Idiopathic pulmonary fibrosis therapeutics coming of age: ATS 2016

Dr Marilyn Glassberg recently attended the American Thoracic Society’s 2016 International Conference alongside 15,000 other pulmonary, critical care, and sleep researchers. She talks more about the conference in this blog, focusing particularly on idiopathic pulmonary fibrosis.

My specific area of interest is idiopathic pulmonary fibrosis (IPF), an incurable and fatal disease characterized by a progressive cycle of pathologic connective tissue accumulation and scar tissue formation.

As the name suggests, the etiology is unclear and until very recently the therapeutic outlook was bleak with an estimated mean survival of 2–5 years from the time of diagnosis. Despite being a reasonably rare disease, in 2014 IPF was estimated to kill up to 65,000 Europeans and 17,000 people in the USA every year.

European patients with IPF received encouraging news in 2011 when the European Medicines Agency (EMA) approved Roche’s Esbriet (pirfenidone) for offering the promise of slowing disease progression.

Approval by the Food and Drug Administration (FDA) followed in 2014 alongside Boehringer Ingelheim’s Ofev (nintedanib), which was approved by the EMA the next year. It is a time of great change within the IPF therapeutic arena so it was with excitement that we got to review our growing clinical experience and discuss important new research building upon the initial pivotal trials at this year’s ATS 2016.

Patient profiles
IPF is a poorly understood and rare condition, with only ~100,000 affected individuals in the USA. One of the most obvious benefits of the explosion in IPF research is a better understanding of the patients and their disease.

I presented a study of cardiovascular (CV) risk factors, comorbidities and concomitant medication use seen in the pooled ASCEND and CAPACITY Phase III pirfenidone randomized controlled trials (RCTs) versus real-life data from three international registries: PASSPORT, INSIGHTS-IPF and IPF-PRO.

The significant CV risk factors (especially hypertension, 52%), conditions (predominantly coronary artery/heart disease, 17%) and medication use (with high usage rates of statins, 51%; aspirin, 48%; and renin-angiotensin inhibitors, 39%) recorded in the RCT populations were consistent with those observed in the registries.

Real-life cohorts are extremely valuable as they describe actual in-clinic use, beyond the strict confines of controlled studies, and thus help us validate and have increased confidence in RCT results.

Drug safety
We urgently need more drug safety data in this at-risk population, including real-life adverse event data, to inform clinical decision-making and support patient education; especially as there is no clear efficacy advantage to either of the approved agents.

Pirfenidone’s registration trial safety profile had previously been validated in the real-world setting and at ATS a poster by Noth et al. provided welcome external validation of the nintedanib safety profile observed in its INPULSIS RCT program in ~6700 post-marketing surveillance patients in the USA.

As more than a third of IPF patients suffer from CV disease, I presented a post-hoc analysis of CV safety events in the pooled ASCEND and CAPACITY Phase III pirfenidone studies. We showed that treatment-emergent major adverse CV events (MACE) and bleeding events were similar over ~14 months of treatment with either placebo or pirfenidone.

Drug safety data like these have real clinical impact; for instance, these results suggest that patients undergoing lung transplant surgery may not need to interrupt pirfenidone treatment because of worries about increasing bleeding risks.

Clinically meaningful efficacy

With experience building on both approved agents, clinicians are looking for data on disease progression to help calibrate their and their patients’ expectations
Furthermore, with experience building on both approved agents, clinicians are looking for data on disease progression to help calibrate their and their patients’ expectations, as well as to support management decisions.

Exacerbations – unpleasant and acute symptom deterioration typically leading to hospitalization – can be fatal and are associated with worsening disease and progressive shortness of breath. For patients and their physicians, exacerbations thus serve as both undesirable outcomes in and of themselves as well as clinically meaningful yardsticks of progression.

Promising data was presented from the INPULSIS studies, showing that nintedanib significantly reduced the risk of a first acute exacerbation reported by the investigator as a serious adverse event versus placebo.

Similarly, in the pooled ASCEND and CAPACITY populations, pirfenidone-treated patients were shown to be significantly less likely to experience respiratory-related hospitalization than those receiving placebo.

Understanding and slowing disease progression

IPF is a progressive condition and as such defining treatment failure is problematic. Data that enhance our understanding of the course of disease, with and without treatment, are needed. A ≥10% decline in forced vital capacity (FVC) is indicative of poorer outcomes and is commonly used as the threshold of failure in IPF clinical studies, but previously there were no data to support everyday clinical decision making after such a ‘failure’.

It was heartening therefore to be part of a robust analysis of the pooled ASCEND and CAPACITY populations, building on a recent publication investigating a ≥10% absolute decline in FVC, also showing that patients experiencing a ≥10% relative decline in FVC over six months, continued to benefit from pirfenidone therapy.

Of those patients in either the placebo or pirfenidone arms whose FVC had relatively declined ≥10% in the first six months, significantly fewer pirfenidone-treated patients experienced a further ≥10% decline or death in the subsequent six months, compared with placebo-treated patients.

These data should reassure patients and their physicians of the value of continuing therapy after initial decline. Moreover, as both the nintedanib and pirfenidone pivotal studies only looked at patients with mild-to-moderate disease (FVC 50–90% of predicted in ASCEND/CAPACITY; ≥50% in INPULSIS), any new efficacy data in less healthy patients are especially welcome.

As the presenting author Dr Steven Nathan from INOVA Fairfax Hospital in Virginia, USA, commented, “It is clear from these findings that respiratory specialists treating patients with pirfenidone should persist with treatment beyond six months even in the context of a meaningful decline in lung function since patients will still derive significant clinical benefits”.

This article originally appeared on Biomed Central. Dr Glassberg is  a pulmonologist specializing in interstitial and rare lung diseases.

She has conducted NIH-funded, industry-sponsored, and investigator-initiated clinical trials in patients with idiopathic pulmonary fibrosis (IPF), pulmonary hypertension, and lymphangioleiomyomatosis.

She has completed the first clinical trial on the safety of intravenous infusion of bone-marrow derived mesenchymal stem cells (MSCs) in patients with IPF endorsed by the US Food and Drug Administration (FDA) and reported safety.

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