FDA Grants Breakthrough Therapy Designation to Sanofi/Regeneron’s Dupixent for Eosinophilic Esophagitis Based on Positive Phase III Results

September 15, 2020 /BioonBIOON/ -- Sanofi and its partner Regeneron recently announced jointly that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) to the novel anti-inflammatory drug Dupixent (Chinese brand name: Dabito; generic name: dupilumab) for the treatment of patients aged ≥12 years with eosinophilic esophagitis (EoE). This BTD is based on positive results from Part A of a pivotal Phase III trial evaluating Dupixent in patients with EoE. In 2017,FDAOrphan Drug Designation (ODD) was also granted for Dupixent in the treatment of EoE.

Currently, there is noFDADrugs Approved for the Treatment of EoE.Eosinophilic esophagitis (EoE) is a chronic and progressive type 2 inflammatory disease that damages the esophagus and impairs its normal function. Over time, excessive type 2 inflammation leads to esophageal scarring and strictures, causing difficulty in swallowing. If left untreated, EoE can affect patients’ ability to eat and result in food getting stuck after swallowing (food impaction), leading to medical emergencies. In the United States alone, approximately 160,000 patients with EoE are being treated with various unapproved therapies or dietary adjustments, among whom about 50,000 have failed multiple treatment options.

Breakthrough Therapy Designation (BTD) is a new drug review pathway established by the FDA in 2012, aimed at accelerating the development and review of new drugs intended to treat serious or life-threatening diseases, where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Drugs granted BTD can receive, during research and development, includingFDACloser guidance, including from senior officials, to ensure that new treatment options are made available to patients in the shortest possible time.

In May this year, Sanofi and Regeneron announced that the pivotal Phase III trial simultaneously met both co-primary endpoints and all key secondary endpoints. According to this study,Dupixent is the first and only in Phase IIIClinical TrialsBiologics that demonstrated positive and clinically meaningful outcomes in patients with eosinophilic esophagitis (EoE) aged ≥12 years.Part B of this ongoing Phase III trial is evaluating an additional dosing regimen for Dupixent, with patients continuing into a 28-week extended active treatment period (Part C) after completing Part A or Part B. In this trial, nearly half of the patients had undergone procedures such as esophageal dilation, and nearly three-quarters had previously received corticosteroid therapy.

Eosinophilic Esophagitis (Image source: frontiersin.org)

This pivotal Phase III trial is a randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Dupixent in adolescent and adult patients with eosinophilic esophagitis (EoE). Part A of the trial enrolled 81 patients aged ≥12 years with EoE, confirmed by histology and patient-reported outcomes. In the study, patients were randomized to receive either subcutaneous injections of Dupixent 300 mg once weekly (n=) or placebo (n=39) for 24 weeks. The co-primary endpoints were: the change from baseline in the Dysphagia Symptom Questionnaire (DSQ, a patient-reported measure of dysphagia) at Week 24, and the proportion of patients achieving a peak esophageal intraepithelial eosinophil count ≤6 eosinophils per high-power field (eos/hpf, a measure of esophageal inflammation). Among patients in Part A, the mean baseline DSQ score was 34, and the mean baseline peak eosinophil level was 89 eos/hpf.

The results showed that from baseline to Week 24 of treatment: (1) Disease symptoms decreased by 69% in the Dupixent group and by 32% in the placebo group (p=0.0002). Disease symptoms were measured using the Dysphagia Symptom Questionnaire (DSQ), which was one of the co-primary endpoints of the study: on a scale of 0–84, the Dupixent group showed an improvement of 21.92 points, while the placebo group showed an improvement of 9.60 points. (2) In the Dupixent group, 60% of patients achieved a reduction in eosinophil counts to within the normal range, compared with 5% in the placebo group; this was the other co-primary endpoint of the study. (3) Endoscopic abnormalities decreased by 39% in the Dupixent group and by 0.6% in the placebo group, as measured by the Eosinophilic Esophagitis Endoscopic Reference Score (EoE-EREFS); the Dupixent group showed a reduction of 3.2 points, while the placebo group showed a reduction of 0.3 points (p<0.0001).

The trial demonstrated that the safety profile of Dupixent was consistent with the known safety profile in its approved indications. During the 24-week treatment period, the overall incidence of adverse events was 86% in the Dupixent group and 82% in the placebo group. Adverse events more commonly observed with Dupixent treatment included injection site reactions (15 cases in the Dupixent group vs. 12 in the placebo group) and upper respiratory tract infections (11 cases in the Dupixent group vs. 6 in the placebo group). One patient in the Dupixent group discontinued treatment due to arthralgia.

Dupixent was launched in late March 2017 and has currently been approved for the treatment of three diseases caused by type 2 inflammation: moderate-to-severe atopic dermatitis (patients aged ≥6 years), moderate-to-severeAsthma(≥12 years of age), chronic rhinosinusitis with nasal polyps (CRSwNP, adult patients).

Dupixent is a fully human monoclonal antibody that inhibits the signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13). From DupixentClinical TrialData show that IL-4 and IL-13 are key drivers of type 2 inflammation, inAsthma, plays a key role in CRSwNP and atopic dermatitis. Across all approved indications globally, more than 170,000 patients have been treated with Dupixent.

In China, Dupixent (dupilumab) was approved by the National Medical Products Administration (NMPA) in June this year for the treatment of moderate-to-severe atopic dermatitis (AD) in adults.Dupixent is the first and only targeted biologic approved worldwide for the treatment of moderate-to-severe atopic dermatitis in adults, addressing an unmet clinical need in China by rapidly, significantly, and sustainably improving skin lesions and pruritus in patients with atopic dermatitis. Benefiting from regulatory reforms, Dupixent was approved in China two years ahead of schedule, providing Chinese patients with a novel therapeutic option.

Currently, Sanofi and Regeneron are also conducting an extensive clinical program to evaluate Dupixent for the treatment of diseases caused by allergies and other type 2 inflammation, including: pediatric patientsAsthma(6–11 years, Phase III), pediatric atopic dermatitis (6 months to 5 years, Phase III), eosinophilic esophagitis (Phase III), chronic obstructive pulmonary disease (Phase III), bullous pemphigoid (Phase III), prurigo nodularis (Phase III), chronic spontaneous urticaria (Phase III), and food and environmental allergies (Phase II).

Dupixent is another key product co-developed by Sanofi and Regeneron following their collaboration on the PCSK9 inhibitor lipid-lowering drug Praluent, and it holds promise as a game-changing therapy. Currently, the indications for Dupixent are steadily expanding. EvaluatePharma, a pharmaceutical market research firm, previously predicted that global sales of this drug could reach $8 billion in 2024. (Bioon.com)

Original Source:FDA Grants Dupixent® (dupilumab) Breakthrough Therapy Designation for Eosinophilic Esophagitis