A post-hoc analysis showed that nebulized ensifentrine (RPL544) is highly effective for relieving respiratory symptoms in chronic obstructive pulmonary disease (COPD) patients with either reversible or non-reversible airway obstruction, although the effect is greater for those with reversible disease, according to Verona Pharma, ensifentrine’s developer.
Over a treatment period of four weeks, ensifentrine’s beneficial effects increased and appeared to result from the agent’s anti-inflammatory and bronchodilation activities, the study shows.
The results of the Phase 2b study were recently presented in a poster titled “RPL554 (Dual PDE3/4 Enzyme Inhibitor): Baseline Airway Reversibility Impacts Immediate Bronchodilation, in Contrast to Progressive Symptom Improvement” at the American Thoracic Society (ATS) 2019 International Conference in Dallas.
Ensifentrine is an inhaled inhibitor of phosphodiesterase 3 (PDE3) and 4 (PDE4), two proteins involved in smooth muscle contraction and immune cell-derived inflammation, respectively. Consistent with these effects, ensifentrine has demonstrated to have bronchodilating, bronchoprotective, and anti-inflammatory properties.
Verona Pharma is developing a nebulized formulation of the therapy for maintenance treatment of COPD, as well as for the treatment of cystic fibrosis and asthma. The treatment is also being developed as an add-on therapy to be used with other standard COPD treatments. Other formulations, namely a dry powder inhaled formulation (DPI) and metered dose inhaler (MDI) are also under development.
The poster presented at the ATS conference refers to data from the Phase 2b study (NCT03443414) assessing ensifentrine’s safety and tolerability. In the trial, 403 COPD patients (mean age 63.2 years) were randomly assigned to one of four doses of ensifentrine (0.75 mg, 1.5 mg, 3 mg, or 6 mg) or placebo, twice daily over four weeks.
Previous data showed that a four-week treatment with ensifentrine was sufficient to improve lung function and reduced respiratory symptoms in COPD patients, as measured by the Evaluating Respiratory Symptoms (E-RS) scale, recorded in patient diaries.
The results presented at ATS are an expanded analysis of the trial data, in which patients were divided according to whether their airway obstruction at the study’s start responded to, and could significantly reverse, upon treatment with albuterol — a short-acting bronchodilator also known as salbutamol.
Results showed that of the 403 patients enrolled, 133 (33%) had reversible lung function; the remaining 270 (67%) did not.
At week four, the change in peak forced expiratory volume during one second (FEV1; a measure of lung function) between ensifentrine and placebo groups was higher for those with reversible function — mean 216 to 293 mL — compared with the non-reversible group — mean 85 to 128 mL.
In contrast, a similar relief in symptoms, as judged by ER-S, was reported by ensifentrine-treated patients, independent of their baseline reversibility.
In both groups, peak FEV1 was consistent from the first week onward, with greater improvements over time until the end of the treatment at week four.
“The effects of RPL554 on lung function differed according to baseline reversibility, whereas a similar symptom improvement was observed in both groups, with the effect on symptoms improving over time,” researchers said.
“These encouraging data suggest that ensifentrine’s dual mode of action combining anti-inflammatory and bronchodilator effects will lead to additional symptom benefits in COPD patients,” Dave Singh, MD, professor at University of Manchester, U.K., and the presenter of the results at the ATS conference, said in a press release.
“Importantly, ensifentrine was highly effective in improving symptoms independently of the magnitude of the bronchodilator response, suggesting that the activity of the PDE3/4 inhibitor is different to that of available bronchodilators when used alone or in combination. The anti-inflammatory activity may be responsible for this effect as it cannot be explained by bronchodilation alone,” Singh said.
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