Peanut Antidote Served Boiled, Processed, and Packaged

Ingrid Hein

February 28, 2019

As the number of clinical trials that show the benefits of oral immunotherapy for peanut allergy increases, allergists are facing mounting pressure from patients and parents to offer immunotherapy in the clinic.

However, there is a lot of controversy surrounding oral immunotherapy, explain Lianne Soller, PhD, and her colleagues from the University of British Columbia in Vancouver in a recent update on the issue (Ann Allergy Asthma Immunol. Published online February 19, 2019).

Allergists still have questions about safety and efficacy, and disagree about whether the clinical world is ready to unveil oral immunotherapy to real-world patients.

"Most international food allergy guidelines do not currently recommend oral immunotherapy in clinical practice," Soller's team reports; however, some organizations are cautiously looking at the therapy.

The European Academy of Allergy and Clinical Immunology (EAACI) recently stated that oral immunotherapy should "only be undertaken in highly specialized clinical centers with expertise and facilities to safely deliver this therapy" (Allergy. 2018;73:799-815).

In addition, the Spanish Society of Pediatric Allergology, Asthma and Clinical Immunology (SEICAP) and the and Spanish Society of Allergology and Clinical Immunology (SEAIC) established recommendations for oral immunotherapy for milk and egg allergies (J Investig Allergol Clin Immunol. 2017;27:225-237).

In anticipation of the demand for safe and cheap options for peanut immunotherapy, researchers are studying available — and soon to be available — options, from pharmaceutical products to a boiled peanut.

Results from three studies of three different delivery options were presented at the American Academy of Allergy, Asthma and Immunology 2019 Meeting in San Francisco.

AR101: Peanut in a Capsule

A pharmaceutically packaged peanut-derived oral immunotherapy, AR101 (Aimmune Therapeutics), showed promise in the phase 3 PALISADE study, as reported by Medscape Medical News.

Patients who were able to tolerate only 100 mg of peanut protein at baseline were more likely to tolerate more than 600 mg of peanut protein in a double-blind, placebo-controlled food challenge after AR101 treatment than after placebo (67% vs 4%; < .001).

Results from a PALISADE follow-on study, presented during a poster session at the conference by Tara Carr, MD, from the University of Arizona College of Medicine–Tucson, showed that continuous dosing with 300 mg for 1 year can lead to even more tolerability.

"Almost half of the children in the follow-on study were able to tolerate the 1000 mg dose, suggesting that the efficacy in the immunotherapy continues," she told Medscape Medical News.

After an additional 28 weeks of daily AR101 treatment, the median tolerated dose during the food challenge was 1000 mg of peanut protein, and 48.6% of the 53 patients were able to tolerate a challenge dose of 2000 mg, Carr reported.

The adverse event rate in the follow-on was similar to that in the original PALISADE study (81.2% vs 88.0%). Of the three patients (2.6%) in the follow-on who discontinued therapy because of adverse events, two were treatment-related: one case of eosinophilic esophagitis and one mild systemic reaction.

"We can have even bigger outcomes with longer exposure," said Carr. "It's a huge step forward for patients with food allergy, specifically for protecting against accidental exposure ensuring a level of safety."

People die; we take this very seriously. My inclination is to be as cautious as possible when providing immunotherapy.

AR101 is more expensive than peanut butter. The cost of the drug is not yet known, but estimates are that it will cost somewhere in the range of $1000 a month. However, the added safety of using a consistent dose is worth the trade-off, particularly for children, Carr said.

"We are trying to mitigate risk as much as possible because we know that risk of anaphylaxis is high and can be devastating," she explained. "People die; we take this very seriously. My inclination is to be as cautious as possible when providing immunotherapy."

In addition, "AR101 is processed or packaged with a lubricant that helps it get absorbed more consistently and evenly in system," Carr pointed out. The capsules contain accurate doses of peanut protein, "which can be mixed in food product, apple sauce, or pudding — age-appropriate food."

AR101 tastes like peanut, because it is peanut. "Some of the older kids had a harder time tolerating it; they reacted to the taste and smell of peanut because they're so conditioned against peanut," she said.

The capsule is expected to be available to allergists in the coming months.

A Store-Bought Snack for Oral Immunotherapy

A real-world study of oral peanut immunotherapy in 270 preschool children 9 months to 5 years of age, conducted by Soller and a team of academic and community allergists in Canada, has also shown promise.

Parents and allergists chose one of three protocols: a peanut-containing snack food called Bamba; a capsule filled with peanut flour or powdered peanut butter, known as PB2 powder; and a hybrid that started with the capsule and ended with Bamba.

Bamba, a favorite with children in Israel, has a consistency similar to Cheetos but "has more of a peanut butter flavor," Soller told Medscape Medical News. "It's pretty good."

"We wanted to remain flexible with the families. Some wanted to make sure they had the exact amount, others wanted the convenience of buying the food in the store," she explained.

Investigators assessed dosing during biweekly clinic visits and a maintenance dose of up to 300 mg was administered at home for 16 weeks.

To be eligible for participation, children with a history of peanut reaction in the previous 6 months had either a skin prick test reaction larger than 3 mm or a serum peanut-specific immunoglobulin (Ig)E level above 0.35 kU/L. Children with no history of allergic reaction and no known peanut exposure had a positive prick skin test and a peanut-specific IgE level above 5 kU/L.

As of November 2018, 243 patients (90%) had built up to 300 mg of peanut protein, or about four sticks of Bamba.

