NEJM editorial slams design of GSK’s pivotal trial of 3-in-1 COPD drug Trelegy

GlaxoSmithKline has so much riding on the success of its new 3-in-1 COPD drug, Trelegy Ellipta, that last month the company rejiggered its sales and marketing operations so it could pour more resources into making the product a success. But that marketing challenge may get a lot harder, thanks to a blistering new editorial in the prestigious New England Journal of Medicine.

The editorial accompanies the publication of data from GSK’s IMPACT trial, which compared Trelegy to Glaxo's own dual-therapy drugs, Breo and Anoro. The company reported that patients taking Trelegy saw a 34% reduction in hospitalizations vs. those taking Anoro—a statistically significant result.

The 13% reduction in hospitalizations over patients taking Breo was not significant, however, the company said. But as GSK pointed out, the trial suggested Trelegy outperformed both dual therapies in reducing the annual rate of moderate or severe exacerbations of COPD.

But the trial itself was misleading, the editorial contends. Nearly 70% of patients enrolled in the trial were taking an inhaled glucocorticoid along with their dual therapy. Trelegy includes a glucocorticoid, but patients who were randomized to be in the dual-therapy arm of the trial were taken off that medicine for the purposes of the trial—a “design peculiarity” that could have caused their COPD to get worse during the first month.

In the subsequent 11 months, the editorial authors pointed out, the exacerbation of symptoms in the dual-therapy group was “practically identical” to that experienced by trial subjects taking Trelegy. The editorial was penned by Samy Suissa, Ph.D., director of the Centre for Clinical Epidemiology at McGill University, and Harvard professor and NEJM Editor-in-Chief Jeffrey M. Drazen, M.D.

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GSK’s trial design “probably resulted in falsely exaggerating the benefit of triple therapy,” Suissa and Drazen wrote. The patients selected for the trial “most of whom were already treated with inhaled glucocorticoids and some of whom had a history of asthma, were not the natural population in which to study” the question of Trelegy’s effectiveness, they added.

They went on to recommend that physicians adhere to guidelines released last year by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which suggest that triple therapy should be limited to patients who experience frequent exacerbations while on dual-drug regimens. GSK’s trial, they wrote, “falls short of providing the awaited robust evidence to better understand the potential for stepping up to single-inhaler triple therapy in clinical practice.”

“We disagree with the editorial critique of study design and patient population," a GSK spokesperson said in a statement emailed to FiercePharma. "The results clearly demonstrate the range of clinically relevant patient benefits of Trelegy Ellipta vs. Anoro and Breo. These include reducing moderate/severe exacerbations and improving lung function and quality of life, as well reducing [hospitalizations] and on-treatment all-cause mortality compared to Anoro."

He added that the the study was designed with the input of the FDA and that it included patients that GOLD recommended as good candidates for triple therapy.

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The NEJM editorial will no doubt toss a wrinkle into what is already an ultra-competitive COPD market. GSK's next-gen drugs have been fighting for market share against a host of rivals, not the least of which is Novartis, which has been touting the advantages of its dual therapy, Ultibro, against GSK’s Anora. Boehringer Ingelheim’s Stiolto Respimat and AstraZeneca’s Bevespi Aerosphere are also contenders in the dual-therapy space. And AZ has been out trumpeting positive data on its newest entry, Duaklir.

The Trelegy marketing task will be helmed by AZ veteran Luke Miels, who was pegged by GSK chief Emma Walmsley in January to head up the pharma division. Miels has been axing 30 noncore R&D projects and looking to shave 20% from costs so the company can focus on a few prized therapeutic classes, including respiratory.

With so many choices in COPD dual therapies—and now two high-profile experts questioning the benefits of triple treatment—GSK investors will no doubt be watching closely to see if the company’s new talent can come up with an effective sales strategy for Trelegy.