Approval for first medical Tx for children with peanut allergies in 2019

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Peanut allergy conceptThe first medical treatment for children with peanut allergies is likely to be approved next year but there are concerns about its affordability, even though it consists essentially of peanut flour. The Guardian reports a study in the US and at the UK’s Evelina Children’s Hospital shows that gradually increasing a tiny initial dose of peanut protein over six months enabled two-thirds of children eventually to eat two peanuts without ill effects. The paper follows a similar, smaller trial in Cambridge, UK, four years ago.

The report says the latest results are from scientists funded by Aimmune Therapeutics, which was launched to investigate this treatment for peanut allergies. They believe they will have approval for their treatment, delivered in a capsule that is broken open and sprinkled over food, in the middle of next year.

The difference between their trial of a treatment they call AR101 in 550 children and those that have gone before “is the rigour with which the whole process was undertaken” said allergist Dr Stephen Tillis, professor at the University of Washington in Seattle and co-author of the study.

“It is a pharmaceutical-grade treatment product. It is not just peanut flour that you can buy somewhere.” It is, he said, “a grade that the US Food and Drug Administration (FDA), which licences drugs in the US here would be satisfied with”.

The report says children in the trial were given treatment in three phases, beginning with a very low dose, which was increased every two weeks for a minimum of 20 weeks, with daily dosing at home all the way through, up to 12 months. Most of the children on the trial began with a reaction to anything more than 10mg peanut protein – a US peanut contains about 300mg and a smaller UK peanut about 160mg. By the end of the trial, the median amount tolerated was 1000mg, or about four peanuts. “To me that is astounding,” said Tilles.

Scientists think children will have to continue to consume peanut protein to remain safe, possibly for life.

Peanut allergy is a potential killer, the report says. The owners of a takeaway restaurant in Lancashire were recently jailed over the death of 15-year-old Megan Lee who suffered an asthma attack after eating food widely contaminated with peanut protein. Two years ago Natasha Ednan-Laperouse died after eating a Pret sandwich containing sesame seeds.

That makes a peanut allergy treatment both much needed and potentially highly lucrative, the report says. Tillis says their treatment will not be priced like a biological treatment – which are extremely expensive. “It will not be tens of thousands of dollars, but priced like an innovative new medication,” he said.

Peanut allergy emerged in the 1990s and now affects over 100,000 children in the UK – about one in 50 – and more than 1.5m in the US. It has been estimated the market for a treatment could be $4.8bn a year.

The report says in Cambridge, Dr Andrew Clark and colleagues, whose paper in 2014, generated huge excitement, are also working towards a treatment which should come out in a couple of years. “We have commercialised it,” said Clark. He says he hopes theirs will be gentler, pointing out that 20% of children dropped out in the AR101 trial, including 12% because of side effects.

Since their report, they have treated 180 patients privately because the NHS will not fund it. Only four have dropped out, he says. Their treatment, now costing around £17,000 per child, is unlikely to be much cheaper than AR101, but includes the staffing and hospital costs involved in treating children safely.

Dr Michael Perkin, honorary consultant in paediatric allergies at St George’s Hospital in London, says in an editorial in the NEJM that it is salutary to remember that the treatment used in Cambridge was “a bag of peanut flour costing peanuts”. “It’s not like this is some sort of fancy wonder drug that’s been created with a monoclonal antibody in some clever laboratory. They’ve got exactly the same peanut flour and shoved it inside a capsule,” he is quoted in the report as saying.

But there are dangers in trying to desensitise a child at home. “The ability to flake off the right amount of peanut or buy a bag of peanut flour to do it is going to be fraught with potential hazards. If a parent’s hand wavers they could end up with 10 or 20 or 50 times the dose and trigger a significant reaction,” he said.

It could mean families finding the money to put their child through the first six months with a licensed treatment – and then buying peanuts to keep them protected.

“Certainly, that is one scenario,” said Tillis. Small groups in the US were already doing what he called “off-label peanut immunotherapy” – treatment with something that does not have a medical licence. “A lot of those patients end up with some store-bought food.” But he added: “We don’t know if that is the equivalent of the maintenance dose of AR101.”

Abstract 1
Background: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.
Methods: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.
Results: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older.
Conclusions: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo.

Authors
The PALISADE Group of Clinical Investigators

Abstract 2
Background: Small studies suggest peanut oral immunotherapy (OIT) might be effective in the treatment of peanut allergy. We aimed to establish the efficacy of OIT for the desensitisation of children with allergy to peanuts.
Methods: We did a randomised controlled crossover trial to compare the efficacy of active OIT (using characterised peanut flour; protein doses of 2–800 mg/day) with control (peanut avoidance, the present standard of care) at the NIHR/Wellcome Trust Cambridge Clinical Research Facility (Cambridge, UK). Randomisation (1:1) was by use of an audited online system; group allocation was not masked. Eligible participants were aged 7–16 years with an immediate hypersensitivity reaction after peanut ingestion, positive skin prick test to peanuts, and positive by double-blind placebo-controlled food challenge (DBPCFC). We excluded participants if they had a major chronic illness, if the care provider or a present household member had suspected or diagnosed allergy to peanuts, or if there was an unwillingness or inability to comply with study procedures. Our primary outcome was desensitisation, defined as negative peanut challenge (1400 mg protein in DBPCFC) at 6 months (first phase). Control participants underwent OIT during the second phase, with subsequent DBPCFC. Immunological parameters and disease-specific quality-of-life scores were measured. Analysis was by intention to treat. Fisher’s exact test was used to compare the proportion of those with desensitisation to peanut after 6 months between the active and control group at the end of the first phase. This trial is registered with Current Controlled Trials, number ISRCTN62416244.
Findings: The primary outcome, desensitisation, was recorded for 62% (24 of 39 participants; 95% CI 45–78) in the active group and none of the control group after the first phase (0 of 46; 95% CI 0–9; p<0·001). 84% (95% CI 70–93) of the active group tolerated daily ingestion of 800 mg protein (equivalent to roughly five peanuts). Median increase in peanut threshold after OIT was 1345 mg (range 45–1400; p<0·001) or 25·5 times (range 1·82–280; p<0·001). After the second phase, 54% (95% CI 35–72) tolerated 1400 mg challenge (equivalent to roughly ten peanuts) and 91% (79–98) tolerated daily ingestion of 800 mg protein. Quality-of-life scores improved (decreased) after OIT (median change −1·61; p<0·001). Side-effects were mild in most participants. Gastrointestinal symptoms were, collectively, most common (31 participants with nausea, 31 with vomiting, and one with diarrhoea), then oral pruritus after 6·3% of doses (76 participants) and wheeze after 0·41% of doses (21 participants). Intramuscular adrenaline was used after 0·01% of doses (one participant).
Interpretation: OIT successfully induced desensitisation in most children within the study population with peanut allergy of any severity, with a clinically meaningful increase in peanut threshold. Quality of life improved after intervention and there was a good safety profile. Immunological changes corresponded with clinical desensitisation. Further studies in wider populations are recommended; peanut OIT should not be done in non-specialist settings, but it is effective and well tolerated in the studied age group.

Authors
Katherine Anagnostou, Sabita Islam, Yvonne King, Loraine Foley, Laura Pasea, Simon Bond, Chris Palmer, John Deighton, Pamela Ewan, Andrew Clark

The Guardian report
New England Journal of Medicine abstract
New England Journal of Medicine editorial
The Lancet article summary 2014


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