Food allergy (FA) is a persistent condition characterized by an adverse immune response to specific dietary proteins, typically manifesting within the first few minutes to 2 hours after ingestion. Its prevalence is increasing globally, with estimates ranging from 0.2% to over 10%.¹ In the United States alone, it is estimated that approximately 8% of children live with FA. While some individuals may outgrow their FA as they age, a notable 10.8% of adults also contend with this condition.² Figure 1 describes the growing burden of FA.^1,2

Understanding the Condition

Whereas natural tolerance rates are generally high for common allergens, such as eggs, milk, and wheat, allergies to other foods often persist beyond childhood. For instance, approximately 72.2% of individuals with egg allergies outgrow them by the age of 8, whereas only about 15.8% outgrow peanut allergies. Despite the likelihood of tolerance for certain allergenic foods, some patients do not develop tolerance, particularly those with elevated immunoglobulin E (IgE) levels triggered by specific foods or a history of anaphylaxis. In cases of cow’s milk allergy, for example, only 5% of individuals with a maximum IgE level of 50 kU/L were observed to become tolerant by the age of 10.²

Furthermore, FA can have detrimental effects on the nutritional status and overall quality of life for both individuals with allergies and their families, imposing emotional, social, and economic burdens. Adhering to an elimination diet, especially for common allergens, such as milk and eggs, can be challenging, often leading to accidental exposures and subsequent adverse reactions.³

Traditionally, managing FA has centered around strict avoidance of allergenic foods and the prompt administration of emergency medications in case of accidental exposure.⁴ Although emergency medications, such as epinephrine, are life-saving, they provide only temporary relief and do not address the underlying immunologic mechanisms driving allergic responses.⁵ Despite these precautionary measures, the incidence of severe allergic reactions, including anaphylaxis, remains alarmingly high, particularly among children, underscoring the urgent need for more effective treatment modalities.³

Oral Immunotherapy

In response to the limitations of traditional management strategies, such as allergen avoidance and emergency interventions, oral immunotherapy (OIT) has emerged as a promising treatment modality. OIT involves the systematic administration of allergenic foods in gradually increasing doses to desensitize patients to specific allergens, aiming to mitigate allergic reactions, including severe conditions such as anaphylaxis, resulting from unintentional exposure to allergens.²

Palforzia, a powder containing peanut allergens, is approved by the US Food and Drug  Administration (FDA) for OIT in people aged 4 to 17 years who have peanut allergy. It is designed to mitigate allergic reactions, including the severe condition of anaphylaxis, resulting from unintentional exposure to peanuts.^1,6 Although OIT effectively promotes desensitization to numerous food allergens, it is hindered by various limitations. For example, a substantial percentage of children worldwide with FA, ranging from 43% to 86%, are allergic to multiple foods, making sequential OIT for multiple allergens a time-consuming and arduous process for both patients and their families.⁷

Moreover, although OIT can enhance the tolerable amount of food, achieving sustained unresponsiveness is often elusive. Studies evaluating OIT for egg allergy, for instance, found that while over 75% of patients tolerate the target dose after 22 months, only 28% pass the oral food challenge following a 2-month period of complete avoidance. Similarly, in peanut OIT, only 31% of patients who achieved desensitization attained sustained unresponsiveness. Furthermore, allergic reactions are frequently reported during therapy, with more than 90% of patients undergoing oral OIT experiencing reactions, necessitating epinephrine administration in 10% to 20% of cases during desensitization. Some people also encounter difficulties in sustaining the therapy due to psychological challenges, such as eating difficulties and therapy-related anxiety.²

The escalating prevalence and profound impact of FA on both individual quality of life and broader public health underscore the pressing need for innovative therapeutic approaches. Hence, there is a growing imperative for the development of innovative therapeutics capable of modifying the reactivity threshold to multiple food allergens in children and adults.⁷

