Dry Powder Inhaler Formulation of Ensifentrine Improves Lung Function, Phase 2 Data Show

Treatment with a dry powder inhaler (DPI) formulation of ensifentrine led to clinically meaningful and sustained improvement in lung function in people with moderate to severe chronic obstructive pulmonary disease (COPD), according to early data from a Phase 2 trial.

Ensifentrine (RPL554) is an inhibitor of the phosphodiesterase proteins 3 and 4, which play a role in smooth muscle contraction and immune cell-derived inflammation, respectively. The investigational therapy, being developed by Verona Pharma, is intended to have both bronchodilator and anti-inflammatory properties.

Ensifentrine’s safety and efficacy are being tested in a two-part Phase 2 clinical trial in patients with moderate to severe COPD. Results were released from the first part of the study, in which 37 patients were treated with a single dose of ensifentrine — either 150 µg, 500 µg, 1,500 µg, 3,000 µg, or 6,000 µg — or a placebo.

Results showed that patients treated with ensifentrine had a statistically significant and clinically meaningful improvement in lung function compared to placebo, as assessed by forced expiratory volume in one second (FEV₁). Specifically, ensifentrine led to an increase in peak FEV₁ from baseline in a dose-dependent manner, ranging from 68 mL to 333 mL for 1,500 µg or higher doses.

Analysis of average FEV₁ between 0–4 hours and 0–12 hours after treatment revealed a dose-dependent and sustained effect — ranging from 68 mL to 296 mL for doses of 500 µg or higher at 0-4 hours, and from 54 mL to 254 mL for doses of 1,500 µg or greater at 0-12 hours.

According to the company, the lung function results support twice-daily dosing of the investigational treatment.

The DPI formulation of ensifentrine was well-tolerated across all doses, with associated adverse events similar to placebo.

Overall, these positive safety and efficacy results support the start of the second part of the trial.

“The large bronchodilator response, 12-hour duration of action, and good tolerability observed with the DPI ensifentrine formulation in the first portion of this study are very encouraging, and we look forward to proceeding with the second part to evaluate treatment over a one-week period,” Jan-Anders Karlsson, PhD, Verona Pharma’s CEO, said in a press release.

“Positive data from this and future studies with inhaler formulations could dramatically expand the clinical utility and commercial opportunity for ensifentrine, not only in the treatment of COPD, but potentially in other respiratory diseases such as asthma,” Karlsson said.

The second part of the trial will be a double-blind, placebo-controlled analysis of the DPI formulation of ensifentrine at a site in the U.S. Participants will be randomized to one of four doses — 150 µg, 500 µg, 1,500 µg, or 3,000 µg — or placebo, given twice daily over one week. All COPD patients will receive each dose and placebo over five seven-day treatment periods.

The primary goal is the bronchodilator response of repeated doses of ensifentrine (assessed through peak FEV₁). Secondary goals include safety, tolerability, bronchodilator profile, and pharmacokinetics (a compound’s absorption, distribution, metabolism, and excretion) of repeat doses of the therapy.

Full results from the Phase 2 study are expected in the second half of 2019.

Given the widespread use of inhalers for maintenance treatment of COPD, this formulation of ensifentrine may enable combination therapies with existing treatments delivered by handheld inhalers, according to Verona Pharma.

A nebulized formulation of ensifentrine is currently being tested as an add-on treatment in COPD patients. Results of a three-day Phase 2 trial (NCT03673670) in 79 patients showed that adding either 1.5 mg or 6.0 mg of ensifentrine to the bronchodilator therapy Stiolto Respimat (tiotropium bromide and olodaterol, marketed by Boehringer Ingelheim) was well-tolerated, and significantly improved lung function and lung elasticity — determined by measuring residual air volume in the lungs after passive exhalation — on day three.

Verona Pharma expects to initiate a Phase 2 trial of self-administered, pressurized, metered-dose, inhaled formulation of ensifentrine in COPD patients in the second quarter of 2019.

Apart from COPD, the potential therapy is also being developed for people with cystic fibrosis (NCT02919995) and asthma.