The Future of Clinical Trials in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) currently affects about 100 000 individuals in the US, and millions globally. Patients living with IPF experience disabling symptoms and progressive loss of lung function. 1 The 2 treatments approved by the US Food and Drug Administration to treat IPF, nintedanib and pirfenidone, slow disease progression but do not stop or reverse lung fibrosis. 2,3 Both drugs are poorly tolerated by a substantial number of patients, and use is further limited by high cost and lack of perceived benefit on symptoms and quality of life. Many patients with IPF are eager to participate in clinical trials. Yet in the era of approved antifibrotic therapy, patients and their physicians must consider how potential investigational drugs will fit into the current standard of care.In this issue of JAMA, the results from the ISABELA 1 and ISABELA 2 randomized clinical trials, 4 one of the first phase 3 clinical trial programs in IPF to be completed since the approval of nintedanib and pirfenidone, are presented. The 2 identically designed trials randomized a total of 1306 patients to 1 of 2 doses of oral ziritaxestat (an autotaxin inhibitor that lowers levels of lysophosphatidic acid, which is a profibrotic mediator) or placebo. The trials allowed the continuation or initiation of background antifibrotic therapy.The trials were terminated early after an interim analysis raised safety concerns and revealed a lack of efficacy in the treatment groups. Neither dose of ziritaxestat demonstrated any benefit on the rate of decline for forced vital capacity (FVC) over 52 weeks. There was no benefit on any of the reported secondary outcomes. In fact, time to first respiratory-related hospitalization, respiratory-related mortality, and first acute IPF exacerbation were all worse in the ziritaxestat groups. All-cause mortality was highest in the high-dose ziritaxestat group, and in the ISABELA 2 trial, all-cause mortality was double that of placebo. Respiratory-related deaths were the primary cause of death.The ISABELA trials highlight the complexity of conducting IPF clinical trials in the era of approved antifibrotic therapy. 5 Each trial had 3 groups: high-dose ziritaxestat (600 mg/d), lowdose ziritaxestat (200 mg/d), and placebo. It also had 3 standard of care treatment options: pirfenidone, nintedanib, and neither; there was approximately equal distribution of participants among these 3 options. The study was well designed and conducted. Participants were recruited from 227 sites in 26 countries. There were missed clinic visits due to the COVID-19 pandemic, but this does not seem to have impacted the results. The enrolled patients had a centrally reviewed diagnosis of IPF and mild to moderate disease. There was good target engagement. Despite early termination, the 15. Martinez FJ, Yow E, Flaherty KR, 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...

Pharmacological treatment in Idiopathic Pulmonary Fibrosis: current issues and future perspectives

“…The reason for this might not have a univocal explanation: while admittedly it could be true that some of the analysed molecules are ineffective in treating IPF, the reverse may still be true; we must still improve on phase II trials to yield more robust and reliable data, which will allow us to design high quality phase III studies. As stated by Podolanczuk et al, the crucial points for avoiding current issues in future clinical trials are several [ 85 ]: phase II trials must be sufficiently powered to assess safety and heterogeneity of treatment response considering background antifibrotic use, underlining so the importance of an adequate sample size, considering then ethnic and sex differences, with the option to use reliable biomarkers in future for a precision-based approach. Another point to evaluate is to consider other outcomes: longitudinal change of FVC is recognized as the most clinically relevant parameter in IPF, due to its demonstrated correlation to death; but sometimes its measurement might be susceptible to missing data or patient difficulties in performing spirometry.…”

Multiomic analysis of monocyte-derived alveolar macrophages in idiopathic pulmonary fibrosis

“…Mo_AMs have been found to promote the conversion from fibroblasts to myofibroblasts by secreting TGFß and PDGF, while fibroblasts promote the maturation of Mo_AMs through secreting MCSF [ 8 , 9 ]. In contrast, while pirfenidone and nintedanib act by suppressing TGFß and PDGF secretion in fibroblasts, these treatments cannot reverse or even stop fibrosis and FVC%pred (forced vital capacity) [ 2 , 10 ]. FVC, which measures the total amount of gas exhaled from the point of maximal inspiration during the pulmonary ventilation tests, has long been used as a standard and established measurement for evaluating levels of lung fibrosis in interstitial lung disease.…”

The Added Power of Synthetic Control Groups: Challenging Conventional Wisdom and Trial Design in Idiopathic Pulmonary Fibrosis Research

“…However, RCTs are expensive, inefficient, and can lack generalizability to patients outside of the tightly coordinated study environment. These problems become especially apparent when trying to design trials for a rare, deadly disease like idiopathic pulmonary fibrosis (IPF), which is part of why the antifibrotic drugs pirfenidone and nintedanib remain the only two approved medications for use in patients with IPF ( 1 ). Although the data indicating the effectiveness of the antifibrotic agents continue to grow for IPF and other forms of fibrotic lung disease, additional therapeutics with superior efficacy, improved tolerability, and reduced cost are desperately needed for patients living with IPF ( 1 – 6 ).…”

“…These problems become especially apparent when trying to design trials for a rare, deadly disease like idiopathic pulmonary fibrosis (IPF), which is part of why the antifibrotic drugs pirfenidone and nintedanib remain the only two approved medications for use in patients with IPF ( 1 ). Although the data indicating the effectiveness of the antifibrotic agents continue to grow for IPF and other forms of fibrotic lung disease, additional therapeutics with superior efficacy, improved tolerability, and reduced cost are desperately needed for patients living with IPF ( 1 – 6 ). Given the challenges with traditional RCTs, novel approaches to trial designs and methodology, as well as leveraging of “big data” sources, will likely be required.…”