This interview has been updated to reflect the latest guidance from the US Food and Drug Administration.
The US Food and Drug Administration (FDA) has just approved the first oral immunotherapy for treatment of peanut allergy. Palforzia (Aimmune Therapeutics) has been approved for use in children 4-17 years of age. Medscape sat down with Jonathan Spergel, MD, PhD, chief of the allergy program at Children's Hospital of Philadelphia and a member of the PALISADE Group of Clinical Investigators, which conducted this research, to discuss what we know about how to use this new therapy.
Why is this such a big deal?
This is not just the first oral immunotherapy (OIT)—this is the first-ever therapy of any kind for kids with peanut allergy, which can be life-threatening and is certainly life-altering for affected children. Prior to this, all we could offer was avoidance and epinephrine to treat an accidental exposure. So this is indeed a big deal.
Can you describe the research underpinning this approval?
The approval follows publication of the results of a manufacturer-sponsored double-blind, placebo-controlled, phase 3 trial which was conducted at multiple sites in North America and Europe. That trial included just over 500 kids in whom peanut allergy was authenticated with a blinded food challenge. Only children who exhibited rate-limiting symptoms—hives, vomiting, wheeze, shortness of breath, anaphylaxis—following exposure to a 100-mg dose of peanut protein powder (about the amount found in a third of a peanut) were included. Children who exhibited a severe life-threatening allergy, requiring multiple doses of epinephrine or care in an intensive care unit, and those with uncontrolled asthma or eosinophilic esophagitis (EoE) were not eligible for the study.
The children were then randomly assigned, with three quarters receiving peanut flour (the component in this new oral immunotherapy) and one quarter receiving placebo. The trial lasted a year, with updosing occurring about every 2 weeks in children who could tolerate that. And at the end of the trial, the investigators performed another food challenge to determine whether children in the treatment group could tolerate 600 mg of peanut protein powder, the equivalent of about two peanuts, without any more than mild symptoms.
It is important to emphasize that the goal of this therapy is not to make children nonallergic to peanuts, but rather to make them less sensitive and decrease the incidence of reactions. That means that that child can go out into the world and worry less about an accidental exposure. It does not mean that they are going to be able to eat a peanut butter and jelly sandwich.
After a year of treatment, about two thirds of the kids in the active arm were able to reach the endpoint of tolerating 600 mg of peanut protein compared with about 4% with placebo. That's the exciting part.
But here is the downside. Almost all of the children in the active treatment arm had some kind of minor reaction, like itchy mouth, at some point during the updosing phase of the trial, and 20% had a severe-enough reaction—most commonly abdominal pain and vomiting—that they had to drop out. Just over 12% had anaphylaxis.
Who is the ideal child for this therapy? Were there any particular populations that were likely to develop tolerance? For example, are older kids more or less likely to be successful? Ethnic or gender differences?
That is difficult to say because the study was not designed to answer that question. But it did appear that younger children as well as those with milder forms of peanut allergy did better.
The product was also tested in adults but did not appear to be as successful, though that may be a function of a smaller number of adults in the trial as well as the fact that adults typically exhibit a wider range of symptoms and their symptoms may be more subjective.
What is the process for administering OIT? Who should do it?
The children who participated in the trial had to have a documented prescription for injectable epinephrine, and the child and/or parent signed an attestation that the child would carry that epinephrine pen with them.
OIT must be administered by a clinician who has been trained in food allergy and can treat anaphylaxis who has also been certified to prescribe it and adheres to the other requirements of the Risk Evaluation and Mitigation Strategies (REMS). So this is not something that can be done at home or in a general pediatrics office unless that clinician meets the certification and REMS requirements.
The dose must be administered on a full stomach. Children should not be given a dose immediately before strenuous exercise and for 3 hours after exercise. They should also avoid hot showers or baths immediately before or until 3 hours after exercise.. Reactions are worse if the child is ill, so you have to be careful if administering a dose to a child with a cold, acute gastroenteritis, or other symptoms suggestive of a viral illness. Reactions like itchy mouth can occur because you are giving the child something to which he or she is allergic.
