First-in-Class COPD Drug Eases Symptoms

Maureen Salamon

September 17, 2018

PARIS — A first-in-class dual PDE3/4 inhibitor significantly improves bronchodilation and symptoms in patients with chronic obstructive pulmonary disease (COPD), results from a phase 2 multicenter study show.

The inhaled agent prompted sustained bronchodilation over 4 weeks and reduced the use of rescue salbutamol, said Dave Singh, MD, from the University of Manchester in the United Kingdom.

"Many patients on bronchodilators still suffer with a significant burden of symptoms, exacerbations and, for some, accelerated lung function decline," told Medscape Medical News.

For patients with COPD, inhaled steroids are currently used to address inflammation and bronchodilators are used to target symptoms. But "this molecule addresses both features," he pointed out.

PDE3 inhibitors alleviate smooth muscle constriction, whereas PDE4 inhibitors have anti-inflammatory effects, Singh explained here at the European Respiratory Society (ERS) International Congress 2018.

PDE3/4 Inhibitors

In the dose-ranging study, Singh and his colleagues randomized 403 patients with moderate to severe COPD to one of four doses of RPL554 administered twice-daily: 0.75 mg, 1.5 mg, 3 mg, or 6 mg.

Spirometry was performed before the administration of RPL554 and up to 12 hours after administration on day 1 and at week 4, and participants recorded daily symptoms in an electronic diary.

In general, forced expiratory volume in 1 second (FEV₁) was used to indicate bronchodilator response, and trough FEV₁ was used as an indicator of anti-inflammatory response. Average age of the study participants was 63 years.

During the 4-week study, all participants discontinued bronchodilator therapy but 39% continued to use inhaled steroids.

All doses were associated with bronchodilation that continued throughout the first 12 hours, but optimal sustained effects were achieved with the 3 mg dose.

At all doses, the improvement in symptoms was significant and progressive and, except for the 0.75 mg group, salbutamol use decreased in all groups.

Previous studies have shown that PDE3/4 inhibition produces anti-inflammatory effects in healthy volunteers, but this has not yet been demonstrated in COPD patients, Singh pointed out.

"What remains to be seen is how much it reduces exacerbations," he said.

The drug was well tolerated and produced no significant adverse events. Effects typically associated with oral PDE3 or PDE4 agents — such as cardiac issues, nausea, and diarrhea — were minor.

The drug's safety profile, with its "limited systemic exposure," is encouraging, Singh said.

"When you have bronchodilators, you do get some increase in heart rate," he noted. When you develop a drug, you always have to watch for cardiac effects, "and it's good we're not observing any of these issues."

"In the future, I think this will be used on top of other medications," he added. Long-term studies will be needed to determine the optimum mix of therapies.

"Huge Potential"

The presentation of the findings from this study was well-received by specialists in the audience, who expressed a need for new COPD treatment options.

"I think there's huge potential," said Ian Adcock, PhD, from Imperial College London.

"It will be really interesting if it proves effective on inflammation. It has to go to a bigger, longer-term study, but I think it's really exciting," he told Medscape Medical News.

The data on the performance of this drug "look very promising," said Loes Kistemaker, PhD, PharmD, from the University of Groningen in the Netherlands.

It can be difficult to identify COPD compounds that address both symptoms and bronchodilation, she told Medscape Medical News.

Singh reports financial relationships with Apellis, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Skypharma, Teva, Theravance, and Verona. Adcock and Kistemaker have disclosed no relevant financial relationships.

European Respiratory Society (ERS) International Congress 2018: Abstract OA1940. Presented September 17, 2018.

Follow Medscape on Twitter @Medscape and Maureen Salamon @maureensalamon

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