Ensifentrine, in Pressurized Dose Inhaler, Showing Efficacy in COPD Trial

A single dose of a pressurized metered-dose inhaler formulation of ensifentrine (RPL544) significantly improved lung function, compared to a placebo, in people with moderate-to-severe chronic obstructive pulmonary disease (COPD), Verona Pharma announced.

These results are from part A, the single-dose part, of a Phase 2 trial (NCT04091360) underway in two sites, London and Wythenshawe, in the U.K. Part B is on temporary hold due the COVID-19 pandemic, and the trial will resume at a later date.

Ensifentrine is an inhibitor of phosphodiesterase (PDE) proteins PDE3, which is involved in smooth muscle contraction, and PDE4, involved in immune cell-derived inflammation. As such, the dual inhibitor is designed to have bronchodilation (relaxing the muscle bands around the airways) and anti-inflammatory properties.

Verona is developing three formulations of ensifentrine to potentially treat COPD: nebulized, dry powder inhaled formulation (DPI), and pressurized metered-dose inhaler (pMDI).

The Phase 2 study is divided into two parts. In part A, 40 participants with moderate-to-severe COPD were randomized to a placebo or to one of five doses of pMDI ensifentrine — 100 micrograms (mcg), 300 mcg, 1,000 mcg, 3,000 mcg, or 6,000 mcg. Each single-dose treatment was administered in two inhalations, or two puffs on an inhaler.

The main goal of part A was to determine the best dose for use in part B.

Additional goals included assessments of the therapy’s safety, its pharmacokinetic profile — absorption, distribution, and metabolism in the body, and its excretion — and efficacy as measured by forced expiratory volume in one second (FEV1). FEV1 is a standard measure of lung function, capturing how much air can be exhaled in one second after a deep breath.

The results, announced by Verona, showed that for doses of 300 mcg and above, ensifentrine led to significant improvements in peak FEV1, ranging from 47 milliliters (mL) to 391 mL when corrected for placebo.

Improvements were seen over four hours, during which average FEV1 scores ranged between 69 and 345 mL; and from 48 mL to 222 mL over 12 hours.

Ensifentrine in a pMDI formulation was well-tolerated at each dose, with a profile of adverse effects similar to that of placebo.

“The results from the single dose part of this pMDI study are very encouraging and essentially consistent with data from Phase 2 clinical trials with nebulized and DPI formulations of ensifentrine,” David Zaccardelli, president and CEO of Verona Pharma, said in a press release.

A previous Phase 2b trial testing nebulized ensifentrine showed the therapy effectively improved lung function and lessened COPD symptoms, including breathlessness. Use of nebulized ensifentrine, either alone or in combination with the bronchodilator Spiriva (tiotropium), was also seen to open COPD patients’ airways, improving their lung function, and reducing inflammation.

Data from a Phase 2 study testing a DPI formulation of ensifentrine also showed that the therapy was safe and significantly improved lung function in people with moderate-to-severe COPD.

“Across all three inhaled formulations, ensifentrine has demonstrated statistically significant and clinically meaningful lung function improvements and duration of action, supporting twice-daily dosing and a safety profile similar to placebo,” Zaccardelli said.

These positive part A trial results support the initiation of the study’s part B (a multiple-dose part), which will evaluate the pMDI formulation, given twice daily for seven days, in COPD patients.

No official date is set for opening part B, postponed due to safety concerns for patients and trial investigators during the pandemic.

“We will continue to monitor this evolving situation and will provide an updated timeline for the start of Part B at a later date,” the release stated.

But a planned meeting with the U.S. Food and Drug Administration, due to take place by June, is going ahead, Zaccardelli said, as are plans to launch Phase 3 trials for its nebulized formulation of ensifentrine later this year.

Verona is also investigating ensifentrine as a potential treatment for cystic fibrosis and asthma.