FDA Advisory Committee Meeting

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.