Omalizumab in food allergy: Risks and benefits

Abstract

Omalizumab is approved for the management of immunoglobulin E–mediated food allergy in individuals ages ≥ 1 year. Approval for food allergy followed the Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Participants (OUtMATCH) study, which demonstrated that omalizumab increases the threshold dose of multiple food allergens needed to elicit an allergic reaction. Despite the demonstrated efficacy in food allergy and favorable safety profile, many questions remain. This review addresses the efficacy of omalizumab for the management of food allergy, as monotherapy, and in conjunction with oral immunotherapy. Safety in children is paramount, and this review addresses noted adverse events of anaphylaxis and malignancy. There is minimal knowledge with regard to the real-world impact on food allergy–related quality of life. Many questions still remain, including identifying who is the ideal patient for omalizumab, determining the role of oral food challenges before and during therapy with omalizumab, evaluating food allergy tolerance while on treatment, and optimizing the cost-effectiveness of this efficacious and well-tolerated management option for food allergy.

Immunoglobulin E (IgE) mediated food allergy affects up to 8% of children in the United States,¹ and up to 30% of individuals with food allergy are allergic to multiple foods.² Living with food allergy has a negative impact on nutrition as well as quality of life (QoL), while also increasing health-care utilization.^3,4 For decades, management focused on strict avoidance of the food allergen and prompt treatment of accidental exposures. Despite best efforts, accidental exposures are common and often result in medical evaluation in urgent care and emergency departments.^5,6 In 2020, the U.S. Food and Drug Administration (FDA) approved peanut oral immunotherapy (OIT) for use in individuals 4–17 years of age.⁷ Despite this important breakthrough in the management of food allergy, therapy is indefinite and is associated with frequent adverse effects, and uptake of OIT remains low.^8,9 In 2024, after the results of the Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Participants (OUtMATCH) study,¹⁰ the FDA approved omalizumab for management of food allergy in individuals ages ≥ 1 year. Nevertheless, adoption of this notable advancement has been limited, and many questions remain. This review summarizes the evidence to date for using omalizumab in the management of food allergy and addresses potential adverse effects. Importantly, the review also discusses real-world outcomes and many yet-to-be answered questions surrounding the use of omalizumab for management of food allergy.

METHODOLOGY

We performed a narrative literature review through PubMed by using the following search terms: food allergy, omalizumab, OIT, anaphylaxis, desensitization, biologic, and QoL. The search was limited to peer-reviewed articles since 2003, with the majority being published within the past 5 years.

EFFICACY

The FDA approved omalizumab in 2003 to treat moderate-to-severe persistent allergic asthma in patients ages ≥ 12 years. Years of real-world experience have proven both efficacy and safety of omalizumab in asthma.^11–13 Since its initial approval for asthma, omalizumab has now been approved for chronic urticaria for patients ages ≥ 12 years (2014), allergic asthma in patients ages 6 ≥ years (2016), chronic rhinosinusitis with nasal polyps in patients ages ≥ 18 years (2020), and, most recently, food allergy for patients ages ≥ 1 year (2024).¹⁴ Of note, before its approval in the management of food allergy, there were limited data on the use of omalizumab in patients ages <6 years. In addition to the conditions mentioned above, omalizumab is used in clinical practice for off-label indications, including allergic bronchopulmonary aspergillosis, inducible urticaria, idiopathic anaphylaxis, and mast cell activation syndrome.

With the use of omalizumab for asthma, incidental findings revealed its effects on additional type 2 mediated conditions, including food allergy. Often seen as a secondary observation during treatment for other conditions, mainly in case reports or small real-world case series, patients with food allergy were able to tolerate higher doses of their food allergen while being treated with omalizumab.^15–17

Efficacy in Food Allergy in Combination with OIT

Multiple studies have demonstrated the favorable impact of combining omalizumab with OIT for food allergies compared with using omalizumab alone. Whereas omalizumab monotherapy is a beneficial option for many, it is not always effective. In addition, patients with food allergy may have an interest in incorporating their food allergens into their diet on a regular basis, which may be facilitated by combination omalizumab and OIT. Several trials demonstrated that omalizumab can aid in facilitating OIT.¹⁸ In a small case series of 13 patients, children with peanut allergy experienced increased frequency of adverse reactions after discontinuation of omalizumab while still on OIT.¹⁹ In clinical trials, omalizumab is typically started before initiating OIT and continued for a predetermined duration. When used this way, studies^20–22 have shown that omalizumab decreases adverse effects of OIT, thus increasing tolerability and allowing for more rapid desensitization. In addition, QoL improvement is thought to be greater with OIT plus omalizumab compared with OIT alone.^20–22 Moreover, sustained unresponsiveness in OIT is achieved more frequently when paired with omalizumab.^{19,20,23–26}

