Two Phase 2 Trials Demonstrate RPL554 Has Potential to Enhance Bronchodilators’ Efficacy in COPD

Two Phase 2 Trials Demonstrate RPL554 Has Potential to Enhance Bronchodilators’ Efficacy in COPD

The addition of Verona Pharma’s investigational agent RPL554 to standard short- and long-acting bronchodilators offers greater clinical benefits to patients with chronic obstructive pulmonary disease (COPD).

Results of two Phase 2 clinical trials (NCT02542254 and NCT03028142) demonstrated that the RPL554 add-on could enhance the bronchodilation action of commonly used agents and potentially reduce hyperinflation (overinflated lungs, considered a cause of breathlessness in COPD).

The results were reported in the study The short term bronchodilator effects of the dual PDE3 and PDE4 inhibitor RPL554 in COPD” published in the European Respiratory Journal.

RPL554 is being developed for treatment of acute exacerbations in COPD patients whose disease is not adequately managed with standard care therapies. It works as both a bronchodilator (a substance that widens airways) and an anti-inflammatory agent by inhibiting the phosphodiesterase 3 and 4 (PDE3 and PDE4) enzymes linked to COPD development.

The first study enrolled 36 patients with COPD who were randomized to receive 6 mg nebulized RPL554 or a placebo in addition to salbutamol (sold under several brand names) or Atrovent (ipratropium).

The second study included 30 COPD patients who received either 1.5 or 6 mg of nebulized RPL554 or a placebo in addition to Spiriva (tiotropium), one of the most commonly used drugs to treat COPD.

In both studies, participants who were taking inhaled corticosteroids were allowed to continue the treatment during the study period.

The data revealed that addition of RPL554 to any of the common bronchodilator agents tested could effectively improve the patients’ lung function.

RPL554 combined with Atrovent or salbutamol lead to a mean increase on average FEV1 (forced expiratory volume in one second, measured over an 8-hour period; a measure of lung function) of 64 mL and 112 mL compared to each of the standard agents alone.

A similar positive effect was reported three days after treatment with RPL554 plus Spiriva, in which patients treated with 6 mg RPL554 had an average FEV1 (measured over a 12-hour period) of 65 mL compared to Spiriva alone.

Assessment of different measures of overall lung function, including functional residual capacity, residual volume, total lung capacity, and airway conductance, showed significant improvements upon RPL554 combo treatment compared to standard therapies alone.

“The statistically significant results from the two Phase 2 trials detailed in this important paper continue to highlight the potential and differentiated profile of RPL554 as an add-on therapy to improve lung function and reduce symptom severity in COPD patients whose disease is not being adequately managed by the current standard of care,” Jan-Anders Karlsson, PhD, CEO of Verona Pharma, said in a press release.

In addition to the beneficial effects of add-on RPL554, combo treatments were also shown to promote faster effects than standard care agents alone.

The median time of onset of action, determined as positive changes of 10% or more, for RPL554 plus salbutamol or Atrovent was about 5 and 1.3 times faster than these medicines alone, taking just 3.6 and 4.8 minutes to act. For RPL554 combined with Spiriva, the median time of onset of action on day 1 was 4.6 minutes compared to 37.6 minutes of Spiriva alone.

“[These results] not only profile the significant effect of RPL554 on improving lung function in COPD patients when used alone or in combination with commonly used bronchodilators, but also its rapid onset of action, especially when used in combination,” said Dave Singh, MD, professor at University of Manchester and principal investigator of the studies.

Verona Pharma has launched a Phase 2 study to evaluate RPL554’s potential to improve the outcome of patients with COPD being treated with Stiolto Respimat (tiotropium bromide/olodaterol) and inhaled corticosteroid.

Data from this Phase 2 comprehensive clinical program will support the planning and implementation of a Phase 3 developmental program for this investigational agent for COPD.

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