Dupilumab improves eosinophilic esophagitis outcomes through 52 weeks
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Weekly subcutaneous doses of dupilumab improved histologic outcomes and alleviated symptoms for adults and adolescents with eosinophilic esophagitis, according to a study published in The New England Journal of Medicine.
“The surprising result was that clinical symptom improvement only occurred with weekly dosing even though all other endpoints improved with every-other-week dosing,” Marc E. Rothenberg, MD, PhD, director of the division of allergy and immunology at Cincinnati Children’s Hospital and a Healio Allergy/Asthma Peer Perspective Board Member, told Healio, adding that the FDA used these data to recently approve dupilumab (Dupixent; Sanofi, Regeneron) for adults and children aged 12 years and older with EoE.
Study design
The phase 3 study involved patients aged 12 years and older with EoE. In Part A, researchers randomly assigned 81 patients (mean age, 3.15 years; 40% women) 1:1 to receive 300 mg of dupilumab (Dupixent; Sanofi, Regeneron) or matching placebo weekly. In Part B, researchers randomly assigned 240 patients (mean age, 28.1 years; 36% women) 1:1:1 to receive dupilumab every week or every 2 weeks or placebo for 24 weeks.
The study then extended the previous work through 52 weeks in Part C, which included 40 patients assigned dupilumab who completed Part A and 37 patients on placebo in Part A who began taking 300 mg of dupilumab. Part C that included patients from Part B who continued with dupilumab is ongoing.
Mean duration of EoE was 5 years for the cohort from Part A and 5.6 years for the cohort from Part B, with corresponding mean Dysphagia Symptom Questionnaire (DSQ) scores of 33.6 and 36.7.
Histologic remission — defined as 6 eosinophils per high power frequency (eos/hpf) or less — and change from baseline in DSQ score, for which higher scores on a scale of 0 to 84 indicate frequent or more severe dysphagia, served as the study’s two primary endpoints at week 24.
Primary endpoints
At week 24, histologic remission occurred among 25 of 42 patients (60%) receiving weekly dupilumab and two of 39 patients (5%) receiving placebo in Part A, with an adjusted between-group difference of 55 percentage points (95% CI, 40-71; P < .001), and, in Part B, five of 79 patients (6%) assigned placebo compared with 47 of 80 patients (59%) assigned weekly dupilumab (between-group difference, 54 percentage points; 95% CI, 41-66; P < .001) and 49 of 81 patients (60%) assigned dupilumab every 2 weeks (between group difference, 56 percentage points; 95% CI, 43-69). The differences for the 2-week regimen did not reach statistical significance per the study’s hierarchal plan.
The patients taking dupilumab in Group A also had greater reductions in DSQ scores between baseline and week 24 than those on placebo (least-squares mean change, –21.92 points vs. –9.6 points; difference, –12.32 points; 95% CI, –19.11 to –5.54). The difference in DSQ scores for Part B also was significantly greater for those assigned dupilumab weekly (–9.92; 95% CI, –14.81 to –5.02) but not every 2 weeks (–0.51; 95% CI, –5.42 to 4.41).
Part C data
According to the researchers, these effects were sustained among patients from Group A who continued receiving dupilumab in Group C through week 52, with 19 of 34 patients (56%) achieving histologic remission and 28 of 34 patients (82%) with fewer than 15 eos/hpf.
The patients who received placebo in Part A and then began dupilumab in Group C experienced effects at week 52 resembling those experienced at week 24 by the patients taking dupilumab in Group A. Specifically, 18 of 30 patients (60%) experienced histologic remission and 21 (70%) had fewer than 15 eos/hpf.
Regarding DSQ scores, researchers saw sustained improvements for patients who continued dupilumab from Group A through Group C (mean change from baseline, –23.44 points; 95% CI, –29.58 to –17.3), with similar improvements to those observed with weekly dupilumab in Part A for those who switched from placebo (–21.71 points; 95% CI, –29.13 to –14.3).
Quality of life, safety
Compared with those on placebo, patients in Part A assigned dupilumab demonstrated improvements in EoE Impact Questionnaire (least-squares mean between-group difference, –0.37 points; 95% CI, –0.64 to –0.1) and EoE Symptom Questionnaire frequency (least-squares mean between-group difference, –1.7 points; 95% CI, –2.93 to –0.52) and severity scores (least-squares mean between-group difference, –2; 95% CI, –3.87 to –0.03) at week 24. Data from Part B generally showed greater differences compared with placebo for those assigned weekly vs. every 2 weeks dupilumab.
These improvements were sustained for patients who received dupilumab in Parts A and C, and those patients on placebo in Part A who began dupilumab in Part C saw similar improvements, both at week 52.
Adverse event incidences ranged from 60% to 86% across the trial groups during the treatment period, most frequently involving injection-site reactions, with rare incidences of conjunctivitis and no deaths reported.
Looking ahead
Overall, the researchers concluded, weekly doses of 300 mg of dupilumab improved histologic outcomes and reduced symptoms among adolescents and adults with EoE through 52 weeks.
“Dupilumab is very effective and safe for EoE and should be considered for patients refractory to current management,” Rothenberg said, adding that it especially would benefit those who are refractory to protein pump inhibitors.
Next, the researchers aim to complete their study of children aged 12 years and younger, hopefully with FDA approval, Rothenberg said. They also want to examine the durability and side effects of the treatment.
Further, research will examine which patients do not respond to treatment, why they do not improve clinically with dosing every other week even with the achievement of all other endpoints and to understand if diet therapy could be advanced with dupilumab, among other goals.
Despite these findings, several questions remain regarding the use of dupilumab, according to an accompanying editorial written by Alex Straumann, MD, of the department of gastroenterology at University Hospital Zurich in Switzerland. Specifically, these questions include where to position dupilumab in the EoE treatment algorithm, and whether EoE should be treated systemically given that topical glucocorticoids have been shown to be as effective as prednisone.
“Dupilumab is the [FDA]-approved biologic with proven efficacy in reducing inflammation and symptoms in patients with esophageal eosinophilia,” Straumann wrote. “However, whether dupilumab is better than the good old topical glucocorticoids in improving disease outcomes, particularly in light of considerable costs associated with this treatment, remains to be demonstrated.”
For more information:
Marc E. Rothenberg, MD, PhD, can be reached at marc.rothenberg@cchmc.org.