In a phase II sentinel study,¹⁸ the participants received either omalizumab or placebo for 16 weeks, with multifood OIT starting at week 8. At the week-36 double-blinded, placebo controlled food challenge, 83% of the participants in the omalizumab group successfully passed 2-g challenge to ≥ 2 allergens compared with 33% in the placebo group. In addition, the omalizumab group experienced significantly fewer adverse events while on OIT.¹⁸ This pivotal study demonstrated the potential for combing omalizumab with OIT to significantly improve desensitization outcomes and reduce adverse events in patients with multiple food allergies, paving the way for advancements in this treatment strategy. Although OIT combined with omalizumab shows promise, e.g., OIT monotherapy, patients generally need to maintain ongoing OIT dosing indefinitely to sustain desensitization.

Efficacy as Monotherapy in Food Allergy

Anti-IgE therapies have been explored for the treatment of food allergy for >20 years (Fig. 1).^27,28 In a study published in 2003, anti-IgE was used to treat patients with peanut allergy to evaluate the change from baseline in the threshold dose that induced hypersensitivity to peanut flour, as assessed by oral food challenge (OFC). The results revealed significant efficacy in increasing the threshold dose of peanut allergen needed to elicit a clinically meaningful reaction to a dose that imparted protection from the majority of unintended exposures of peanut.²⁷

Figure 1.

Timeline of anti–immunoglobulin E (IgE) in food allergy.

Even before the OUtMATCH trial, results of preliminary studies suggested that omalizumab, in addition to being used as an adjunct to multi-OIT, had potential as monotherapy.²⁹ In a study of patients with severe allergic asthma and food allergy treated with omalizumab alone, there was an 8.6-fold increase in the reaction threshold dose and a decrease in reactions due to accidental ingestions, from 47% to 2%.¹⁵ In a phase II trial of omalizumab in patients with peanut allergy by Sampson et al.,³⁰ 44.4% of the patients treated with omalizumab could tolerate >1000 mg of peanut flour during OFC after 24 weeks of omalizumab monotherapy. Another study investigated the efficacy of open-label omalizumab in 14 patients with a median age of 23 years, all of whom had baseline peanut allergies confirmed by challenge. After 4 to 8 weeks of treatment, the median cumulative eliciting dose of peanut protein increased significantly, from 80 mg (range, 30–380 mg) to 6500 mg (range, 1830–10,000 mg).³¹

The FDA approval of omalizumab followed the success of the OUtMATCH trial, which demonstrated that omalizumab is effective as a monotherapy for food allergy. In the first stage of the OUtMATCH trial, 177 children and adolescents with peanut allergy and at least two other food allergies were randomly assigned to receive either omalizumab or placebo for 16 weeks, followed by double-blind, placebo controlled food challenges. Among those in the active group, 67% were able to consume a single dose of at least 600 mg of peanut protein (1044 mg cumulative) without dose-limiting symptoms compared with only 7% of those who received placebo. Similar outcomes were observed for other study foods, including egg, cow’s milk, walnut, hazelnut, and wheat. Overall, 69% of the participants were able to consume at least 1044 mg of two food allergens and 47% tolerated this dose for all three foods.¹⁰ Monotherapy with omalizumab represents a significant breakthrough for patients with food allergy, particularly those with multiple food allergies or those reluctant to consume their allergens.

ADVERSE EFFECTS

Anaphylaxis

When omalizumab was approved for moderate-to-severe asthma in 2003, it was given a black box warning for anaphylaxis due to reports of severe allergic reactions in early studies. The risk of anaphylaxis has likely affected prescribing habits for omalizumab, especially by specialists not trained in the recognition and management of anaphylaxis, e.g., pulmonologists.³² These concerns were likely further amplified as additional biologics for asthma and other atopic conditions became FDA approved, many with indications for home administration. Although the reported risk of anaphylaxis to omalizumab is 0.1–0.2%, there are several features of these reactions that would be atypical for an IgE-mediated process. Reactions have been reported with the first dose, and a significant percentage has been reported beyond 2 hours after administration, up to 24 hours.³³ Omalizumab is also rarely associated with antidrug antibodies,³⁴ and the presence of IgE antibodies does not correlate with skin-test reactivity to omalizumab or frequency of anaphylaxis.³⁵ Lieberman et al.³⁶ reported that the majority of cases of patients with anaphylaxis occurred with the first three doses and within 90 minutes of administration of omalizumab. No episodes of anaphylaxis have resulted in disability or death.³⁷ A real-life analysis from Italy provided reassuring results of no systemic reactions in >10,000 doses administered.³⁸ Therefore, although hypersensitivity reactions and anaphylaxis have been reported, the incidence is low, and reactions have been successfully managed to date. Administration of omalizumab for food allergy should be initiated in a medical setting when feasible³⁹; but, patients and families can be transitioned to home administration based on shared decision-making.⁴⁰ Patients and families should ensure that they have epinephrine readily available because it is already a crucial component of managing their IgE-mediated food allergy.

