FDA Pulmonary-Allergy Drugs Advisory Committee votes against approval of Nucala as add-on therapy for patients with eosinophilic COPD
The debate over the existence of an eosinophilic Chronic Obstructive Pulmonary Disease (COPD) population continued in the FDA Pulmonary-Allergy Drugs Advisory Committee (PADAC) meeting on July 25, 2018, as committee members were not convinced of the efficacy Nucala has in COPD.
GlaxoSmithKline’s Nucala (mepolizumab) is a monoclonal antibody that targets eosinophils by binding to IL-5 and preventing it from accessing the IL-5 receptor, which decreases the blood eosinophil count. Nucala was approved as the first biologic for asthma in over a decade in the United States in November 2015 (and in December 2015 in Europe), indicated for the treatment of severe asthma in patients with an eosinophilic phenotype in combination with other medicines used to treat asthma. Clinical trials in asthma focused on patients with blood eosinophils of greater than or equal to 150 cells/mcL and demonstrated significantly fewer exacerbations in patients treated with Nucala compared with placebo.
The trials discussed at the July 25th meeting were two Phase 3 trials evaluating safety and efficacy of Nucala: MEA117106 (study 106) and MEA117113 (study 113)1. Both were multinational, randomized, double-blind, placebo-controlled, 52-week trials including COPD patients who were receiving triple therapy with inhaled corticosteroids, a long-acting beta agonist, and a long-acting muscarinic antagonist. The primary efficacy end point in both studies was the rate of moderate to severe exacerbation of COPD at 52 weeks. Study 106 achieved the primary end point (P = 0.04 in patients in the high-eosinophil stratum), but study 113 did not (P = 0.07 with 100 mg dose, P = 0.14 with 300 mg dose).
It was the opinion of several PADAC members in the 16 to 3 vote against Nucala’s approval for COPD that GSK relied too heavily on the asthma clinical trials in their case for approval in COPD, particularly in establishing the appropriate dose selection for Nucala’s COPD indication, despite earlier conversations where the FDA requested COPD-specific dose-ranging data. Specific concerns were raised including questions surrounding the precision of the eosinophil cut-off value and timing of testing: if a patient tests over the 150 cells/mcL reference value and thus qualifies for Nucala treatment, and tests within the normal range the following month, does her treatment with Nucala stop? These details, PADAC members said, were lacking in the July 25th meeting and cause for their vote against approval of GSK’s drug.
In fact, GSK’s reliance on the Nucala asthma studies was problematic throughout the meeting; voters against Nucala’s approval in COPD suggested flaws in the COPD Phase 3 trials ̶ such as the lack of female participants ̶ and proposed the link between patients’ eosinophil count and Nucala’s efficacy in COPD patients may be nonexistent. Nucala’s COPD trials excluded participants who had a current asthma diagnosis but did not exclude those with asthma history. The distinction here may be important; pulmonologists interviewed by DRG consistently mention COPD patients with a history of asthma (or an asthma overlap), including those with prior diagnosis or childhood diagnosis, when discussing possible candidates for Nucala treatment. The pathophysiological differences between those COPD patients who have a history with asthma and those who do not are unknown; as such, concerns about whether the significance found in study 106 can be attributed to patients with asthma history go unanswered.
Those who voted in favor of Nucala’s approval in COPD argue the eosinophilic COPD population is apparent and that an unmet need exists for patients who meet the eosinophilic qualifications and are symptomatic despite maximal treatment. Physicians interviewed by DRG have reported use of high eosinophil count in COPD patients as a candidacy indicator for treatment with inhaled corticosteroids, suggesting the marker exists and can be useful in COPD. One PADAC voter in favor of Nucala for COPD suggested approval and use of the drug will help to satisfy the unanswered questions about its efficacy in COPD. Nonetheless, the indiscretion between asthma and COPD continues, and it is up to the FDA to decide what to make of the potential COPD-asthma overlap before making their final decision on Nucala in COPD by early September.
- https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM614138.pdf (Accessed July 31, 2018)