PARIS -- A first-in-class dual inhibitor of phosphodiesterase 3 and 4 (PDE3/4) improved lung function and reduced symptom burden for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) in a dose-ranging phase IIb study presented here.
Four weeks of treatment with RPL554 resulted in peak improvements in forced expiratory volume in 1 second (FEV1), ranging from 75 mL to 100 mL depending on dose (P<0.001 versus placebo for all), reported David Singh, MD, of the University of Manchester in England, at the European Respiratory Society (ERS) congress.
RPL554 has been in development for more than 10 years, and its ancestry goes back even further, to the early 1980s, when a dual PDE3/4 inhibitor called was first synthesized.
"This is an interesting molecule," said Singh. "I occasionally get the chance to present novel molecules here at this meeting, and I think this is one of the few times I can say this keeps working -- we keep testing it in COPD and we keep seeing bronchodilation."
He noted that in current clinical practice, inflammation and airflow obstruction are addressed separately with inhaled steroids and bronchodilators, respectively. RPL554, on the other hand, is a bi-functional molecule with the capability of addressing both, Singh said.
While lung function stability was achieved early and remained consistent from weeks 1 through 4 of treatment, respiratory symptoms steadily improved as the course of treatment went on, achieving a minimum clinically important difference on the Evaluating Respiratory Symptoms (E-RS) tool by week 4 for all the RPL554 doses. Singh speculated that this could have been due to the anti-inflammatory effect of the PDE3/4 inhibitor "kicking in" after a couple of weeks.
Patient health status was also improved with the study drug. As measured by mean change in the 100-point St. George's Respiratory Questionnaire COPD score (where higher scores are worse), reductions of 2 to 4 points were seen across the different RPL554 doses compared with no change in the placebo group.
"For the first time, because we've gone for a longer duration, we're seeing an impact on symptoms," said Singh.
For trough FEV1, the average for the RPL554 groups showed close to no effect -- the highest being roughly 50 mL from baseline for the 3.0-mg dose, which overall appeared to be the dose that performed best. But the effect on trough FEV1 was seen more prominently among patients responsive to albuterol during the study's screening period (>100 mL at the lowest three RPL554 doses in these patients).
"In all likelihood if this gets through the later phases of clinical development, I think it will be an add-on treatment," said Singh, pointing to a potential role in combination with single, dual, and triple therapies.
"RPL554 appears to have two interesting benefits -- reducing inflammation and reversing bronchoconstriction," Matthew Drake, MD, of Oregon Health and Science University in Portland, told ֱ.
"Its nebulized delivery may also contribute to the lower reported GI side effects as compared to the currently available oral PDE inhibitor," added Drake, who was not involved in the study but was also presenting during the ERS session on novel drug targets in asthma and COPD.
A previous smaller and shorter study tested RPL554 in combination with tiotropium and demonstrated peak FEV1 improvements of 104 mL at the 1.5-mg dose and 127 mL at the 6.0-mg dose compared with tiotropium alone.
The current study randomized 403 moderate-to-severe COPD patients at 45 centers for 4 weeks of RPL554 treatment at doses of 0.75 mg, 1.5 mg, 3.0 mg, or 6.0 mg versus placebo. During the run-in phase, patients ceased use of long-acting bronchodilators but those on inhaled corticosteroids (39%) were allowed to stay on therapy.
The adverse event (AE) profile with RPL554 was similar to that of placebo. AEs of any type and severity occurred in 39.2% of those on placebo compared with 33.3%, 44.4%, 35.4%, and 36.3% of the increasing RPL554 doses, respectively.
Serious and severe AEs were infrequent and mostly similar across the study arms. AEs leading to death occurred in two patients, one in the 1.5-mg and 6.0-mg RPL554 groups each.
PDE3 inhibition carries concerns of cardiac toxicities, but Singh reported that these were not seen in the trial. And compared with the oral PDE4 inhibitor roflumilast (Daliresp) -- the use of which has been limited by AEs such as nausea and diarrhea -- RPL554 is inhaled, potentially reducing systemic exposure. "It was reassuring that we didn't see the typical PDE4 side effects," he said.
Drugmaker Verona Pharma is also . In addition to the nebulizer delivery, the firm is looking into a dry powder/metered dose inhaler formulation.
Disclosures
The study was funded by Verona Pharma.
Singh reported disclosed relationships with Verona Pharma as well as AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Johnson and Johnson, Mundipharma, Novartis, Pfizer, Teva, and others.
Blake reported no disclosures.
Primary Source
European Respiratory Society
Singh D, et al “RPL554, a first-in-class dual PDE3/4 inhibitor, causes significant bronchodilation and symptom relief; a phase 2b COPD study” ERS 2018; Abstract OA1940.