The FDA has approved the first oral immunotherapy for peanut allergies, but specialists are not convinced the benefits of the treatment outweigh the risks
The idea of eating peanuts to treat peanut allergies is not a new one. It’s called oral immunotherapy and although it’s been floating around in the scientific literature since the 1930s, it’s only entered clinical practice in the past decade or so, and only in some countries.
Oral immunotherapy (OIT) involves a patient eating a gradually increasing amount of peanut protein over several months, with the aim of being able to safely consume a standard serving of peanuts by the end of the treatment.
Over the past decade, some paediatricians in the US, Europe and Japan have been offering oral immunotherapy in the form of small, increasing doses of peanut flour. The treatment technically works, in that most allergists agree that it is possible to raise people’s tolerance to peanuts by feeding them peanut flour in ever-increasing doses.
However, OIT has remained controversial because it’s considered risky and has unclear benefits. People have more allergic reactions when doing OIT than when strictly avoiding the food allergen. It’s also uncertain how long desensitisation lasts; people may have to continue the treatment regimen for their whole lives in order to continue tolerating peanuts.
Australian allergists remain extremely cautious about OIT and the leading body for allergists and immunologists, ASCIA, recommends against its use, outside of the few clinical trials that are currently running in Australia.
In February, however, the FDA in the US pushed this treatment into the spotlight by approving the use of first peanut OIT product, Palforzia.
Palforzia provides a standardised dose of peanut protein in the form of powder inside a capsule that then is sprinkled over food.
This product, manufactured by Aimmune Therapeutics, costs patients around US$11,000 a year.
It’s unclear what benefits Palforzia has over the old method of simply weighing out inexpensive peanut flour on a set of scales.
There are a few other peanut immunotherapies being trialled, including sublingual immunotherapy (SLIT) where patients place a smaller dose of allergen under their tongue.
SLIT is effective but it takes longer, and the extent of desensitisation is less than oral immunotherapy by the end of treatment.
Another product in development is Viaskin Peanut, which is a peanut patch. This is now finishing up its phase III clinical trials.
As Palforzia and these other products have not yet been approved by the TGA, Australian patients can’t access these novel OITs.
However, the FDA’s announcement did cause the Australasian Society of Clinical Immunology and Allergy (ASCIA) to update its website in March to reiterate its position that OIT was still not ready for prime time. The best advice for patients with food allergies was still complete avoidance of confirmed food allergens, ASCIA said.
The FDA announcement has also deepened divisions between allergists in the US.
While a handful of US allergists have been doing OIT for years, they’ve largely been operating on the fringes of the specialty.
The leaders in the allergy field in the US are “vigorously opposed” to the use of OIT in clinical practice. “It’s actively discouraged,” says Dr Richard Wasserman, a paediatric allergist based in Dallas, Texas, who has been using OIT for 11 years.
But, at the same time, some allergists in the US are “very enthusiastic about the commercial oral immunotherapy products” such as Palforzia, which smacks of conflicts of interest, he says.
The core of Aimmune Therapeutics’ business model is that patients need standardised peanut protein doses to commence OIT, says Dr Wasserman.
But there’s no evidence that Palforzia is practically any different to weighed doses of peanut flour when it comes to desensitising people with peanut allergies, he says.
FDA approval doesn’t establish the superiority of Palforzia over peanut flour, it just means the product was shown to be safe and effective, such as in the PALISADE trial (NEJM, 2018).
So why would patients or parents pay thousands of dollars for a product they can get from a supermarket at a fraction of the price?
One possibility is that patients are scared to try shelf-bought peanut products but feel safer with a commercialised peanut protein.
In Australia, OIT for peanut allergies is still very much in the research phase.
The focus has been on whether combining OIT with co-treatments, such as probiotics or dietary fibre supplements, can make it longer lasting, less harmful or more effective.
Professor Mimi Tang, a paediatric allergist and clinical immunologist at the Murdoch Children’s Research Institute, has been trialling the probiotic Lactobacillus rhamnosus combined with OIT.
Professor Tang says her research team has spent hundreds of thousands of dollars in the manufacture of precise OIT doses for just 62 patients involved in the trial.
The manufacture of precise OIT doses must be carried out under tight quality processes due to the potentially devastating consequences of any errors in dosing, she says.
