Add-on benralizumab not linked to lower exacerbation rates in COPD

DALLAS — In patients with moderate to very severe chronic obstructive pulmonary disease who had a history of exacerbations, were on double or triple therapy and had eosinophilic inflammation, add-on benralizumab did not reduce the rate of exacerbations more than placebo, according to the GALATHEA and TERRANOVA studies presented at the American Thoracic Society International Conference.

The randomized, phase 3, double-blind, placebo-controlled, parallel-group GALATHEA and TERRANOVA trials enrolled patients aged 40 to 85 years with moderate to severe COPD who were still experiencing frequent exacerbations despite receiving guideline-directed medical therapy in a 2:1 fashion based on whether their eosinophil counts were greater or less than 220 cells/µL.

All patients underwent a 4-week run-in period and then were randomly assigned 30 mg or 100 mg of benralizumab (Fasenra, AstraZeneca) or placebo in GALATHEA and 10 mg, 30 mg, 100 mg benralizumab or placebo in the TERRANOVA trials.

In both trials, the primary endpoint was the treatment effect of benralizumab, measured as the annual rate ratio of COPD exacerbations, compared with placebo in patients with baseline eosinophil counts of 220 cells/µL or greater at 56 weeks.

“There is a whole story of the eosinophilia perhaps being involved in COPD exacerbations because between 20% and 40% of patients have eosinophilic inflammation, whether tested in the sputum or in the blood,” Bartolome R. Celli, MD, professor of medicine at Brigham and Women’s Hospital, who presented the TERRANOVA trial, said at the meeting. “Several well-conducted trials have shown there is an association between greater numbers of eosinophils and the presence of exacerbations. The theory is that if we are able to reduce eosinophils to a normal or low level, it is conceivable that we could improve the outcome of those patients who had moderate to severe exacerbations, and we know that benralizumab has been useful in this area in patients with asthma.”

GALATHEA

In the GALATHEA trial, which included 1,120 patients with baseline eosinophil counts of 220 cells/µL or greater, the annualized COPD exacerbation rate at 56 weeks numerically favored benralizumab over placebo, according to Gerard J. Criner, MD, FACP, FACCP, chair and professor of thoracic medicine and surgery at Temple University’s Lewis Katz School of Medicine. However, the finding did not reach statistical significance, he said. Specifically, annualized exacerbation rate estimates were 1.19 per year (95% CI, 1.04-1.36) in the 30-mg group, 1.03 per year (95% CI, 0.9-1.19) in the 100-mg group and 1.24 per year (95% CI, 1.08-1.42) in the placebo group. When compared with placebo, the rate ratios were 0.96 (P = .65) for the 30-mg group and 0.83 (P = .05) for the 100-mg group.

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The researchers also found that benralizumab had no consistent dose effect on the annualized exacerbation rate. The annualized rates of severe exacerbations, which served as the sensitivity analysis, were 0.25 per year (95% CI, 0.19-0.33) in the 30-mg group, 0.12 per year (95% CI, 0.08-0.17) in the 100-mg group and 0.21 per year (95% CI, 0.15-0.28) in the placebo group. When compared with placebo, the rate ratios were 1.2 for those on benralizumab 10 mg and 0.57 for those on 100 mg.

In terms of secondary endpoints, the differences in mean change from baseline in prebronchodilator forced expiratory volume in 1 second (FEV₁) for benralizumab vs. placebo was 7 mL (95% CI, –35 to 48) for the 30-mg group and 21 mL (95% CI, –21 to 62) for the 100-mg group. The differences in the change from baseline in St. George’s Respiratory Questionnaire total score for benralizumab vs. placebo were –1.011 (95% CI, 2.887 to 0.865) in the 30-mg group and 2.136 (95% CI, 4.020 to 0.251) in the 100-mg group. However, these results were also not statistically significant.

In post hoc analyses, patients with a history of three or more prior exacerbations or on triple inhaled therapy had greater effect on exacerbation reduction with treatment with 100 mg benralizumab, Criner said. Also, baseline eosinophil levels greater than 300 cells were associated with greater benralizumab effect in those treated with the 100-mg dose.

“Future studies using these selection criteria may identify a patient group who may benefit from this therapy,” Criner told Healio Pulmonology.

TERRANOVA

Results from the TERRANOVA trial, which included 1,545 patients with baseline eosinophil counts of 220 cells/µL, were similar to those observed in GALATHEA.

For the primary endpoint, the annualized COPD exacerbation rate ratios for benralizumab vs. placebo were 0.85 (P = .06) in the 10-mg group, 1.04 (P = .66) in the 30-mg group and 0.93 (P = .4) in the 100-mg group. Annualized exacerbation rates were 0.99 per year (95% CI, 0.87-1.13) in the 10-mg group, 1.21 per year (95% CI, 1.08-1.37) in the 30-mg group, 1.09 per year (95% CI, 0.96-1.23) in the 100-mg group and 1.17 per year (95% CI, 0.96-1.23) in the placebo group.

The differences for benralizumab vs. placebo in the mean change from baseline in prebronchodilator FEV₁ was 15 mL (95% CI, 29 to 59) in the 10-mg group and 20 mL (95% CI, 24 to 64) in the 100-mg group. Paradoxically, there was no improvement seen in FEV₁ with the 30-m dose (7 mL; 95% CI, 51 to 37). The differences for benralizumab vs. placebo in mean change from baseline in St. George’s Respiratory Questionnaire total score were 1.011 (95% CI, 3.192 to 1.171), 1.388 (95% CI, 3.562 to 0.786) and 0.602 (95% CI, 2.763 to 1.560) for the 10-mg, 30-mg and 100-mg groups, respectively. Again, all of these differences failed to reach statistical significance, Celli noted.

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Future directions

In both trials, there were no significant differences regarding treatment effect based on baseline eosinophil counts.

Celli noted that the data potentially suggest that patients with more severe exacerbations and those on triple therapy may benefit from add-on benralizumab but cautioned that the evidence is not yet strong enough to draw firm conclusions.

Adverse event rates, however, were low in both trials.

“The happy ending is that we did not see any major complications, including infections or pneumonia in these patients, who were sick to begin with, as they had two or more exacerbations in the previous year that required hospitalizations,” Celli said.

“In conclusion, patients with moderate to severe COPD with prior exacerbations of blood eosinophil count higher than 220 cells/µL, add-on benralizumab — whether the dose was 10 mg, 30 mg or 100 mg — produced no statistically significant improvement in annual exacerbation rate, severe exacerbation rate, lung function and SGRQ total score,” he said. “Also, we learned that it is a safe drug in our patients who are older and sicker. And finally, if you want to think of who could conceivably undergo another trial, it would be individuals who have more than three exacerbations in the previous year and may be receiving triple therapy.” – by Melissa Foster

References:

Celli BR. Abstract A2625.

Criner GJ. Abstract A2626. Both presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.

Criner GJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1905248.

Disclosures: The GALATHEA and TERRANOVA trials were supported by AstraZeneca and GALATHEA was supported by Kyowa Hakka Kirin. Celli reports he has received grants from GlaxoSmithKline and he has received personal fees from Almirall, Boehringer Ingelheim, GlaxoSmithKline, Novartis AG, SA and Takeda Pharmaceutical Company Limited. Criner reports he has received grants from Actelion, Aeris, AstraZeneca, Forest, GlaxoSmithKline, Ikaria, MedImmune, Novartis, PneumRx, Pulmonx and Respironics; he has received personal fees from Amirall, Boehringer Ingelheim, GlaxoSmithKline and Holaira; and he has financial ties to HE Health Care Solutions Inc.