Nebulized ensifentrine (RPL554) — which works both to widen the airways and as an anti-inflammatory — showed a significant early effect on breathlessness in people with chronic obstructive pulmonary disease (COPD), according to the therapy’s developer, Verona Pharma.
Apart from easing breathlessness, in four weeks of treatment ensifentrine also showed a significant positive effect on cough and chest symptoms, and induced improvements in health-related quality of life.
These results were reported in “Symptom Improvement Following Treatment with the Inhaled Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine in Patients with Moderate to Severe COPD – A Detailed Analysis,” a study published in the International Journal of Chronic Obstructive Pulmonary Disease.
Although effective therapies are available for COPD, daily symptoms, exacerbations (a flare-up of severe symptoms), and lung function deterioration are still experienced by many people with the disease.
Ensifentrine is an inhaled, first-in-class dual inhibitor of phosphodiesterase 3 (PDE3) and 4 (PDE4), two molecules involved in the contraction of airway muscles and in inflammation — two of the main clinical features of COPD.
The combined inhibition of PDE3 and PDE4 allows ensifentrine to have both bronchodilator (airway-widening) and anti-inflammatory properties, with previously demonstrated efficacy in patients with COPD.
Verona has tested the safety and efficacy of a range of ensifentrine doses in a Phase 2b clinical trial (NCT03443414) involving more than 400 patients. Participants were randomly assigned to receive one of four doses of ensifentrine — 0.75 mg, 1.5 mg, 3 mg, or 6 mg — or a placebo, twice daily over four weeks.
Previous data from the trial showed that patients receiving ensifentrine had significantly improved lung function at all doses tested.
Now, the researchers analyzed other trial endpoints, or goals, to better characterize the effects of ensifentrine on COPD symptoms.
Three specific tools were used to assess respiratory symptoms: the Evaluating Respiratory Symptoms (E-RS:COPD) questionnaire, the Transition Dyspnea Index (TDI), and St. George’s Respiratory Questionnaire – COPD Specific (SGRQ-C).
The results showed clinically relevant and progressive improvements in respiratory symptoms with all ensifentrine doses in E-RS:COPD, especially in the subscale related to symptoms of breathlessness. Ensifentrine also improved scores on the cough/sputum and chest symptoms subscales.
A similar result was found with the TDI scores, as all ensifentrine doses were superior to the placebo at improving respiratory symptoms.
In the SGRQ-C total score at week four, there also were improvements with all four ensifentrine doses, compared with placebo, although these differences were not statistically significant. A significant result was seen, however, with the 6 mg dose in the SGRQ-C symptoms domain, compared with the placebo.
Overall, “ensifentrine demonstrated a notable early and meaningful effect on dyspnea [breathlessness], with this effect observed across two different assessment tools,” the researchers wrote.
These benefits are of particular interest since breathlessness has a substantial impact on overall health-related quality of life in COPD and is one of the main reasons patients pursue medical care.
“The fast and meaningful effect of ensifentrine on COPD symptoms, particularly breathlessness, is very encouraging over this relatively short 4-week study,” Henrik Watz, MD, of the Pulmonary Research Institute at Lung Clinic Grosshansdorf and the study’s lead author, said in a press release.
“Ensifentrine’s anti-inflammatory activity may be responsible for this impact on symptoms, which adds to its potential as a novel COPD treatment,” Watz added.
The data supports the dual mechanism of action of ensifentrine — as both a bronchodilator and an anti-inflammatory agent — the researchers said.
“The rapid bronchodilator effect of ensifentrine could be translating into an early patient-perceived improvement in breathlessness, whereas the effect of ensifentrine on cough/sputum and chest symptoms may due (at least in part) to a more gradual anti-inflammatory effect,” they wrote.
The team emphasized, however, that future studies are needed to address a more distinguishable impact of different symptoms — such as breathlessness, cough, and sputum — on individual patients’ lives, thus allowing detailed cross-comparisons on specific symptom improvements.
Of note, positive results in lung function also were recently reported in a Phase 2b study (NCT03937479) assessing a combination therapy of ensifentrine with another bronchodilator, tiotropium (brand name Spiriva Respimat), in people with COPD.