Peanut protein is a potential allergen so manufacturers can’t just use any machinery to produce doses for OIT – separate or specially cleaned equipment is needed to reduce cross-contamination.
The OIT plus probiotic treatment was shown to be very effective in the first RCT led by Professor Tang, which ended in 2013 and involved 62 children aged one to 10 years.
By the end of the trial, around 80% of children were able to tolerate peanuts. Four years later, the majority were still eating peanuts as part of their normal diet and 70% of children passed a challenge test confirming their long-term tolerance to peanut.
But the initial trial couldn’t show whether the probiotic had additional benefits over the OIT alone, but a follow up trial testing this should be completed by the end of the year.
While no Australian allergists are willing to use OIT in clinical practice just yet, there are many allergists overseas who swear by the treatment.
Dr Wasserman has used OIT to treat over 850 patients with a variety of food allergies over the years. His patient cohort is mostly paediatric, including infants, children and teenagers, but he also treats adults.
Some of his patients were severely allergic to certain foods and had experienced anaphylaxis prior to starting OIT.
“We take all comers regardless of the degree of allergy,” he says.
Dr Wasserman treats patients with peanut, egg and milk allergies following the same protocol he developed a dozen years ago.
He introduces a low dose of the problem food into a patient’s diet and gradually increases the dose over several months.
While all patients must have an EpiPen on them during treatment, Dr Wasserman says there have been no deaths as a result of OIT anywhere in the world. And none of his patients has ever needed to stay in hospital overnight due to an allergic reaction to food.
Patients with peanut allergies are instructed to consume small portions of peanut flour every day diluted in liquid.
By the end of the treatment, which takes 28 weeks on average, all of his patients can safely eat foods with the warning “may contain traces of nuts” and, on average, around 85% reach the target dose of being able to safely eat 24 peanuts in one day.
Around 15% of patients drop out of treatment due to gastrointestinal effects because of reactions treated with epinephrine or because they dislike the taste of the allergenic food.
Most patients have to keep taking the allergenic food for life to maintain desensitisation, he says.
The hesitancy towards OIT in Australia is not a world-wide phenomenon, he says.
“Japan has dozens of children’s hospitals doing OIT and I personally know of 80 allergists in the US that do OIT.”
These US-based allergists have published some of their clinical findings.
Dr Wasserman and his colleagues published a paper on oral immunotherapy in The Annals of Allergy, Asthma, & Immunology (a peer-reviewed journal and the official publication of The American College of Allergy, Asthma & Immunology) in 2018.
This paper reported a meeting the year before among 68 clinicians who had treated 2,280 patients with OIT for food allergies.
“Families talk about how oral immunotherapy has ‘changed our lives’,” the paper reads.
Australia is in a “sweet spot” when it comes to paediatric care because the community is small enough that allergists can be unified and consistent in their approach, says Dr Lara Ford, the chair of the ASCIA paediatric committee and a paediatric allergist and immunologist at The Children’s Hospital at Westmead.
“As a group, when we look at the data, ASCIA feels that we haven’t reached the point where oral immunotherapy should be offered outside the study setting,” she says. “Everyone agrees that you can get people to tolerate a higher dose of peanut protein with OIT. But, on balance, right now it doesn’t seem worth the potential benefits.”
Palforzia aims to desensitise patients to the point where they can safety eat two peanuts or 600mg of peanut protein.
In the pivotal trial of around 500 patients, 67% taking Palforzia were able to consume 600mg of peanut protein without dose-limiting symptoms, compared with 4% of the placebo group.
However, it’s unclear whether this is a “patient important outcome” or not, says Dr Ford.
Patients successfully treated with Palforzia still have to carry around an EpiPen and they can’t eat large amounts of peanuts. They still have to avoid peanuts, she says.
Moreover, OIT increases the risk of anaphylaxis compared with strict avoidance of food allergens, she says.
The meta-analysis published in The Lancet in June 2019 looked at 12 randomised controlled trials of oral immunotherapy for peanut allergy, involving 1,041 patients aged between five and 11.
It found that patients on OIT for peanut allergy were over three times more likely to experience anaphylaxis. The frequency of anaphylaxis and epinephrine use was more than twice as high in the group treated with OIT compared with the placebo group.
