COPD: Combo Tx Promising for Rapid Bronchodilation

SAN DIEGO -- An investigational agent paired with tiotropium (Spiriva) therapy led to rapid additional bronchodilation in patients with moderate to severe chronic obstructive pulmonary disease (COPD), researchers said here.

In the dose-ranging study, the median time to onset, defined as a ≥10% improvement in forced expiratory volume in 1 second (FEV₁) occurred in less than 5 minutes with one of two doses of RPL554 plus tiotropium, compared with 38 minutes to achieve that goal with tiotropium alone (P<0.001), according to Dave Singh, MD, of the University of Manchester in England, and colleagues.

"RPL554 represents a potentially first-in-class compound that combines bronchodilator and anti-inflammatory effects in a single molecule and has now been demonstrated to have additional bronchodilation on top of both short and long-acting bronchodilators," Singh said at his poster presentation at the American Thoracic Society annual meeting.

RPL554 is an inhaled dual phosphodiesterase 3/4 inhibitor that has demonstrated bronchodilator, bronchoprotective, and anti-inflammatory effects in clinical studies, the researchers reported.

The early-phase study enrolled 30 individuals (17 men; 13 women; average age 62) with COPD who were studied in a three-way crossover fashion. The patients were eligible if they had a post-bronchodilator FEV₁ that was ≤40% and ≤80% of predicted, and a FEV₁ response to albuterol of <150 ml.

Each patients was treated with tiotropium once daily, and either 1.5 mg of RPL554 or 6 mg of RPL554 twice daily for 3 days in a randomized sequence. Treatment periods were separated by 7-21 days washout period. Singh reported that 26 of 30 patients completed the study.

Singh reported that the average FEV₁ increase in day 3 was greater with tiotropium and the study agent at 6 mg versus tiotropium plus placebo (331 ml versus 266 ml, P=0.0009).

With RPL554 1.5 mg ,the increase was 317 ml (P=0.09 compared with the higher dose).

Peak FEV₁ was greater for RPL554 1.5 mg compared with tiotropium plus placebo (P=0.002) and for RPL554 6 mg versus tiotropium plus placebo (P<0.0001). Singh said this demonstrates a clinically meaningful effect as well as a statistically significant change.

Morning trough FEV₁ was increased 54 ml more than tiotropium plus placebo with the low dose of RPL554 plus tiotropium, and was increased 116 mg with the higher dose (both P<0.001).

Plethysmography showed a significant reduction in residual volume and functional residual capacity with RPL554 plus tiotropium compared with tiotropium plus placebo, Singh reported.

"RPL554 was well tolerated without any gastrointestinal side effects," Singh added, noting that the side effect profile of RPL554 plus tiotropium was similar to the profile of tiotropium plus placebo.

Antonio Anzueta, MD, of the University of Texas Health Science Center in San Antonio, commented that "With these new medications, I really think we need to wait. With RPL554, we need to see if these effects are sustainable."

Anzueta told MedPage Today that RPL554 remains far from being ready for prime time. "We have seen many, many compounds that look interesting in early-stage studies, but then many of them do not go forward from there," he said." It is important that we wait for the next studies with this agent."

Singh noted that "This was a 3-day study, and we are now doing a 1-month dose ranging study in 400 patients."