Public Release:  Monoclonal antibody appears effective and safe in asthma Phase IIa trial

American Thoracic Society

ATS 2013, PHILADELPHIA ─ A novel approach to obstructing the runaway inflammatory response implicated in some types of asthma has shown promise in a Phase IIa clinical trial, according to U. S. researchers.

Their research will be presented at the American Thoracic Society 2013 International Conference and published simultaneously online in the New England Journal of Medicine.

The randomized, double-blind, placebo-controlled trial tested the efficacy and safety of the monoclonal antibody, dupilumab, in patients with "persistent, moderate-to-severe asthma" and elevated eosinophils, which are immune cells that mobilize in response to allergens and infections and are commonly seen in asthma.

According to lead author Sally Wenzel, MD, director of the University of Pittsburgh Asthma Institute, the combination of inhaled glucocorticosteroids (ICS) and long-acting beta agonists (LABA), which is a cornerstone of asthma controller therapy, does not work sufficiently in 10 to 20 percent of asthma patients in the United States.

"Asthma that is difficult to treat is increasingly recognized as comprising different phenotypes," she said. "With this study, we wanted to see whether dupilumab would reduce a surrogate index for asthma exacerbations when given with ICS and LABA and when those two therapies were withdrawn."

Dupilumab, a fully human monoclonal antibody discovered by Regeneron Pharmaceuticals and being developed by Regeneron and Sanofi, thwarts activation of the Th2 immune response implicated in asthma by blocking two cytokines, interleukin-4 and interleukin-13.

Over the course of a 12-week blinded treatment period and an 8-week follow-up, those patients who had received weekly injections of dupilumab experienced an 87 percent reduction in protocol defined asthma exacerbations, the primary endpoint of the study, vs. weekly placebo injections (odds ratio [95% CI]=0.08 [0.021 to 0.28]; p<0.01). Significant improvements were also reported for other relevant asthma outcomes such as lung function as assessed by forced expiratory volume in one second (FEV1) and morning peak expiratory flow, asthma symptoms and control, as well as, asthma reliever medication use. Many of these improvements were seen when dupilumab was added to ICS/LABA, with efficacy maintained despite background therapy withdrawal.

"Intriguingly," noted Dr. Wenzel, "dupilumab showed substantial efficacy in objective and patient-reported endpoints when added to ICS and LABA and when those therapies were discontinued."

Patients in the study received dupilumab or placebo added to their regular, twice daily dose of fluticasone/salmeterol. At Week 4, patients were instructed to withdraw the LABA (salmeterol). Between Weeks 6 and 9, they tapered off fluticasone, the ICS.

A total of 104 patients, aged 18 to 65, participated in the study. Half received the monoclonal antibody; half received placebo. All had persistent, moderate-to-severe asthma that was not well-controlled by medium to high doses of combined ICS and LABA therapy. The patients also had elevated blood (≥ 300 cells/µl) or sputum (≥3%) eosinophils at screening.

The study found no clear change in blood eosinophils with dupilumab therapy; however, other biomarkers decreased, including fractional exhaled nitric oxide, thymus and activation regulated chemokine, immunoglobulin E and eotaxin-3, confirming the biologic activity of dupilumab.

Side effects occurring more frequently in the patients receiving the monoclonal antibody vs. placebo included injection site reactions, nasopharyngitis, nausea and headache, but were not considered severe.

According to Dr. Wenzel, the current study, exhibited a "magnitude and breadth" of efficacy that exceeded other studies of cytokine inhibition in asthma. She and her investigator colleagues speculate that the stronger outcome came as a result of blocking two cytokines, IL-4 and IL-13, rather than a single one.

They called for further studies to confirm these observations and better define the target population, dosing regimen, and long-term efficacy and safety

The trial was sponsored by Sanofi and Regeneron.

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* Please note that numbers in this release may differ slightly from those in the abstract. Many of these investigations are ongoing; the release represents the most up-to-date data available at press time.

Abstract 45245

Efficacy And Safety Of SAR231893/REGN668 In Patients With Moderate-To-Severe, Persistent Asthma And Elevated Eosinophil Levels

Type: Late Breaking Abstract

Category: 01.23 - Therapy (AII)

Authors: S.E. Wenzel1, G. Pirozzi2, L. Wang2, S. Kirkesseli3, R. Rocklin2, A. Radin4, F. Skobieranda2; 1University of Pittsburgh - Pittsburgh, PA/US, 2Sanofi - Bridgewater, NJ/US, 3Sanofi - Chilly-Mazarin/FR, 4Regeneron Pharmaceuticals - Tarrytown, NY/US

Abstract Body

RATIONALE

Determine whether SAR231893/REGN668, a fully human monoclonal antibody against the interleukin (IL) 4 receptor α chain, thus a potent inhibitor of both IL-4 and IL-13 cytokines, is safe and effective in asthma.

METHODS

Patients with moderate-to-severe, persistent asthma treated with medium-to-high dose combination inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA) and with blood eosinophils ≥300 cells/µL (101 patients) or sputum eosinophils ≥3% (3 patients) were administered SAR231893/REGN668 or placebo subcutaneously for 12 weeks or until asthma exacerbation. At randomization, patients were switched to fluticasone/salmeterol for 4 weeks, after which LABA was withdrawn. Next, fluticasone was withdrawn over 3-4 weeks. The primary endpoint was the incidence of asthma exacerbations after 12 weeks, defined by: ≥30% reduction in morning expiratory flow rate (PEF) on 2 consecutive days; or ≥6 additional albuterol puffs per 24 hours on 2 consecutive days; or ≥4 times ICS increase; or oral or parenteral corticosteroids; or hospitalization. Secondary efficacy measures included changes in forced expiratory volume in 1 second (FEV1), morning (AM) / evening (PM) PEF, reliever use, 5-item Asthma Control Questionnaire (ACQ5), asthma symptom scores, nocturnal awakenings, and the Sino-Nasal Outcome Test (SNOT-22). Tolerability measures included the proportions of patients with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and discontinuations due to TEAEs.

RESULTS

Baseline characteristics were similar between treatment groups (Table). Three patients had an asthma exacerbation during treatment with SAR231893/REGN668 (5.8%) versus 23 (44.2%) with placebo, corresponding to an 87% relative risk reduction (odds ratio [95% CI] = 0.077 [0.021, 0.279]; p<0.0001). Clinically meaningful and statistically significant (without multiplicity adjustment) differences were observed for lung function (FEV1, AM PEF), ACQ, symptom scores, reliever medication use and SNOT-22 score (positive trends were observed for PM PEF and nocturnal awakenings). Efficacy was present early and sustained over time (Figures). No imbalance in TEAEs was observed (80.8% in SAR231893/REGN668; 76.9% in placebo), except for injection site reactions, nasopharyngitis, nausea and headache. Four patients experienced SAEs (SAR231893/REGN668: bipolar disorder; placebo: ankle fracture, gunshot wound and pneumothorax, asthma and pneumonia). Six patients discontinued due to TEAE (SAR231893/REGN668: bipolar disorder, angioedema, asthma and wheezing; placebo: upper respiratory tract infection, asthma, and psoriasis).

CONCLUSIONS

SAR231893/REGN668 demonstrated clinically meaningful efficacy with regard to asthma exacerbations, lung function, and symptom control, both after addition to ICS/LABA and following ICS/LABA withdrawal, and was well tolerated in patients with moderate-to-severe, persistent asthma with elevated eosinophil levels.

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