Getting diagnosed with a serious disease of any sort can be frightening, but for many patients, actually having a concrete diagnosis—and by association, knowledge of possible treatment plans—is a relief. In the case of idiopathic pulmonary fibrosis (IPF), which shares symptoms with other pulmonary diseases, aid in differentiating IPF and enabling tailored treatment options is particularly welcome. IPF is a chronic, progressive lung disease characterized by scarring of the lungs, and patients with this disease gradually lose lung function. New guidelines for diagnosing IPF were released recently, which could lead to more accurate and earlier diagnoses for IPF patients.
The guidelines were issued in early September as a collaborative effort by the American Thoracic Society (ATS), the European Respiratory Society (ERS), the Japanese Respiratory Society (JRS) and the Latin American Thoracic Society (the Asociación Latinoamericana de Tórax, or ALAT). The updated diagnostic standards were published under the title “Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline” in the American Journal of Respiratory and Critical Care Medicine. Among the new guidelines are more specific criteria related to patterns of usual interstitial pneumonia (UIP, a form of lung disease hallmarked by progressive scarring of the lungs); the role of HRCT scanning in diagnosis; and instances in which different types of lung biopsies are—and aren't—recommended. (The updated recommendations can be found here: https://www.atsjournals.org/doi/full/10.1164/rccm.201807-1255ST)
Moving from IPF diagnosis to treatment, this year's European Respiratory Society International Congress, which took place shortly after the issuance of the new guidelines, included encouraging results from one IPF compound. Administration of Genentech's Esbriet (pirfenidone) was found to maintain pulmonary function in IPF patients, thanks to an analysis of real-world data from the PROOF study. The observational PROOF registry consisted of IPF patients from eight centers based on Belgium and Luxembourg.
Dr. Wim Wuyts of the Department of Respiratory Medicine at University Hospitals Leuven, who served as principal investigator on the PROOF Registry, spoke with us regarding the new recommendations and additional study data for Esbriet.
DDNews: What kind of impact could these updated guidelines have on future studies in IPF?
Dr. Wim Wuyts: IPF is rare and can be challenging to diagnose because its symptoms may closely resemble those of other chronic lung conditions. As a result, clinical guidelines and consensus publications are critical to helping physicians arrive at an accurate diagnosis of IPF and an appropriate treatment plan based on the latest medical research. The latest ATS guidelines aim to clarify the diagnostic criteria for IPF. Specifically, previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis.
IPF is rare, and doctors are unlikely to regularly encounter cases of IPF. The latest ATS/ERS/JRS/ALAT IPF Clinical Guidelines aim to clarify the pathway to IPF diagnosis. The diagnosis of IPF requires exclusion of known causes of interstitial lung disease (ILD), and confirmation of specific radiological and/or histological patterns. High-resolution computed tomography (HRCT) imaging is an important tool to differentiate usual interstitial pneumonia (UIP) that is associated with IPF from UIP associated with other conditions. The updated guideline helps clarify the role of UIP in diagnosis of IPF. The recent update of the guideline distinguishes four UIP patterns on HRCT.
DDNews: In broad terms, how big of a market need does IPF represent?
Wuyts: There are approximately 100,000 people in the United States and 110,000 people in Europe living with IPF, and over a million people worldwide.
DDNews: What kind of benefit does Esbriet offer over existing therapies in terms of delaying disease progression?
Wuyts: More than 35,000 people worldwide have been treated with Esbriet for idiopathic pulmonary fibrosis. In three clinical trials called ASCEND, CAPACITY 004 and CAPACITY 006, the effect of Esbriet on lung function (how well the lungs work) was measured by forced vital capacity (FVC). FVC measures the amount of air you can exhale with force after you inhale as deeply as possible. FVC is used to help diagnose and monitor IPF during the course of the disease.
In the 52-week ASCEND trial, patients on Esbriet maintained an average of 193 mL more lung function at 52 weeks vs placebo (–235 mL vs –428 mL; P<0.001), indicating that Esbriet delayed progression of IPF vs. placebo through a sustained impact on reducing lung function decline. Fifteen percent fewer patients on Esbriet had a meaningful decline in lung function (defined as ≥10 percent decline in FVC) compared with those who did not take Esbriet. This means only about half as many patients taking Esbriet experienced a meaningful decline in lung function, compared with patients who did not take Esbriet.
Esbriet was also studied in two 72-week Phase 3 studies, CAPACITY 004 and CAPACITY 006. CAPACITY 004 showed patients taking Esbriet had a lower percent change in FVC from baseline to the end of the study, compared with patients who did not take Esbriet. CAPACITY 006 did not show a statistically significant change in FVC between patients who received Esbriet and those who did not.
DDNews: How important are retrospective studies such as PROOF in determining the effectiveness of a treatment?
Wuyts: Although clinical trials provide essential data regarding the efficacy and safety of treatments, the restrictive inclusion and exclusion criteria can generate uncertainty when applying results to real-world populations of patients. Currently, there is a lack of data available on longitudinal treatment outcomes in real-world populations of patients with IPF.
DDNews: What is the next step in terms of advancing Esbriet's development program?
Genentech: Esbriet is studied in additional treatment settings in order to maximize its potential for patients with IPF and other lung diseases. The study combining Esbriet and nintedanib showed a similar safety profile for the combination treatment to that expected for each treatment alone.
Also, an ongoing Phase 2 trial with approximately 250 adults is exploring the potential of Esbriet in progressive fibrosing ILD. This is important, as 10 to 25 percent of patients with interstitial lung disease have a disease that is considered unclassifiable. An ongoing Roche-sponsored Phase 2b study will evaluate the efficacy, safety and tolerability of sildenafil or placebo in patients with advanced IPF and risk of pulmonary hypertension who are tolerating Esbriet at a stable dose. Pulmonary hypertension is prevalent in patients with advanced IPF, and combination treatment with Esbriet and sildenafil may have the potential to address unmet needs for those with both conditions.
Dr. Wim Wuyts is an associated professor at the Catholic University of Leuven and is responsible for the unit for interstitial lung diseases of the department of Respiratory Medicine at the University Hospitals Leuven and the laboratory of respiratory medicine of the K U Leuven, Belgium. He also further specialized in pulmonary arterial hypertension.
