Nebulized Ensifentrine Shows Promise as Add-on Therapy

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by Vanda Pinto, PhD |

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Verona Pharma has announced positive efficacy and safety results about using nebulized ensifentrine as an add-on therapy to tiotropium (Spiriva Respimat) for treating symptomatic chronic obstructive pulmonary disease (COPD).

Results from the Phase 2b clinical trial (NCT03937479) show that ensifentrine treatment, combined with maintenance tiotropium, results in significant improvements in lung function and quality of life in COPD patients who have impaired lung function and disease symptoms.

“These data in symptomatic COPD patients on maintenance bronchodilator therapy [tiotropium], combined with ensifentrine’s unique mode of action, support its potential as a novel COPD therapy. The improvements in patient quality of life and lung function when added to tiotropium highlight the potential of this novel mechanism of action,” Gary T. Ferguson, MD, said in a press release. Ferguson is director of the Pulmonary Research Institute of Southeast Michigan and principal investigator of the trial.

The findings of the study, “A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy,” were published in the International Journal of Chronic Obstructive Pulmonary Disease.

Ensifentrine is a dual inhibitor of phosphodiesterase 3 (PDE3) and 4 (PDE4) that acts both as a bronchodilator to widen the airways and as an anti-inflammatory agent. Tiotropium, marketed as Spiriva Respimat by Boehringer Ingelheim, is a long-acting anti-muscarinic (LAMA) bronchodilator commonly used as a maintenance treatment in COPD patients.

The Phase 2b clinical trial enrolled 416 people with moderate-to-severe COPD receiving tiotropium (two puffs, 2.5 micrograms once a day) and either placebo or nebulized ensifentrine — 0.375, 0.75, 1.5, or 3.0 milligrams (mg) — twice a day for four weeks.

The patient group analyzed had a mean age of 64.3 years (range between 45–80 years), a majority of the patients were white (90.1%), and 57.5% were women. A total of 373 (89.7%) participants completed the four-week study.

Previous top-line results from the trial already indicated that ensifentrine — when added as a nebulized suspension to tiotropium — could improve the patients’ lung function and quality of life significantly.

Researchers now are reporting the final results of that trial. They found that  after four weeks of treatment with ensifentrine and tiotropium COPD patients experienced improvements in their lung function. This was measured by the forced expiratory volume in one second, also known as FEV1, which  determines the total amount of air forcefully exhaled in one second.

The results were found to be dose-dependent, meaning that higher doses of ensifentrine led to greater forced expiratory volumes and improved lung function. A placebo-corrected difference in FEV1 of 77.5 mL was reported for people receiving the 0.375 mg dose, 91.2 mL for those on 0.75 mg, 107.2 mL for 1.5 mg, and 124.2 mL for the maximum dose of 3.0 mg.

“When nebulized ensifentrine was added on to tiotropium maintenance therapy, it produced dose-dependent, clinically important improvements in lung function over 4 weeks in COPD patients receiving tiotropium who demonstrated symptoms and lung function impairment,” the researchers wrote.

The data also showed statistically significant sustained improvements in lung function over 12 hours with the 3.0 mg ensifentrine dose (the higher dose tested), but not with other dose regimens.

The overall quality of life was measured with the COPD-specific St. George’s Respiratory Questionnaire (SGRQ-C). Patients receiving the highest doses (1.5 or 3 mg of ensifentrine) experienced significant improvements in their quality of life, compared to placebo — exceeding the “minimally clinically important difference of 4 units.”

“This represents an unprecedented improvement in quality of life over only 4 weeks of treatment in patients with COPD who continued to have impaired lung function and remain highly symptomatic despite maintenance use of tiotropium,” the researchers wrote.

Although participants also reported reduced severity in their symptoms, as determined by the Evaluating Respiratory Symptoms (E-RS) questionnaire, the results did not reach statistical significance. The researchers speculated the cause could be related to the relatively low numbers of patients per group (about 80) and the large variation of symptoms at baseline.

Regarding safety, ensifentrine was well-tolerated at all doses tested, and gastrointestinal and heart disorders were rare. The most reported treatment-emergent adverse event (side effect) was headaches, reported by six patients (1.8%) receiving ensifentrine, versus one patient (1.2%) in the placebo group. No serious drug-related adverse events were reported and there were no deaths during the study.

Overall, “the data on lung function, symptoms and quality of life improvement described herein, support the twice-daily dosing of ensifentrine in patients with moderate-to-severe COPD as a potential add-on to maintenance bronchodilators for symptomatic COPD patients,” the team concluded.

The researchers noted, however, that the trial “was a short-term study over a 4-week treatment period; thus, longer-term efficacy and safety needs to be established.”

Verona Pharma is currently conducting two Phase 3 trials, ENHANCE-1 (NCT04535986) and ENHANCE-2 (NCT04542057), to assess the safety and effectiveness of ensifentrine as a maintenance treatment for COPD.

ENHANCE-1 is recruiting COPD patients at multiple clinical sites in the U.S. More information on enrollment is available here. Recruitment for ENHANCE-2 also has started across the U.S. and Canada, and trial locations can be found here.