Transitioning Toward Novel Treatment Modalities: Biologics

The landscape of FA management is undergoing a transformation with the introduction of biologic therapies, heralding a new era in the approach to this complex condition. Biologic therapies offer promise in reducing adverse events associated with OIT. Unlike OIT, which specifically addresses individual food allergens, biologics target the fundamental pathways underlying allergic reactions. These include mechanisms involving IgE, interleukin (IL)-4, and IL-13, as well as alarmins such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25. Consequently, biologics possess the potential to alleviate or halt allergic responses triggered by food antigens in a manner independent of specific antigens.⁷

Anti-IgE Therapy

Since many allergic reactions are mediated by IgE antibodies, they serve as a prime target in allergic diseases like FA. When allergens are accidentally ingested, IgE-mediated FA initiates a cascade of allergic responses through the activation of high-affinity IgE receptors (FcεRI) on basophils and mast cells.^1,8 This activation leads to the release of inflammatory mediators affecting various bodily systems and is a primary cause of severe to fatal anaphylactic reactions, affecting people of all ages.¹

Omalizumab

Omalizumab, an anti-IgE monoclonal antibody, represents a significant advancement in the field of FA management by targeting IgE-mediated pathways. Functioning by preventing IgE from binding to FcεRI on the surface of mast cells, basophils, eosinophils, and dendritic cells, omalizumab leads to the downregulation of FcεRI on these cellular surfaces.^2,3 This mechanism offers a unique advantage in addressing the underlying immunologic mechanisms driving FA, rather than solely managing symptoms.

In a clinical trial involving patients with IgE-mediated FA, the administration of omalizumab resulted in a decrease in serum free IgE levels while causing an elevation in serum total IgE levels, mirroring observations seen in patients with asthma. Participants initially exhibited an average total IgE concentration of 810 IU/mL. However, following repeated dosing every 2 or 4 weeks, the mean pre-dose free IgE concentration dramatically decreased to 10 IU/mL by week 16. Notably, the mean serum total IgE levels exhibited a roughly 2.4-fold increase, attributed to the formation of omalizumab-IgE complexes characterized by an extended half-life compared with free IgE.⁹

The safety and efficacy of omalizumab were assessed in the OUtMATCH multi-center randomized, controlled trial focusing on FA (ClinicalTrials.gov identifier: NCT03881696), with a total of 168 participants aged 1 year to less than 56 years. This diverse cohort included people with allergies to peanut and at least 2 other common foods, such as milk, egg, wheat, cashew, hazelnut, or walnut. Following treatment, each participant underwent a double-blind, placebo-controlled food challenge (DBPCFC) involving placebo and their 3 studied foods. The efficacy analysis focused on 165 pediatric patients, with an average age of 8 years, comprising the primary endpoint of the percentage of patients capable of consuming a single dose of at least 600 mg of peanut protein during DBPCFC without experiencing dose-limiting symptoms. The results revealed a significantly higher response rate (68%) in the omalizumab group compared with placebo (5%). Secondary efficacy endpoints included the ability to tolerate at least 1000 mg of cashew, milk, or egg protein without dose-limiting symptoms during DBPCFC, where omalizumab treatment demonstrated statistically superior response rates compared with placebo for all 3 foods (Table 1).⁹

Further analysis uncovered notable insights into dose-limiting symptoms, with 17% of omalizumab-treated patients experiencing such symptoms upon consuming at least 100 mg of peanut protein. Similar challenges were observed with milk, egg, or cashew protein, affecting 18%, 22%, and 41% of patients, respectively. Moreover, additional secondary analyses explored patients’ ability to tolerate multiple foods during DBPCFC, showcasing omalizumab’s effectiveness across various allergens. Importantly, the trial’s outcomes in pediatric patients provided supportive evidence for omalizumab’s efficacy in adults, emphasizing its broad applicability across different age groups.⁹

Although uncontrolled, open-label studies cannot establish efficacy, an extension study involving 38 pediatric patients who continued omalizumab treatment for 24 to 28 weeks showed sustained improvement, with a consistent percentage of patients able to tolerate specified doses of peanut, egg, milk, and cashew proteins without experiencing significant symptoms.⁹

