Targeting IgE to facilitate oral immunotherapy for food allergy: a potential new role for anti-IgE therapy?

Abstract

Food allergy is a major public health problem without satisfactory treatment options. Of several new treatments being studied, oral immunotherapy (OIT) appears to be the most promising. Unfortunately, OIT is associated with an unacceptably high frequency of allergic reactions. However, recent studies suggest that OIT might be made safer and faster when performed in conjunction with anti-IgE monoclonal antibody as an adjunctive treatment.

Keywords::

• desensitization
• food allergy
• milk allergy
• oral immunotherapy
• peanut allergy

Food allergy is a major, worldwide public health problem estimated to affect 220–250 million individuals [1]. In the USA, in 2009–2010, 8% of children were estimated to have food allergy, and 39% of these children experienced severe reactions [2]. Moreover, the prevalence of food allergy in the USA, UK and China appears to have doubled or tripled over the past 12 years, likely related to environmental changes, for example, decreased prevalence of certain infections or alterations in the intestinal microbiome [3–5]. Furthermore, the increasing prevalence coupled with the absence of effective therapies, other than avoidance of the offending food and prompt treatment of allergic reactions that develop after accidental ingestion, renders food allergy as an urgent clinical problem. Despite strict and careful avoidance, each patient on average experiences a food reaction every 1–4 years, because many of the major food allergens are occultly present in prepared foods or may be present due to cross-contamination [2,6]. The constant threat of possible allergic reactions is disruptive and disabling for many families [7]. The resulting economic costs are considerable, estimated to be US$25 billion/year in the US alone [8].

Novel therapies

Fortunately, over the past 5 years, there has been substantial progress in the development of new treatments for food allergy [9]. Several treatments are potentially disease modifying and food immunotherapy may be the most promising among these. Sublingual, transdermal or oral approaches are being investigated, and all start with very small doses, with increasing amounts given as tolerated over periods of months to years, reaching maintenance doses 10- to 1000-fold greater than the initial dose. Doses given sublingually or transdermally have both been shown to be safe [10,11], but efficacy may be limited by the smaller amounts of food antigens that can be absorbed through the skin or oral mucosa. These approaches with smaller doses might reduce the severity of allergic reactions on accidental ingestions, but higher absorbed doses, for example that might be attained with oral immunotherapy (OIT), may be necessary to allow consumption of relatively unrestricted dietary amounts of the allergenic food.

However, the higher doses of food allergen given with OIT are associated with significant and frequent allergic reactions, including anaphylaxis. It is estimated that >90% of patients undergoing oral desensitization develop reactions, and because of frequent allergic reactions, desensitization must be prolonged (1–2 years) before efficacious maintenance dosing can be achieved. In addition, 10–30% of patients, generally those with higher initial food-specific IgE levels, have repeated reactions and are thus refractory to OIT [12–14]. Indeed, recent meta-analyses of oral desensitization studies suggest that the frequent serious adverse reactions might outweigh the benefits of OIT [15,16]. Therefore, OIT is not currently recommended for the treatment of food allergy, is considered experimental and is performed primarily in academic centers.

Targeting IgE

A new approach to oral desensitization focused on limiting the allergic reactions was proposed in 2007 using concomitant anti-IgE mAb. This idea was based on the premise that food-specific IgE plays a critical role in IgE-mediated food allergy (but not in non-IgE mediated reactions, such as celiac disease or eosinophilic esophagitis) [17], and if neutralized, might allow oral desensitization to occur more safely, rapidly and effectively. Previous studies provided additional support for such an approach: treatment with anti-IgE mAbs, TNX 901 or omalizumab increased the threshold peanut protein dose for eliciting allergic reactions during an oral food challenge [18–20]. These studies, however, focused on the therapeutic goal of limiting allergic reactions that might occur with accidental food ingestion, rather than on facilitating oral desensitization to ultimately obviate reactions on unrestricted diets.

The first study to use omalizumab to facilitate oral desensitization involved the oral desensitization of patients with high-risk milk allergy [21]. Eleven children with high milk-specific IgE (median 50 kU/l, range 42–342 kU/l) were pretreated with omalizumab before starting desensitization. Nine of the 11 patients tolerated the first 11 doses given on the first day, up to a dose of 1000 mg of milk powder (cumulative dose 2000 mg, equivalent to about two ounces of milk). Nine patients subsequently reached the top daily maintenance dose of 2000 mg in a median time of 8 weeks. Omalizumab was then discontinued, after which the nine patients tolerated a double-blind, placebo-controlled food challenge with >8 ounces of milk. Most of these patients subsequently were able to enjoy eating ice cream, pizza and other milk-containing foods.

A second study with omalizumab followed in high-risk peanut allergic patients [22]. Thirteen children with histories of severe allergic reactions to peanut (not requiring intubation) were recruited (median peanut specific IgE, 229 kU/l, the highest median for any oral peanut desensitization study; range 21–617 kU/l). A double-blind, placebo-controlled food challenge prior to desensitization demonstrated that all of the patients reacted to low doses of oral peanut (median dose of 50 mg peanut flour [about ¼ peanut]). The patients were then placed on omalizumab followed by oral desensitization. On the first day of desensitization, all 13 children rapidly progressed to the top dose of 500 mg peanut flour (cumulative dose, 990 mg, equivalent to >two peanuts) with minimal or no symptoms. Then in a median time of 8 weeks, 12 of the 13 patients reached the highest attempted maintenance dose of 4000 mg of peanut flour. Moreover, after stopping omalizumab, the 12 children continued on daily oral maintenance peanut and exhibited a negative double-blind, placebo-controlled food challenge at doses of approximately 20 peanuts, tolerating 160–400 times more peanut than they did before desensitization.

