The US Food and Drug Administration (FDA) convened a meeting of the Allergenic Products Advisory Committee last Thursday to discuss progress toward effective Allergy Immunotherapy (AIT) and solicit input regarding how such therapies should be developed and approved, especially for children younger than 5 years of age.
Included in their meeting preparation materials, the FDA distributed two briefing documents summarizing the current state of AIT development for food allergies and allergic respiratory diseases. The document entitled Clinical Development of Allergen Immunotherapies for the Treatment of Food Allergy provides a primer on the prevalence of food allergy, the current state of investigational AIT toward a treatment, and the difficulties determining the efficacy of any treatment, especially in young children.
Here follows a summary of that document which provides an informative primer for individuals new to the world of food allergies and therapies under investigation.
Food Allergy Statistics
The document begins with well-known statistics regarding food allergy:
- The most common food allergens are peanut, tree nut, milk, egg, soy, wheat, and shellfish. These foods constitute more than 90% of food allergies in children. Some food allergies (milk, egg, wheat, and soy) have an increased chance of resolving with age whereas others (peanut, tree nut, and shellfish) tend to be persistent over time.
- Food allergy affects up to 15 million people in the U.S., approximately 6 million of whom are children. Prevalence has been increasing, particularly in children; the National Center for Health Statistics reports that the prevalence increased from 3.4% in 1997-1999 to 5.1% in 2009-2011 in individuals 0 to 17 years of age.
- Quality of life in food-allergic individuals and their caregivers is often adversely affected due to the fear of accidental ingestion as well as the burden of avoiding allergenic foods. The potential consequences of accidental exposure can be serious and life-threatening. About 50% of cases of anaphylaxis reported by emergency departments are due to a food allergen.
- Fatalities due to anaphylaxis from food allergies are estimated at about 100 per year with most deaths occurring during early adulthood.
Current Therapies Under Investigation
Describing the objective of AIT “to induce a state of desensitization in food-allergic individuals to prevent a catastrophic response following accidental exposure”, the document goes on to provide a concise summary of each class of immunotherapy currently being investigated:
Oral Immunotherapy (OIT)
In OIT, individuals with confirmed IgE-mediated allergy to food ingest increasing amounts of the allergenic food protein. Typical protocols include an initial rapid dose escalation done in one day followed by bi-weekly dose increases until the maintenance dose is reached.
Subjects are usually instructed to ingest the maintenance dose daily while continuing to avoid the food allergen in their regular diet. Although the definitions and criteria for desensitization have not been uniform, several published studies have reported promising efficacy results in the induction of desensitization.
OIT is associated with a relatively high rate of adverse events, most commonly oral and gastrointestinal side effects. The inability to tolerate therapy leads to a subject withdrawal rate of 10-20%. Serious events such as anaphylaxis, asthma exacerbations, and oropharyngeal edema have been reported with the use of OIT. Younger study participants such as infants and toddlers may be at increased risk for systemic or serious reactions because they may not be able to communicate early symptoms of an allergen reaction such as oral itching or abdominal discomfort. Another safety consideration with the use of OIT is the possibility of the development of eosinophilic esophagitis (EoE) in participants. This has been reported in trials studying milk OIT.
Sublingual immunotherapy (SLIT)
SLIT is similar to OIT in that the food to which the subject is sensitive is administered orally. In SLIT small amounts of food extract are placed and held under the tongue for 2-3 minutes, then spit out or swallowed. While few studies have evaluated this route of administration for food AIT, the available data suggest that desensitization is less often achieved compared with OIT. However, these data also suggest that the safety profile may be improved relative to OIT. As with OIT, EoE is a safety concern that must be monitored in SLIT studies.
Subcutaneous immunotherapy (SCIT)
Studies that evaluate SCIT for treatment of food allergy have reported relatively high rates of adverse events, particularly systemic reactions during the build-up phase, including one fatality that occurred when a subject received an injection of peanut SCIT. The limited efficacy data from these studies indicate that among subjects who complete the regimen, ~50% experience some degree of desensitization.
Epicutaneous immunotherapy (EPIT)
In EPIT intact skin is exposed to small amounts of the food allergen, typically through the use of a patch. The rationale for this approach is to present antigen to dendritic cells, which are thought to induce tolerizing pathways of the immune system. This route of administration has been studied for treatment of milk allergy. The safety profile was reported to be reassuring; however therapy did not appear to be successful in inducing desensitization to milk. Studies using EPIT to treat other food allergies (e.g., peanut) are ongoing.
Determining the Efficacy of Therapies
To determine the effectiveness of the therapies described above, the gold standard involves administering double-blind placebo-controlled food challenges, all of which are conducted in a similar manner:
- Exposing the subject prior to the therapy to increasing amounts of the allergen to determine the minimum amount that elicits signs of a reaction (known as the eliciting dose or ED);
- Repeating the food challenge after therapy to determine if the ED has been raised significantly beyond the baseline;
- Monitor the subject to determine whether the treatment results in long term desensitization known as sustained unresponsiveness.
Challenges to Determining Efficacy
There are a number of issues regarding this standard. Establishing the ED in infants and toddlers is especially difficult as the symptoms of an allergic reaction – which include drooling, vomiting, scratching and drowsiness – can often be overlooked or mistaken for normal findings.
There are no guidelines for how long sustained unresponsiveness should be maintained for a clinically meaningful benefit to be realized, nor has tolerance – the complete and permanent resolution of clinical response following exposure to any amount of the identified allergenic food – been demonstrated in any controlled trial of AIT to date.
Last but not least, exposing subjects with severe food allergies to food challenges poses a risk for anaphylaxis and recruitment challenges for study sponsors. The document describes two possible alternatives, each with their own limitations:
- Clinical field efficacy trials – involves following subjects and collecting information regarding the rate and severity of reactions outside of the clinical setting. This would involve large cohorts and increased study durations which would delay the determination of efficacy of a treatment;
- Biomarker testing – The analysis of biomarker data – including IgE, IgG4 and basophil activation – may some day provide insight into the efficacy of treatments, but at this point in time, none are well-established.
We encourage you to read the brief, as well as the companion document entitled Prevention of Respiratory Allergic Diseases with Allergen Immunotherapy which provides a similar primer on the state of development of therapies for asthma and other respiratory diseases.
