Verona Pharma shares plunge on latest drug trial results

Verona Pharma shares were well into the red on Monday, after the clinical-stage biopharmaceutical company announced top-line data from its latest trial of RPL554, failing to reach its primary endpoint.

The AIM-traded firm said the three-day Phase 2 clinical pharmacology trial, which evaluated the effect of two different doses - 1.5 mg and 6.0 mg, twice daily - of nebulised ensifentrine (RPL554) when used on top of an inhaled long-acting muscarinic antagonist/long-acting beta2 agonist - tiotropium/olodaterol (‘Stiolto Respimat’).

It said LAMA/LABA therapies were commonly used in the maintenance treatment of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).

Patients already receiving inhaled corticosteroid (ICS) therapy were allowed to continue to receive a stable dose of ICS throughout the study, thus providing additional data on what the company described as ‘triple therapy’ use.

It described ensifentrine as an investigational first-in-class, inhaled, dual inhibitor of the enzymes phosphodiesterase 3 and 4, designed to have bronchodilator and anti-inflammatory properties, which was currently in development for the maintenance treatment of COPD, cystic fibrosis and asthma.

The primary endpoint of peak forced expiratory volume in one second (FEV1) after morning dose on day three of treatment was not met with statistical significance, Verona reported, although it did note that the ensifentrine 1.5 mg morning dose improved peak FEV1 by 46 mL, compared to placebo.

It said improvement in FEV1, compared to placebo, with the 1.5 mg dose was maintained throughout the 24-hour period as measured on day three.

Importantly, peak FEV1 after evening dose on day three showed “statistically significant” improvement compared to placebo with both doses, with ensifentrine 1.5 mg showing a 130 mL improvement and ensifentrine 6.0 mg showing an 81 mL improvement.

Verona said ensifentrine at a 1.5 mg dose produced consistent improvements compared to placebo, in average FEV1 over 12 hours following the morning dose on days one to three, with an improvement of approximately 50 mL on day three.

Those improvements were not shown to be statistically significant when adjusted for multiple doses.

Reductions in residual volume compared to placebo, as measured by plethysmography, were observed at all time points on day three with the 1.5 mg dose.

Statistically significant reductions in mean residual volume were observed 15 minutes following the evening dose on day three, with ensifentrine 1.5 mg showing a reduction of 259 mL and ensifentrine 6.0 mg showing a reduction of 142 mL.

Ensifentrine 6.0 mg did not result in greater improvement in lung function as compared with the ensifentrine 1.5 mg dose, the board reported.

It did say that ensifentrine was well tolerated at both doses, with an adverse event profile consistent with that observed in prior studies.

“Achieving additional bronchodilator response of this magnitude in COPD patients that have previously been considered to be maximally bronchodilated on background dual or triple therapy in a short, three-day study is clinically meaningful and unprecedented,” said Dave Singh, professor of clinical pharmacology and respiratory medicine at the Medicines Evaluation Unit of the University of Manchester.

“The statistically significant reduction observed in residual volume for the ensifentrine 1.5 mg dose at certain time points, which is closely related to dyspnea or breathlessness, highlights the potential for ensifentrine to provide symptomatic improvement for patients with this progressive and debilitating disease.

“I look forward to seeing data from longer-term studies evaluating the bronchodilator and anti-inflammatory activity of this unique mechanism of action.”

Verona Pharma chief executive officer Jan-Anders Karlsson said that, having demonstrated in previous studies the potential of ensifentrine to deliver benefits to patients on no or single bronchodilator therapy, the company believed that the short study continued to support its view that ensifentrine could also be of benefit to more severe COPD patients on dual and triple therapy, for whom there were few other treatment options.

“While we are disappointed that this exploratory Phase 2 study did not achieve statistical significance for its primary endpoint, these data give us clarity on the design, including dose and background therapy, for future long-term studies.

“We now have the opportunity to also include patients on dual and triple therapy, with the goal of further evaluating ensifentrine’s potential to produce sustained bronchodilation and anti-inflammatory effect in this large number of symptomatic COPD patients.”

In Phase 2 clinical trials completed to date, ensifentrine had been observed to result in bronchodilator effects when used alone or as an add-on treatment to other COPD bronchodilators, and had also shown anti-inflammatory effects in a standard challenge study with COPD-like inflammation in human subjects.

Verona Pharma said it was currently conducting a Phase 2 trial to evaluate a dry powder inhaler formulation of ensifentrine for the maintenance treatment of COPD.

The company said it also planned to evaluate ensifentrine in a metered-dose inhaler formulation as part of a comprehensive clinical programme, intended to fully demonstrate the clinical utility of ensifentrine in improving the standard of care for COPD.