HOUSTON – Reslizumab, a next-generation molecular-based asthma therapy, achieved its primary and secondary endpoints and demonstrated favorable safety in patients with moderate to severe asthma and eosinophilia in two pivotal clinical trials.

“We believe that reslizumab is an effective therapy for controlling asthma in patients with elevated blood eosinophils who are inadequately controlled on medium to high dose inhaled corticosteroid–based regimens,” Dr. Mario Castro concluded in presenting the two phase III results at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

The frequency of clinical asthma exacerbations was reduced by more than half in reslizumab-treated patients, compared with controls in the two year-long studies. In addition, the reslizumab group experienced an early improvement in lung function as expressed in forced expiratory volume in 1 second (FEV₁) that was sustained throughout the year-long trials, as well as improvements in other measures of asthma control, including quality of life, reported Dr. Castro, professor of pulmonary and critical care medicine and pediatrics at Washington University in St. Louis.

Elevated blood and sputum levels of eosinophils define an asthma phenotype at increased risk for serious asthma exacerbations. Reslizumab is a humanized monoclonal antibody that binds circulating interleukin-5 and prevents binding to the IL-5 receptor, thereby disrupting eosinophil production and function.

Dr. Castro presented two identically designed phase III, double-blind, placebo-controlled, 12-month studies totaling 953 adolescents and adults. They were randomized to intravenous reslizumab at 3 mg/kg or placebo every 4 weeks for a year.

The primary endpoint was frequency of clinical asthma exacerbations (CAEs), an independently adjudicated composite outcome which required an episode featuring an increase in corticosteroids, an asthma-related ER visit or unscheduled office visit, evidence of asthma worsening in the form of at least a 20% drop from baseline in FEV₁ or a 30% reduction in peak expiratory flow rate on 2 consecutive days, and worsening clinical symptoms.

Participants averaged two CAEs during the year prior to enrollment. The placebo-treated controls maintained that event rate during the two year-long studies, while the reslizumab-treated patients experienced 50% and 59% reductions relative to controls (P < .0001).

Reslizumab also increased the time to first CAE. In the two trials, 61% and 73% of reslizumab-treated patients didn’t develop a single CAE during 52 weeks, compared with 44% and 52% of controls.

The more CAEs a patient had in the year prior to enrollment, the greater the magnitude of benefit with reslizumab. While the relative risk reduction was 54%, compared with placebo in the combined studies, it climbed to 64% in patients with four or more CAEs in the previous year.

FEV₁ improved after the first dose of reslizumab. The benefit – placebo-subtracted gains of 0.126 L in one trial and 0.09 L in the other – was sustained throughout the 52 weeks.

The reslizumab group also outperformed controls in terms of Asthma Control Questionnaire scores and Asthma Quality of Life Questionnaire scores. For example, 74% and 73% of reslizumab-treated patients in the two studies experienced at least a 0.5-point improvement in the AQLQ, which is considered the minimal clinically important difference, compared with 65% and 62% of controls, Dr. Castro continued.

Study discontinuation due to adverse events occurred in 2% of patients on reslizumab, with worsening asthma the No. 1 reason. Two patients on reslizumab experienced anaphylactoid reactions, neither requiring epinephrine. Three percent of reslizumab-treated patients developed low-titer, generally transient antidrug antibodies that didn’t affect eosinophil levels, which plunged with the first dose of reslizumab and stayed low throughout.

Reslizumab is one of a cluster of novel agents in development for severe or treatment-resistant asthma. These are targeted therapies directed at specific patient phenotypes. Biomarkers such as eosinophilia provide guidance as to the specific asthmatic inflammatory pathways involved.

Recent European Respiratory Society/American Thoracic Society guidelines stress the major unmet need for new treatments for severe asthma (Eur. Respir. J. 2014;43:343-73).

In an interview, Dr. James E. Gern, who wasn’t involved in the reslizumab studies, said the various severe asthma phenotypes account for a relatively small proportion of the total asthma population, but a tremendously disproportionate amount of health care utilization.

“These new medications that are coming out are probably going to be indicated for a relatively small number of people. But for those people, it’ll make a huge difference because of the huge burden that severe asthma has on quality of life,” said Dr. Gern, professor of pediatrics at the University of Wisconsin, Madison.

The two pivotal reslizumab studies were sponsored by Teva. Dr. Castro is on the company’s speakers’ bureau and receives research grants from more than a dozen pharmaceutical and device companies as well as from the National Institutes of Health and Centers for Disease Control and Prevention. Simultaneously with Dr. Castro’s presentation at AAAAI, the study results were published online (Lancet Respir. Med. 2015 [doi.org/10.1016/S2213-2600(15)00042-9]).

bjancin@frontlinemedcom.com

Reslizumab aces pivotal trials in asthma with eosinophilia