The Treacherous Journey Toward Immunity for Patients with Food Allergies: Past to Present

It would not be a stretch to state that most everyone knows someone with some form of allergy to food, though the ubiquity of food allergy belies its serious threat for many of those who face the condition.

In the US each year, there are around 200,000 individuals that need emergency medical care for allergic reactions to different food products. In fact, more than half of the 33 million US adults with food allergies have experienced a severe reaction.¹

Prior to the US Food and Drug Administration (FDA) landmark approval of AR101 (Palforzia), the landscape of food immunotherapy treatments for patients with allergies was essentially empty. Yet this approval occurred in 2020, barely a few years removed from the present day.

The introduction of food products to children’s diets has been a hotly contested one as well, due in part to the inherent danger in allergic reactions of children and the lack of awareness about early exposure.

All of this is to say that the landscape for food allergy is considered by many to be woefully underdeveloped and in dire need of improvement to prevent the recent expansion of reported allergies and lack of immunity among children and adults.

Recent Shifts in Mindset Among Allergists

The field of food immunotherapy is, in some ways, still in its infancy. In fact, the changes seen in the ways in which allergists preemptively treat and respond to allergies over the past 20 years has represented nothing short of a seismic shift.

“Food immunotherapy probably started picking up about 20 or so years ago,” David Fleischer, MD, the director of the Allergy and Immunology Center at Children’s Hospital Colorado, told HCPLive. “Oral immunotherapy started, the first reports, in the 1900s with egg, but it really didn't start taking off until about 20 years ago and that was really the start of immunotherapy.”

Many Americans may recall the early 21st century period in which the overall mindset for allergy management in the medical community could be encapsulated into a single word: avoidance. As allergies to peanut, tree nuts, and other common products appeared to rise among children, the recommendation was to avoid said products at all costs.²

“2000 is when the American Academy of Pediatrics recommended avoidance of major allergens like peanuts and tree nuts, until you were 3 years old, milk until you were a year old, egg until you're 2 and fish until you were 3,” Fleischer explained. “Then, shortly after that…in 2008, they said you shouldn't avoid these things. But it wasn't until the LEAP (Learning Early About Peanut Allergy) trial that came out in 2015 said you really should eat these things early to try to prevent the development of allergy and that the avoidance of things, waiting until your immune system was more mature, was not the way to do things.”

This assessment highlights the very real concerns that occurred among food specialists in the years after the 2000 recommendations by the American Academy of Pediatrics (AAP). The specialists had noted that from 2000 to around 2009 there had been some alarming food allergy trends among younger children.⁴

As these trends progressed, and more and more children appeared to be strongly affected by peanut allergies and others, a change in mindset gradually appeared to take place among allergists. The LEAP trial could be considered one of the biggest paradigm shifts in the field, showing early introduction of peanut diminished allergy development among the children featured in the study.⁵

“Now, recommendations and guidelines across the world from allergy societies are now recommending the early introduction of all major allergens to try to prevent allergy,” Fleischer said. “It's worked to some degree. I think the acceptance of early introduction is now the norm but it's whether the message is getting out there to the practitioners, the general practitioners, the family practitioners, the pediatricians to tell their patients to do it.”

Major Leaps Forward

Oral immunotherapy (OIT), the gradual exposure of allergic individuals to increasing amounts of a food allergen to raise their reaction threshold, does not cure allergies. It does aim to provide protection against the accidental ingestion of allergens, and it has made strides in recent years.

“Early on—we’re talking way back into the 1980s—they actually looked into the concept of allergy shots for peanut allergy specifically, allergy shots being sort of the bread-and-butter treatment that allergists provide for environmental allergies,” Edwin Kim, MD, associate professor of pediatrics of University of North Carolina’s School of Medicine, told HCPLive.

Kim noted that researchers found that the allergy shots may have been able to desensitize somewhat, but there were too many side effects with the treatment itself that it was effectively abandoned in the 1980s.

The question became whether patients could still be desensitized, making the immune system less reactive, but treated in a different way. This was considered to be where the oral immunotherapy approach was born, with experts like Wesley Burks, MD, leading the way.

“Originally, Dr. Burks started some of this work at Duke University looking into peanut, milk, as well as egg oral immunotherapy,” Kim explained. “And then he brought that research over to the University of North Carolina, where we then got involved with multiple studies, each one of them showing that oral immunotherapy could be very effective.”

Then in 2020, the US Food and Drug Administration (FDA) finally approved the first immunotherapy indicated for food allergies: AR101 (Palforzia). AR101 is an oral peanut-protein immunotherapy designed for reducing reaction incidence and reaction severity in individuals aged 4-17 years old that are allergic to peanuts.

“There was a lot of debate and a lot of questions, because it is a difficult treatment, but they ultimately approved it,” Kim explained. “And to me, this was a key moment in food allergy because, to me, that's a signal. Of course, it was the Palforzia drug getting approved, but to me it was much bigger than that. It really signaled, first of all, food allergy is a disease that deserves a treatment…We have a way to do it.”

