For the millions of people with peanut allergies, oral immunotherapy offers the possibility of fewer allergic reactions and a life lived with far less anxiety. That life could be on the horizon: the US Food and Drug Administration (FDA) is expected to rule on the first peanut desensitization product, Aimmune Therapeutics’ biologic, AR101, later this year.
But a recent meta-analysis highlights an underappreciated issue. For many, the treatments actually increase allergic reactions. The study, published in The Lancet, analyzed 12 randomized clinical trials involving 1041 participants followed up for a median of 1 year. The trials compared oral immunotherapy with placebo, peanut avoidance, or, in 1 case, sublingual immunotherapy. In all the studies, both the treatment and control groups were told to continue avoiding peanuts, the current approach to managing peanut allergies.
Oral immunotherapy outperformed no oral immunotherapy on the standard primary end point: an estimated 40% of the treatment group passed a supervised, in-clinic oral food challenge, or “provocation,” at the end of the studies compared with about 3% of the control group. But the oral immunotherapy group had an increased risk of serious adverse events.
No deaths occurred, but based on the 9 trials that measured anaphylaxis—both treatment-related and accidental—the researchers estimated the risk to be 22% with oral immunotherapy compared with just 7% without it. They reported that oral immunotherapy would lead to an additional 15 anaphylaxis events per 100 treated individuals. The treatment group also had more frequent anaphylaxis, used epinephrine more often, and had more reactions like asthma attacks, hives, swelling, and vomiting.
Unreliable Protection
Over the past decade, hundreds of patients—most of them children—have participated in randomized trials of peanut desensitization treatments. In these studies, the new analysis showed that those who received oral immunotherapy were much more likely to pass an exit food challenge. So why did they also have more allergic reactions?
According to Derek Chu, MD, PhD, the study’s lead author and an allergist and clinical immunologist at McMaster University in Hamilton, Ontario, there’s a disconnect between the in-clinic test—a surrogate for preventing out-of-clinic reactions—and hard end points like anaphylaxis and epinephrine use.
During the desensitization process, oral immunotherapy participants ate a tiny daily dose of peanut flour, paste, or extract mixed in food at home. Every 2 weeks or so, they visited the clinic for a supervised dose increase. At the end of this buildup period, they were instructed to take a daily maintenance dose. If they passed a provocation test after completing the predetermined maintenance phase, the treatment was considered a success.
But for some participants, the protection appeared to fluctuate during the treatment, resulting in allergic reactions to doses they previously tolerated both during the buildup and maintenance phases, which together usually lasted a year or 2.
“It does reflect a real limitation that we are all aware of, which is that particularly during the dosing increase [phase] we see a lot of reactions,” said Alkis Togias, MD, chief of the Allergy, Asthma, and Airway Biology Branch of the National Institute of Allergy and Infectious Diseases, which funds food allergy research.
Reducing the number of reactions is a research priority, Togias said, but some allergic reactions are to be expected. “When you attempt to treat allergy by exposing people to the thing they’re allergic to, you’re going to get allergic side effects,” said Brian Vickery, MD, an associate professor of pediatrics at Emory University in Atlanta and director of the Food Allergy Center at Children’s Healthcare of Atlanta. “Those side effects are potentially serious in small numbers of patients. They are less serious in many more patients.”
Vickery led a recent phase 3 trial of Aimmune’s investigational treatment, the largest clinical trial of peanut oral immunotherapy to date. To his point, serious or severe adverse events were low overall: less than 6% of participants in the active-drug group and less than 2% in the placebo group experienced them. However, around 67% of participants who received AR101 passed the exit food challenge compared with just 4% who took a placebo, and Vickery said that many were desensitized with few adverse events. (Vickery is a member of Aimmune’s scientific advisory board.)
Amal Assa’ad, MD, who also has conducted studies of AR101, oversees the Allergy Clinic at Cincinnati Children’s Hospital, one of a handful of academic medical centers already offering peanut oral immunotherapy outside of trials. In her experience, the roughly 6-month buildup phase causes patients anxiety and “a lot of symptoms.” However, she said, “once you get them over the hump, then most of them do really well.” As time goes on, patients may have fewer reactions during maintenance therapy, but more long-term data are needed, she said. Those data will be important because maintenance dosing is currently recommended indefinitely.
There’s another key argument for oral immunotherapy despite its attendant risks. Some people with peanut allergies might be willing to accept the possibility of dose-related reactions at home, with rescue medication and a family member at their side, if they gain protection from accidental exposures outside of the home, according to Vickery and others. In his study, the vast majority of allergic reactions occurred with dosing. “The numbers of accidental reactions to peanut in the real world are very small compared to the number that are dose related,” he said.
