PALFORZIA: A Burdensome Peanut-Allergen Drug With Serious Risks and Unknown Long-Term Benefits

Affecting approximately one million American children,[1] peanut allergy is a common cause of anaphylactic reactions (systemic allergic reactions of any severity) and anaphylaxis (a sudden, potentially life-threatening, severe generalized allergic reaction).

In January 2020, the Food and Drug Administration (FDA) approved a peanut allergen protein powder (PALFORZIA) as an oral desensitization immunotherapy for children and adolescents (age four to 17 years) with a confirmed diagnosis of peanut allergy.[2] This drug, the first of its type, does not cure peanut allergies and is to be used in conjunction with a strict peanut-free diet.

A powder drug, Palforzia comes in either capsules with various dosages (used in initiation and titration stages of treatment) or as a sachet (used in the maintenance stage of treatment) that are only to be opened and consumed after they are mixed with a small amount of soft food (such as a fruit puree or yogurt). The drug is intended to help increase tolerance for peanuts, resulting in less severe allergic reactions in the event of an accidental exposure. Palforzia is not a treatment for allergic reactions and should not be taken during an allergic reaction. In addition to daily lifelong treatment with Palforzia and the strict peanut-free diet, individuals must constantly carry (and know how to use) auto-injectable epinephrine (ADRENACLICK, EPIPEN, EPIPEN JR, SYMJEPI or generics) for emergency treatment of allergic reactions.

To reduce the risks of Palforzia, the FDA made the drug available only through a Risk Evaluation and Mitigation Strategy, a specific restricted program that requires children to enroll in this program and initiate treatments of the drug in a health care setting that is certified in the program and has on-site access to equipment and personnel trained to manage anaphylaxis. Palforzia also has a boxed warning (the most prominent warning required by the FDA) for anaphylaxis, which may be life-threatening and can occur at any time during therapy. The drug is not to be administered to patients with uncontrolled asthma.

Public Citizen’s Health Research Group understands the need for new therapies for peanut allergy and the courage of children and their caregivers to be willing to try this new drug and comply with its requirements. However, we share the views of other independent drug-review publications, such as Prescrire International, that the overall benefit–risk profile of Palforzia is unfavorable.[3] We have designated Palforzia as a Do Not Use drug.

Vetting evidence from clinical trials

The efficacy evidence used to support the FDA approval of Palforzia is comprised of a single randomized, double-blind, placebo-controlled trial in which 496 children and adolescents with peanut allergy who did not have severe persistent or uncontrolled asthma received at least one dose of the assigned treatment.[4] Of these subjects, 372 received Palforzia, and the remaining 124 subjects received a placebo. After an initial dosage escalation and titration period (ranging from 20 to 40 weeks), Palforzia-treated subjects received a daily maintenance dose of 300 milligrams (mg) of the drug, the equivalent of one peanut, over the course of 24 to 28 weeks. At the end of this period, 67% of Palforzia-treated subjects tolerated an oral challenge test with a single 600-mg dose of peanut protein (twice the daily maintenance dose of Palforzia) with no more than mild allergic symptoms, compared with 4% of placebo-treated subjects. Notably, no efficacy results are available from this trial for Palforzia-treated subjects who did not progress to maintenance therapy.

Integrated safety evidence from Palforzia clinical trials showed that treatment-related systemic allergic reactions occurred in 15.1% of Palforzia-treated subjects (including 0.6% during initial dose escalation, 8.7% during updosing [dose titration] and 9.9% during maintenance).[5] Anaphylaxis was reported for 1% of Palforzia-treated subjects. Although the goal is to reduce the severity of allergic reactions to peanuts, the safety evidence indicates that systemic allergic reactions during treatment with this drug do not decrease over time. In clinical trials, several modifiable (including exercise or taking a hot bath) and nonmodifiable (including fatigue, illness, menstruation or sleep deprivation) factors as well as non-adherence to daily treatment increased the risk of treatment-related adverse allergic reactions.

Another important safety risk associated with Palforzia is eosinophilic esophagitis, an allergic condition that, without treatment, can cause lasting damage to the esophagus.[6] Overall, 12 of 1,050 Palforzia-treated subjects in the safety studies of this drug had a biopsy-confirmed diagnosis of eosinophilic esophagitis, compared with none among 292 placebo-treated subjects.

Overall, at least one in four Palforzia-treated subjects in clinical trials experienced any of the following adverse effects: abdominal pain, nausea, vomiting, throat irritation, urticaria (hives) or itching (including in the mouth).[7]

In clinical trials supporting the efficacy of Palforzia, 21.4% of Palforzia-treated subjects discontinued the drug, mostly due to adverse effects, compared with only 8% of placebo-treated subjects.[8] According to the FDA medical reviewer, “[i]t is unclear if, had these subjects chosen to continue in [the trial], a higher rate of adverse reactions would have been reported in the treatment arm.” This reviewer also cautioned that the durability of protection from accidental peanut exposure after discontinuing Palforzia has not been evaluated.