Based on these findings, omalizumab received US FDA approval indicated for the reduction of allergic reactions, including anaphylaxis, that may occur with accidental exposure to 1 or more foods in adult and pediatric patients aged 1 year and older with IgE-mediated FA. Omalizumab should be used in conjunction with food allergen avoidance. The medication, designed for recurrent administration, aims to lower the incidence of allergic reactions but is not meant for immediate emergency intervention during allergic episodes, including anaphylaxis. The most common adverse reactions to omalizumab are injection-site reactions and fever; other warnings and precautions include anaphylaxis, malignancy, joint pain, rash, parasitic infection, and abnormal laboratory tests.^6,9

Looking ahead, although biologic therapy shows promise in managing FA, challenges remain. Determining optimal dosing and patient selection is crucial for balancing effectiveness and safety. Collaborative decision-making between healthcare providers and patients is essential for tailoring treatment plans.

References

1. Zuberbier T, Wood RA, Bindslev-Jensen C, et al. Omalizumab in IgE-mediated food allergy: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2023;11(4):1134-1146. doi:10.1016/j.jaip.2022.11.036

2. Honda A, Okada Y, Matsushita T, et al. Efficacy of biological agents combined with oral immunotherapy (OIT) for food allergy: a protocol for a systematic review and meta-analysis. BMJ Open. 2024;14(2):e075253. doi:10.1136/bmjopen-2023-075253

3. Arasi S, Mennini M, Cafarotti A, Fiocchi A. Omalizumab as monotherapy for food allergy. Curr Opin Allergy Clin Immunol. 2021;21(3):286-291. doi:10.1097/ACI.0000000000000744

4. Dantzer JA, Kim EH, Chinthrajah RS, Wood RA. Treatment for food allergy: current status and unmet needs. J Allergy Clin Immunol. 2023;151(1):1-14. doi:10.1016/j.jaci.2022.08.008

5. Phelps A, Bruton K, Grydziuszko E, Koenig JFE, Jordana M. The road toward transformative treatments for food allergy. Front Allergy. 2022;3:826623. doi:10.3389/falgy.2022.826623

6. FDA approves first medication to help reduce allergic reactions to multiple foods after accidental exposure. News release. US Food and Drug Administration. February 25, 2024. Accessed February 25, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-medication-help-reduce-allergic-reactions-multiple-foods-after-accidental

7. Sindher SB, Fiocchi A, Zuberbier T, Arasi S, Wood RA, Chinthrajah RS. The role of biologics in the treatment of food allergy. J Allergy Clin Immunol Pract. 2023:S2213-2198(23)01301-6. doi:10.1016/j.jaip.2023.11.032

8. Sindher SB, Hillier C, Anderson B, Long A, Chinthrajah RS. Treatment of food allergy: oral immunotherapy, biologics, and beyond. Ann Allergy Asthma Immunol. 2023;131(1):29-36. doi:10.1016/j.anai.2023.04.023

9. Xolair. Prescribing information. Genentech USA, Inc; 2024. Accessed February 25, 2024. https://www.gene.com/download/pdf/xolair_prescribing.pdf

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s production.

Reviewed March 2024

Menopause is marked by the cessation of ovulation and is officially diagnosed after 12 consecutive months of amenorrhea.¹ The median age at which menopause occurs is 51 years. However, premature menopause, which may be triggered by medical conditions such as chemotherapy or hysterectomy, can occur before age 40.² Declining estrogen levels directly affect the hypothalamus, thereby altering the central thermal regulatory neutral zone and contributing to menopause-related vasomotor symptoms (VMS).³ VMS, including hot flashes, sleep disruption, and night sweats, are troublesome symptoms experienced by women during menopause. Other symptoms of menopause may include anxiety, depression, and fatigue, which can negatively affect work performance and quality of life.⁴ VMS reportedly can persist for up to 10 years and affect as many as 80% of women during the menopausal transition.⁵

