Dupilumab Reduces GI Symptoms During Multi-Allergen OIT, With Sayantani Sindher, MD

Late-breaking data presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting in Philadelphia suggest that adding dupilumab to omalizumab-facilitated multi-allergen oral immunotherapy (OIT) may improve desensitization outcomes and reduce gastrointestinal adverse events, though it did not significantly increase sustained unresponsiveness.

The findings come from the COMBINE trial, which evaluated whether adjunct dupilumab could enhance outcomes in patients undergoing multi-allergen OIT supported by omalizumab. In an interview with HCPLive during the meeting, Sayantani Sindher, MD, clinical associate professor of medicine at Stanford University, explained that the study was designed in part to address a persistent clinical challenge in OIT: gastrointestinal symptoms and treatment-related adverse events that can limit patient adherence and long-term success.

“We were hoping that with the study, we [would] get a better insight into the participants who are developing GI symptoms and whether we can do something about it for this subgroup of patients and improve long-term positive treatment outcomes,” Sindher said.

The randomized trial enrolled 108 individuals with multiple food allergies, including peanut plus 1 or 2 additional allergens. Participants were assigned to receive omalizumab followed by placebo plus OIT, omalizumab followed by dupilumab plus OIT, or a smaller mechanistic arm. Omalizumab was administered during the first 8 weeks, followed by dupilumab or placebo with OIT from weeks 8 through 32. All therapies were discontinued at week 32, and sustained unresponsiveness was assessed at week 44 using double-blind, placebo-controlled food challenges.

The primary endpoint, sustained unresponsiveness to ≥ 1043 mg of peanut protein, was achieved in 39% of patients receiving omalizumab plus OIT and 55% of those receiving dupilumab plus OIT, a difference that did not reach statistical significance (P = .16). Sindher noted that sample size likely contributed to the lack of statistical significance despite a numerical difference between the groups.

Although the primary endpoint was not met, secondary analyses showed meaningful differences in desensitization and tolerability. At week 32, a significantly greater proportion of patients receiving dupilumab tolerated the highest tested cumulative dose of a single allergen (4043 mg) during food challenge compared with those receiving OIT alone (92% vs 63%; adjusted P = .013).

Sindher emphasized that the ability to tolerate approximately 4 grams of allergen protein, roughly equivalent to a full serving size of food, can be clinically meaningful for many patients and families.

“In terms of clinical meaningfulness…this is where shared decision making comes through,” Sindher said. “For some of our patients, they're like, ‘That's great, but I never want to eat the food again. I just want to do the bare minimum so I can sustain my effectiveness,’ in which case we would say, ‘okay, sure, you can absolutely do lower doses of OIT, but you just know that you're protected against much higher doses in case of accidental exposure.’ And then in our younger group, who may [be] too young to even understand food allergy and don't have the fear of the food yet, it gives parents an opportunity to actually introduce full serving size amounts of the foods of their allergens and incorporate it as part of their diet.”

Safety findings also highlighted potential advantages of adding dupilumab. Withdrawals due to adverse events, most commonly gastrointestinal symptoms, occurred only in the omalizumab-plus-OIT arm (n = 8; P = .006). Additionally, gastrointestinal symptoms per OIT dose were significantly lower in the dupilumab group (0.013 vs 0.033; P = .04).

“What was also interesting, and I see this in my outpatient clinical care practice, and we see this in this study, is as helpful as dupilumab [is]… the effects are not long lasting, so the kids revert back to the state they would have been with just multi-OIT by itself,” Sindher said. “What this means is that dupiumab may be a great addition to the toolkit for our treatment options for our patients, depending on what their side effects are, and just allow us to do more precision medicine, but to do that more we need a better understanding of the underlying mechanisms and identify better biomarkers that can predict different profiles of kids, and that will allow us to pick the right tool for the kid that we have in front of us.”

A relevant disclosure for Sindher includes Genentech USA.

References

Sindher S, Long A, Garcia-llorett M, et al. The addition of dupilumab enhances desensitization and reduces gastrointestinal symptoms in omalizumab-facilitated multi-allergen oral immunotherapy in the COMBINE trial. Journal of Allergy and Clinical Immunology. 2026;157(2):AB415. doi:https://doi.org/10.1016/j.jaci.2025.12.917