Sanofi and Regeneron Announce Positive Pivotal Phase 2b Dupilumab Data in Asthma Presented at the American Thoracic Society 2015 International Conference

OREANDA-NEWS. May 19, 2015. Sanofi and Regeneron Pharmaceuticals, Inc. today shared additional positive results from an interim analysis of a pivotal Phase 2b study of dupilumab in adult patients with moderate-to-severe asthma who are uncontrolled despite treatment with inhaled corticosteroids and long-acting beta agonists (ICS/LABA). As previously reported, the study met its primary endpoint of improving lung function in asthma patients with high blood eosinophils counts (greater than or equal to 300 eosinophilic cells/microliter). Such high counts are thought to be a marker for patients more likely to have "atopic" or "allergic" asthma. New data on secondary endpoints presented at the American Thoracic Society 2015 International Conference included positive results in study patients with low blood eosinophils (less than 300 eosinophilic cells/microliter) who are thought to be less likely to suffer from "allergic" asthma and thus less likely to respond to Th2 targeted therapies. Dupilumab is an investigational therapy in clinical development that inhibits signaling of IL-4 and IL-13, two cytokines required for the Th2 (or Type 2) immune response.

Based on discussions with the U.S. Food and Drug Administration (FDA), this Phase 2b study may be considered one of two pivotal efficacy studies required for a potential dupilumab biologics license application (BLA) in asthma. The companies also announced the initiation of a Phase 3 clinical trial of dupilumab in patients with uncontrolled persistent asthma, known as LIBERTY ASTHMA QUEST, which will serve as the second required pivotal efficacy study. The global, placebo-controlled Phase 3 study will enroll more than 1,600 patients with uncontrolled persistent asthma and will evaluate two doses of dupilumab, 200 milligrams (mg) and 300 mg, subcutaneously administered every other week (Q2W). 

The new results focused on asthma patients with low eosinophil counts (LEos, less than 300 eosinophilic cells/microliter). In this population, patients treated with either 200 mg or 300 mg Q2W doses of dupilumab showed an approximately 8 percent improvement in forced expiratory volume over one second (FEV1, a standard measure of lung function) at Week 12  (p<0.001), in comparison to placebo, both in combination with ICS/LABA. Additionally, the 200 mg and 300 mg Q2W doses of dupilumab in combination with ICS/LABA showed 68 percent and 62 percent reductions, respectively, in adjusted annualized rate of severe exacerbations in the LEos population (p<0.01 and p<0.05), in comparison to placebo in combination with ICS/LABA.

These results are consistent with previously reported positive results in asthma patients with high eosinophils (HEos, greater than or equal to 300 eosinophilic cells/microliter) and the overall patient population, in which the two Q2W doses of dupilumab in combination with ICS/LABA demonstrated a statistically significant 12 to 15 percent improvement in FEV1 over placebo at Week 12 and a 64 to 75 percent improvement in annualized rate of severe exacerbations over placebo.

Dupilumab also significantly reduced mean fractional exhaled nitric oxide (FeNO) for both Q2W doses tested (200 and 300 mg) and the three patient populations (overall, LEos and HEos), in a roughly dose-dependent manner. FeNO is recommended by the American Thoracic Society clinical practice guidelines to assess airway inflammation, since higher than normal levels of nitric oxide may be released when a patient has a chronic airway disease, such as asthma.

The most common adverse event was injection site reaction, which was more frequent in the dupilumab dose groups (13 to 25 percent) compared to placebo (12 percent). Other common adverse events in the study included upper respiratory tract infection (10 to 13 percent dupilumab; 13 percent placebo), headache (5 to 10 percent dupilumab; 8 percent placebo), nasopharyngitis (3 to 10 percent dupilumab; 6 percent placebo) and bronchitis (5 to 8 percent dupilumab; 8 percent placebo). The incidence of infections was balanced across treatment groups (42 to 45 percent dupilumab; 46 percent placebo), as was the incidence of serious adverse events (3 to 7 percent dupilumab; 5 percent placebo).

"Despite available treatments, many patients with asthma continue to have regular symptoms and recurring attacks, which have a serious and detrimental impact on their daily lives," said Sally Wenzel, M.D., lead investigator from The University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine. "In the study, dupilumab added to standard-of-care therapy demonstrated fewer exacerbations and improved lung function across both the high and low baseline eosinophil groups. We look forward to the continued clinical development of dupilumab as a potential option for a broad population of patients with uncontrolled asthma."

Dupilumab is an investigational agent under clinical development and its safety and efficacy have not been fully evaluated by any regulatory agency.

These results were based on a pre-specified interim analysis, which occurred when all patients had reached Week 12 of the 24-week treatment period; the average treatment duration at the time of the analysis was 21.4 weeks. The primary endpoint of the study was improvement from baseline in FEV1 at Week 12 in the HEos group. Final analyses on exacerbations and safety will be conducted after 24 weeks of treatment and a 16-week follow-up period.

About the Phase 2b Study
The double-blind, placebo-controlled, 24-week, dose-ranging study enrolled 776 adult patients with moderate-to-severe uncontrolled asthma, as defined by the Global Initiative for Asthma 2014 Guidelines. Trial participants were randomized to receive one of four doses of dupilumab (300 mg every other week, 200 mg every other week, 300 mg monthly, 200 mg monthly) or placebo. Approximately 42 percent of patients had high eosinophils across the dose groups. During the treatment period, patients continued their stable medium- or high-dose inhaled corticosteroid and long-acting beta agonist (ICS/LABA) combination product. Patients could have administered inhaled rescue medication as needed during the study. A severe exacerbation event during the study was defined as a deterioration of asthma requiring the use of systemic corticosteroids for three or more days, or hospitalization or an emergency room visit.