Menopause-related VMS, especially when they reach moderate to severe status, have substantial negative impacts on physical and emotional well-being among women worldwide; these impacts are particularly concerning because the number of women reaching or at menopausal age is projected to increase as the global population grows.⁶ In the United States (US), people aged 65 years and older are expected to outnumber people aged 17 years and younger by 2034.⁷ Despite the negative impacts of moderate to severe VMS, many women do not seek treatment from health care professionals.⁵ Untreated VMS can increase health care costs (Figure 1) and negatively affect quality of life (Figure 2).⁸

According to the North American Menopause Society, hormone therapy remains the most effective treatment for menopause-related VMS.⁹ However, many women have refused hormone therapy, especially since the 2003 publication of the Women’s Health Initiative trial, which suggested an increased risk for breast cancer.¹⁰ Considering the significant negative impacts of menopause-related moderate to severe VMS, alternative nonhormonal treatment options are needed, particularly for women with contraindications to hormone therapy and women who refuse hormone therapy. This article focuses on nonhormonal US Food and Drug Administration (FDA)-approved therapies that alleviate VMS by targeting the underlying pathophysiological mechanisms.

Understanding the Pathophysiology of VMS

The suspected pathophysiology of VMS involves the neurokinin B (NKB) signaling pathway.¹¹ Specifically, NKB is a neuropeptide that preferentially binds to the neurokinin 3 receptor (NK3R).¹² The binding of the NKB neuropeptide to specialized kisspeptin, NKB, and dynorphin (KNDy) neurons is presumed to mediate the hypothalamic-pituitary-gonadal axis; these neurons are likely to act on thermoregulatory regions of the brain.^11,13 Before menopause, NKB binding and activation of KNDy neurons is inhibited by estrogen. As estrogen levels decline during menopause, the inhibition of NKB binding to NK3R also declines, leading to altered activity within the brain’s thermoregulatory center. It has been suggested that the pathophysiology of VMS, particularly hot flashes, is triggered by decreasing estrogen levels and subsequent hypertrophy of KNDy neurons.¹³ Therefore, therapies that target NKB and KNDy neurons have emerged as the main nonhormonal treatments for VMS.

Treatment of VMS With Nonhormonal Therapies

In a cross-sectional survey of 3460 postmenopausal women with moderate to severe VMS conducted in the US, Europe, and Japan, 54% to 79% of women reported an aversion to hormone therapy; 8% to 12% of women had a contraindication to hormone therapy.⁵ Nonhormonal treatment is an option for these women. Currently, 2 nonhormonal therapies are FDA-approved: paroxetine and fezolinetant (Table 1).^14,15

Paroxetine

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), and the low-dose formulation (7.5 mg daily) is FDA-approved as a nonhormonal therapy for moderate to severe menopause-related VMS.¹⁴ Studies of patients with VMS showed that paroxetine treatment led to a 33% to 65% reduction in the frequency of hot flashes after 6 to 12 weeks of treatment, compared with 17% to 38% reduction among patients receiving placebo. After 4 weeks of paroxetine treatment, patients reported a significant decrease in VMS-related night-time awakening and a significant increase in sleep duration.³

Although clinical studies of paroxetine often used doses of 10 mg to 25 mg, VMS were significantly reduced with low-dose paroxetine (7.5 mg daily), which had a tolerable adverse effect profile and did not cause withdrawal symptoms when discontinued without tapering.³ The most common adverse effects reported in clinical trials of paroxetine were headache, fatigue, and nausea or vomiting. It should be noted that paroxetine carries a black box warning for suicidal ideation. Moreover, paroxetine is contraindicated in patients who are concurrently using thioridazine or pimozide, are concurrently using or have used monoamine oxidase inhibitors (MAOIs) within the past 14 days, are pregnant, or are hypersensitive to paroxetine or any other ingredient in its formulation. Paroxetine is also a strong CYP2D6 inhibitor and may alter the concentrations of other drugs metabolized by CYP2D6; this property should be considered before prescribing paroxetine to any patient.¹⁴

