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LONDON – Two large phase III trials with lebrikizumab, a monoclonal antibody that blocks the activity of interleukin-13 (IL-13), produced inconsistent evidence of benefit in patients with uncontrolled asthma, according to a presentation of both sets of data at the annual congress of the European Respiratory Society.
The two phase III studies compared lebrikizumab in doses of 37.5 mg and 125 mg to placebo, each administered subcutaneously every 4 weeks. The results were mixed not only for the primary endpoint, which was a reduction in the rate of exacerbations, but also for several secondary outcomes.
Evenly randomized into three treatment arms, 1,081 patients were enrolled in LAVOLTA I and 1,081 in LAVOLTA II. For entry, patients were required to have a forced expiratory volume in 1 second (FEV1) between 40% and 80% of predicted. Lebrikizumab was added on top of stable background therapy. For the efficacy analyses, patients were divided into those who were biomarker high, defined as having levels of periostin greater than 50 ng/mL or blood eosinophils greater than 300 mcg/L, or biomarker low, defined as having lower levels of periostin and blood eosinophils.
Over the 52-week study period in the biomarker high patients enrolled in LAVOLTA I, the rate of exacerbations was 51% lower among those randomized to the 37.5 mg dose (P less than .001) and 30% lower (P = .0232) among those randomized to the 125-mg dose relative to placebo. In the biomarker low group, a statistically significant 45% reduction in exacerbations was achieved with the 37.5 mg dose relative to placebo (P = .0318), but a 28% reduction in exacerbations, which was achieved in patients taking the 125-mg dose, was not statistically significant.
In the biomarker high patients enrolled in LAVOLTA II, both the 37.5-mg and the 125-mg doses reduced the rate of exacerbations by 26% relative to placebo, but neither reduction reached statistical significance. In the biomarker low patients, the 37.5-mg dose was associated with a 46% increase in exacerbations and the 125-mg dose was associated with a 6% increase in exacerbations relative to placebo.
In LAVOLTA I, lung function (as measured by FEV1) improved in biomarker high patients in both active treatment arms relative to placebo. The relative advantage of taking lebrikizumab was seen only in the biomarker low patients who took the 125-mg dose.
In LAVOLTA II, a similar advantage was observed in biomarker high patients who took both doses of lebrikizumab over biomarker high patients who took the placebo. There were no significant differences in outcomes observed between any treatment arms in the biomarker low group of LAVOLTA II.
Changes in other secondary endpoints were also inconsistent between the two studies. For example, the time to first exacerbation was significantly increased by lebrikizumab in LAVOLTA I but not in LAVOLTA II. Although use of rescue medications was significantly lower in patients receiving lebrikizumab in both studies, the rate of urgent health care utilization, such as emergency department visits, was lower in patients who took lebrikizumab in LAVOLTA 1, but not in those patients who too the drug in LAVOLTA II.
One consistency between the two studies’ outcomes was a lack of “meaningful improvements” having occurred in patients’ quality of life, as measured by the Asthma Quality of Life Questionnaire and the 5-item Asthma Control Questionnaire, according to Dr. Hanania.
The only difference in the occurrences of events associated with impaired immune function observed between any of the groups was a slight increase in the rate of herpes zoster among those treated with lebrikizumab relative to placebo (1.1% vs. 0.3%), Dr. Hanania reported. The only death that occurred in either study involved a patient in a placebo group. The rates of other side effects were comparable among patients in the active treatment and placebo groups.
An improvement in exacerbations would be consistent with the purported mechanism of lebrikizumab, because IL-13 is believed to induce expression of periostin, which, in turn, is thought to mediate bronchial hyper-responsiveness. In previously completed phase II trials, lebrikizumab was associated with a significant reduction in the rate of exacerbations over 24 weeks among patients with moderate to severe asthma (Thorax. 2015;80:748-56).
Asked in the discussion period whether the results of LAVOLTA I and II signaled the end of lebrikizumab studies in asthma control, Dr. Hanania deferred the question to Roche, which is developing this agent.
He noted that additional studies in a more select group of patients may be warranted and that lebrikizumab is still being evaluated for use in other lung diseases, such as idiopathic pulmonary fibrosis.
Dr. Hanania reports financial relationships with Forest, GlaxoSmithKline, Novartis, Pfizer, and Roche.
LONDON – Two large phase III trials with lebrikizumab, a monoclonal antibody that blocks the activity of interleukin-13 (IL-13), produced inconsistent evidence of benefit in patients with uncontrolled asthma, according to a presentation of both sets of data at the annual congress of the European Respiratory Society.
