Evaluating dupilumab use in omalizumab-facilitated multi-allergen OIT: The COMBINE study

Q. Could you provide an overview of the established efficacy and safety profile of mOIT in food allergy treatment?

Multi-food oral immunotherapy (mOIT) has demonstrated meaningful efficacy in inducing desensitization across many foods, with success rates ranging from 85% in optimally conducted trials down to 19% in some cohorts, reflecting variability based on study design and participant retention. However, gastrointestinal adverse events remain a significant clinical challenge, occurring frequently enough to limit the tolerability of therapy and contribute to treatment discontinuation in some patients. This safety profile highlights the need for strategies to improve both tolerability and durability of response.

Q. What was the rationale for the addition of dupilumab to an mOIT treatment protocol?

While omalizumab effectively facilitates mOIT by reducing anaphylaxis risk, gastrointestinal symptoms remain common and problematic for many patients. Dupilumab offers a complementary mechanism of action: it gradually reduces IgE levels, suppresses Th2 polarization, and inhibits IgE class switching. We hypothesized that dupilumab would provide a synergistic effect with omalizumab during mOIT, potentially enhancing both safety and efficacy outcomes.

Q. What were the aims and methodology of the COMBINE trial?

COMBINE was designed to determine whether adding dupilumab to omalizumab-facilitated mOIT would improve sustained unresponsiveness and reduce adverse events compared to omalizumab-facilitated mOIT alone.

We enrolled 108 participants, aged 4–55 years, with double‐blind placebo‐controlled food challenge-confirmed IgE-mediated allergies to peanut plus two–three additional foods (almond, cashew, egg, fish, hazelnut, milk, sesame, shellfish, soy, walnut, or wheat). Participants were randomized to one of three groups:

• OPmOIT: omalizumab followed by placebo + mOIT (n=49).
• ODmOIT: omalizumab followed by dupilumab + mOIT (n=49).
• PDmOIT: placebo followed by dupilumab + mOIT mechanistic arm (n=10).

The protocol included an 8-week run-in with omalizumab or placebo, followed by 24 weeks of mOIT combined with dupilumab or placebo. Desensitization was assessed at Week 32 (immediately after treatment), and sustained unresponsiveness was evaluated at Week 44 (12 weeks after treatment cessation) with food challenge. Secondary endpoints included desensitization rates, frequency and severity of adverse events, immunological markers (sIgE, sIgG4, basophil activation), and quality of life measures.

Q. What were the safety and efficacy findings from the study, and were all endpoints met?

The primary endpoint of increased sustained unresponsiveness of peanut at Week 44 was not met, there were no significant differences between the omalizumab-alone and omalizumab-plus-dupilumab arms. We did have some notable findings. We found that dupilumab substantially improved the safety profile and tolerability. At Week 32, desensitization to a dose of 4,043 mg for any allergen increased from 63% in the OPmOIT arm to 92% in the ODmOIT arm and was statistically significant. More notably, dupilumab dramatically improved safety: all eight adverse event–related withdrawals occurred in the OPmOIT arm, with zero withdrawals in the ODmOIT arm. This safety benefit was driven largely by a reduction in gastrointestinal symptoms, which decreased from 0.033 symptoms per dose in the OPmOIT group to 0.013 per dose in the ODmOIT arm, a clinically meaningful 60% reduction.

Q. How might these findings impact prescribing in clinical practice, and what future research is planned after COMBINE?

These findings suggest an important clinical application for dupilumab in mOIT. Many patients discontinue oral immunotherapy due to tolerability issues, particularly gastrointestinal symptoms. COMBINE demonstrates that dupilumab can significantly reduce these symptoms and improve treatment completion rates, making it a potential tool for patients who would otherwise be unable to tolerate mOIT alone. While dupilumab did not improve sustained unresponsiveness, it could be selectively valuable for patients experiencing or are at risk for GI symptoms-related treatment failure.