Oral Immunotherapy with Standardized Peanut Extract: A Game-Changer for Peanut Allergy

Abstract

Peanut allergy is a persistent and potentially life-threatening condition affecting millions worldwide, necessitating effective therapeutic strategies beyond strict avoidance. Oral immunotherapy (OIT) has emerged as a promising approach, with peanut (Arachis hypogaea) allergen powder dnfp (Palforzia Aimmune therapeutics Brisbane Calif]) being the first FDA-approved standardized OIT for peanut allergy. This review synthesizes current clinical evidence on PTAH (peanut-tolerant Arachis hypogea), focusing on its efficacy, safety, and long-term outcomes. A systematic literature search was conducted, analyzing key phase 3 trials, including PALISADE, ARTEMIS, and POSEIDON, as well as long-term extension studies such as ARC004 and ARC008. Findings indicate that PTAH significantly increases the peanut protein threshold tolerated by allergic individuals, reducing the risk of severe reactions upon accidental exposure. While adverse events such as gastrointestinal symptoms and anaphylaxis occur, they are generally manageable and decline over time with continued therapy. Notably, younger children in the POSEIDON trial exhibited higher desensitization rates, suggesting the potential benefits of early intervention. Long-term studies demonstrate sustained immune modulation, with reductions in peanut-specific IgE and an increase in IgG4, indicative of developing tolerance. Despite limitations such as adherence challenges and the need for ongoing maintenance dosing, PTAH represents a paradigm shift in peanut allergy management, offering improved safety and quality of life for patients and caregivers.

1. Introduction

Peanut allergy (PA) is a significant and growing public health concern, affecting millions of individuals worldwide [1,2]. Peanuts are among the most reported food allergens in children and adults in the US and Europe and are associated with more severe reactions than other food allergens [3,4]. Although slightly lower, prevalence in countries like Italy and across Europe has also shown an upward trend in recent decades [4]. This increase is alarming given the serious implications of peanut allergy, which remains the leading cause of food-induced anaphylaxis and accounts for a disproportionate number of fatal allergic reactions globally [5]. The European Anaphylaxis Registry [6] shows that peanuts are a major cause of anaphylaxis triggers in children and adolescents, accounting for 26.3% and 18.3% of cases, respectively [7]. According to the most recent meta-analysis, peanut-induced mortalities had an incidence of 2.13 per million person-years, a significant amount among food allergies [7]. Unlike other food allergies, such as those towards milk and eggs, which mostly resolve in childhood or adolescence, PA persists into adulthood in 75–80% of the cases [3]. This condition considerably burdens patients and their families, restricting dietary choices, social interactions, and overall quality of life. For many, the risk of accidental exposure, despite strict avoidance measures, contributes to a state of hypervigilance that can lead to chronic anxiety [8].

The current management of peanut allergy includes dietary avoidance of peanuts and, for patients at risk of anaphylaxis, the use of self-injectable adrenaline [9,10]. While this approach reduces the risk of severe reactions, it does not alleviate the psychosocial burden of living with the risk of accidental exposure. In addition, strict avoidance is cumbersome, especially for children who may encounter peanuts in social or school settings where cross-contamination is common. Finally, dietary avoidance may also increase the risks of nutritional deficiencies and compromised growth in young children [11]. The limitations of this approach highlight the need for therapies that not only tackle the risk of accidental exposure but also address the root immunological mechanisms of the allergy.

In recent years, oral immunotherapy (OIT) has emerged as a promising therapeutic option for peanut allergy [12,13,14]. OIT involves the controlled, gradual introduction of peanut protein in small, carefully measured doses to increase the threshold number of allergic reactions [2]. Unlike traditional avoidance strategies, OIT seeks to modify the immune response to peanut allergens, desensitizing the patient and reducing the severity of reactions to accidental exposure [15]. This approach offers the potential to shift the paradigm of peanut allergy management from passive avoidance to active immunomodulation. One of the main limitations of AIT is that, although since 2018, EAACI guidelines [16] recommend the prescription of standardized AIT products with good evidence and effectiveness, most protocols still rely on non-standardized food extracts.