While the field of food allergy management has made enormous strides, there remain several major concerns from those affected.

Biggest Setbacks in the Field

OIT is an advantage that parents have in helping to immunize their children, but those undergoing OIT still need to carry epinephrine and remain vigilant. The use of auto-injectable epinephrine for anaphylaxis is considered by many parents to be a major concern and a constant worry.

Anaphylaxis can only be prevented through use of an autoinjector, and no other options exist to date. In addition to the obvious difficulties in rapidly injecting a child with epinephrine in the event of anaphylaxis, exponential price increases of the EpiPen auto-injector have made it difficult to afford the vital medication.⁶

In September of 2023, a promising development in alternative epinephrine medication came into light: an intranasal epinephrine spray known as ‘neffy.’ Neffy, designed to treat Type 1 allergic reactions including anaphylaxis, would have been the first needle-free nasal spray epinephrine alternative.⁷

However, ARS Pharmaceuticals was given a Complete Response Letter (CRL) from the FDA for neffy, surprising many allergists and patients who had eagerly-anticipated an approval by the agency. The decision remains, to some, one of the most surprising FDA decisions in the field of allergy management this year.

Another setback was the partial clinical hold placed on the VITESSE (Viaskin Peanut Immunotherapy Trial to Evaluate Safety, Simplicity and Efficacy) trial assessing an epicutaneous immunotherapy. The immunotherapy treatment is a modified Viaskin Peanut 250 µg patch known as DBV712, designed for peanut-allergic children aged 4-7 years.

In the partial clinical hold letter, the FDA had asked for alterations to specific elements of the trial’s protocol in view of a future Biologics License Application (BLA) submission. This was considered a setback, as it would provide an epicutaneous alternative to OIT, though it should be noted that the clinical hold on the VITESSE trial was lifted, and the study protocol was adjusted based on FDA guidance.

“Going back to some of the negatives, or the difficulties with the oral immunotherapy, one I didn't mention before is many, if not most, of our patients with peanut allergy actually have a really, really strong oral aversion to the peanut itself,” Kim noted in his discussion with HCPLive. “Meaning that just the smell of it, the taste of it, the texture of it, it really drives them crazy.”

Kim added that while AR101 uses around 300 milligrams of peanut exposure per day, the Viaskin peanut patch contains 250 micrograms per day and is used on a daily basis. This is 1000 times less and, Kim noted in his interview, seemed to be far safer.

An FDA approval of the patch remains a hope for many seeking alternatives to OIT, but it remains to be seen whether setbacks like these will be alleviated in the coming months. For many parents of children with allergies, it cannot come soon enough.

Looking Toward the Future

While improved options for patients with food allergies remain scarce, there is hope on the horizon. New therapies are being tested and the necessary alterations in design are being made by researchers.

One notable alternative to OIT for patients is offered by some allergists, though it is not easy to find: Sublingual (“beneath the tongue”) immunotherapy, also known as SLIT. In SLIT, a food allergen becomes dissolved into a small measure of liquid and kept under the tongue for several minutes prior to being swallowed or spat out.⁸

SLIT is used to provide undigested allergen to cells found in the mouth’s lining, working to promote improved tolerance. It has been used for allergies to peanut, kiwi, milk, hazelnut, and peach.

There is also a treatment under investigation known as ADP101, a multi-allergen oral immunotherapy OIT designed to help make patients with multiple food allergies become less reactive. Recent phase 1/2 findings from the HARMONY study showed that subjects receiving ADP101 had dose-dependent and clinically meaningful treatment responses.

Additionally, the investigators favorable safety and tolerability profile for the OIT treatment in pediatric patients that had multiple allergies to different food sources. Time will tell if the treatment becomes approved by the FDA for use among the wider public.

These recent developments in the landscape of allergy treatment highlight an important message: though the field may be in its infancy, there may have been no better time than the present to be a patient with food allergies. The growing number of studies on different options for management and treatment demonstrate the rising awareness of different institutions and even the general public about food immunotherapy.

The food immunotherapy field has been marked by a paradigm shift from avoidance to early introduction, as well as the emergence of OIT. The recent FDA approval of AR101 in 2020 has proven to be a momentous occasion, signifying a pivotal recognition of food allergies as something that can be treated.

While challenges with the auto-injectable epinephrine alternative to the EpiPen and unexpected FDA decisions surrounding the Viaskin peanut patch demonstrate the ongoing hurdles in the field, the future of food immunotherapy continues to hold promise in so many ways.

Current research examining treatment options such as sublingual immunotherapy highlight the potential for growth in the field of allergy management, and those with severe food allergies may look to the future with a glimmer of hope.

References

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7. ^{Smith T. FDA Declines to Approve of Epinephrine Alternative to EpiPen, Requests Further Study. HCPLive. September 20, 2023. https://www.hcplive.com/view/fda-declines-to-approve-of-epinephrine-alternative-to-epipen-requests-further-study. Date accessed: December 21, 2023.}
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