Sanofi and Regeneron Pharmaceuticals have announced that the phase 3 investigational study evaluating dupilumab in adults and adolescents with severe, steroid-dependent asthma met its primary endpoint and key secondary endpoints.

For the primary endpoint, at 24 weeks in the overall population, dupilumab added to standard therapies significantly reduced the use of maintenance oral corticosteroids (OCS) by 70 percent on average (median reduction of 100 percent) compared to 42 percent with placebo (median reduction of 50 percent) (p less than 0.0001). In prespecified analyses of patients with baseline eosinophil counts greater than or equal to 300 cells/microliter, adding dupilumab significantly reduced OCS use by 80 percent on average (median reduction of 100 percent) compared to 43 percent for placebo (median reduction of 50 percent)(nominal p equals 0.0001).

At 24 weeks, despite the reduced use of OCS, patients treated with dupilumab had 59 percent fewer attacks (exacerbations) in the overall population (p less than 0.0001) and 71 percent fewer attacks in patients with eosinophil counts greater than or equal to 300 cells/microliter. Also at 24 weeks, compared to placebo, dupilumab improved lung function, as assessed by forced expiratory volume over one second (FEV1) by 220ml (15 percent) in the overall population (p equals 0.0007) and by 320ml (25 percent) in patients with eosinophil counts greater than or equal to 300 cells/microliter (nominal p equals 0.0049).

"This phase 3 study showed that most severe asthma patients could substantially reduce their dependence on oral corticosteroids, with half completely eliminating their use of oral corticosteroids, which are not recommended for long-term use and can carry significant and potentially irreversible safety risks. Importantly, despite a reduction in oral corticosteroid use, dupilumab was associated with an improvement in lung function.  This is the third study in which dupilumab has demonstrated a reduction in asthma attacks and improvement in lung function in a broad group of patients with uncontrolled asthma - this effect was most profound in patients with elevated markers of Type 2 allergic inflammation, such as an eosinophil count over 300," said George D. Yancopoulos, M.D., Ph.D., president and chief scientific officer of Regeneron. "Dupilumab blocks the IL-4/IL-13 pathway, which is emerging as a central driver of Type 2 allergic inflammation. We remain committed to investigating dupilumab in other Type 2 inflammatory diseases including eosinophilic esophagitis, nasal polyps, pediatric atopic dermatitis and food allergy."

"This phase 3 study enrolled severe steroid-dependent asthma patients regardless of eosinophil levels or other biomarkers at baseline, and the results showed improvements compared to placebo on lung function and exacerbations across patient subgroups - those with baseline eosinophil counts above 300 cells/microliter, above 150 cells/microliter and below 150 cells/microliter," said Elias Zerhouni, M.D., president, Global R&D, Sanofi. "It is striking that dupilumab showed a consistent improvement in lung function across the pivotal asthma program, as this is critically important for patients with severe asthma struggling with declines in their everyday breathing ability."

The safety and tolerability profile of dupilumab in this study was consistent with previous studies. There were more dupilumab treated patients with injection site reactions (9 percent dupilumab vs. 4 percent placebo).  There were more dupilumab treated patients with an increase in eosinophil counts (14 percent dupilumab vs. 1 percent placebo), most of which were mild and the vast majority of which resolved.  The overall rates of adverse events, including infections, conjunctivitis, and herpes were comparable between the dupilumab and placebo groups.

Patients with severe chronic asthma live with a profound decrease in their lung function, approximately 52 percent of predicted normal for those in this study at baseline, which impacts their ability to breathe normally, and may lead to frequent exacerbations that require acute treatment. These problems occur even in patients who are treated with chronic OCS to manage their symptoms.

In the phase 3 study, known as liberty asthma venture, additional secondary endpoint results at 24 weeks included the following:  In the overall population, 80 percent of patients who received dupilumab reduced their OCS dose by at least half while maintaining overall asthma control compared to 50 percent of patients who received placebo (p less than 0.0001). In patients with eosinophil counts greater than or equal to 300 cells/microliter (high EOS), dupilumab allowed for a reduction in the OCS dose by at least half in 88 percent of patients compared to 52 percent for placebo (nominal p equals 0.0011).

In the overall population, 69 percent of patients who received dupilumab reduced their OCS dose to less than 5 mg per day while maintaining asthma control compared to 33 percent of patients who received placebo (p less than 0.0001); in the high EOS group, 84 percent of dupilumab patients reduced their OCS dose to less than 5 mg per day compared to 40 percent for placebo (nominal p equals 0.0002).

"Severe, uncontrolled asthma can lead to a dependence on oral corticosteroids, with systemic steroid exposure potentially leading to serious short- and long-term adverse effects, including weight gain, diabetes, osteoporosis, glaucoma, anxiety, depression, cardiovascular disease and immunosuppression," said Professor Mario Castro, M.D., MPH, FCCP, Washington University School of Medicine in St. Louis.  "There is an urgent need for new therapies that can decrease or eliminate chronic oral corticosteroid use, as well as  reduce severe asthma attacks and improve lung function in this difficult-to-treat patient population."

The Venture study enrolled 210 patients (103 in the dupilumab arm and 107 in the placebo arm) with severe asthma and regular use of maintenance OCS in the six months prior to enrollment in the study. In the study, the prescribed OCS was prednisone or prednisolone. Patients were randomized using a 1:1 ratio and treated with either dupilumab (300 mg every other week with a loading dose of 600 mg) or placebo.  The median baseline eosinophil count in the study was 260 eosinophils/microliter.

Detailed results from this study will be submitted for presentation at a future medical congress. VENTURE is the third trial in the uncontrolled persistent asthma pivotal clinical program  and follows positive results from the phase 3 QUEST study and phase 2b pivotal study of dupilumab. The companies plan to submit a Supplemental Biologics License Application (sBLA) to the US Food and Drug Administration (FDA) by the end of this year. Also included in the liberty asthma clinical development program is the traverse trial, a long-term safety extension study. The potential use of dupilumab in asthma is currently under clinical development and the safety and efficacy have not been fully evaluated by any regulatory authority.  

In March 2017, the US Food and Drug Administration (FDA) approved Dupixent (dupilumab) in the US for the treatment of adults with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies. The European Commission (EC) also granted marketing authorization for Dupixent for use in adults with moderate-to-severe atopic dermatitis who are candidates for systemic therapy in September 2017.