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MADRID -- Intravenous pamrevlumab reduced loss of lung function in patients with idiopathic pulmonary fibrosis (IPF) at 48 weeks, a phase II trial presented here found.

In 103 patients with at least 55% predicted forced vital capacity (FVC), those given 30 mg/kg of pamrevlumab every three weeks had significantly reduced FVC decline compared to placebo (difference 4.3 percentage points, 95% CI 0.4-8.3, P=0.033), reported Luca Richeldi, MD, of Università Cattolica del Sacro Cuore in Rome, at the annual .

"As expected ... in this population, there is statistically significant reduction in the loss of lung function, which is in relative terms around 60%, at 48 weeks," Richeldi said while presenting his findings.

As well, fewer patients receiving pamrevlumab versus placebo showed signs of disease progression, defined as death or a decline in FVC (as percent of predicted) of 10 points or more at week 48 (10% vs 31.4%, P=0.013), he added.

Topline findings from the trial were presented at ERS 2018; full results were published in this week to coincide with this year's meeting.

Need for New Therapies

Pamrevlumab is an investigational, fully human monoclonal antibody that targets connective tissue growth factor, which has been associated with the progression of certain diseases like pancreatic cancer, Duchenne muscular dystrophy, and IPF.

Currently, pirfenidone (Esbriet) and nintedanib (Ofev), both approved in 2014, are the only two therapies available for patients with IPF. Pamrevlumab was granted by the FDA last year following the finalized phase II trial.

Pirfenidone and nintedanib are known by some as "dirty drugs" because they are highly pleiotropic antifibrotic treatments that target many co-activated pathways, wrote Athol Wells, MD, of the Royal Brompton Hospital in London, England, in an .

Consequently, these agents have been met with skepticism in some clinical communities despite their proven efficacy, he said. Regardless, more validated treatments are necessary.

The findings presented here, though "striking," should be "treated with caution" until evaluated in a phase III study, wrote Wells.

"We have been here before: apparently striking treatment effects in idiopathic pulmonary fibrosis have been greeted with enthusiasm, but ultimately led to disappointment, as in an initial report of the efficacy of interferon gamma in idiopathic pulmonary fibrosis, admittedly in a tiny cohort," Wells wrote.

However, if confirmed in phase III, the implications of the study are "far-reaching," and have the potential to pave the way for "a new era idiopathic pulmonary fibrosis treatment," Wells said.

Not only did the trial find an observed treatment effect greater than the trials of the two approved IPF therapies, but the treatment effect was also observed in parallel domains of function, including imaging and symptoms -- altogether strengthening the findings, Wells said.

Importantly, there were no large differences in terms of side effects between groups, something that also sets pamrevlumab apart from pirfenidone and nintedanib, as they have been associated with gastrointestinal events that can influence quality of life, Wells said.

"It might be possible, for the first time, to show a clear improvement in quality of life with active treatment in idiopathic pulmonary fibrosis in the phase 3 pamrevlumab trial," he wrote.

Study Details & Further Findings

For the trial, Richeldi and his team enrolled patients with definite or possible usual interstitial pneumonia (UIP) patterns on chest high-resolution CT as well as lung biopsy that confirmed UIP patterns. Patients using either of the two approved therapies were ineligible.

Overall, 76% of the 103 patients completed the trial; about half of those discontinuing did so because of disease progression. Mean patient age was 68, 74% were men, and 83% were white. Characteristics and comorbidities were well balanced between groups except for sex (the placebo group had relatively more men).

The relatively small sample size and sex differences between groups were limitations of the study, but more importantly, more patients dropped out in the intervention arm than placebo, with patients with more severe disease dropping out earlier; this may have decreased the observed treatment effect, the authors noted.

Three and six patients died in the pamrevlumab and placebo arms, respectively. More patients on the active drug experienced treatment-emergent serious adverse events than with placebo (24% vs 15%), which were mostly respiratory related. Patients on pamrevlumab overall had more fatigue (20% vs 8%), urinary tract infections (20% vs 8%), and diarrhea (16% vs 8%) compared to placebo, Richeldi said.

"The lower mortality ... despite similar baseline Gender, Age and Pulmonary function (GAP) scores, is an important and encouraging clinical finding," he and colleagues wrote in their journal paper. "However, since a statistical analysis was not done to assess mortality, these results should be interpreted with caution."

Patients in the intervention group had numerically lower scores (mean difference -5.4, 95% CI -11.7 to 1.0) on the for quality of life -- higher scores indicate more limitations -- although this was nonsignificant and "should be interpreted with caution," the authors reported.

Symptoms, activity levels, and total SGRQ scores trended towards improvement in the pamrevlumab group as the trial neared completion, whereas there were patterns of decline in the placebo arm, Richeldi noted in his ERS presentation.

Pamrevlumab is now in a phase III trial called expected to be completed in 2023.

"I think this is a promising trial because it will allow us to see if the multiple signals we have been seen in phase II can be shown in phase III," Richeldi said.

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