Hyposensitisation with AR101 for peanut allergy: proof of lesser benefit

The agent AR101, a peanut protein powder in a defined dose, is approved for the permanent oral therapy of patients with diagnostically confirmed peanut allergy who are 4 to 17 years old at the start of therapy. In an early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined whether the substance has an added benefit for the patients.

The Institute's conclusion: Apart from one artificial surrogate outcome, the novel treatment has exclusively disadvantages in patient-relevant outcomes, resulting in a proof of lesser benefit of AR101 compared to the appropriate comparator therapy.

Two studies in summary

The drug manufacturer's dossier contains data of two randomized, double-blind approval studies that compared AR101 with placebo. A peanut-avoiding diet was prescribed in each of both study arms, and the use of medications such as antihistamines or adrenaline was permitted in the case of allergic symptoms. This corresponds to the appropriate comparator therapy specified by the Federal Joint Committee (G-BA). The differences between the studies were small enough to be summarized in a meta-analysis.

In hyposensitisation with AR101, an initial dose is followed by an increase phase of 20 to 40 weeks until the maintenance dose of 300 mg per day is reached. In the studies, the medication was stopped after a maintenance phase of another 12 to 28 weeks; however, in everyday life, the medication must be continued permanently. Due to the risk of allergic reactions, the initiation of treatment and the increase in dosage take place under medical supervision. Moreover, those taking the medication cannot do without a peanut-avoiding diet or an adrenaline pen.

Provocation test result as artificial surrogate outcome

No deaths occurred in the studies. In the morbidity category, there was no statistically significant difference between the study arms for the patient-relevant outcome "allergic reactions due to accidental exposure to peanuts": Such reactions occurred in 8.6% of the participants in the AR101 arm of the longer study and in 10.5% in the comparator arm; in the shorter study, these reactions appeared in 2.3% of the participants with and in 4.7% of the participants without AR101 treatment. About one third of these allergic reactions were systemic. An added benefit is therefore not proven for this outcome.

Absence of symptoms was also recorded in a double-blind, placebo-controlled provocation test with 1000 mg peanut protein at the end of the maintenance phase. However, it is not clear whether this surrogate outcome allows predictions to be made about allergic reactions after accidental peanut exposure in the course of out-patient hyposensitisation therapy for peanut allergy: It is possible that even smaller amounts of peanut protein can cause allergic reactions in everyday life, for example, if the affected persons have exerted themselves physically or taken a hot shower, their stomach is empty or they have an infection at the same time.

The benefit observed in the studies in the surrogate outcome was not reflected in a decrease in allergic reactions after accidental peanut exposure or in allergic reactions overall. Even in the maintenance phase, an increase in allergic reactions versus the comparator arm was observed instead.

More treatment discontinuations and side effects

Treatment with AR101 was discontinued more often due to adverse events than the appropriate comparator therapy; approximately one in ten patients discontinued treatment with AR101 prematurely: proof of greater harm. Systemic allergic reactions were also more common after the administration of AR101 peanut protein powder than after placebo, occurring in 14.3% versus 3.2% of participants in the longer study and in 12.1% versus 2.3% in the shorter study. This is another proof of greater harm.

Moreover, there were disadvantages in the outcomes "abdominal pain", "pain in the upper abdomen", "itching in the oral cavity", "paraesthesia oral", "tightness in the throat" and "ear and labyrinth disorders", each of which resulted in proof of greater harm of AR101 compared to the appropriate comparator therapy. All of these symptoms are typical allergic reactions to peanut protein. Treatment with AR101 thus leads to an increased occurrence of the very symptoms that hyposensitisation is intended to prevent.
There were no statistically significant differences between the treatment arms in the outcomes "serious adverse events", "severe adverse events" and "severe systemic allergic reactions".

No data on health-related quality of life

The health-related quality of life of the study participants was also recorded in addition to symptoms, but the questionnaires were not used adequately. For example, a single survey at the end of the therapy cannot adequately capture the burden during the different therapy phases nor the burden of the allergy after the hyposensitisation study. An added benefit is therefore not proven for the health-related quality of life.

"Data on health-related quality of life would be particularly important for assessing the influence of permanent therapy on patients," says Daniela Preukschat from IQWiG's Drug Assessment Department. “After all, they must continue a peanut-free diet and avoid anything in their diet and lifestyle that could lower the threshold for an allergic reaction. For instance, they should avoid physical exertion immediately before and three hours after treatment." Systemic allergic reactions also occurred more often in the studies than under the comparator therapy until the very end, including the maintenance phase. All of this might impair the quality of life.

Follow-up data are lacking

“It also remains unclear how long the treatment should be continued," says Preukschat. "In principle, information on allergic reactions after treatment discontinuation would be necessary for food allergies. Because even if hyposensitisation causes a certain tolerance, this could possibly disappear a short time after treatment is discontinued. As long as no appropriate data are available, the disadvantages of the therapy must also be considered against the background of a potentially lifelong intake. Meaningful data are urgently needed, as numerous people are very hopeful for an effective therapy for their allergies."

The fact that apart from one artificial surrogate outcome, treatment with AR101 had exclusively negative effects, results in the following conclusion: For patients with a confirmed diagnosis of peanut allergy who are 4 to 17 years old at the start of treatment, there is proof of lesser benefit versus the appropriate comparator therapy based on the currently available evidence.

G-BA decides on the extent of added benefit

The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.

More English-language information will be available soon (extract of the dossier assessment). If you would like to be informed when this document is available, please send an e-mail to info@iqwig.de.