Reasons for dropping out of the study included allergic reactions (a few patients required epinephrine), the child not liking peanut, and an unwillingness to adhere to the daily dose of peanut protein (either Bamba or the capsule). "Those who dropped out had higher blood-test levels but there was no difference in reaction rates," Soller reported.

About two-thirds of the children (67.8%) experienced reactions during build-up.

Only one patient (0.4%) experienced a severe reaction — grade 4 on the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System with adaptations specific to allergic reactions in infants. The other reactions were less severe, with 36.3% experiencing a grade 1 reaction, 31.1% a grade 2 reaction, and no patients experiencing a grade 3 reaction.

In the PALISADE trial of 496 children 4 to 17 years of age, which compared AR101 with placebo, the rate of severe adverse events in the immunotherapy group was 4.3%. The reason this is much higher than the rate of 0.4% could be related to "anaphylaxis in older children," Soller pointed out.

"We were happy with the results," she said.

More than 41,000 doses of immunotherapy were given over the course of the study and only 12 doses of epinephrine were administered. "That's 0.03% of the doses that received epinephrine. That's extremely small," she added.

The Boiled Peanut Option

A few years ago, a researcher in Southeast Asia noticed that children in Australia who were allergic to peanut butter had no problem eating boiled peanuts, reported Paul Turner, BM BCh, PhD, from Imperial College London and the Medical Research Council in the United Kingdom.

"How was that possible?" he wondered.

Further investigation revealed that "when you boil the peanut, a lot of the proteins that cause allergy leak out into the water," Turner explained (J Allergy Clin Immunol. 2014;134:751-753). This makes the boiled peanut a possible low-allergy peanut product that could serve as an oral immunotherapy option.

So he and his colleagues identified 47 children 8 to 17 years of age with a peanut allergy for their phase 2b/3 randomized controlled trial of boiled peanut oral immunotherapy.

Of the 32 patients randomized to receive active treatment and the 15 randomized to the control group, 24 and 14, respectively, completed the full course of immunotherapy.

The rate of anaphylaxis in the cohort was 40%. "We had a very allergic group of kids," said Turner.

The parents were taught how to boil the peanuts. "We gave them a simple one-page recipe with pictures," said Turner. You basically boil a peanut like boiling an egg." The instructions included how many hours to boil the peanut and how many peanuts to eat.

The recipe has not been made public. "We are being careful because we don't want people to do this without access to someone who can help with adverse events," he explained. "The last thing we want is parents doing this on their own."

Updosing continued for about 6 months and was followed by maintenance with roasted peanut.

At baseline, the median cumulative eliciting dose of peanut protein was 143 mg. Desensitization to more than 1.4 g of peanut protein was achieved by all 24 patients who completed immunotherapy (P < .0001), and 14 patients tolerated more than 4.4 g. There was no significant change in desensitization in the control group (P > .05).

There were 19 episodes of anaphylaxis in 10 patients.

"The advantage of boiled peanut is you don't have to weigh out tiny amounts," Turner pointed out.

"Even children who had reacted to 3 mg of peanut were able to tolerate the boiled peanut. All of the children who completed the study were able to tolerate at least six to eight peanuts," he reported.

Turner's team is currently working on a head-to-head comparison of PB2 powder and boiled peanut.

"We think there might be a more favorable safety signal with boiled peanuts," he said.

Another advantage is that "it would be hard to categorize boiled peanut as a drug," he noted. "It still looks like peanut, and it won't cost a fortune because it won't need FDA approval."

Meanwhile, the pressure from parents continues.

A Peanut a Day Keeps Anaphylaxis Away?

A group of parents of children with peanut allergy — who self-identify as "a bunch of moms" — have created a website that identifies allergists in the United States who offer oral immunotherapy outside of a research setting.

The group has expressed impatience because immunotherapy is not widely available.

"Mother Nature already made a peanut pill: it's peanuts. And they cost peanuts," they write.

They acknowledge risks and are careful to state that immunotherapy should only be attempted with a "licensed doctor who is a board-certified allergist," but their frustration is palpable: "A whole generation of kids has had this withheld from them by the oral immunotherapy researchers. 10 years where millions of kids could have been treated have been lost."

A 2013 study showed that only 13.8% of allergists in the United States were offering oral immunotherapy for food allergies (J Allergy Clin Immunol Pract. 2015;3:33-38). However, nearly 2.5% of American children have a peanut allergy, according to a 2017 national survey, as reported by Medscape Medical News, so parents have few options.

There is a cost to doing nothing, Soller and her colleagues point out in their controversy update.

This includes, they write, "the risk of accidental ingestion, fear of fatality, the low rate of outgrowing peanut allergy, the economic impact of food allergy, and the significant impact on quality of life."

Soller has disclosed no relevant financial relationships. Carr reports receiving funding from the National Institutes of Health, working with Aimmune Therapeutics, a local sponsor of her study, and consulting for AstraZeneca and Sanofi Regeneron. Turner reports receiving funding from the UK Medical Research Council and Imperial/NIHR Biomedical Research Centre, and being a member of advisory boards for Aimmune Therapeutics and DBV Technologies.

American Academy of Allergy, Asthma and Immunology (AAAAI) 2019 Meeting: Abstracts 776, 794, 252. Presented February 25, 2019.

Follow Medscape on Twitter @Medscape and Ingrid Hein @ingridhein

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