Hedgehog pathway inhibitor safe, improves lung function in IPF

Key takeaways:

• Adverse events reported with ENV-101 have been seen with other hedgehog inhibitors.
• Another trial is already planned to further study ENV-101 in two types of pulmonary fibrosis: idiopathic and progressive.

SAN DIEGO — After receiving a hedgehog pathway inhibitor for 12 weeks, adults with idiopathic pulmonary fibrosis had better lung function, according to research presented at the American Thoracic Society International Conference.

The novel hedgehog pathway inhibitor assessed in this trial is called ENV-101 (Endeavor BioMedicines), according to the presentation.

“In totality, the findings from this study are compelling justification to move into phase 2b, where we’ll continue to study the potential of ENV-101 in IPF patients,” Toby M. Maher, MD, PhD, professor of medicine and director of interstitial lung disease at Keck School of Medicine, University of Southern California, Los Angeles, told Healio.

“The community of pulmonologists who treat IPF patients are well aware of the tremendous need for treatments that do more than slow the decline of lung function,” Maher continued. “There is obviously much more work to do in terms of studying ENV-101 in a larger and longer study, but I do think the community will be keeping a close eye on this program moving forward.”

In a multicenter, randomized, double-blind, placebo-controlled phase 2a trial, Maher and colleagues assessed 41 adults with IPF not currently taking antifibrotics to determine whether 200 mg of once-daily ENV-101 for 12 weeks is safe vs. placebo.

Researchers also evaluated changes in baseline percent-predicted FVC, FVC mL and measures on high-resolution CT at week 12 between the two groups.

Notably, patients included in this population met certain measures of lung function, such as a FVC greater than 50% predicted and diffusing capacity of the lung for carbon monoxide (DLCO) of at least 35% predicted.

Of the total cohort, 21 patients (mean age, 69.7 years; 86% men; mean FVC, 80.6% predicted) received ENV-101, and 20 patients (mean age, 71.2 years; 80% men; mean FVC, 85.1% predicted) received placebo.

The ENV-101 group and the placebo group had several similar demographics at baseline: BMI, DLCO, time since IPF diagnosis and proportion of patients who previously received pirfenidone.

A slightly greater proportion of patients receiving ENV-101 vs. placebo experienced a treatment-emergent adverse event (n = 18; 85.7% vs. n = 15; 75%), and more patients in the ENV-101 group had an event related to the assigned treatment (n = 15; 71.4% vs. n = 3; 15%).

Dysgeusia (57%) was the most frequent treatment-emergent adverse event related to ENV-101, followed by alopecia (52%) and muscle spasms (43%), all of which researchers said are events that have been seen with other hedgehog inhibitors.

In both groups, no patients had a treatment-related serious adverse event, a treatment-related grade 3 or 4 adverse event or a treatment-emergent adverse event that resulted in death, according to the presentation.

Within the cohort receiving ENV-101, five patients stopped treatment. Reasons for discontinuation included consent withdrawal (n = 3), an adverse event (n = 1) and lost to follow-up (n = 1).

Researchers had data for 15 patients receiving ENV-101 and 19 patients receiving placebo for the remaining outcomes.

From baseline to week 12, researchers found improvement in percent-predicted FVC with ENV-101 vs. placebo (mean change, 1.9% predicted vs. –1.3% predicted; P = .035), as well as in FVC mL (mean change, 60 mL vs. –46.8 mL).

“The placebo group acted as a placebo group should in this type of trial, which is to say that they lost lung function over the course of the 12 weeks,” Maher told Healio. “What was exciting is that the treatment arm demonstrated a continuous and statistically significant improvement in lung function.

“This really distinguishes the data generated in this trial vs. what we’ve seen with other studies in the past, where we might only see a slowing of disease progression,” he added.

By high-resolution CT, researchers assessed four measures: total lung capacity, percentage of quantitative ILD, percentage of quantitative lung fibrosis and percentage of quantitative ground glass.

In addition to improvement in lung function, patients receiving ENV-101 had better total lung capacity at week 12 vs. patients receiving placebo (mean change from baseline, 200 mL vs. –56 mL; P = .005).

The ENV-101 group vs. the placebo group also had lower percentages of quantitative ILD (mean change, –9.4% vs. 1.1%; P < .05), lung fibrosis (mean change, –2% vs. 0.87%) and ground glass (mean change, –4.6% vs. 0.29%) between baseline and week 12, according to a press release from Endeavor BioMedicines.

“The combination of the improved lung function and decline of fibrosis measures provides justification to move into phase 2b, where we’ll continue to study these endpoints with ENV-101,” Maher said.

In terms of future studies, Maher provided details on the WHISTLE-PF trial.

“We are looking forward to initiating the WHISTLE-PF trial, which will begin enrolling in 2024,” he said. “The WHISTLE-PF trial will be a global, randomized, double-blind, dose-ranging trial that will include a phase 2b cohort in patients with IPF and a parallel phase 2 cohort in patients with [progressive] PF. This will be a longer study, 6 months of treatment, in more patients that will evaluate multiple different dose levels of ENV-101 to find the ideal balance of safety, tolerability and efficacy.”

Reference:

• New phase 2a clinical trial results demonstrate Endeavor BioMedicines’ ENV-101 improved lung function and reversed key measures of lung fibrosis in patients with idiopathic pulmonary fibrosis. https://endeavorbiomedicines.com/new-phase-2a-clinical-trial-results-demonstrate-endeavor-biomedicines-env-101-improved-lung-function-and-reversed-key-measures-of-lung-fibrosis-in-patients-with-idiopathic-pulmonary-fibrosis/. Published May 19, 2024. Accessed May 23, 2024.