Clinical Trials

Date: 2016-10-01

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

Company: Sanofi (France) Regeneron Pharmaceuticals (USA - NY)

Product: Dupixent® (dupilumab)

Action mechanism:

• monoclonal antibody. Dupilumab, a fully-human monoclonal antibody, is directed against the shared IL-4 receptor alpha subunit, which blocks signaling from both IL-4 and IL-13. IL-4 and IL-13 are key cytokines that are required for the initiation and maintenance of the Th2 (Type 2 helper T-cell) immune response, which is believed to be a critical pathway in allergic inflammation.
• Dupilumab was created using Regeneron's pioneering VelocImmune® technology and is being co-developed with Sanofi in asthma, atopic dermatitis and chronic sinusitis with nasal polyposis. The FDA granted dupilumab breakthrough therapy designation in atopic dermatitis in November 2014.

Disease: moderate-to-severe atopic dermatitis

Therapeutic area: Dermatological diseases - Inflammatory diseases

Country: Bulgaria, Canada, Denmark, Estonia, Finland, France, Germany, Hong Kong, Japan, Republic of Korea, Lithuania, Poland, Singapore, Spain, Sweden, UK, USA

Trial details:

• The Liberty AD Phase 3 clinical program consists of five trials of patients with moderate-to-severe atopic dermatitis (AD) at sites worldwide. The SOLO1 and SOLO2 studies are randomized, double-blind, placebo-controlled, parallel group studies to confirm the efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis. A total of 1,379 adult patients with moderate-to-severe AD were enrolled in the identically designed SOLO 1 and SOLO 2 trials. Patients were enrolled if they were not adequately controlled with topical medications, or if topical treatment was not medically advisable. All patients were assessed via the 5-point Investigator’s Global Assessment (IGA) scale, ranging from 0 (clear) to 4 (severe); entry criteria required a baseline score of 3 or 4. Patients were also assessed using the Eczema Area and Severity Index (EASI) and other measures. Patients were randomized into one of three treatment groups: Dupixent 300 mg subcutaneously once per week, Dupixent 300 mg subcutaneously every two weeks, or placebo for 16 weeks following an initial Dupixent loading dose of 600 mg subcutaneously, or placebo. (SOLO1 and SOLO2)

Latest news:

