A particular headline captured the attention of many doctors and families in the world of food allergy: “Omalizumab Is Superior to Oral Immunotherapy in Multi-Food Allergy Treatment Study.”
The OUtMATCH study included children with multiple food allergies. Stage 1 demonstrated that omalizumab could protect against anaphylaxis by raising most subjects’ reaction threshold, i.e., many peanut-allergic children who pre-omalizumab would react to less than half a peanut could now eat two peanuts and not react. Stage 2 compared omalizumab to multi-food oral immunotherapy (OIT), and the investigators’ conclusion was that omalizumab is better than OIT.
But is omalizumab better?
What is Omalizumab?
Omalizumab — known by the brand name Xolair — is a biologic medication that reduces blood IgE levels and inhibits binding of IgE to mast cells and basophils. This can decrease the risk of anaphylaxis. Simply stated, food-induced anaphylaxis requires three things:
- food allergen
- allergen-specific IgE
- allergy cells (mast cells and basophils)
For example, for a patient with an anaphylactic peanut allergy, the person has peanut-specific IgE on their allergy cells. Upon eating peanuts, peanut proteins binds to peanut-specific IgE, triggering degranulation. When these cells degranulate, granular contents infiltrate the tissues and bloodstream. Contents include histamine and other vasoactive compounds, tryptase and other proteases, cytokines, and more. These compounds are responsible for the signs and symptoms of anaphylaxis. Anaphylaxis should then be treated with epinephrine (not just an antihistamine because the reaction is caused by more than just histamine — epinephrine can reverse all the signs and symptoms of anaphylaxis —whereas antihistamines only address histamine-mediated symptoms).
Because omalizumab results in little to no IgE on the surfaces of allergy cells, mast cell degranulation and, thus, anaphylaxis is difficult to trigger. Awesome.
What is OIT?
OIT is a treatment for food allergies in which a patient is given small, increasing amounts of a food over months to years, thereby teaching the immune system to tolerate the food. OIT is akin to allergen immunotherapy for pollen allergies, which was first identified as a treatment for hayfever over 100 years ago. The concept is to expose the immune system to small, increasing amounts of the allergen over time to grow tolerance to the allergen. The development away from an allergic response and to an immune milieu of tolerance is regulated by T cells. Over time, allergen-specific IgE decreases because of this development of tolerance.
The most well-studied OIT protocol is that of peanut allergen powder, which, until omalizumab, was the only FDA-approved treatment for peanut allergy. Peanut allergen powder is defatted peanut flour and comes in dose-specific capsules that are opened into a small serving of food to be ingested every day. There are other effective OIT protocols that use store-bought peanut products, such as butter, to treat peanut allergies. Likewise, evidence-based OIT protocols exist for other foods, such as using pasteurized liquid egg whites for egg OIT. Multi-food OIT is OIT performed to multiple foods at the same time. OIT poses risks, the biggest being allergic reactions. Until a patient’s immune system fully tolerates the food, as demonstrated by a negative food challenge (in which a patient eats an entire serving of the food, typically a much larger amount than the maintenance OIT dose), patients undergoing OIT must not exercise one hour prior and two hours after their OIT dose or risk having an allergic reaction. This limitation and other dosing restrictions make OIT too burdensome for many patients.
How did OUtMATCH compare omalizumab to OIT?
In OUtMATCH Stage 2, subjects were randomly placed in one of two groups: omalizumab plus placebo-OIT or placebo-omalizumab plus OIT; however, prior to receiving treatment or placebo omalizumab, all subjects received omalizumab for 16 weeks plus whatever they’d received in Stage 1 (so no subjects were omalizumab-naïve). Subjects then continued in their respective study groups for 44 weeks. The primary endpoint was defined as successful ingestion of >/= 4,044mg of allergenic protein for all three allergenic foods at the completion of this stage. In the subjects who completed the study, 37% of those in the placebo-omalizumab plus OIT group met that endpoint, whereas 41% of subjects in the omalizumab plus placebo-OIT group met that endpoint. Subjects in the placebo-omalizumab plus OIT group had significantly more adverse events than subjects receiving omalizumab plus placebo-OIT, resulting in 49% of the placebo-omalizumab plus OIT subjects not completing the study, whereas only 12% of the omalizumab plus placebo-OIT group did not complete the study. This reaction rate is the crux of the statement that omalizumab is “superior” to OIT.
So does OUtMATCH prove omalizumab is superior to OIT?
No. It proved that aggressive OIT results in more reactions than omalizumab. The OUtMATCH OIT protocol was far more aggressive than typical OIT protocols, such as peanut allergen powder protocol. In the studies that earned peanut allergen powder FDA-approval, most subjects experienced an adverse event related to the drug, some (14.2%) even having anaphylaxis, underscoring that this protocol is not conservative. When asked at the AAAAI meeting why the OUtMATCH OIT Protocol was this aggressive, Dr. Wood answered (I paraphrase) that “because the subjects had been on omalizumab, it was thought the subjects would tolerate the protocol.” In my opinion, a more well-studied OIT protocol that is akin to commonly used protocols should have been used. Also, in a true head-to-head, subjects should be omalizumab-naïve.
Neither omalizumab nor OIT cures food allergies, and each does different things: omalizumab helps protect against reactions from accidental ingestions while on the drug; and OIT builds tolerance to the food when the food is intentionally ingested. Each approach has pros and cons, and the term “superior” should be reserved for what’s decided through shared decision-making processes and evidence-based techniques. This methodology is the best option for each individual patient.
Dr. Hoyt has no relevant conflicts of interest to report.
Illustration by Jennifer Bogartz