The only postmarketing evidence that the FDA required for Palforzia is a pregnancy registry.[9] In contrast, the European Medicines Agency required long-term data from an ongoing trial to assess the maintenance of desensitization of Palforzia in children and to monitor safety concerns related to anaphylaxis or systemic allergic reactions, eosinophilic esophagitis, possible rebound after discontinuation of treatment and the effects on long-term immune-mediated reactions.[10]

What You Can Do

Per standard treatment, children who are allergic to peanuts should stick to a strict peanut-free diet.[11] This is the only way to eliminate the risk of allergic reactions. Until further evidence demonstrates durable, long-term benefits of Palforzia that outweigh its risks, it is best to avoid this cumbersome, expensive drug (listed yearly cost was about $11,000 in 2020).[12]

Children with peanut allergy (or their parents or caregivers) need to carry auto-injectable epinephrine at all times and be prepared to inject it in the upper thigh muscle as soon as there is any concern for an allergic peanut reaction.[13] Immediately after injection, emergency medical attention should be sought until the allergic symptoms have fully resolved.

Parents of infants should follow guidelines of the National Institute for Allergy and Infectious Diseases (NIAID), which recommend introducing peanuts to infants as early as four to six months of age, depending on their risk factors (including family history and signs of eczema) in order to prevent the development of peanut allergy.[14],[15] Notably, if a child is at high risk of peanut allergy, these guidelines recommend testing for peanut allergy, with a skin test or blood test. Depending on the results, the clinician may recommend an initial trial of peanuts under medical observation.
 

References

[1] Food and Drug Administration. FDA news release: FDA approves first drug for treatment of peanut allergy for children. January 31, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treatment-peanut-allergy-children. Accessed September 5, 2023.

[2] Aimmune Therapeutics, Inc. Label: peanut (Arachis hypogaea) allergen powder (PALFORZIA). March 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=17f5be03-6705-4ac9-b8f3-bc4993ebc0eb&type=display. Accessed September 5, 2023.

[3] Peanut protein (PALFORZIA) for oral desensitisation. Prescrire Int. 2022;31(238):153-156.

[4] Aimmune Therapeutics, Inc. Label: peanut (Arachis hypogaea) allergen powder (PALFORZIA). March 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=17f5be03-6705-4ac9-b8f3-bc4993ebc0eb&type=display. Accessed September 5, 2023.

[5] European Medicines Agency. European public assessment report: defatted powder of arachis hypogaea L. (Palforzia). October 15, 2020. https://www.ema.europa.eu/en/documents/assessment-report/palforzia-epar-public-assessment-report_en.pdf. Accessed September 5, 2023.

[6] Aimmune Therapeutics, Inc. Label: peanut (Arachis hypogaea) allergen powder (PALFORZIA). March 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=17f5be03-6705-4ac9-b8f3-bc4993ebc0eb&type=display. Accessed September 5, 2023.

[7] European Medicines Agency. European public assessment report: defatted powder of arachis hypogaea L. (Palforzia). October 15, 2020. https://www.ema.europa.eu/en/documents/assessment-report/palforzia-epar-public-assessment-report_en.pdf. Accessed September 5, 2023.

[8] Food and Drug Administration. BLA clinical review memorandum for STN BLA 125696, peanut (arachis hypogaea) allergen powder (Palforzia). January 29, 2020. https://www.fda.gov/media/135486/download?attachment. Accessed September 5, 2023.

[9] Food and Drug Administration. Approval letter to Aimmune Therapeutics, Inc for STN BLA 125696, peanut (arachis hypogaea) allergen powder (Palforzia). January 31, 2020. https://www.fda.gov/media/135486/download?attachment. Accessed September 5, 2023.

[10] European Medicines Agency. European public assessment report: defatted powder of arachis hypogaea L. (Palforzia). October 15, 2020. https://www.ema.europa.eu/en/documents/assessment-report/palforzia-epar-public-assessment-report_en.pdf. Accessed September 5, 2023.

[11] Peanut allergen powder (Palforzia). Med Lett Drugs Ther. 2020;62(1593):33-34.

[12] Guiao E, Ogurchak J. Clinical Insights: Palforzia is the first FDA-approved treatment of peanut allergy. Pharmacy Times. October 28, 2020. https://www.pharmacytimes.com/view/clinical-insights-palforzia-is-the-first-fda-approved-treatment-of-peanut-allergy. Accessed September 5, 2023.

[13] Highlights of the new guidelines for severe allergic reaction. Worst Pills, Best Pills News. November 2020. https://www.worstpills.org/newsletters/view/1366. Accessed September 5, 2023.

[14] Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States. JAAPA. 2017;30(3):1-5.

[15] Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: Report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 Suppl):S1-S58.