Dupixent® (dupilumab) Shows Significant Improvement in Eosinophilic Esophagitis in Pivotal Phase 3 Trial

Compiled by Keke

On October 26, Regeneron and Sanofi announced additional positive results from Part A of the pivotal Phase 3 clinical trial evaluating Dupixent® (dupilumab) for the treatment of patients aged 12 years and older with eosinophilic esophagitis (EoE), at the American College of Gastroenterology (ACG) Annual Meeting and the United European Gastroenterology (UEG) Week 2020.

Previously released results showed that the trial met both its primary endpoint and all key secondary endpoints. The latest data now demonstrate further improvement in disease severity and progression at the microscopic level, along with normalization of gene expression patterns associated with type 2 inflammation.

The two companies noted that previously reported results demonstrated that Dupixent improved symptoms, structural abnormalities, and histological endpoints in eosinophilic esophagitis (EoE). However, the use of Dupixent for the treatment of EoE remains investigational and has not yet undergone comprehensive evaluation by any regulatory authority.

A randomized, double-blind, placebo-controlled Phase 3 clinical trial evaluated the efficacy and safety of Dupixent in adolescents and adults. Part A of the trial enrolled 81 patients aged 12 years and older with eosinophilic esophagitis (EoE) (42 receiving Dupixent and 39 receiving placebo), based on histological and patient-reported outcomes; 85% of these patients had at least one concurrent allergic condition. During the 24-week treatment period, patients received either 300 mg of Dupixent or placebo weekly.

The co-primary endpoints of the trial were the change in the Dysphagia Symptom Questionnaire (DSQ) score, a patient-reported measure of dysphagia severity, and the proportion of patients achieving a peak esophageal intraepithelial eosinophil count ≤6 eos/hpf (eosinophils per high-power field) at Week 24, which is an indicator of esophageal inflammation. The key secondary endpoint assessed histopathological indicators of the severity and progression of esophageal tissue fibrosis, including the grading and staging scores of the Eosinophilic Esophagitis Histologic Scoring System (EoE-HSS), as well as the proportion of patients achieving a peak esophageal intraepithelial eosinophil count <15 eos/hpf at Week 24. Other secondary endpoints evaluated the relative change from baseline to Week 24 in the Normalized Enrichment Score (NES) for EoE diagnosis and the type 2 inflammatory transcriptomic signature.

The latest results show that patients treated with Dupixent experienced the following changes:

Rapid Improvement in Swallowing Ability and Comfort: Patients reported significant improvements in their DSQ as early as 4 weeks of treatment, with sustained improvement over 24 weeks (p<0.05 and p<0.001, respectively).

Reduction in Esophageal Eosinophil Count Below the Diagnostic Threshold for Disease: Within 24 weeks, 64% of patients in the Dupixent treatment group achieved <15 eos/hpf, compared to 8% in the placebo group (p<0.001). Compared with the placebo group, the peak esophageal eosinophil count in the Dupixent group decreased by 71% from baseline (p<0.001).

Reduction in Disease Severity and Progression at the Microscopic Level: At 24 weeks, compared with the placebo group, patients in the Dupixent group showed reductions of 0.761 and 0.753 in the grade and stage scores, respectively, for disease-related histologic changes in esophageal tissue; changes were also observed in the EoE-HSS grade and stage scores across eight cellular and tissue features measured by four subscales (all p-values <0.001).

Normalization of Gene Expression in Esophageal Tissue: As measured by NES, gene expression patterns associated with type 2 inflammation and EoE were reduced by 1.97-fold and 2.66-fold, respectively, from baseline to week 24 in patients treated with Dupixent, compared with reductions of 0.32-fold and 0.16-fold in the placebo group. NES assessed a set of genes associated with type 2 inflammation or EoE (all p-values <0.001). The changes observed in the Dupixent group indicate a shift in gene expression patterns from a disease-like profile resembling EoE to a profile similar to that of healthy controls.

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

It is reported that there are currently no FDA-approved treatments for eosinophilic esophagitis (EoE), a chronic and progressive inflammatory disease that damages the esophagus and impairs its normal function. Over time, excessive type 2 inflammation may lead to esophageal scarring and strictures, causing difficulty in swallowing. EoE can affect patients’ ability to eat and result in food getting stuck after swallowing (food impaction), leading to medical emergencies.

As the primary growth driver for Sanofi and Regeneron, Dupixent is a blockbuster drug that has received three approvals, with both pharmaceutical companies strategizing to achieve sustained growth through multiple clinical indications. In June 2020, the two partners outlined the next steps in the clinical development of Dupixent, including clinical trials for eosinophilic esophagitis (EoE), chronic obstructive pulmonary disease (COPD), prurigo nodularis, chronic spontaneous urticaria, and bullous pemphigoid.

The most advanced progress has been made in two Phase 3 trials for prurigo nodularis, a condition characterized by hard, itchy bumps on the skin for which there are currently no FDA-approved treatments in the United States. Regeneron stated that the latest data from these studies would be released as early as the second half of 2021, with regulatory submissions expected by the end of the year. Earlier this year, the two pharmaceutical companies enrolled 240 patients with chronic spontaneous urticaria in a clinical trial evaluating Dupixent, and they aim to submit approval applications for eosinophilic esophagitis (EoE) and chronic spontaneous urticaria in 2022. Additionally, Sanofi and Regeneron plan to submit regulatory filings for bullous pemphigoid and chronic obstructive pulmonary disease (COPD) in 2023 and 2024, respectively.

The two companies will maintain their 50-50 revenue split. In February, Sanofi CEO Paul Hudson predicted that Dupixent, which achieved $2.56 billion in sales in 2019, could ultimately reach annual sales of $10.97 billion. Also in February, SVB Leerink projected Dupixent’s sales to be $3.84 billion this year and $10 billion in 2026. This long-term forecast is 10%-15% higher than consensus expectations.

Reference Source:

1.Sanofi, Regeneron chase 4th Dupixent approval with rare esophageal disease data

2.Dupixent® (dupilumab) Late-breaking Pivotal Data Showing Significant Improvement in Eosinophilic Esophagitis Signs and Symptoms Presented for the First Time at Scientific Meetings