The development of (Arachis hypogaea) allergen powder dnfp (PTAH; previously known as AR101), commercially known as Palforzia, has marked a significant milestone in the field of OIT. The active ingredient in PTAH (Palforzia) is defatted, lightly roasted peanut flour that undergoes extensive characterization. Analytical methods such as high-performance liquid chromatography (HPLC), enzyme-linked immunosorbent assay (ELISA), and total protein assays are employed to ensure product quality. The characterization process includes the assessment of the relative potency of key peanut allergens—Ara h 1, Ara h 2, and Ara h 6—as well as content uniformity for lot release. Additional protein profiling, including detecting Ara h 3 and Ara h 8, is conducted to confirm their consistent presence across different batches of the peanut flour used in manufacturing [17]. Approved by regulatory bodies such as the US Food and Drug Administration (FDA) [18] and the European Medicines Agency (EMA) [19], PTAH is the first standardized OIT product for peanut allergy. It provides a structured and rigorously tested regimen, ensuring consistency in dosing and safety monitoring, previously variable in experimental OIT protocols. PTAH aims to desensitize patients, reduce the risk of severe reactions, and improve overall quality of life.

This review aims to report current evidence on the first oral immunotherapy approved for peanut allergy, PTAH. We aimed to analyze efficacy, tolerability, and safety data in a cohort of patients ranging from 1 to 55 years of age. A focus was also placed on the psychosocial aspects of subjects allergic to peanuts before and after oral immunotherapy, which was evaluated through validated questionnaires like the Food Allergy Quality of Life Questionnaire (FAQLQ) [20].

Finally, we aimed to delve into the future perspectives regarding PTAH, especially regarding clinical applications and the currently unavailable real-life evidence.

2. Materials and Methods

An extensive search of the following scientific databases, PubMed, NCBI, and Cochrane Library, was conducted for this review. A comprehensive set of MeSH terms and free-text keywords was developed based on the research question. The search strategy included OIT, food allergies, AR101, PTAH, efficacy, safety, and quality of life. Initially, an overview of the available literature on the recent advances in oral immunotherapy was carried out, including relevant clinical trials, clinical databases, systematic reviews, and research articles published from database inception to December 2024, with no language restrictions. Exclusion criteria were applied during the title and abstract screening phase, followed by a full-text review to ensure that only studies meeting the predefined eligibility criteria were included in the final analysis. Inclusion criteria were used to identify clinical trials that analyzed the safety, efficacy, and quality of life improvements of PTAH’s only FDA-approved standardized peanut extract. Potentially eligible studies were then evaluated in full text.

3. Results

This review’s objective was to provide an update on the safety, efficacy, and quality of life of patients undergoing desensitization with PTAH.

After extensive research, we included the following studies in this review: PALISADE [21], ARTEMIS [22], and POSEIDON [23], three multicenter, double-blind, placebo-controlled phase 3 trials, and two long-term extension trials, ARC004 [24] and ARC008 [25]. We evaluated the efficacy, safety, and quality of life with extended daily OIT with PTAH in children from 1 to 17 years of age.

PALISADE and ARTEMIS’s (ClinicalTrials.gov reference numbers NCT02635776 and NCT03201003, respectively) primary objective was to demonstrate the efficacy of PTAH in children aged 4–17 years through a reduction in clinical reactivity after an exit food challenge test, where limited amounts of peanut allergens are given in peanut-allergic children that have undergone a period of oral immunotherapy with PTAH. These studies vary slightly in inclusion criteria and primary endpoint. The POSEIDON trial (NCT03736447) had similar inclusion criteria and clinical outcomes compared to PALISADE [21] and ARTEMIS [22], but analyzed a younger population aged from one to four years old.

ARC004 [24] and ARC008 [26] are long-term follow-up studies about PTAH treatment. These follow-up studies, which explored long-term PTAH therapy and alternative dosing regimens, demonstrated a potential benefit with continued daily PTAH treatment beyond 1 year, particularly 1.5/2 years in the ARC004 trial and more than 2 years in the ongoing ARC008 trial [26].

3.1. Efficacy

For clarity purposes, results outlining the characteristics of each study, comparing safety, efficacy, and quality of life improvements, are summarized in

Table 1. Comparison of the main PTAH Trials.