A small survey of 80 board-certified allergists and immunologists who had treated at least five patients with OIT was presented at last year's American College of Allergy, Asthma & Immunology meeting. Participants were asked not just about their experience in administering this therapy but also about how it affected workload. The conclusion was that it was going to take more time, particularly the initial visits. Does that reflect your experience?
This definitely is going to take some more time, at least at first. More patient education is required. The OIT regimen is more rigorous and involves multiple visits over the course of a year-long updosing process.
This trial suggests that the rate of anaphylaxis as compared to what we see with allergy shots will be higher. We're going to have to take time to learn all of the little tricks to make it safer.
While I would anticipate that some community allergists will be very comfortable incorporating this into their armamentarium, that will be clinician dependent.
Is the process of updosing similar to that of any other immunotherapy? If a child does develop symptoms, do you go back to the previously tolerated dose and try it again?
That's really very dependent on the patient and the symptoms. Sometimes you will hold the dose or go back to the previously tolerated dose. Sometimes you will try the same dose again, making sure that the child is taking it on a full stomach or perhaps simultaneously administering an antacid.
There are a lot of little tricks to try, all of the very subtle things that are the art of treating patients.
Were there children who developed EoE during the trial?
Yes. In the clinical trial, about 10% of the patients developed symptoms consistent with mucosal eosinophilia or EoE in an acute timeframe of about 6 months. That number is a bit uncertain, however, because most of the children who developed severe abdominal pain and vomiting (symptoms suggestive of EoE) were not biopsied. In the group that was biopsied, not all were found to have EoE. Reassuringly, though, the treatment for those children who do develop EoE in response to peanuts is to stop that exposure.
What happens after a year for the kids who do develop tolerance?
Children in this trial were treated for a full year, but the open-label extension trial documented that if OIT is stopped after 1 year, 75% of the patients will lose their tolerance within 2 months; they will react again to peanuts. So what we have done in the real world is switch the kids who have demonstrated by blinded food challenge that they can tolerate 600 mg of peanut protein to a more edible version of peanut, something that they like to take, like a small peanut candy. We educate kids and their parents that this should be treated like a daily multivitamin—something that becomes routine to administer at home every single day.
Most of these kids hate the taste of peanuts, so this isn't necessarily medicine that they will like. But our rule is take it daily for the first 3 years and then we can slowly wean down.
There are also trials currently being conducted examining alternate dosing regimens, including for long-term maintenance.
To reiterate, the goal of this trial is to increase tolerance to an accidental exposure to peanut. This therapy is not foolproof and these kids should not be eating peanut butter cookies. They still need to carry their epinephrine device and they still need to pay attention to food labels.
Is there any concern that long-term ingestion of even low doses of peanut powder by a child who is sensitive to it could induce other allergic disease, including mucosal eosinophilia, down the line?
The bottom-line answer is yes. The question, though, is how often does that occur? It's a little bit tricky. Does it occur in longer-timeframe periods? Probably yes. But we don't know. There's some hint that it does, but it's not been well studied to find out how often. But we've definitely seen it in real-world scenarios.
For example, children who have outgrown a milk allergy and are able to tolerate milk can develop EoE in response to milk many years down the line. This has occurred even in children who were daily milk drinkers.
What about the third of children who did not achieve tolerance? Do they simply go back to avoidance and carrying rescue epinephrine?
Correct. Right now, that's where we're at. There are some other treatments currently being tested in clinical trials. Two biologic agents, dupilumab and omalizumab, are being studied. An epicutaneous immunotherapy which involves wearing a patch containing peanut allergen is under FDA review.
It's important to emphasize that we're early on in the development of immunotherapies. A lot is likely to change in the next several years.
Jonathan Spergel, MD, PhD, is chief of the allergy program at Children's Hospital of Philadelphia. His clinical interests include food allergy, eosinophilic gastrointestinal disease, and atopic dermatitis, particularly the link between these conditions.
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Cite this: Treating Peanut Allergy With Oral Immunotherapy: Insights From an Insider - Medscape - Mar 02, 2020.
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