Navigating FDA's rules to get a fixed-dose combination therapy for chronic obstructive pulmonary disease approved required a large study and a specific population.
When GlaxoSmithKline designed the IMPACT trial for Trelegy Ellipta, it sought to fill gaps in the evidence: would adding an inhaled corticosteroid (ICS) benefit patients with chronic obstructive pulmonary disease (COPD) who were having exacerbations?
“There has been a long controversy in the use of inhaled corticosteroids in COPD,” said David Lipson, director of clinical drug discovery for GlaxoSmithKline, in an interview with The American Journal of Managed Care®.
“We know that inhaled steroids reduce risk of exacerbation. But they also increase risk of pneumonia. Globally, there’s been a question about the benefit-risk balance of using inhaled corticosteroids in COPD,” he said.
Lipson presented full results from IMPACT on Sunday, at the American Thoracic Society (ATS) 2018 International Conference, and on Monday an FDA official described how the trial’s design addressed specific requirements in the agency’s rule for fixed-dose combinations. This allowed Trelegy Ellipta to go from a narrow indication in September 2017 to a broader approval on April 24, 2018, based on results from IMPACT.
What’s more, in designing a large trial for a specific population—patients with a history of exacerbations—GlaxoSmithKline found that its drug produced a dramatic reduction in all-cause mortality, compared with the treatment many patients would be taking before they tried triple therapy.
Officials from the FDA Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) explained how the agency’s processes led to 2 landmark decisions in the past year involving combination therapy in asthma and COPD, during Monday’s update for attendees at the annual ATS meeting, taking place in San Diego, California.
Besides the September approval for Trelegy Ellipta, in December FDA removed the boxed warning from several therapies that combine an inhaled corticosteroid (ICS) and a long-acting beta2-adrenergic agonist (LABA). FDA’s Banu Kamiri-Shah, MD, discussed how the fixed-dose combination therapy rule works for COPD medications, and how the rule was interpreted in the approval process for triple therapy.
The session also covered upcoming label changes for cough syrup to keep medicines with opioids away from children, a new treatment for cystic fibrosis, and more choices for treating severe asthma.
The triple therapy from GlaxoSmithKline combines the inhaled glucocorticoid fluticasone furoate (FF) with umeclidinium (UMEC), a long-acting muscarinic antagonist (LAMA), and the LABA vilanterol (VI). Some COPD patients with severe symptoms were already using all 3 therapies with multiple inhalers, but this new therapy offered the chance to combine all 3 molecules in a single inhaler, used once a day.
IMPACT’s size and its direct comparison to the LAMA/LABA combination—taken with the same inhaler at the same time of day—revealed the benefit of adding the ICS, Lipson said during the interview. As Karimi-Shah later explained, that design, along with the data the study produced, allowed the FDA to favorably interpret the combination therapy rule for the triple therapy.
Lipson said IMPACT will continue to produce results as researchers glean more insights from the data. The results confirm the longstanding challenge that ICS increases the risk of pneumonia compared with LAMA/LABA. But Lipson noted in his presentation Sunday that raw numbers were quite small and more than offset by the exacerbations avoided. Some doctors are worried, but “there are others who look at the data and feel the benefit is favorable,” he said. “The controversy has existed for years,” he said. Until now, “there’s never been a good data set that answers that question with symptomatic COPD that answers that question.”
Meeting FDA Criteria for Combination Therapy
At the FDA session, Karimi-Shah explained the approval process for fixed-dose combination therapy calls for a factorial design, which would measure each monotherapy against the other monotherapies in the combination. Ideally, these monotherapies are already approved for these same indications, and the approval is sought for an enhanced benefit. The benefit being studied in COPD is key, Karimi-Shah said, and each component’s mechanism is considered.
“The agency has considered the anti-inflammatory effects of inhaled corticosteroids in combinations with LABAs on exacerbation benefit in COPD in determining the study designs for exacerbation claims, for ICS/LABA combo products, as well as the triple combination,” she said.
Recently, indirect evidence has played a role as well, Karimi-Shah said.
Today, there are 3 ICS/LABA products approved for COPD; the lung function benefit was approved first, and the exacerbation benefit was approved later with additional studies, Karimi-Shah said. When the lung function benefits were approved, a full factorial design was required, but a partial design was required for the exacerbation benefit.
Turning to the LAMA/LABA combinations, Karimi-Shah, said at present there are none yet with an exacerbation indication, although there is one LAMA ingredient (tiotropium bromide) approved for this in COPD. Thus, she said, there is a “plausible scenario” from showing this benefit in LAMA/LABAs, but to show the efficacy of the LABA ingredient would mean that the LAMA efficacy had been established.
This brought Karimi-Shah to triple therapy: as she explained, a full combination factorial program would have required comparing the contributions of single ingredients FF, UMEC and VI. “All of these comparisons were not required,” she said. The initial approval was based on an open administration study, of the LAMA ingredient and Breo Ellipta, and evaluated air flow obstruction. The September approval was for patients with a history of exacerbations, who were taking the FF/VI combination or all 3 therapies through multiple inhalers.
What IMPACT Revealed
“The story moves forward,” Karimi-Shah said. “Notably, the development program was a partial factorial program, with a clinical program designed to demonstrate the contribution of the ICS.”
The 52-week trial showed a 25% reduction in exacerbations with the triple therapy compared with the LAMA/LABA, along with improved air flow. Lipson notes that the data also show improved quality of life scores, as well as reduced hospitalization and a significant mortality benefit.
With these results, FDA approved a broader indication statement. The expanded indication allows physicians to prescribe the therapy to COPD patients with airflow limitation or who have experienced a worsening of respiratory symptoms. “The indication patient includes an important characteristic—that is, patients with a history of exacerbations—to help guide healthcare providers,” Karimi-Shah said.
The Mortality Benefit
IMPACT included a prespecified endpoint not always seen in COPD and asthma therapy trials: all-cause mortality. Patients using the triple therapy had a 42.1% risk reduction in all-cause mortality compared with the LAMA/LABA combination, yet as one commenter in Lipson’s presentation noted, this was not mentioned in the New England Journal of Medicine editorial. It’s a far cry from what happened in 2015, when word that a diabetes drug had unexpectedly reduced deaths by 38% was front page news, and drug makers now ask the FDA to include such information on the label.
Lipson explained that many COPD patients have underlying comorbid cardiovascular problems, and that a key to this result may be that ICS reduces exacerbations over time, keeping patients out of the hospital. “if you reduce hospitalization, we know there is a lot of morbidity and mortality associated with hospitalization. You are going to potentially have an impact on mortality,” he said.
This finding may stem from the study population: all patients had a history of exacerbations. By designing a study to meet requirements of the combination rule, IMPACT uncovered a benefit that appears to set Trelegy Ellipta apart. “We want to better understand the mortality signal,” he said.