Neil Canavan

September 10, 2013

BARCELONA, Spain — A once-daily fixed-dose combination of 2 bronchodilators improves lung function and reduces exacerbations in patients with severe chronic obstructive pulmonary disease (COPD), results of the much-anticipated SPARK trial show.

The results, presented to a packed room here at the European Respiratory Society 2013 Annual Congress, show a 10% overall reduction in exacerbations with the fixed-dose combination, compared with monotherapy.

The combination, known as QVA149 (Novartis), contains the long-acting beta2 agonist indacaterol 110 µg and the long-acting muscarinic antagonist glycopyrronium 50 µg.

Long-acting beta2 agonists and muscarinic antagonists have already "demonstrated efficacy in preventing exacerbations of COPD," said lead investigator Jadwiga Wedzicha, MD, from the University College London Medical School in the United Kingdom. However, patients with severe COPD "require intensified therapy to reduce the risk of exacerbations," he explained. We felt that these people could "benefit from additional bronchodilation."

Investigators compared QVA149 with 2 long-acting muscarinic antagonist monotherapies — glycopyrronium and tiotropium. Over the 64-week study period, they assessed rates of COPD exacerbation, lung function, overall health status, and safety in 2224 patients with severe to very severe chronic COPD.

I think a fixed-dose combination...will ultimately prove to be a foundation therapy.

The reduction in mild exacerbations was 15% with the combination, compared with either of the monotherapies (P = .0072). For moderate to severe exacerbations, the reduction was 12%, although it was nonsignificant (P = .038).

Results for forced expiratory volume in 1 second were significantly better with the combination than with either monotherapy and were consistent over the study period (P = .001).

Scores on the St. George's Respiratory Questionnaire were also significantly better with the combination.

"The difference is around 3 units at all time points," Dr. Wedzicha reported. "You will only see bigger differences if you have a placebo arm, and in SPARK, with GOLD stage 3 and 4 patients, you can't ethically do that."

Adverse events, including serious events, were similar in all treatment groups, and were considered manageable.

It is expected that results from the SPARK study will improve the chances of near-term regulatory approval for the QVA149 combination.

Unmet Need

"This does address an unmet need," said Christopher Cooper, MD, from the University of California at Los Angeles. "I think a fixed-dose combination is the direction we're heading, and will ultimately prove to be a foundation therapy for people with a wide range of COPD severity, including moderate disease, although the SPARK study selected only patients with severe disease."

"There are a number of advantages to having a fixed dose," Dr. Cooper noted. "First, the combination of the 2 drugs is better than the individual components alone. It's probably not a synergistic effect, but certainly it's an additive effect. It's advantageous for COPD patients to get the benefit of both classes of medication. Second, it's likely that adherence will be improved if patients feel that symptomatic improvement is better with the combination."

"Obviously, the doses in this combination were carefully selected from dose-ranging studies and deemed to be suitable for most COPD patients," Dr. Cooper noted. "Given the known side-effect profile of these classes of drugs, I think that the fixed-dose combination will be well tolerated."

That said, results from clinical trials do not always illustrate what will happen in the community. One audience member noted that, in his experience, dry mouth is a common adverse effect of these agents — an effect not reported in the study findings.

"It is often the case that we see that," said Dr. Cooper. He pointed out that in the context of a clinical trial, when patients are given the opportunity or even encouraged to report adverse events, many simply choose not to do so. "It's something you have to keep in mind with any new drug."

Dr. Wedzicha reports financial relationships with Novartis, GSK, Boehringer, Pfizer, Almirall, Takeda, Bayer, Chiesi, Vifor Pharma, and Johnson & Johnson. Dr. Cooper has disclosed no relevant financial relationships.

European Respiratory Society (ERS) 2013 Annual Congress: Abstract 181. Presented September 8, 2013.


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