• • On October 1, 2016,  Sanofi and Regeneron Pharmaceuticals announced that detailed results from LIBERTY AD SOLO 1 and SOLO 2, two placebo-controlled Phase 3 studies evaluating investigational Dupixent® (dupilumab) in adult patients with inadequately controlled moderate-to-severe atopic dermatitis , were published in The New England Journal of Medicine.
• The studies met their primary endpoints evaluating extent and severity of the disease. In addition, both trials met key secondary endpoints measuring reduction in itch, improvement in patient-reported anxiety and depression symptoms, and certain quality of life measures. Dupixent® inhibits signaling of IL-4 and IL-13, two key cytokines required for the type 2 (including Th2) immune response, which is believed to be a major driver in AD and in certain atopic or allergic diseases, including asthma and nasal polyposis, where Dupixent is being evaluated in ongoing clinical trials.
• The paper provides data on key endpoints including: At 16 weeks for SOLO 1 and SOLO 2, respectively, 37 and 36 percent of adult patients who received Dupixent® 300 mg weekly, and 38 and 36 percent of patients who received Dupixent 300 mg every two weeks, achieved clearing or near-clearing of skin lesions as measured by the 5-point Investigator’s Global Assessment (IGA) scale, compared to 10 and 8 percent with placebo. This was the primary endpoint of the study in the U.S. and one of the primary endpoints in the EU.
• At 16 weeks for SOLO 1 and SOLO 2, respectively, 52 and 48 percent of adult patients who received Dupixent 300 mg weekly, and 51 and 44 percent of patients who received Dupixent 300 mg every two weeks, achieved a 75 percent or greater reduction in their Eczema Area and Severity Index score (EASI-75) compared to 15 and 12 percent with placebo. This was the key secondary endpoint in the US and one of the primary endpoints in the EU. At 16 weeks for SOLO 1 and SOLO 2, respectively, the percent improvement in EASI from baseline was 72 and 69 percent in patients who received the 300 mg weekly dose, and 72 and 67 percent for patients who received Dupixent 300 mg every two weeks, compared to 38 and 31 percent for placebo. The reduction in the daily intensity of patient-reported itch, as measured by the Pruritus Numerical Rating Scale (NRS), was a secondary endpoint that was met at 2 weeks, 4 weeks and 16 weeks. The Pruritus NRS ranges from 0 (no itch) to 10 (worst itch imaginable). At 16 weeks, for SOLO 1 and SOLO 2, respectively, 41 and 36 percent of patients who received Dupixent 300 mg every two weeks, and 40 and 39 percent of patients who received Dupixent 300 mg weekly, achieved a four-point or greater reduction in their NRS score compared to 12 and 10 percent with placebo (p less than 0.001 for all regimens and trials). Other positive secondary endpoints discussed in the paper include improvement in patient-reported anxiety and depression symptoms and certain quality of life measures as evaluated by Scoring Atopic Dermatitis (SCORAD), Hospital Anxiety and Depression Scale (HADS), Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI). For the 16-week treatment period, the overall rate of adverse events (65-73 percent Dupixent® and 65-72 percent placebo) was comparable between the Dupixent® groups and the placebo groups. The proportion of patients who completed the treatment period was 88-94 percent for Dupixent® and 80.5-82 percent for placebo. The rate of serious adverse events was 1-3 percent for Dupixent® and 5-6 percent for placebo. Serious or severe infections were similar in the Dupixent® and placebo groups in both studies (1 percent Dupixent and 1 percent placebo). Adverse events that were noted to have a higher rate with Dupixent® treatment across both studies included injection site reactions (8-19 percent Dupixent®; 6 percent placebo), conjunctivitis (1-5 percent Dupixent®; 1 percent placebo). No patient discontinued therapy due to injection site reactions and one patient discontinued therapy due to conjunctivitis. The Dupixent® Biologics License Application (BLA) was recently accepted for Priority Review by the FDA with a target action date of March 29, 2017.
• • On April 1, 2016, Regeneron Pharmaceuticals and Sanofi announced that LIBERTY AD SOLO 1 and SOLO 2 met their primary endpoints. In the studies, treatment with dupilumab as monotherapy significantly improved measures of overall disease severity, skin clearing, itching, quality of life, and mental health. Results  included the following:
• For SOLO 1 and SOLO 2, respectively, 37 and 36 percent of patients who received dupilumab 300 mg weekly, and 38 and 36 percent of patients who received dupilumab 300 mg every two weeks, achieved clearing or near-clearing of skin lesions (IGA 0 or 1), compared to 10 and 8.5 percent with placebo (p less than 0.0001). This was the primary endpoint of the study in the U.S. and one of the primary endpoints in the EU.
• For SOLO 1 and SOLO 2, respectively, the percent improvement in EASI from baseline was 72 and 69 percent in patients who received the 300 mg weekly dose, and 72 and 67 percent for patients who received dupilumab 300 mg every two weeks, compared to 38 and 31 percent for placebo (p less than 0.0001).
• For SOLO 1 and SOLO 2, respectively, 52.5 and 48 percent of patients who received dupilumab 300 mg weekly, and 51 and 44 percent of patients who received dupilumab 300 mg every two weeks, achieved EASI-75 compared to 15 and 12 percent with placebo (p less than 0.0001). This was the key secondary endpoint in the US and one of the primary endpoints in the EU.
• For the 16-week treatment period, the overall rate of adverse events (65-73 percent dupilumab and 65-72 percent placebo) was comparable between the dupilumab groups and the placebo groups. The proportion of patients who completed the treatment period was 88-94 percent for dupilumab and 80.5-82 percent for placebo. The rate of serious adverse events was 1-3 percent for dupilumab and 5-6 percent for placebo.
• Serious and severe infections were also numerically higher in the placebo groups in both studies (0.5-1 percent dupilumab and 2-3 percent placebo). Adverse events that were noted to have a higher rate with dupilumab treatment across both studies included injection site reactions (10-20 percent dupilumab; 7-8 percent placebo) and conjunctivitis (7-12 percent dupilumab; 2 percent placebo); approximately 26 percent of patients in both studies reported a history of allergic conjunctivitis at study entry. No patient discontinued therapy due to injection site reactions and only one patient discontinued therapy due to conjunctivitis. More detailed results from SOLO 1 and SOLO 2 will be submitted for presentation at a future medical congress.

 

Is general: Yes