The two phase III studies compared lebrikizumab in doses of 37.5 mg and 125 mg to placebo, each administered subcutaneously every 4 weeks. The results were mixed not only for the primary endpoint, which was a reduction in the rate of exacerbations, but also for several secondary outcomes.
Evenly randomized into three treatment arms, 1,081 patients were enrolled in LAVOLTA I and 1,081 in LAVOLTA II. For entry, patients were required to have a forced expiratory volume in 1 second (FEV1) between 40% and 80% of predicted. Lebrikizumab was added on top of stable background therapy. For the efficacy analyses, patients were divided into those who were biomarker high, defined as having levels of periostin greater than 50 ng/mL or blood eosinophils greater than 300 mcg/L, or biomarker low, defined as having lower levels of periostin and blood eosinophils.
Over the 52-week study period in the biomarker high patients enrolled in LAVOLTA I, the rate of exacerbations was 51% lower among those randomized to the 37.5 mg dose (P less than .001) and 30% lower (P = .0232) among those randomized to the 125-mg dose relative to placebo. In the biomarker low group, a statistically significant 45% reduction in exacerbations was achieved with the 37.5 mg dose relative to placebo (P = .0318), but a 28% reduction in exacerbations, which was achieved in patients taking the 125-mg dose, was not statistically significant.
In the biomarker high patients enrolled in LAVOLTA II, both the 37.5-mg and the 125-mg doses reduced the rate of exacerbations by 26% relative to placebo, but neither reduction reached statistical significance. In the biomarker low patients, the 37.5-mg dose was associated with a 46% increase in exacerbations and the 125-mg dose was associated with a 6% increase in exacerbations relative to placebo.
In LAVOLTA I, lung function (as measured by FEV1) improved in biomarker high patients in both active treatment arms relative to placebo. The relative advantage of taking lebrikizumab was seen only in the biomarker low patients who took the 125-mg dose.
In LAVOLTA II, a similar advantage was observed in biomarker high patients who took both doses of lebrikizumab over biomarker high patients who took the placebo. There were no significant differences in outcomes observed between any treatment arms in the biomarker low group of LAVOLTA II.
Changes in other secondary endpoints were also inconsistent between the two studies. For example, the time to first exacerbation was significantly increased by lebrikizumab in LAVOLTA I but not in LAVOLTA II. Although use of rescue medications was significantly lower in patients receiving lebrikizumab in both studies, the rate of urgent health care utilization, such as emergency department visits, was lower in patients who took lebrikizumab in LAVOLTA 1, but not in those patients who too the drug in LAVOLTA II.
One consistency between the two studies’ outcomes was a lack of “meaningful improvements” having occurred in patients’ quality of life, as measured by the Asthma Quality of Life Questionnaire and the 5-item Asthma Control Questionnaire, according to Dr. Hanania.
The only difference in the occurrences of events associated with impaired immune function observed between any of the groups was a slight increase in the rate of herpes zoster among those treated with lebrikizumab relative to placebo (1.1% vs. 0.3%), Dr. Hanania reported. The only death that occurred in either study involved a patient in a placebo group. The rates of other side effects were comparable among patients in the active treatment and placebo groups.
An improvement in exacerbations would be consistent with the purported mechanism of lebrikizumab, because IL-13 is believed to induce expression of periostin, which, in turn, is thought to mediate bronchial hyper-responsiveness. In previously completed phase II trials, lebrikizumab was associated with a significant reduction in the rate of exacerbations over 24 weeks among patients with moderate to severe asthma (Thorax. 2015;80:748-56).
Asked in the discussion period whether the results of LAVOLTA I and II signaled the end of lebrikizumab studies in asthma control, Dr. Hanania deferred the question to Roche, which is developing this agent.
He noted that additional studies in a more select group of patients may be warranted and that lebrikizumab is still being evaluated for use in other lung diseases, such as idiopathic pulmonary fibrosis.
Dr. Hanania reports financial relationships with Forest, GlaxoSmithKline, Novartis, Pfizer, and Roche.
LONDON – Two large phase III trials with lebrikizumab, a monoclonal antibody that blocks the activity of interleukin-13 (IL-13), produced inconsistent evidence of benefit in patients with uncontrolled asthma, according to a presentation of both sets of data at the annual congress of the European Respiratory Society.