	PALISADE	ARTEMIS	POSEIDON	ARC004	ARC008
Type of study	Randomized double-blind placebo-controlled trial (phase 3)	Randomized double-blind placebo-controlled trial (phase 3)	Randomized double-blind placebo-controlled trial (phase 3)	Open-label long-term study (2 years)	Open-label, longer-term study (>5 years)
Population	551 participants, 4–55 yo (372 treated vs. 124 placebo)	175 participants, 4–17 yo (132 treated vs. 43 placebo)	146 participants, 1–4 yo (98 treated vs. 48 placebo)	261 patients, 4–17 yo (long-term extension)	1127 patients, 4–17 yo (long-term extension)
Inclusion criteria	Positive challenge of ≤100 mg of peanut protein	dose-limiting symptoms to ≤300 mg of peanut protein	dose-limiting symptoms from ≤300 mg of peanut protein	Completion of Palisade DBPFCFG	Completion of Palisade, Poseidon, ARC004
Duration of treatment	12 months (duration of the maintenance phase: 24 weeks)	Approximately 9 months (duration of maintenance phase: 12 weeks)	12 months (duration of maintenance phase: since tolerated 300 mg/day within 40 weeks till the end of the study)	2 years	>5 years
Primary endpoint	Tolerance to 600 mg of peanut protein	Tolerance to 1000 mg of peanut protein	Tolerance to 600 mg (primary) and 2000 mg (secondary) of peanut protein	Maintenance of desensitization over time (2000 mg of peanut protein)	Maintenance of desensitization over time (Decrease in incidence and severity of AE’s)
Efficacy	67.2% of treated participants tolerated 600 mg vs. 4.0% in the placebo group	58% of treated participants tolerated 1000 mg vs. 2% in the placebo group	73.5% of treated participants tolerated 600 mg vs. 6.3% placebo; 61.2% tolerated 2000 mg	80% of participants who completed ARC004 were desensitized to 2000-mg peanut protein	Participants maintained or improved desensitization levels over 5 years
Adverse Events (AE)	Mild-to-moderate AE in >95% of participants (mostly gastrointestinal and oral pruritus); severe reactions in 4.3% of treated participants	AE mostly mild to moderate (mostly gastrointestinal AEs); severe reactions < 1%.	AE in 98% of treated participants, mostly mild to moderate; no severe treatment-related AE	most participants (83%) experienced mild or moderate adverse events	AE decline over time; peanut-sIgE levels decreased, and sIgG4 increased
Quality of life	Not explicitly measured, but reduction in anxiety expected due to increased tolerance thresholds	Improved through validated measures like FAQLQ and FAIM, especially for caregivers	Significant improvement for young children and families; reduced anxiety over accidental exposure	Not explicitly measured, but reduced incidence of reactions likely improved QoL over time	Not explicitly measured, but reduced incidence of reactions likely improved QoL over time
Limitations	High incidence of adverse events; long-term effects not fully assessed	Shorter maintenance phase (3 months); long-term durability of tolerance not evaluated	Only 1-year treatment period; long-term effects and sustained tolerance not assessed	Lacks a placebo, open-label trial design	Lacks a placebo control; durability of tolerance after stopping treatment not established

Table 1: Comparison of safety, efficacy, and QoL improvement in the main Palforzia clinical studies (Palisade, Artemis, Poseidon, ARC004, ARC008).

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In the studies analyzed, the efficacy of PTAH AIT was evaluated through an exit double-blind placebo-controlled food challenge (DBPCFC), with different doses depending on the study. In the POSEIDON study, children aged 1 to 3 years maintained or improved their desensitization levels over several years, with associated immunological changes indicating a durable shift toward tolerance. These findings are critical, as they suggest that initiating OIT at a younger age enhances the efficacy of desensitization and aligns with immunological theories, suggesting a crucial window for tolerance development in young children [12,27]. These studies demonstrate that PTAH can significantly increase the threshold of peanut protein tolerated by allergic individuals. However, the varying doses of peanut powder used in both inclusion criteria and exit food challenges across these trials necessitate careful consideration when comparing efficacy outcomes. On one hand, patients experiencing dose-limiting symptoms at low doses of peanut powder at baseline might not be able to reach the tolerability threshold of the DBPCFC.

