Children achieve remission in eosinophilic esophagitis with dupilumab
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Key takeaways:
- The FDA approved dupilumab for eosinophilic esophagitis in children in January.
- Patients achieved improvements in histologic, endoscopic and transcriptomic measures.
- Adverse events were mild to moderate.
There were significant differences in percentages of children with eosinophilic esophagitis who experienced histologic remission with dupilumab compared with placebo, according to a study published in The New England Journal of Medicine.
Children treated with dupilumab also experienced improvements in seven other endpoints, Mirna Chehade, MD, MPH, professor of pediatrics and medicine at Icahn School of Medicine at Mount Sinai and founding director of the Mount Sinai Center for Eosinophilic Disorders, and colleagues wrote.
EoE is a chronic disease of the esophagus associated with a type 2 allergic inflammation, Chehade told Healio.
“Children with EoE can suffer from multiple symptoms including abdominal pain, vomiting, regurgitation, trouble swallowing and food impaction,” she said. “In addition, when EoE affects children at a young age, it can severely impact their ability to eat and can cause failure to thrive at a critical time of their growth and development.”
In January, the FDA approved dupilumab (Dupixent; Sanofi, Regeneron) to treat children with EoE aged 1 to 11 years who weigh at least 15 kg. As a fully human monoclonal antibody, dupilumab blocks IL-4 and IL-13 pathways to inhibit type 2 inflammation.
“Before dupilumab, there were no treatments approved specifically for EoE in this age group,” Chehade said. “Now, with dupilumab, parents/caregivers have an FDA-approved biologic treatment option that targets key drivers of the type 2 allergic inflammation that contributes to this disease.”
Study design, results
The study included 102 children aged 1 to 11 years (mean age, 7.1 years; 76% boys; 82% white) with active EoE, defined as a peak esophageal intraepithelial eosinophil count of 15 or more per high-power field in at least two of three esophageal regions, along with a lack of response to proton-pump inhibitors.
The three-part trial began with part A, which included 37 patients assigned to higher exposures of dupilumab (mean age, 6.8 years; 76% boys; 86% white), 31 assigned to lower exposures (mean age, 7.2 years; 81% boys; 71% white) and 34 assigned to placebo (mean age, 7.2 years; 74% boys; 84% white) for 16 weeks.
In part B, which ran from week 17 to week 52, the 37 patients (100%) on higher exposure in part A continued this regimen, and 29 patients (94%) who were in the lower exposure group in part A continued with that regimen. Also, 18 patients (53%) in the placebo group switched to a higher exposure regimen, and 14 (41%) switched to lower exposure.
“We were able to demonstrate not only reduction of esophageal eosinophil counts when using dupilumab, but also significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo,” Chehade said.
At week 16, 68% (n = 25) of the higher-exposure group, 58% (n = 18) of the lower-exposure group and 3% (n = 1) of the placebo group experienced histologic remission (P < .001), defined as a peak esophageal intraepithelial eosinophil count of 6 or less per high-power field.
There also were significant differences between the higher-exposure and placebo groups at week 16 in seven secondary endpoints across histologic (peak esophageal intraepithelial eosinophil count and EoE histology scoring system grade and stage scores), transcriptomic (type 2 inflammation and EoE diagnostic panel gene signatures) and endoscopic (total EoE Reference Score) categories.
“These improvements were maintained when children were evaluated after a full year of receiving dupilumab,” Chehade said.
Patients who continued the same dupilumab treatment from part A into part B experienced improvements in histologic and endoscopic measures that were similar to those seen between baseline and week 16, the researchers said.
The patients who switched from placebo to dupilumab between parts A and B saw improvements that were similar to the improvements experienced by the dupilumab groups between baseline and week 16.
Compared with the placebo group, esophageal gene-expression profiles of two gene sets that are associated with active EoE — the type 2 inflammation set and the EoE diagnostic panel set — also saw significant improvement among patients in the higher-exposure group between baseline and week 16, the researchers said.
Specifically, the higher-exposure group had significantly lower normalized enrichment scores for the relative change between baseline and week 16 in the gene-expression signatures of these sets than the placebo group.
The higher-exposure group had mean serum concentrations of dupilumab at weeks 16 and 52 that were approximately twice as high as those of the lower-exposure group, the researchers said.
Also, one patient each in the higher-exposure group and placebo group had antibodies to dupilumab in part A. The patient from the higher-exposure group had relatively low levels of antibodies, the researchers said, with no apparent effect on the biologic’s efficacy. No antibodies to dupilumab were detected in any other patients.
