Mirna Chehade, MD, MPH: “Exciting” Phase 3 Data for Dupilumab in Pediatric Eosinophilic Esophagitis

Treatment with weight-tiered higher dose dupilumab led to significant and sustained improvements in key histologic, endoscopic, and cellular measures of eosinophilic esophagitis (EoE) in children 1-11 years of age, according to phase 3 data from the EoE KIDS trial.¹

Results were published in New England Journal of Medicine and suggest dupilumab’s potential to change the standard of care for young children with EoE, a population for whom there were no US Food and Drug Administration-approved medications prior to dupilumab’s expanded approval for children 1-11 years of age with EoE on January 25, 2024.^1,2

A randomized, double-blind, placebo-controlled phase 3 trial, EoE KIDS assessed the efficacy and safety of dupilumab in children aged 1-11 years with EoE. Part A enrolled 102 patients and evaluated dupilumab at a weight-tiered higher dose or lower dose regimen for 16 weeks, while Part B was a 36-week extended active treatment period in which eligible children in the dupilumab group from Part A maintained their higher or lower dose level, while those in the placebo group switched to higher or lower dose dupilumab. Of note, the trial is ongoing with a 108-week open-label extension period (Part C) to evaluate longer-term outcomes.³

In Part A, histologic remission was observed among 68% of participants in the higher-exposure arm, 58% of subjects in the lower-exposure arm, and 3% of those in the placebo arm, with a 65 percentage point difference in remission rates between the higher-exposure and placebo arms (95% confidence interval [CI], 48-81; P <.001) and a 55 percentage point difference between the lower-exposure arm and the placebo arm (95% CI, 37-73; P < .001). Additionally, significant improvements in participants’ endoscopic, histologic, and transcriptomic outcomes were observed among those with the higher-exposure dupilumab regimen versus placebo.¹

In a Q&A with the editorial team of HCPLive Gastroenterology, Mirna Chehade, MD, MPH, professor of pediatrics and medicine at the Icahn School of Medicine and founding director of the Mount Sinai Center for Eosinophilic Disorders, offered additional insight into the key findings from EoE KIDS and explained how they inform dupilumab’s use in pediatric patients with EoE.

HCPLive Gastroenterology: Can you explain dupilumab’s mechanism of action and what we know about its use in EoE, both in children and older patients?

Chehade: Dupilumab is a fully human monoclonal antibody directed against the IL4 receptor-alpha component of the type 2 receptor, and it inhibits signaling of interleukin-4 (IL-4) and interleukin-13 (IL-13).

Dupilumab has shown significant clinical benefit and a decrease in type 2 inflammation in several phase 3 trials, establishing that IL-4 and IL-13 are key drivers of the type 2 allergic inflammation that plays a major role in multiple related and often co-morbid atopic diseases, including EoE.

In EoE, dupilumab is now approved to treat patients as young as 1 year of age weighing at least 15 kg. Across age groups, the phase 3 placebo-controlled trials demonstrated significant and sustained histologic remission rates up to a year, as well as improvement in symptoms with dupilumab.

HCPLive Gastroenterology: Dupilumab recently earned FDA approval for children with EoE – what was the significance of this pipeline development? What did the burden/unmet need look like in this patient population?

Chehade: Dupilumab was approved in the U.S. to treat children aged 12 years and older in May 2022. Before its recent approval for children 1-11 years old in January 2024, there were no treatments approved for EoE specifically for this age group. Children with EoE received dietary restriction therapies or currently unapproved medications including proton pump inhibitors and topical corticosteroids used in an off-label fashion. Many children are refractory to these therapies including when used in various combinations. The great news is that dupilumab is an FDA-approved treatment option now available for children with EoE, which targets key drivers of the type 2 allergic inflammation that contribute to this disease.

HCPLive Gastroenterology: What were some of the key findings/takeaways from the EoE KIDS data published in NEJM?

Chehade: The trial showed a greater proportion of children aged 1-11 years receiving weight-tiered higher dose dupilumab experienced significant improvements in many key disease measures of EoE, compared to placebo, after 4 months. Higher dose dupilumab significantly improved key histologic, endoscopic and transcriptomic measures in children as young as 1 year of age, with sustained results for up to 1 year. These results reinforce the positive results seen in older patients with EoE and strengthen our understanding of IL-4 and IL-13 as key drivers of the type 2 allergic inflammation underlying this disease.

In addition, numerical reduction in symptoms as observed by caregivers and improvement in body weight for age percentile were seen at week 16, and were sustained at 1 year. These findings are particularly exciting especially for young children with EoE, as many experience food refusal and failure to thrive at a critical time of their growth and development.

HCPLive Gastroenterology: Did these data raise any safety concerns?

Chehade: The safety results in our EoE KIDS trial were generally consistent with the known safety profile of dupilumab in adolescents and adults with EoE. Adverse events more commonly observed with dupilumab (10% or higher) in either weight-based dosing regimen versus placebo in the trial were COVID-19, nausea, injection site pain and headache during the initial 16-week treatment period. The long-term safety profile of dupilumab in children aged 1 to 11 years through the extended treatment period up to 1 year was similar to that observed during the initial treatment period.

References

1. ^{Smith, T. Dupilumab Led to Histologic Remission in High Percentage of Children with EoE. HCPLive. June 27, 2024. Accessed July 3, 2024. https://www.hcplive.com/view/dupilumab-histologic-remission-high-percentage-children-eoe}
2. ^{Brooks, A. Dupilumab's Role in Managing Pediatric EoE, with Evan Dellon, MD, MPH. HCPLive. January 25, 2024. Accessed July 3, 2024. https://www.hcplive.com/view/dupilumab-s-role-in-managing-pediatric-eoe-with-evan-dellon-md-mph}
3. ^{Regeneron. DUPIXENT® (DUPILUMAB) POSITIVE PHASE 3 DATA IN CHILDREN 1 TO 11 YEARS OF AGE WITH EOSINOPHILIC ESOPHAGITIS PUBLISHED IN THE NEW ENGLAND JOURNAL OF MEDICINE. Press Releases. June 26, 2024. Accessed July 3, 2024. https://investor.regeneron.com/news-releases/news-release-details/dupixentr-dupilumab-positive-phase-3-data-children-1-11-years}