Such omalizumab-enhanced OIT results are remarkable, given that in both studies the up-dosing phase was completed in a median time of 8 weeks and because both studies specifically included patients with high food-specific IgE levels, which normally correlate with desensitization failure [12–14]. A third study of omalizumab and OIT recently confirmed the usefulness of omalizumab in facilitating oral desensitization in milk-allergic patients. In this placebo-controlled study, 57 children (median milk-specific IgE about 40 kUA/l) were treated with omalizumab or placebo (1:1) before oral desensitization to milk. Allergy symptoms were greatly reduced in the omalizumab group compared to the placebo group (e.g., overall use of epinephrine was reduced from 17 doses in the placebo group to one dose in the omalizumab group), and maintenance dosing was achieved more rapidly in the omalizumab group (26 weeks) than in the placebo group (31 weeks) (presented at the Annual American Academy of Allergy, Asthma and Immunology meeting, 2014, San Diego, CA). These three studies together suggest that omalizumab can profoundly reduce allergic reactions during, thereby greatly facilitating safer, oral food desensitization.

Unresolved issues

It is noteworthy that in these studies, immunological tolerance or remission from allergy off of maintenance treatment was not examined. While remission may be a long-term goal of desensitization, in previous studies of OIT without omalizumab, the majority of treated patients did not achieve this goal, as most patients regained reactivity within 6 weeks of discontinuing maintenance treatments [23,24]. In our milk and peanut studies with omalizumab [21,22], food-specific IgE levels remained high after 6 months of maintenance dosing (although well below starting levels, which were very high), suggesting that remission was not achieved and that long-term maintenance therapy (e.g., 3–5 years or more, as with subcutaneous immunotherapy for aeroallergens and insect venom) may be required to minimize food-specific IgE levels and induce remission. Thus, the length of the maintenance-dosing period required for sustained benefit will need to be determined with longer-term studies, although the issue of discontinuing maintenance treatment may be less of an issue if patients actively select milk or peanut in their normal daily/weekly diets.

Other issues that need to be addressed with future studies (e.g., [25]) include the following. First, although omalizumab protects against reactions that occur during the desensitization up-dosing period, we need to understand the occasional more severe allergic reactions that occur on maintenance dosing off of omalizumab. Such occasional reactions during maintenance dosing, which have also been noted in OIT studies without omalizumab [26], occur hours after the peanut dose, often associated with exercise, infection, menstruation, heat exposure, non-steroidal anti-inflammatory drug ingestion and possibly alcohol consumption [22]. Whether these episodes become less frequent with longer periods of maintenance therapy as food-specific IgE levels go down or whether omalizumab treatment during maintenance dosing might reduce these symptoms is not yet clear. Second, because of the cost of omalizumab, if omalizumab were proven to be safe and effective in larger trials, we would need to define which food allergic patients are best suited for OIT with omalizumab. It may be that the high cost of omalizumab might limit its use to those patients with ‘difficult-to-desensitize’ food allergy, possibly those with higher levels of food-specific IgE.

Third, because omalizumab is not allergen specific, how should omalizumab be used in patients with multiple food allergies? Should desensitization to different foods be done sequentially or simultaneously? This issue is a very practical one since many patients are allergic to multiple foods, but standardizing protocols for and analyzing study results of patients who might have different combinations of food allergies is logistically difficult, particularly since an important goal of disseminating this treatment widely into the community beyond academic centers will require a simple, easily-followed, safe protocol. In addition, health authorities’ (e.g., US FDA) approval of omalizumab for food allergy will most likely require studies of single foods, which can be designed and interpreted much more easily. On the other hand, a recent open-label pilot study of omalizumab in patients with as many as five different food allergies (median, 4), including peanut, milk, egg, tree nuts (walnut, cashew, almond, pecan, hazelnut) wheat, soy or sesame, showed that maintenance dosing using customized cocktails of foods could be achieved by 40 weeks of desensitization [27]. In this study, allergic reactions appeared to be much reduced compared to reactions that might be observed with OIT without omalizumab, but the great heterogeneity in the patient population makes interpretation difficult.

In summary, targeting IgE with anti-IgE dosing may permit safer and perhaps faster and more effective OIT for food allergy. Importantly, safer OIT may allow OIT to become widely available to patients with food allergy in the next 5–10 years. However, many questions remain to be addressed before such therapies can be recommended for this widespread, debilitating disease.

Key issues

• Food allergy is a major public health problem that is increasing in prevalence and that lacks satisfactory treatment options.

• Oral immunotherapy (OIT) appears to be the most promising new treatment for food allergy being studied, but OIT is associated with significant allergic reactions that reduce its appeal.

• Combining anti-IgE monoclonal antibody (mAb) treatment with OIT appears to greatly improve the safety of OIT and may permit faster and more effective OIT.

• Future larger, placebo-controlled studies are required to confirm recent findings and to optimize the treatment protocol.

• Successful Phase II and III studies could lead to health authority (e.g., US FDA) approval of anti-IgE mAb (e.g., omalizumab) for food allergy.

• Widespread community acceptance of a safe OIT treatment protocol for food allergy facilitated with anti-IgE mAb could significantly improve treatment options available for patients with food allergy.

• Additional studies of anti-IgE facilitated OIT will need to address: the development of immunological tolerance/remission from food allergy following OIT; the length of the maintenance treatment period for OIT; occasional late occurring allergic reactions; defining the specific characteristics of food-allergic patients best suited for OIT with omalizumab; and the treatment of patients with multiple food allergies.

Financial & competing interests disclosure

DT Umetsu is an employee of Genentech. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.