The two phase III studies compared lebrikizumab in doses of 37.5 mg and 125 mg to placebo, each administered subcutaneously every 4 weeks. The results were mixed not only for the primary endpoint, which was a reduction in the rate of exacerbations, but also for several secondary outcomes.
Evenly randomized into three treatment arms, 1,081 patients were enrolled in LAVOLTA I and 1,081 in LAVOLTA II. For entry, patients were required to have a forced expiratory volume in 1 second (FEV1) between 40% and 80% of predicted. Lebrikizumab was added on top of stable background therapy. For the efficacy analyses, patients were divided into those who were biomarker high, defined as having levels of periostin greater than 50 ng/mL or blood eosinophils greater than 300 mcg/L, or biomarker low, defined as having lower levels of periostin and blood eosinophils.
Over the 52-week study period in the biomarker high patients enrolled in LAVOLTA I, the rate of exacerbations was 51% lower among those randomized to the 37.5 mg dose (P less than .001) and 30% lower (P = .0232) among those randomized to the 125-mg dose relative to placebo. In the biomarker low group, a statistically significant 45% reduction in exacerbations was achieved with the 37.5 mg dose relative to placebo (P = .0318), but a 28% reduction in exacerbations, which was achieved in patients taking the 125-mg dose, was not statistically significant.
In the biomarker high patients enrolled in LAVOLTA II, both the 37.5-mg and the 125-mg doses reduced the rate of exacerbations by 26% relative to placebo, but neither reduction reached statistical significance. In the biomarker low patients, the 37.5-mg dose was associated with a 46% increase in exacerbations and the 125-mg dose was associated with a 6% increase in exacerbations relative to placebo.
In LAVOLTA I, lung function (as measured by FEV1) improved in biomarker high patients in both active treatment arms relative to placebo. The relative advantage of taking lebrikizumab was seen only in the biomarker low patients who took the 125-mg dose.
In LAVOLTA II, a similar advantage was observed in biomarker high patients who took both doses of lebrikizumab over biomarker high patients who took the placebo. There were no significant differences in outcomes observed between any treatment arms in the biomarker low group of LAVOLTA II.
Changes in other secondary endpoints were also inconsistent between the two studies. For example, the time to first exacerbation was significantly increased by lebrikizumab in LAVOLTA I but not in LAVOLTA II. Although use of rescue medications was significantly lower in patients receiving lebrikizumab in both studies, the rate of urgent health care utilization, such as emergency department visits, was lower in patients who took lebrikizumab in LAVOLTA 1, but not in those patients who too the drug in LAVOLTA II.
One consistency between the two studies’ outcomes was a lack of “meaningful improvements” having occurred in patients’ quality of life, as measured by the Asthma Quality of Life Questionnaire and the 5-item Asthma Control Questionnaire, according to Dr. Hanania.
The only difference in the occurrences of events associated with impaired immune function observed between any of the groups was a slight increase in the rate of herpes zoster among those treated with lebrikizumab relative to placebo (1.1% vs. 0.3%), Dr. Hanania reported. The only death that occurred in either study involved a patient in a placebo group. The rates of other side effects were comparable among patients in the active treatment and placebo groups.
An improvement in exacerbations would be consistent with the purported mechanism of lebrikizumab, because IL-13 is believed to induce expression of periostin, which, in turn, is thought to mediate bronchial hyper-responsiveness. In previously completed phase II trials, lebrikizumab was associated with a significant reduction in the rate of exacerbations over 24 weeks among patients with moderate to severe asthma (Thorax. 2015;80:748-56).
Asked in the discussion period whether the results of LAVOLTA I and II signaled the end of lebrikizumab studies in asthma control, Dr. Hanania deferred the question to Roche, which is developing this agent.
He noted that additional studies in a more select group of patients may be warranted and that lebrikizumab is still being evaluated for use in other lung diseases, such as idiopathic pulmonary fibrosis.
Dr. Hanania reports financial relationships with Forest, GlaxoSmithKline, Novartis, Pfizer, and Roche.
AT THE ERS CONGRESS 2016
Key clinical point: The primary efficacy endpoint was achieved in only one of two phase III trials of lebrikizumab for treatment of uncontrolled asthma.
Major finding: For lebrikizumab, which targets IL-13, the inconsistency of significant benefit clouds its future as an asthma treatment.
Data source: A placebo-controlled multicenter phase III program.
Disclosures: Dr. Hanania reports financial relationships with Forest, GlaxoSmithKline, Novartis, Pfizer, and Roche.