On the other hand, higher exit challenge doses, as seen in ARTEMIS [22], POSEIDON [23], and ARC004 [26] may reflect greater desensitization but also present more stringent criteria for success, potentially impacting the perceived efficacy rates. For example, in ARTEMIS, the success rate of exit DBPCFC was somewhat lower than in PALISADE [21] (58% vs. 67%), probably due to a higher threshold. However, it still demonstrated a profound improvement over the placebo.

3.2. Safety Considerations and Mitigating Adverse Events

Every OIT protocol deliberately involves ingesting known quantities of allergens. Therefore, adverse events are virtually inevitable (Figure 1). The most reported reactions—abdominal pain, oral itching, and throat irritation—tend to occur during the initial up-dosing phase [1]. Adherence to strict dosing regimens, patient education regarding the importance of interrupting therapy during illness or after vigorous exercise, and clear instructions on when to use epinephrine autoinjectors are essential for risk control [10]. In the ARC008 study, patients who continued PTAH therapy for up to five years generally maintained or improved their tolerance levels, safely ingesting amounts of peanut protein previously considered dangerous. The frequency and intensity of adverse events also declined over time, suggesting that ongoing exposure can lead to greater comfort and stability in daily dosing [26].

In this setting, severe allergic reactions remain rare, especially once patients reach their maintenance dose. Rigorous patient selection further improves safety: patients with uncontrolled asthma, for example, may not be ideal candidates until their respiratory condition stabilizes [15].

Additionally, while eosinophilic esophagitis (EoE) affects about 1% of patients undergoing peanut OIT, the early recognition of specific symptoms like dysphagia and chest pain can prompt timely intervention [28]. If EoE develops, the adjustment or discontinuation of therapy may be required. Future studies should aim to identify high-risk patients for such complications, possibly through genetic or immunological markers, to tailor preventive strategies [29].

Recognized risk factors for adverse events during OIT encompass uncontrolled asthma, younger age, baseline reactivity at very low doses, and concurrent viral infections. Diligent patient selection, the pre-treatment stabilization of comorbid conditions, and education regarding symptom recognition constitute critical mitigation strategies. Complementary therapies, such as anti-IgE (omalizumab), have demonstrated potential in diminishing reactions and enhancing tolerability during dose escalation [30]. A personalized risk–benefit assessment and shared decision-making are fundamental components of OIT protocols [1].

3.3. Quality of Life Enhancements

Beyond objective immunological and clinical endpoints, quality of life (QoL) improvements are among the most compelling reasons to consider OIT (Figure 1). The constant fear of accidental exposure can limit participation in social events, travel, and even normal school activities. Improvements in quality of life were reported across all the studies listed above. In ARTEMIS [22], significant improvements in FAQLQ were observed in participants aged 8–12 years but not in those aged 13–17 years or their caregivers. The FAQLQ evaluates psychosocial aspects of living with a food allergy, including avoidance behaviors, social consequences, and dietary limitations. Since these psychosocial factors tend to change gradually, they can be challenging to assess immediately after unblinding. Consequently, FAQLQ scores may require longer continued treatment post-unblinding to capture more accurate changes. The POSEIDON study particularly noted enhancements in the psychological well-being of families, driven by reduced anxiety over accidental exposures and increased confidence in daily activities.

3.4. Long-Term Immunomodulation

As illustrated in Figure 2, immunologically, long-term therapy was associated with a decrease in peanut-specific IgE and an increase in peanut-specific IgG4 [26]. Elevated IgG4 levels have been linked to immunological tolerance, indicating a shift toward a more regulated immune response [31]. Although the exact timeline and factors required to achieve sustained irresponsiveness without daily dosing remain uncertain, these biomarker trends encourage further exploration. Identifying reliable predictors of stable tolerance could help clinicians determine when and if it is safe to reduce maintenance therapy, easing the daily treatment burden on patients.

4. Discussion

OIT for food allergies offers a promising desensitization approach but presents advantages and challenges. The main benefit is its ability to increase the reactivity threshold, reducing the severity of allergic reactions upon accidental exposure [12,13,14]. This can significantly improve quality of life, allowing individuals to navigate daily life with a reduced fear of severe reactions. However, OIT has notable drawbacks, including a high risk of adverse events, such as gastrointestinal symptoms and anaphylaxis, particularly during the up-dosing phase [26]. Additionally, long-term adherence is a challenge, as continuous exposure to allergens is required to maintain desensitization, and sustained unresponsiveness is not always achieved after stopping therapy.

