Peanut Oral Immunotherapy Is Safe and Effective in Toddlers in Large Placebo-Controlled Trial

Esther Landhuis

January 21, 2022

In a large, blinded study of peanut-allergic toddlers published today in The Lancet, 71% of treated participants could safely consume 5000 mg of peanut protein — equivalent to nearly 17 peanuts — after 2½ years on oral immunotherapy. Even after stopping maintenance dosing for the next 6 months, more than 1 in 5 maintained that level of protection, and nearly 3 in 5 still met the 600-mg benchmark (about 2 peanuts) set by the phase 3 PALISADE trial of the FDA-approved peanut-flour product, Palforzia.

About 2% of children in the United States are allergic to peanuts, and most will not outgrow this allergy. In addition, other research suggests that the immune system is more malleable during early childhood.

Consistent with this idea, prior research showed that toddlers can succeed with peanut oral immunotherapy (OIT) — a regimen that builds tolerance through small amounts of the allergen consumed daily for months. However, that trial (DEVIL) was small, was conducted at a single site, and had no placebo group.

In contrast, the Peanut Oral Immunotherapy in Children Trial (IMPACT) enrolled 146 children aged 1–3 years at five academic medical centers in the United States — the first placebo-controlled study of OIT in this younger age group.

"This is a well-done study," Jaclyn Bjelac, MD, associate director of the Food Allergy Center of Excellence at the Cleveland Clinic, in Cleveland, Ohio, told Medscape Medical News. "We have seen improved outcomes in OIT both in our own experience and other published studies, so while this is no surprise, the outcomes and large number of participants contribute to this being a really exciting publication."

The trial was long and demanding for families. Toddlers who reacted to 500 mg or less of peanut protein in an entry food challenge were randomized in a 2:1 ratio to receive daily peanut flour or oat flour placebo. After initial dose escalation (from 0.1 mg to 6 mg) and biweekly buildup to a 2000-mg target dose by week 30, participants continued with 2000-mg daily maintenance dosing through week 134 — at which point they underwent a food challenge. They then went off treatment for 26 weeks and had another food challenge (week 160). In addition, participants came in for skin-prick and blood tests at baseline and at weeks 30, 82, 134, and 160.

In the placebo group, only 23 of 50 participants (46%) completed the study. "If you did 2½ years of this and then bombed the food challenge, you probably can guess that you were not on the real thing. And they were still asked to come back in 6 months and do it again. So, sure enough, a big chunk of those people chose not to continue, and you can't blame them," said Lancet co-author Edwin Kim, MD, in an interview with Medscape Medical News. Kim directs the UNC Food Allergy Initiative at the University of North Carolina School of Medicine in Chapel Hill.

There was attrition in the treatment group as well. Among 96 children initially assigned to this arm, 68 (71%) passed the 5000-mg peanut challenge at week 134 — but 11 withdrew in the study's off-treatment phase. "It was a very tough decision. How much do you give toward science?" said Kim. "When push came to shove, some of the families couldn't pull the trigger to potentially give up what they worked so hard for."

In the intention-to-treat analysis, 20 of 96 treated participants (21%) could still tolerate 5000 mg of peanut protein after going off therapy for 6 months. That translates to a 29% remission rate in the per-protocol subset (n = 70) who completed the study. Forty (57%) of these completers safely consumed at least 1755 mg of peanut (cumulative dose). By comparison, the PALISADE trial of Palforzia used a 1043-mg cumulative peanut dose to measure treatment efficacy.

On safety, 98% of treated participants — but also 80% of the placebo group — reported reactions, of which 35 were treated with epinephrine in 21 children receiving peanut OIT.

While some have noted that epinephrine use seemed high, "we're actually OK with that, because we'd much rather they overtreat and make sure that 1-year-old is safe than take any chances," Kim said. Overall, the safety profile looks similar to prior OIT studies of older children. "I think it suggests that, yeah, side effects will happen, they're all manageable, and people are not anaphylaxing left and right."

On remission and immunologic parameters, benefits seemed stronger in the youngest subset (12 to 24 months), particularly those with lower peanut-specific IgE at baseline. These trends require further analyses, though, given the limited number of participants under 24 months.

Another noteworthy observation from longitudinal peanut-specific IgE trends in the placebo group: "Avoidance may not be benign," Kim said. "If you look at their labs, they don't stay flat. They actually go up." The results jibe with the long-held idea of an early window of opportunity while a child's immune system is maturing. "If you can grab this kid when his IgE is 10, vs next year when it might be 50, maybe you'll get a different treatment effect," Kim said. "We don't know that for sure, but the placebo labs kind of point toward that."

Beyond the science, there are practical advantages to starting OIT early. "Trying to convince a 9-year-old who's been petrified of peanuts for their whole life to start doing this every day is not an easy task," whereas with a 1- or 2-year-old, "you build it into their routine," Kim said.

Plus, some say there's no need for families to wait for regulatory approval of additional commercial products for very young children. Though some have advocated against the use of "grocery store" products, most peanut OIT research "has used the same 12% light roast defatted peanut flour used in IMPACT," noted Marcus S. Shaker, MD, professor of pediatrics and of medicine at the Dartmouth Geisel School of Medicine and a physician at the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. The commercial product (Palforzia) and grocery-store products "come from the exact same source in the US," he told Medscape. "Both are an option for parents to consider, but a commercial product is not, nor has ever been, a necessity."

Bjelac reports no relevant financial relationships. Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; and grant support from the NIH's National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network; Food Allergy Research and Education, and the Wallace Research Foundation. Shaker has participated in research funded by DBV, is co-chair of the AAAAI/ACAAI Joint Task Force on Practice Parameters, is an associate editor at the Annals of Allergy, Asthma, and Immunology, and is an editorial board member of the Journal of Allergy and Clinical Immunology in Practice.

Lancet. 2022;399:359-371. Abstract

Esther Landhuis is a freelance science journalist in the San Francisco Bay Area. She can be found on Twitter @elandhuis.

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