Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab

Up to 8% of the pediatric population suffers from food allergy and of those 30% have clinical reactivity to more than one food allergen [1‐3]. The estimated cost of food allergies in the U.S. every year is approximately 25 billion U.S. dollars, with most of the burden (~$20 billion) borne by families themselves due to time lost from work, changing careers and emergency room visits [4]. Compared to those with single food allergies, multi-sensitized subjects experience a greater decrease in quality of life [5], are more likely to suffer from dietary deficiencies [6] and are less prone to spontaneously outgrow their allergies [7].

Oral, sublingual, and epicutaneous allergen-specific immunotherapies have been proposed as possible methods of desensitization for foods. Several prior studies have shown some success in using these approaches for single specific food allergens such as milk [8‐15], egg [13, 14, 16‐18], peanut [19‐24], and hazelnut [25]. These current types of experimental treatments need to be tested for optimization in safety, efficacy, and length of time [26‐34]. Safety is of critical importance at all phases of any protocol (initial dose escalation day, dose escalation, and maintenance phases) and allergic reactions while on OIT remain an important feature in long-term follow-up studies and in determining the overall success of food allergen immunotherapy [35]. However, one major limitation to the clinical application of current protocols is their use in participants with more than one food allergy, which would require multiple sequential rounds of immunotherapy over many years. We have recently reported that up to 5 allergens can be desensitized simultaneously without an increase in reaction rate when compared to single allergen desensitization [36]. However this protocol remained time consuming with a median of 85 weeks to reach maintenance dose (range = 54–156).

The use of IgE immunomodulatory therapies, including monoclonal antibodies and small molecules, has been under investigation in food allergies and has been reviewed recently in the literature [37‐45]. Specifically, omalizumab has been shown to increase the threshold for adverse reactions on food challenge by up to 80 fold [41]. After obtaining pharmacodynamic data using basophil assays and free IgE measurements in subjects with food allergies who received standard omalizumab dosing, we found that 8 weeks post standard omalizumab therapy is an optimal time to start oral immunotherapy [46, 47]. This concept of rush immunotherapy with omalizumab was previously used in immunotherapy studies involving pollens, milk and peanut with promising results [28, 30, 48‐52]. Combined with food OIT, omalizumab is posited to increase dose tolerability, thus allowing for the possibility of a higher initial starting dose and faster treatment progression.

The objective of this trial was to study the safety and dose tolerability of a phase 1, open-label, rush OIT protocol, which included up to 5 foods simultaneously. The primary endpoint of our investigation was safety (i.e. the occurrence of allergic reactions throughout the course of the study). The secondary endpoints (i.e. tolerability) were i) the time to reach and maintain doses of 300 mg, 1000 mg and 4000 mg per food allergen protein as well as ii) a 10 fold increase from the baseline reactivity threshold to each of the food allergen proteins.

This open-label, phase 1 study was performed in a single center hospital setting, with Institutional Review Board (IRB) and Investigational New Drug (IND) approvals. This project was approved by the IRB committee at Stanford University.

In this phase 1 safety study, we have shown that participants allergic to multiple foods were safely and rapidly desensitized to up to five food allergens simultaneously, using a rush OIT protocol with concomitant treatment with omalizumab. To the best of our knowledge, this is the first study to use omalizumab with OIT to multiple allergens simultaneously. These findings are particularly relevant considering the already high (~30%) and likely growing number of food allergic participants who are sensitized to more than one food allergen [3, 53‐56].

This study was designed as a proof of concept, open-label phase 1 study, with safety measurements as the primary endpoint. The rate of reactions observed in the rush mOIT group was similar to a group with the same eligibility and demographics undergoing mOIT in a previous study without omalizumab, despite the more rapid desensitization schedule [36]. The goal of adding omalizumab in this phase 1 study was primarily to enable rapid desensitization rather than to suppress allergic symptoms during OIT.

As the half-life of omalizumab is 24 days, we further hypothesized that any protective safety effect might wane over time. Participants were observed closely for the development of symptoms, including hives, worsening of eczema, or wheezing after omalizumab discontinuation (at 8 weeks after initial dose escalation), and were instructed to keep a diary of food allergy symptoms throughout the study. Our data show that the home reaction rate actually went down after 24 weeks of therapy from 11 to 3 per 100 doses (p < 0.0001) (Figure 4). This increase in safety could relate to the fact that participants were not up-dosing anymore at that point. However, the only use of epinephrine occurred shortly after the participant had reached the maintenance phase, thus vigilance should not be relaxed at any point. Rescue epinephrine was also required during the maintenance phase of previous rush studies using omalizumab (2 of 2 and 1 of 4 in peanut and milk rush OIT respectively) [28, 52].

In addition to the safety data, this phase 1 study of rush mOIT provides initial preliminary evidence of increased dose tolerability. The median time at which participants on rush mOIT reached their maintenance dose (4000 mg per allergen) was 67 weeks earlier than that reported in a previous report on mOIT without omalizumab [36]. This represents a difference of about 34 dose escalations and about 67 additional weeks of enrollment. This might be relevant from a pharmaco-economic perspective. Considering a cost per visit in 2013 of approximately $160 [approximate cost of an office open food challenge per MediCare or public health insurance in Canada (RAMQ)], those 34 extra visits represent a minimal additional cost of approximately $5,440 in 2013 [57]. This could possibly offset the cost of omalizumab at the current time, which varies between $2,164 and $10,824 for 16 weeks, depending on the patient’s weight and total IgE levels. Furthermore, these calculations do not take into account the additional cost and impact of absenteeism from school and work for the participant and his/her parents during these approximate 34 additional visits [4]. However, one should be cautious when comparing these two phase 1 trials as the dose progression schedules were different. A phase 2 study comparing omalizumab to placebo in participants with a similar dosing schedule is needed to truly assess the efficacy gained from the addition of omalizumab to mOIT.

There are limitations to this study. Oral immunotherapy regimens were customized to the participant’s food allergies. This has led to some diversity when comparing the composition of specific food allergies between subjects. However, no one food allergen was found to be associated with greater dose tolerability or safety. This is consistent with one of the key long term goals of the study which was to begin to develop customized, patient-based, regimens for oral immunotherapy that could be tested for safety, and dose tolerability.

Importantly, our study showed desensitization but not tolerance. Clinical tolerance is proven by demonstrating sustained unresponsiveness to the food after stopping the maintenance dose for a prolonged period of time. Future phase 2 trials on the use of omalizumab combined with OIT will be useful to see if omalizumab affects this outcome.

Our cohort did not include subjects with high total serum IgE levels as this is sometimes the case for children with multiple food allergies. Three subjects had total serum IgE slightly greater than 1500 kUa/L and received the maximum dose of Omalizumab (600 mg every 2 weeks). The optimal dosing for subjects with higher levels would require further study.

Serological analyses were performed for peanut to allow for consistent comparisons between participants, as this was the most frequent allergen. The serologic changes after 52 weeks of therapy were identical to those previously reported in subjects undergoing non-rush OIT (without omalizumab) [36, 58].

In conclusion, the data from a single site, phase 1 study demonstrate that a rush OIT protocol to multiple food allergens using adjunct omalizumab can be performed safely in a hospital setting. At this time, rush mOIT is an experimental treatment and should be conducted by trained research personnel with immediate access to emergency equipment. Phase 2, blinded, multicenter trials are needed to continue to determine safety and efficacy parameters of rush mOIT in larger numbers of multi-sensitized participants.