Nov 032017

The injectible monoclonal antibody mepolizumab (Nucala, GSK) is FDA-approved for severe asthma with blood eosinophilia, uncontrolled with standard controller inhaler treatments. Two randomized placebo-controlled trials keep alive for GSK the possibility of an FDA indication to reduce exacerbations in people with chronic obstructive pulmonary disease (COPD) with high blood eosinophil counts, expanding the drug's market.

The ~1,500 patients enrolled in the two trials had severe COPD (FEV1 ~45% predicted) with two to three exacerbations in the previous 12 months. Patients were already receiving triple therapy (corticosteroids, long-acting beta agonist, and antimuscarinic inhalers) for at least three months. In one study (METREX), patients with or without eosinophilia were enrolled. In the other (METREO), all patients had eosinophilia of varying severity.

The findings were mixed.

In METREO, which compared 'apples to apples' (all patients with eosinophilia), mepolizumab reduced yearly exacerbations by about 15-20% compared to placebo, but the result just missed statistical significance (P=0.07), and the higher dose (300 mg) was less effective than the lower dose (100 mg). Thus, a negative trial.

However, in METREX (some patients with eosinophilia, some not), mepolizumab reduced exacerbations by 14% in the pre-specified subgroup of patients with eosinophilia (P=0.04). The trials' results were published together in the New England Journal of Medicine.

GSK designed the trials so they could combine all the patients in lots of pre-specified meta-analyses and post-hoc analyses, slicing the population into multiple demographics (those who had previously had eosinophilia but now did not, those who had mild, moderate, or severe eosinophilia, those who had exacerbations treated with only steroids, vs. only antibiotics, etc.). While this increased the chances of finding COPD patients who might benefit from mepolizumab, it was also a sophisticated strategy to bolster the case for FDA approval, even if the primary endpoint was not met.

This design allowed GSK to show that although mepolizumab had no statistically significant benefit in any of the eosinophilia-stratified subgroups even after combining patients in the prespecified analysis ... the drug did have a clear dose-response relationship (see figure 5 in the paper). The higher the eosinophilia in patients with COPD, the greater the (non-statistically significant) response to mepolizumab. The subgroup of patients with the highest counts of ≥300 eosinophils/mm³ experienced 38% fewer COPD exacerbations while using mepolizumab, compared to placebo (albeit with a confidence interval just crossing 1).

Also, the patients who had lower eosinophil counts (<150/mm³) at enrollment, but had previously had at least one eosinophil count >300/mm³, had the largest (non-significant) effect. The clinical-biologic idea here being a sudden flare of increased eosinophilia could be contributory to COPD exacerbations, and would be ameliorated by mepolizumab.

Both mepolizumab and placebo patients experienced a higher than expected rate of pneumonia (~10%), which authors attributed to their severe COPD and use of inhaled glucocorticoids, which increase risk for pneumonia. The rate of adverse events among patients taking mepolizumab was similar to that with placebo.

Mepolizumab is an injectible monoclonal antibody directed against interleukin-5, which decreases maturation and release of eosinophils from the bone marrow. The drug did not show benefit in COPD with eosinophilia in a previous underpowered pilot study, among only 18 patients.

Nucala hit the U.S. asthma treatment market in 2015 with an estimated $32,500/year price tag. Teva's competing anti-eosinophilic injectible reslizumab (Cinqair) was approved by FDA for severe asthma with eosinophilia in 2016.

After results of the two trials were released, GlaxoSmithKline announced it would seek FDA approval for Nucala to treat COPD with eosinophilia.

About 12 million people in the U.S. are diagnosed with COPD. It's unknown how many patients have severe COPD and high eosinophils, uncontrolled on triple therapy with frequent exacerbations, who might benefit from anti-eosinophil injectible antibodies.

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Mepolizumab reduced exacerbations in COPD with eosinophilia, but missed target