Malignancy

Pooled data demonstrated a higher frequency of malignancy in individuals on omalizumab compared with individuals on placebo, 0.5% versus 0.2%, respectively. The timing of cancer diagnosis as well as the type of cancer were varied, and, although there was no clear mechanistic explanation for this potential adverse effect, it warranted further evaluation. The EXCELS study⁴¹ was a 5-year registry of >7000 individuals treated with omalizumab for asthma compared with a non–omalizumab-treated cohort. This important work showed that the rate of malignancy was similar in the omalizumab and non–omalizumab-treated cohorts.⁴¹ From the EXCELS study, cardiovascular adverse effects were higher in the omalizumab-treated cohort (13.4 per 1000 person years) compared with the non–omalizumab-treated cohort (8.1 per 1000 person years). The omalizumab-treated group, however, had more patients with severe asthma and more patients treated with systemic corticosteroids, both known risk factors for cardiovascular disease. Cardiovascular risk is therefore not a significant consideration when discussing management of food allergy with omalizumab, especially in a pediatric or younger population. It is important to note that through the EXPECT Registry, omalizumab also was demonstrated to be safe in women during pregnancy.⁴²

Utilization of biologics in the management of atopic conditions has revolutionized patient care, but questions remain. Although data from clinical trials are reassuring, long-term safety outcomes are essential. Omalizumab has now been prescribed for >2 decades for multiple disease states and continues to have a reassuring safety profile, with no emerging concerns for adverse effects. With the indication for food allergy for omalizumab now extending to patients as young as 1 year of age, demonstrating safety in this pediatrics age group is paramount, particularly with regard to immune development and the safety and efficacy of vaccinations. Optimal patient and family counseling will rely heavily on future research and real-world outcomes.

REAL-WORLD OUTCOMES

Impact on QoL

There is evidence that children and teens with food allergy have a reduced health-related QoL.⁴³ This is particularly true in older children and in those with more severe manifestations of their food allergy.⁴³ The impact on QoL in pediatric patients with food allergy is primarily driven by concerns about exposures outside the home and the social repercussions of the condition.⁴³ Measuring QoL can be challenging, particularly with new therapies, and there are limited and varying data on QoL outcomes for children and their families’ undergoing treatment for food allergies, including OIT and/or omalizumab.

A real-life study that involved patients with food allergy and who were treated for asthma demonstrated an increase in food allergen thresholds, along with improved QoL, due to improved asthma control and a reduction in dietary restrictions.¹⁵ In the first comprehensive assessment of the overall efficacy and safety of omalizumab and omalizumab plus OIT in subjects with single or multiple IgE-mediated food allergy, patients showed a significant improvement in QoL.²³ In this review, assessment of QoL in patients receiving omalizumab or omalizumab plus OIT and their parents were evaluated by using multiple QoL scales, including the FAQLQ-CF, FAQLQ-TF, FAQL-PB, and PedsQL. In patients with peanut allergy and who were receiving omalizumab and OIT, there were significant improvements in the parental and patients’ QoL. In addition, omalizumab monotherapy for 17 weeks significantly improved both parents and patients’ QoL.^15,23 These improvements may be attributed to fewer dietary restrictions, a reduction in allergic reactions from accidental food exposure, and a lower risk of anaphylaxis.

Miscellaneous

As mentioned, an important caveat for use of omalizumab in food allergy is its indication for use in conjunction with strict allergen avoidance and continued epinephrine availability.¹⁴ Currently, there are no long-term studies to suggest if or when patients on omalizumab therapy without or without OIT can ingest their food allergen without restrictions. In addition, to date, there are no extensive data on the impact of omalizumab on food allergy outcomes, such as the frequency and severity of allergic reactions from accidental ingestions or emergency department or urgent care visits due to food allergen exposure or food allergy–related mortality.

UNANSWERED QUESTIONS

As of October 2023, allergists held mixed views about the use of biologics to manage food allergy.⁴⁴ With publication of the OUtMATCH study in February 2024, and FDA approval, omalizumab is now available for management of food allergy in clinical practice. Despite being a well-designed, blinded, randomized study with a rigorous trial design and multiple OFCs, there were a mere 177 participants, and only 3 adults. To date, only results from stage 1 have been published, and thus, there are many unanswered questions with regard to optimal utility of omalizumab in the management of food allergy (Fig. 2).

Figure 2.

Unanswered question with regard to omalizumab for food allergy.