Togias added, “If you take that dose at home, and parents are present and the epinephrine is available, in general you don’t get into severe reactions. The chances that the reaction is going to be worse are truly higher in the field compared to under treatment.”
These arguments don’t entirely convince Chu, who was diagnosed with peanut allergies when he was 1 or 2 years old. “Just because one doses at home does not necessarily make it more safe or more ‘in control,’” he said in an email. He pointed out that, outside of desensitization trials, multiple studies show that most anaphylactic reactions occur in the home setting.
Plus, the food challenge was developed to diagnose or rule out allergies and has not been validated as a tool to predict future reactions. Because this test has been the historical measure of efficacy, it’s yet to be proven definitively that oral immunotherapy protects people during real-life accidental exposures, the true goal of desensitization.
What Matters to Patients?
Late last year, Aimmune reported no treatment-related serious adverse events during the initial up-dosing period in a safety trial of AR101. But Chu said the findings may be misleading.
The trial enrolled patients with a history of physician-diagnosed peanut allergy confirmed by a skin prick challenge and immunoglobulin E testing. In Chu’s analysis, up to 40% of people enrolling in oral immunotherapy trials who were thought to be peanut allergic turned out not to be based on food challenges at the start of the studies. Trials that didn’t confirm participants’ allergies with a food challenge had more than 6 times lower risk of adverse reactions causing study discontinuation.
Including participants in an oral immunotherapy trial who don’t have peanut allergies or who have mild allergies or grew out of them, as some people do, could make the treatments look safer than they really are. In practice, however, Assa’ad said that many families refuse the food challenge her clinic encourages before kids start treatment. This means that some patients may be undergoing a long and tedious therapy for a condition they don’t even have.
The treatments come with practical considerations. In the trials Chu analyzed, certain behaviors or circumstances—some unavoidable—appeared to undermine desensitization. Factors associated with adverse reactions after dosing included exercising or showering, being tired or going to sleep, having an infection or a fever, menstruating, or having an asthma flare-up. Most of the trials had dosing restrictions around these triggers or introduced them during the study. In many cases, no trigger was identified.
“Knowing what I know now, I wouldn’t accept the practical implications of peanut oral immunotherapy as well as the increased risk of reactions,” Chu said. Yet, he acknowledged that peanut allergies are highly personal and that some people may opt for oral immunotherapy despite knowing the risks. “The challenge is trying to understand those preferences or values from the full spectrum of patient perspectives,” he said. Both he and Vickery stressed the need for research on patient-centric outcomes to understand what matters to people with peanut allergies. Although desensitization didn’t appear to improve quality of life in the meta-analysis, only a few trials measured it.
Not a Condemnation
Chu wants researchers to set a higher bar for evaluating food allergy treatments than passing an exit food challenge. “This means large, rigorously done randomized trials to develop proven treatments for patient-important outcomes,” he said.
He emphasized that his study is not a condemnation of peanut oral immunotherapy, an approach he firmly believes has merit. (The study does not speak to desensitization for other food allergies, such as egg or milk. Treatments for existing peanut allergies also shouldn’t be confused with a recent recommendation to introduce high-risk infants to peanuts to prevent allergies.)
Next-generation optimized regimens—peanut oral immunotherapy 2.0, as he calls it—could help to improve safety. Some groups, for example, are testing desensitization in combination with anti-inflammatories, such as omalizumab and dupilumab, or with probiotics. Others are studying a protocol using boiled peanuts, a process intended to make the doses less allergenic. Researchers are also experimenting with different treatment doses and durations and are developing nonoral therapies, such as skin patches and monthly injections of peanut peptides.
It’s also likely that there are “good” and “bad” candidates for peanut desensitization, Vickery said, based on factors such as biology and treatment compliance. Some people may be better off waiting for different treatments, but research is needed to pinpoint who they are. “The unfortunate thing about all this work so far is that we have no markers of who is going to do well and who is not,” Assa’ad said.
A critical goal is to improve the treatments so patients don’t have to take a daily maintenance dose indefinitely. Vickery has shown that a proportion of children in oral immunotherapy trials demonstrate so-called sustained unresponsiveness to peanuts a month after stopping daily dosing. Ultimately, Togias said, oral immunotherapy should create a lasting tolerance to peanuts.
“There’s clearly more work that is needed in this field,” he said. “It’s truly very early.” Yet, with a possible FDA greenlight looming and a few academic medical centers and many more allergists in private practice already offering peanut oral immunotherapy, increasing numbers of individuals with peanut allergies and their families will have to decide whether the potential benefits of treatment are worth the risk of more reactions, he said. “At this stage of the game, this is where the dilemma is going to come for the patient.”
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