Dupilumab confers remission of eosinophilic esophagitis among young children
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Children aged 1 to 11 years with eosinophilic esophagitis safely achieved histologic disease remission after 16 weeks of treatment with the fully human monoclonal antibody dupilumab, according to the results of a phase 3 trial.
Dupilumab (Dupixent, Sanofi Genzyme/Regeneron) inhibits the signaling of the IL-4 and IL-13 pathways, which drive type 2 inflammation. It is currently FDA approved for treating eosinophilic esophagitis in adults and children aged 12 years and older.
“Eosinophilic esophagitis can turn the basic and life-sustaining act of eating into a painful experience at a point in children’s lives when proper nutrition and achieving a healthy weight is critical to ensuring they grow and thrive,” George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, said in a company press release.
“The positive results from this phase 3 pediatric trial show Dupixent has the potential to improve signs of eosinophilic esophagitis and support healthy weight gain in children from their first birthday,” said Yancopoulos, who also is the principal inventor of dupilumab.
Children with EoE experience vomiting, abdominal discomfort, trouble swallowing and failure to thrive, according to the press release, impacting growth and development while causing food-related fear and anxiety that can persist into adulthood.
Treatment primarily consists of diet adjustments, in addition to proton pump inhibitors, swallowed topical corticosteroids and, in severe cases, feeding tubes to ensure proper caloric intake and weight gain. Yet about 9,000 of the approximately 21,000 children aged younger than 12 years in the United States with EoE do not satisfactorily respond to treatment.
“The lack of treatment options for children living with eosinophilic esophagitis leaves many caregivers with the stress and burden of adapting their child’s meals and their entire family’s schedules to ensure healthy growth and development,” Namish Patel, MD, senior vice president, head of global development, immunology and inflammation at Sanofi, said in the press release.
“In some cases, they must resort to off-label use of poorly studied treatments like steroids that can pose serious health risks when used long term,” Patel continued.
The trial included 102 children aged 1 to 11 years who received a higher dose of dupilumab (n = 37), a lower dose (n = 31) or placebo (n = 34). Doses were subcutaneous and administered every 2 or 4 weeks, based on weight.
“The faster and larger than anticipated enrollment in this trial further emphasizes the unmet treatment needs for children with EoE and underscores the significance of these first-ever positive results,” Patel said.
At 16 weeks, 68% of the higher-dose group and 58% of the lower-dose group achieved significant histologic disease remission, defined as a peak esophageal intraepithelial eosinophil count of 6 or fewer eosinophils/high power field, compared with 3% on placebo (both, P < .0001).
Also at 16 weeks, the children in the higher-dose group experienced:
- an 86% reduction in peak esophageal intraepithelial eosinophil count from baseline vs. a 21% increase for placebo (P < .0001);
- a 0.88 reduction in disease severity and a 0.84 reduction in disease extent from baseline as measured at the microscopic level in biopsy specimens compared with a 0.02 and 0.05 increase for placebo (both, P < .0001);
- a 3.5-point reduction from baseline in abnormal endoscopic findings vs. a 0.3-point increase for placebo (P < .0001);
- a numerical, but statistically non-significant, improvement from baseline in the proportion of days that children experienced EoE symptoms based on a caregiver questionnaire compared with placebo; and
- a 3.09 percentile increase from baseline in body weight for age percentile vs. 0.29 for placebo.
The children in the lower-dose group also experienced nominally significant results in histological, anatomic and cellular secondary endpoints that generally were comparable with the higher dose, the researchers said.
The researchers also said safety results generally were consistent with dupilumab’s known safety profile in treating patients for EoE aged 12 years and older who weigh at least 40 kg, with a 79% adverse event rate for dupilumab and a 91% adverse event rate for placebo.
Adverse events more commonly observed with dupilumab than with placebo included COVID-19 (21% dupilumab, 0% placebo), rash (9% dupilumab, 6% placebo), headache (8% dupilumab, 3% placebo), viral gastroenteritis (6% dupilumab, 3% placebo), diarrhea (6% dupilumab, 3% placebo) and nausea (6% dupilumab, 0% placebo).
The trial is continuing with a 36-week extended active treatment period to evaluate long-term outcomes. The companies said they will discuss their data with global regulatory authorities beginning later this year and share more detailed results at an upcoming medical meeting.
Perspective
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These are not necessarily surprising results, but they are very significant, as it is extraordinary to study a biological agent in children aged as young as 1 year and also to show its positive effect. This is fantastic, as it will likely open new therapy for young children, an age group that often lags behind therapy.
This treatment is necessary for children in this age range because EoE presents at many ages. In fact, our research found that presentation before 18 months of life is a form of the disease that we call very early-onset EoE, or vEoE. In fact, this is the most common age range for EoE in children.
This long-awaited treatment will help these children live a better life. Next, research should follow young children on the drug for a longer period of time to understand the natural history of the disease and how dupilumab impacts it.
Reference:
Lyles JL, et al. J Allergy Clin Immunol. 2021;doi:10.1016/j.jaci.2020.10.017.
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