Arguably the first and most important question for clinicians remains, who is the “right patient” for treatment with omalizumab.⁴⁵ Given the broad FDA-approved label of “for people 1 year of age and older at risk of food allergic reactions after accidental exposure,” we encourage allergists to maintain open-mindedness and follow a genuine process of shared decision-making.⁴⁶ Although it is not practical to require confirmatory OFC for all patients, any patient considering omalizumab should have a confirmed food allergy, with a convincing clinical history and appropriate diagnostic testing (skin-prick testing and specific IgE levels). Certain clinical characteristics may be deemed favorable for management with omalizumab, such as multiple IgE-mediated food allergies, individuals considered to be high risk for accidental exposures (i.e., teenagers), or those with a history of accidental exposures, especially requiring treatment with epinephrine. Conversely, individuals with needle phobia or those unable to tolerate regular injections, whether it be at home or at a medical facility, may be less desirable candidates for omalizumab. The most important criteria for the “right patient,” however, may be the patient most affected by his or her food allergy diagnosis. Omalizumab has been consistently shown to improve QoL in both patients and parents with food allergy,²³ so objectively assessing QoL has increased significance in the era of new food allergy therapeutics. There are several validated questionnaires to help objectively assess food allergy–related QoL in children,⁴⁷ parents,⁴⁸ and adults.⁴⁹

Although OFCs should not be required for all patients considering treatment with omalizumab, they can provide invaluable clinical information. For any patient with an uncertain diagnosis of food allergy, an OFC should be completed to confirm or refute the diagnosis.⁴⁵ In addition, in a patient with confirmed food allergy, an OFC can establish a threshold dose. Individuals with a low threshold dose may be more inclined to pursue therapy with omalizumab as opposed to a patient with a higher threshold dose. Given the lack of biomarkers to determine efficacy of omalizumab in food allergy, all patients should be offered OFC to evaluate efficacy after 16 weeks of therapy. Low-dose OFC can confirm protection from accidental exposure or full-dose OFC may facilitate introduction of the food allergen into the patient’s diet, as is being studied in stage 3 of the OUtMATCH study.⁵⁰ Although current use of omalizumab for food allergy is indicated to be used in conjunction with strict food allergen avoidance, omalizumab may facilitate introduction of the food allergen into the diet, and more research is eagerly awaited.

Once on omalizumab, it becomes difficult to evaluate for tolerance to a food with skin-prick testing or specific-IgE levels. This is particularly important for foods with a favorable natural history, such as cow’s milk, egg, and wheat. It remains unclear on how to best evaluate for acquisition of tolerance for foods over time while on omalizumab. This could be achieved by periodically stopping therapy to complete the evaluation, but this is complicated by the long half-life of omalizumab, which would take 4 months to completely clear the system. In addition, if omalizumab is restarted, then it would take another 16 weeks to regain full efficacy. Even in the absence of disease modification, the alternative approach to evaluate tolerance over time would be to introduce the food into the diet through full-dose OFC while on omalizumab and then to discontinue omalizumab after a certain time interval. More guidance is needed on the duration of therapy with omalizumab. For patients on omalizumab for an extended period of time, the dose should be adjusted based on updated weight and pretreated total IgE level to maintain maximal efficacy.

Biologics have transformed the management of atopic conditions, but cost-effectiveness is an important consideration. Shaker et al.⁵¹ concluded that, at current pricing, omalizumab is not cost-effective for food allergy, but it could be cost effective if it creates large shifts in health utility. Many patients with food allergy have other allergic comorbidities, e.g., asthma,⁵² and cost-effectiveness may be meaningfully improved when treating multiple conditions such as comorbid food allergy and asthma, especially if omalizumab allows for stepping down or discontinuing multiple asthma medications. Although all clinicians should be stewards of limited health-care resources, the cost of omalizumab should not impede shared decision-making between the allergist and the patient with food allergy and/or the family. Per a policy paper by the American College of Physicians, “resource allocation decisions are policy decisions that are most appropriately made at the system level, not at the bedside.”⁵³ Importantly, the out-of-pocket cost to the patient may be minimized by the use of an embedded health system specialty pharmacy because this has been shown for the use of biologics in other atopic conditions.⁵⁴

CONCLUSION

Omalizumab has been used in clinical practice for >2 decades for a variety of atopic conditions. The FDA approval for the management of food allergy is a significant step forward because omalizumab has demonstrated efficacy in the management of food allergy, with an excellent safety profile. Nevertheless, the impact on real-world outcomes of QoL and the effect on accidental ingestions and resulting health-care utilization remain to be determined. Clinicians eagerly await additional research to address important unanswered questions. Given that omalizumab for food allergy serves an important unmet need, we encourage a genuine process of shared decision-making between the allergist and patients with food allergy and their families.