Verona Pharma’s treatment candidate for chronic obstructive pulmonary disease (COPD) RPL554 works to open the airways of the lungs, aiding bronchodilation, when used with Spiriva (tiotropium), and its newer inhaled formulation is safe and appropriate for patient use, clinical trial data being presented at ATS 2018 report.
RPL554 is designed to block the activity of two enzymes, PDE3 and PDE4. The compound has both anti-inflammatory and bronchodilator properties, and offers patients a possible alternative for long-term maintenance treatment.
The first study, “RPL554, A First-In-Class Dual PDE3/4 Inhibitor, Causes Rapid Additional Bronchodilation When Dosed with Tiotropium in COPD Patients,” will be presented as part of the “Clinical Trials and Studies in COPD” session on May 21.
Its investigators assessed the dose-ranging effects of RPL554 in combination with Spiriva, a bronchodilator, in patients with moderate to severe COPD.
In a previous Phase 2a trial (NCT03028142/2016-004450-15), RPL554 treatment, either alone or in combination with Spiriva, showed ability to open COPD patients’ airways, improve their lung function, and reduce inflammation. Spiriva is an approved long-term and maintenance COPD therapy from Boehringer Ingelheim.
For this data, scientists conducted a randomized, double-blind study involving 30 COPD patients (mean age, 62). Each received Spiriva once daily and either RPL554 (at 1.5 or 6 mg) or placebo twice daily for three days in randomized sequences. Treatment periods were separated by washout periods of seven to 21 days.
Twenty-six patients completed the study. Results revealed that combining RPL554 with Spiriva resulted in greater bronchodilation. Compared to Spiriva alone, combined treatment with 1.5 mg of RPL554 led to an increase in peak forced expiratory volume in one second (FEV1) of 104 ml, while the 6 mg dose improved FEV1 by 127 ml. (A measure of lung function, FEV1 is the amount of air a personal can forcibly exhale in one second.)
Measures of changes in lung volume — assessing lung hyperinflation, a common occurrence in COPD — also showed durable benefits in the combination of Spiriva plus RPL554.
RPL554 was seen to be well-tolerated and safe.
“RPL554 caused rapid additional bronchodilation when dosed on top of tiotropium [Spiriva] in COPD patients,” the researchers wrote, adding that the drug “represents a potentially first in class compound that combines bronchodilator and anti-inflammatory effects in a single molecule.”
Data from a second study, “Low Oral Bioavailability of RPL554, a First-in-Class Dual PDE3/4 Inhibitor, Demonstrates that Its Nebulized, Inhaled Formulation Is Appropriate for Delivering Optimal Pulmonary Dose” will be presented at the “COPD: Maintenance Therapy” session, also on May 21 .
As an inhaled formulation, some of RPL554 “is deposited in the mouth and then swallowed by the subject,” the researchers wrote. To determine the proportion of medication that enters the bloodstream via the gastrointestinal (GI) tract, the team tested the drug in 12 healthy volunteers.
Each participant (mean age, 25.4) was given two 6 mg doses of RPL554 via nebulizer, one with and one without a charcoal block. Each treatment was separated by three- to 14-day washout. Actidose Aqua, an activated charcoal used to avoid overdosing, was given pre-dose, as well as 12 minutes and one, two and four hours after a dose.
Results found 10.4% of an inhaled dose of RPL554 was entering the bloodstream via the GI tract, suggesting a limited contribution to its effectiveness.
“In this study, the low oral bioavailability and plasma concentrations of RPL554 seen as a result of the swallowed medication suggests only a limited contribution to the systemic effects of RPL554 after nebulized administration,” the researchers wrote.
“These results indicate that the nebulized, inhaled formulation of RPL554 is an appropriate form of administration to human subjects,” they added.
The treatment candidate was again found to be well-tolerated and safe.
Researchers also noted that RPL554’s plasma half-life (11.9 hours) — the time required to reduce by half a product’s concentration — supported a twice-daily dosing regimen for COPD patients.
RPL554 is also being studied as a possible cystic fibrosis treatment.