乌鸦传媒

Dupilumab (Dupixent) was superior to placebo in the phase III trial underpinning its approval last spring for eosinophilic esophagitis (EoE), researchers said.

About 60% of patients receiving the active drug -- a monoclonal antibody targeting interleukin (IL) types 4 and 13 -- achieved histologic remission, compared with just 5%-6% assigned to placebo in the multi-part study by week 24, according to Evan S. Dellon, MD, MPH, of the University of North Carolina at Chapel Hill, and colleagues.

As well, Dysphagia Symptom Questionnaire (DSQ) scores -- the trial's co-primary endpoint -- declined more in the dupilumab groups, by approximately 10-12 points relative to placebo, they reported in the .

Safety findings generally matched expectations, given that dupilumab has an established record from its already approved uses in asthma, atopic dermatitis, and chronic rhinosinusitis. The FDA in May largely on the strength of the , making it the first drug to carry an official EoE indication in the U.S.

In an , Alex Straumann, MD, of University Hospital Zurich, welcomed the approval for "extend[ing] the limited armamentarium of medications now available" for EoE.

He cautioned, though, that dupilumab doesn't necessarily move to the head of the line for EoE therapy. Straumann questioned "whether patients with eosinophilic esophagitis, a disease localized to esophagus, stand to benefit from drugs that act systemically," given that locally acting agents, such as swallowed corticosteroids, also bring histologic remission to most patients. Straumann also pointed out that other types of topical therapy, perhaps with Janus kinase or calcineurin inhibitors, might prove even more effective. "[T]heir use should be further evaluated for the treatment of eosinophilic esophagitis, particularly the difficult-to-treat form," he wrote.

The study was divided into three parts, testing two dupilumab dosing regimens (300 mg weekly or every other week) and including an extension phase in which the placebo groups were switched to dupilumab. In Part A, 81 patients were randomized to placebo or the active drug at 300 mg weekly for 24 weeks. Part B randomized a separate group of 240 patients 1:1:1 to dupilumab at 300 mg weekly or biweekly or to placebo, also for 24 weeks. At the end of Parts A and B, Part C commenced with all patients in the placebo group given dupilumab for an additional 28 weeks; those coming from Part A were all dosed at 300-mg weekly, while those from Part B were re-randomized 1:1 to the two dupilumab regimens. The extension phase from Part B was not completed in time for the NEJM report.

Roughly 60% of all participants were men. Patients as young as age 12 years were eligible; participants' mean age was approximately 30, with disease duration averaging about 5 years. Most had used swallowed steroids, and most of those did not obtain good responses. DSQ scores at baseline averaged about 35 on the instrument's 84-point scale, with higher values reflecting more severe symptoms.

Histologic remission rates at week 24 were almost identical for the two dupilumab regimens across both Parts A and B, at 59%-60%. Only a handful of patients assigned to placebo obtained histologic remission. The difference in response rates between placebo and both dupilumab dosing regimens was also massive, at 55 percentage points in Part A, 54 percentage points for Part B with weekly dosing, and 56 percentage points in Part B with biweekly dosing. Yet this latter difference was judged statistically insignificant in hierarchical testing, and the FDA only allowed the 30-mg weekly dose in its approval for EoE.

Most patients experienced adverse events (AEs) but with little difference between placebo and the active drug, with injection-site reactions accounting for the majority. Only seven patients withdrew from the study because of AEs in Parts A and B, including two receiving placebo.

Perhaps the most significant limitation in the trial, as noted by Straumann, was the placebo control. "[W]hether dupilumab is better than the good old topical glucocorticoids in improving disease outcomes, particularly in light of considerable costs associated with [dupilumab] treatment, remains to be demonstrated," he observed.

An oral tablet form of the steroid budesonide called Jorveza has been since 2018, but its maker appears to have made no effort to gain U.S. approval. Also, Takeda had been seeking the okay for a liquid budesonide suspension until the a year ago; the company then altogether.

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