PTAH aims to address some of these limitations by providing a standardized dose regimen and safety monitoring under medical supervision. Unlike traditional OIT protocols, which rely on variable food sources, PTAH offers a controlled, pharmaceutical-grade preparation to improve consistency in dosing. Since its approval, PTAH has been evaluated extensively in clinical trials across diverse populations, from children aged 4 to 17 years to younger pediatric cohorts as young as 1 year. Studies such as PALISADE [21], ARTEMIS [22], and the long-term extension trials ARC004 [24] and ARC008 [25] have demonstrated its efficacy and safety over varying durations and under different conditions. More recently, the POSEIDON trial [23] has expanded the evidence base by exploring the use of PTAH in preschool-age children, offering insights into early intervention and its potential to alter the natural progression of peanut allergy.

These studies collectively provide a robust framework for understanding the impact of PTAH on peanut allergy management. However, they also highlight important questions about its long-term efficacy, safety, and practical implementation in real-world settings. For example, while most trials demonstrate that PTAH can raise the threshold for allergic reactions, the durability of desensitization and the potential for sustained unresponsiveness after discontinuing therapy remain areas of active investigation. Additionally, questions persist regarding the optimal timing of intervention, particularly for younger children, and the management of adverse events, which are an inherent aspect of allergen exposure therapies.

Notwithstanding this review’s strengths, which include high-quality phase 3 trials and long-term follow-up studies, certain limitations must be recognized. Firstly, the applicability of the findings in real-world scenarios may be constrained, owing to disparities between clinical trial environments and routine practice. Secondly, the durability of long-term desensitization after the discontinuation of therapy remains uncertain. Thirdly, data about adherence, psychosocial impacts, and risk stratification are not consistently reported across trials. Finally, while the principal emphasis of this review was on PTAH, comparative data with other food allergens and OIT products are insufficient.

Beyond the peanut allergy, oral immunotherapy is currently being investigated for other food allergens, including cow’s milk, hen’s eggs, and tree nuts [32,33,34]. Nevertheless, standardized products and regulatory approvals for these allergens remain limited. The immunological mechanisms appear to possess common characteristics (such as increased allergen-specific IgG4 and the induction of regulatory T cells) [35]. Yet, the response rates and adverse event profiles differ significantly across various allergens. Practical challenges that hinder the broader adoption of oral immunotherapy include the absence of approved products, variability in treatment protocols, the necessity for long-term commitment, and the training requirements for healthcare professionals [36]. The enhanced harmonization of treatment standards and effective real-world implementation strategies are essential for expanding oral immunotherapy beyond peanut allergies [36].

Relevance and Future Directions

As peanut allergies continue to rise in prevalence and severity, the need for effective, scalable, and patient-friendly treatments become increasingly urgent. PTAH represents a significant step forward, but its integration into clinical practice requires the careful consideration of patient selection, safety protocols, and long-term monitoring. Moreover, ongoing trials exploring adjunct therapies, such as biologics and probiotics, may enhance the safety and efficacy of OIT, broadening its applicability and appeal [30]. Ultimately, a deeper understanding of the mechanisms underlying desensitization and tolerance could pave the way for personalized treatment strategies, reducing the burden of peanut allergy and improving the quality of life for millions of affected individuals.

5. Conclusions

Continued daily therapeutic maintenance dosing with PTAH shows consistent safety and tolerability with a potential for a lower frequency of adverse events, ongoing immune response, and increased desensitization to peanut protein that improves over time. Although regulatory agencies interested in the efficacy and safety of an intervention in a clinical trial setting have guided food challenges to assess the degree of desensitization objectively, these practices may not always apply or can be used in the clinical setting [18].

Mitigating reactions due to accidental peanut exposure may have beneficial effects on FAQLQ in peanut-allergic children, teenagers, and their caregivers. PTAH represents a significant advancement in treating peanut allergy, offering a new paradigm from mere avoidance to proactive management. By enabling individuals to tolerate higher doses of peanut protein, PTAH reduces the risk associated with accidental ingestions and significantly improves the quality of life for patients and their families. As additional data become available, the scope of PTAH’s impact will likely expand, setting new benchmarks in allergy care, offering hope for a more effective and enduring solution, and possibly paving the way for standardized therapies to treat other food allergies.