The treatment almost doubled the risk of serious adverse events and reactions such as vomiting, angioedema and respiratory reactions.
Patients treated with OIT were more than 12 times less likely to pass a supervised peanut challenge, but quality of life was not different between the two groups.
A meta-analysis published in Scientific Reports in January added 15 non-controlled trials to the 12 RCTs, raising the number of patients studied to 1,488. Adverse events requiring treatment with epinephrine occurred in 7.6% of participants at a rate of two per 10,000 doses.
“Use of a rush treatment phase and targeting a higher maintenance dose were associated with a higher risk and frequency of epinephrine use, while using co-treatments in addition to peanut OIT was associated with a lower risk of treatment discontinuation due to adverse events,” the authors concluded.
While there are allergists using OIT overseas, the data coming from clinics can be misleading, says Dr Ford.
Sometimes clinics do not confirm that the patient actually has a food allergy before proceeding with OIT. The patient may have a skin test that suggests a food allergy, but this is not followed by a food challenge, she says.
It could be that these OIT success stories actually involve patients who never had a food allergy in the first place, she says.
It could also be that paediatric patients “successfully” treated with OIT had simply outgrown the food allergy, she says. Milk and egg allergies often disappear in children over time, although peanut allergies tend to stick around.
The group that could stand to benefit the most from OIT are those patients with extremely severe allergies. However, this group hasn’t been singled out in the studies, so there’s not much data, says Dr Ford.
And deaths from allergic reactions are fortunately too rare to be studied, so it’s not possible to test whether OIT reduces fatalities, she says.
It’s also very difficult to study whether patients undertaking OIT have fewer reactions to traces of the allergen in food, she says. It’s hard to measure peanut contamination in the average restaurant meal. Without that figure, it’s hard to know how much protection OIT is actually giving people in real-life settings.
One of the major draw-cards for the treatment the reduction of anxiety and fear in patients with severe food allergies.
Having a “buffer zone” against accidental exposure to peanuts in restaurants could be quite important for patients’ quality of life, she says. Patients might have been living a “cotton wool” lifestyle, never eating out, and OIT might help break that fear-driven behaviour.
That is why more long-term quality of life data needs to be collected in these OIT studies, she says.
It’s also unclear whether people can stop taking a daily dose of peanut protein and maintain their desensitisation long-term, she says. This is difficult to test because people involved in clinical trials often don’t want to stop eating the allergen once they’ve become desensitised to it because they fear an allergic reaction.
OIT is “very experimental” still, says Dr Ford. “ASCIA doesn’t endorse doing it outside a study setting. Some of my patients want to try it at home but I advise against it because there is no good prediction of the severity of reactions.”
People can have severe reactions to food allergens even if they’ve never had a severe reaction before, particularly if there are co-factors such as illness or an empty stomach to tip them over the edge, she says.
It’s possible to monitor patients for a period of time after bumping up the allergen dose, but this is very resource intensive, she says.
But co-treatments, or selecting the right patients, might tip that balance in favour of OIT which is why Australian clinical trials are focusing on these questions, she says.
Australia punches above its weight when it comes to clinical studies into OIT.
“Australia is at the forefront of some of the most exciting and cutting-edge research in food allergy,” says Dr Derek Chu, a clinical immunologist and allergist at McMaster University in Canada and the author of the peanut OIT meta-analysis in The Lancet.
The OPIA trial run by The Children’s Hospital at Westmead is testing graded peanut ingestion along with a dietary fibre supplement (high-amylase maize starch with a short chain fatty acid called butyrate) in children aged 10-16 years with peanut allergies.
The EPITOPE trial of children aged 1-3 years is evaluating the safety and efficacy of a novel desensitisation method, called epicutaneous immunotherapy, with the Viaskin Peanut patch.
There’s also a peanut vaccine, called Aravax, being developed by an Australian company.
This research will answer critical questions around whether and how significantly OIT increases eosinophilic esophagitis, the impact on quality of life, how families perceive the severity of reactions from OIT, and long-term outcomes, says Dr Chu.
“Most importantly, is how to develop OIT version 2.0, the next generation that overcomes some of the limitations of currently available options,” he says.