treatment and avoid overtreatment.

Emerging therapies

Hoffmann-Vold, noting that it was exciting to have several emerging therapies for PPF, discussed three ongoing trials. Nerandomilast, an oral, preferential inhibitor of phosphodiesterase (PDE4B), is being assessed in the FIBRONEER-ILD trial, a phase 3, double-blind, placebo-controlled trial that includes patients with PPF. The primary end point, absolute change from baseline FVC, was assessed over 52 weeks. Patients in this trial must be diagnosed with pulmonary fibrosis other than idiopathic pulmonary fibrosis, and they need to show a progressive phenotype. Results from the FIBRONEER-IPF study were very recently shown to be positive.

Admilparant is an oral lysophosphatidic acid receptor 1 (LPA1) antagonist. Results from ALOFT-PPF trial, a phase 2 trial, showed that admilparant reduced or slowed lung function decline and was safe and well tolerated. There are now two ongoing phase 3 trials of the drug.

Treprostinil is a prostacyclin analogue with vasodilator properties. The TETON-PPF trial is a 52-week randomized, double-blind, placebo-controlled phase 3 trial that is enrolling approximately 700 patients with PPF. Background therapy with pirfenidone or nintedanib is allowed. The primary end point is the change in absolute FVC at week 52.

The future of treatment

Until now, the treatments we have mostly slowed down disease progression rather than offered stabilization or improvement, said Hoffmann-Vold. The hope, she said, is that some of the novel drugs assessed in trials will also stabilize, or even improve, lung function. It will be important to look at the inclusion criteria of the patients to identify the right patient for the right drug, she said. The inclusion criteria among the three emerging therapies differ; that might help place them in clinical practice and identify the right patients. The trials of the emerging therapies allow background therapy, noted Hoffmann-Vold, and that will help identify possible combinations with existing drugs.

The hope is that these novel treatments will improve patient outcomes by reducing exacerbations and hospitalizations, improving survival over time, said Hoffmann-Vold.

“We have a very important role in the care of our patients with interstitial lung disease, and even more if they develop PPF,” noted Hoffmann-Vold. “We need to take care of these patients and monitor them tightly. We need to start initiating treatment and change treatment once the patient fails on treatment.” It is important to include the caregivers in the care of patients and to provide written information that they and patients can read at home.

“I think it is very important to spread hope to our patients,” Hoffmann-Vold continued. “There is hope. We do have different treatment options. There are several emerging therapies, so by spreading the word that novel treatment is developed, we can help our patients and support them.” But Hoffmann-Vold also emphasized that many patients with PPF may die of their disease.

“It is important to provide help with palliative care, talk to our patients and inform them about the outcome in a sensitive way,” she said.