Adverse event incidence ranged from 73% to 100% across the study groups and parts. Most were mild or moderate. Three patients discontinued treatment because of adverse events, but these events were not considered serious.
Nine patients reported serious events in parts A and B, but none of them were related to dupilumab or placebo, and none led to death.
Conclusions
Overall, the researchers said, these findings indicate significantly higher rates of remission with dupilumab among children aged 1 to 11 years through 52 weeks compared with placebo, as well as other histologic, endoscopic and transcriptomic improvements with a tolerable safety profile.
Chehade also said that these results led to the FDA’s approval for the use of dupilumab to treat EoE in this age group.
“I am excited because dupilumab has the potential to transform the standard of care for many young children living with EoE,” she said.
By demonstrating that dupilumab can significantly reduce esophageal inflammation and possibly improve symptoms, Chehade said that these findings also bring hope to children with EoE and their caregivers at a critical time of their growth and development.
“Controlling the inflammation in EoE also has the potential to reduce the chance of long-term complications that patients can develop over time if their EoE is left untreated or inadequately treated,” Chehade said.
The open-label extension of the ongoing trial will run through 2 years to enable the researchers to evaluate longer-term outcomes in children with EoE, Chehade said.
For more information:
Mirna Chehade, MD, MPH, can be reached at mirna.chehade@mssm.edu.
Perspective
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These findings in children aged 1 to 11 years are similar to the studies of patients aged 12 years and older, so there are no surprises. Also, dupilumab has been a very effective biologic in a number of allergic diseases. These outcomes in EoE as well as in other approved applications have been life-changing for many patients.
Dupilumab provides effective therapy for those who have failed other modalities, but it should not be considered first-line therapy for a number of reasons. First, it is costly. It also requires frequent injections, which may be a significant impediment for younger children.
The current understanding is that once the medication is stopped, disease returns. (Studies are ongoing.) In younger children, there is the possibility the drug may be “disease modifying,” which means that it slows, reverses or delays progression of the disease.
However, at this point, parents need to consider the possibility of very long-term use. Dupilumab’s short-term safety is good, but its long-term safety is unknown. Also, therapies such as diet elimination can be effective in long-term treatment.
Swallowed topical glucocorticosteroids are now approved for children aged 12 years and older. These medications are used off label in young children with good efficacy and safety, and the lack of FDA approval for children aged younger than 12 years has not been an impediment to use.
Long-term studies with dupilumab, especially regarding disease modification and the impact of stopping the drug, are needed.
As with all therapy, there are pros and cons. This drug provides another option for families and providers. However, with all therapies, especially those with potential long-term use, shared decision-making is essential.
Perspective
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The results are exciting, but not surprising given the clear benefit from dupilumab observed from the former trial, LIBERTY EoE TREET, which was conducted in older children and adults. Still, the results are highly significant given the increasing incidence of EoE observed across age groups, including younger children, over the past 2 decades and, until recently, the lack of available therapies to treat this patient population.
This treatment will likely have a significant impact on the management of younger children with EoE, given this is the only FDA-approved therapy currently for the treatment of EoE in this age group. Evidence supports that early treatment is necessary to prevent development of fibrosis and fibrosis-related complications. The findings from this study provide strong evidence of support that dupilumab, particularly at the higher dose, leads to improvement across multiple indices, including endoscopic, histologic and transcriptomic markers of disease activity.
A key question for many clinicians and investigators is whether there may be an opportunity to decrease dosing, once initial response has been achieved, among children responsive to dupilumab, and if this response can be maintained at this lower dose. Other questions are whether we can fully liberate a child’s diet, once they respond to dupilumab, or whether there are some children for whom dietary elimination strategies must be maintained, even while on dupilumab.
Additionally, another area of research is whether there are children who would benefit from a more rapid escalation to dupilumab therapy, without a protein pump inhibitor trial, such as when these children are significantly impacted by other atopic conditions indicated for treatment with dupilumab. Further, there may be some children who would benefit from a more rapid escalation to dupilumab therapy when a dietary elimination strategy could be contraindicated, such as in children who are experiencing failure to thrive or food avoidance. More research is needed to understand the impact of dupilumab for these potentially more challenging clinical scenarios and whether this could offer more rapid disease resolution. Finally, nearly a third of patients did not respond to dupilumab, so this is an unmet need and a critical area of future research.
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