番茄社区

SAN DIEGO -- Two novel drugs improved lung function in idiopathic pulmonary fibrosis (IPF) in a pair of phase IIa trials, researchers reported here.

In an open-label, single-arm trial of 46 patients using imputation, forced vital capacity (FVC) stabilized and then improved over 36 weeks, with a change from baseline of -50 mL (90% CI -150 to 50) at 24 weeks and 13 mL (90% CI -69 to 96), normalized, at 36 weeks among those who took the novel angiotensin II type 2 receptor agonist buloxibutid.

In the other study, a randomized, double-blind trial, patients assigned to the oral hedgehog inhibitor ENV-101 had better percent predicted FVC mean change from baseline compared with placebo (1.9 vs -1.3 mL, P=0.035), as well as FVC mean change from baseline (60 vs -46.8 mL, P=0.070) at 12 weeks.

In addition, total lung capacity improved in the ENV-101 group versus placebo (mean change from baseline 200 vs -56, P=0.005), as did lung fibrosis (quantitative interstitial lung disease P<0.05; and quantitative lung fibrosis P=0.1).

Both studies were presented at the annual meeting.

"Both studies have their limitations, but it would be transformational if findings from either or both were to be replicated in a 52-week study. In terms of early-phase clinical trial results, these are among the two most exciting sets of results we've seen," said Toby Maher, MD, PhD, of the Keck School of Medicine at the University of Southern California in Los Angeles, a co-investigator on both studies.

In an interview with 番茄社区, Maher explained that IPF is a "desperate condition" that leads to death by respiratory failure. The disease is only slowed by a year or two when patients take the FDA-approved drugs nintedanib (Ofev) and pirfenidone (Esbriet), he said.

IPF is difficult to treat because fibrosis develops prior to presentation and leads to advanced destruction of the lungs, he noted. "By the time we start treatment, they're already a long way down the path to the end stage."

Maher said that both drugs appear to have anti-fibrotic effects.

In regard to quality of life, he said that "over a 12-week period, patients are not going to truly appreciate the change in FVC." However, he pointed out that the FDA has accepted FVC as a surrogate for survival.

Buloxibutid Study Details

In the multicenter , 52 patients with centrally confirmed IPF who were not receiving anti-fibrotic therapy were enrolled. Mean age was 67.3, 77% were men, and 73% were Asian. Mean percent predicted FVC was 75.5%, and mean forced expiratory volume in 1 second (FEV₁)/FVC ratio was 0.80.

Patients were given 100 mg of oral buloxibutid twice daily for 24 weeks, with an optional extension to 36 weeks.

An observed case analysis without imputation showed the FVC change from baseline was 47 mL (90% CI -108 to 203) at 24 weeks in 27 patients, and 235 mL (90% CI 8-389), normalized, at 36 weeks in 19 patients. At week 24 compared with baseline, plasma levels of transforming growth factor beta-1 fell by 57% and levels of matrix metalloproteinase-13 rose by 67% (P=0.01).

No serious adverse events were reported; 10 patients had reversible, mild-to-moderate hair loss.

ENV-101 Study Details

The ENV-101 study was a placebo-controlled trial conducted at 16 centers in Australia, Canada, South Korea, Malaysia, and Mexico in patients with percent predicted FVC of more than 50% and percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO) of at least 35%.

Initially, 21 patients were assigned to take 200 mg of the novel hedgehog inhibitor and 20 were assigned to placebo orally once daily for 12 weeks. Mean age was 69.7 to 71.2, and 80% to 86% were men. Mean percent predicted FVC was 80.6 to 85.1, and mean baseline DLCO was 22.1 to 22.6 mL/min/mm Hg.

Treatment-emergent adverse events (TEAEs) occurred in 85.7% of ENV-101 patients and 75% of placebo patients. The most common TEAEs related to the study drug were dysgeusia (57%), alopecia (52%), and muscle spasms (43%); none were grade 3 or 4. Adverse events were considered typical for hedgehog inhibitors.

Six of the participants taking ENV-101 were not evaluable at 12 weeks for various reasons, with one leaving the trial due to adverse events (dysgeusia/decreased appetite). Disease progressed (over 10% decrease in percent predicted FVC) in two placebo patients and in none of the ENV-101 patients.

A 52-week phase IIb study is planned for buloxibutid in IPF, and a phase IIb study is planned for ENV-101 in IPF and progressive fibrosing interstitial lung disease.