Fezolinetant

Fezolinetant was approved by the FDA in May 2023 as a 45-mg tablet taken once daily for the treatment of moderate to severe menopause-related VMS.¹⁵ Fezolinetant is a nonhormonal selective NK3R antagonist that blocks NKB binding on KNDy neurons; this effect restores normal sensitivity to the brain’s thermoregulatory center.¹³ The safety and efficacy of fezolinetant were investigated in the phase 3, randomized, placebo-controlled trials SKYLIGHT 1 (ClinicalTrials.gov identifier: NCT04003155) and SKYLIGHT 2 (ClinicalTrials.gov identifier: NCT04003142).

SKYLIGHT 1 and SKYLIGHT 2 included women aged 40 to 65 years with moderate to severe VMS who were randomly assigned to receive fezolinetant 30 mg once daily, fezolinetant 45 mg once daily, or placebo.In SKYLIGHT 1 and SKYLIGHT 2, both doses of fezolinetant produced statistically significant reductions from baseline in the frequency and severity of moderate to severe VMS per day at weeks 4 and 12, compared with placebo. Headache was the most common adverse event associated with fezolinetant use in both studies; treatment-emergent serious adverse events were rare (<2% of enrolled patients) in all study arms.^13,16 However, it should be noted that fezolinetant is contraindicated in patients who have known cirrhosis, severe renal impairment, or end-stage renal disease, as well as patients who are concomitantly using CYP1A2 inhibitors. Furthermore, baseline bloodwork to evaluate hepatic function and identify any injury should be conducted before beginning fezolinetant treatment; follow-up bloodwork to evaluate hepatic function should be performed at 3, 6, and 9 months after initiation of fezolinetant and when symptoms of liver damage appear.¹⁵

References

1. Paciuc J. Hormone therapy in menopause. Adv Exp Med Biol. 2020;1242:89-120. doi:10.1007/978-3-030-38474-6_6

2. Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature menopause or early menopause: long-term health consequences. Maturitas. 2010;65(2):161-166. doi:10.1016/j.maturitas.2009.08.003

3. David PS, Smith TL, Nordhues HC, Kling JM. A clinical review on paroxetine and emerging therapies for the treatment of vasomotor symptoms. Int J Womens Health. 2022;14:353-361. doi:10.2147/IJWH.S282396

4. Santoro N, Epperson CN, Mathews SB. Menopausal symptoms and their management. Endocrinol Metab Clin North Am. 2015;44(3):497-515. doi:10.1016/j.ecl.2015.05.001

5. Nappi RE, Kroll R, Siddiqui E, et al. Global cross-sectional survey of women with vasomotor symptoms associated with menopause: prevalence and quality of life burden. Menopause. 2021;28(8):875-882. doi:10.1097/GME.0000000000001793

6. World Health Organization. Menopause. Published October 17, 2022. Accessed June 8, 2023. https://www.who.int/news-room/fact-sheets/detail/menopause

7. Older people projected to outnumber children for first time in U.S. history. News release. United States Census Bureau. October 8, 2019. Accessed May 28, 2023. https://www.census.gov/newsroom/press-releases/2018/cb18-41-population-projections.html

8. DePree B, Houghton K, Shiozawa A, et al. Treatment and resource utilization for menopausal symptoms in the United States: a retrospective review of real-world evidence from US electronic health records. Menopause. 2023;30(1):70-79. doi:10.1097/GME.0000000000002095

9. Faubion SS, Crandall CJ, Davis L, et al; The North American Menopause Society 2022 Hormone Therapy Position Statement Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028

10. Biglia N, Bounous VE, De Seta F, Lello S, Nappi RE, Paoletti AM. Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an update. Ecancermedicalscience. 2019;13:909. doi:10.3332/ecancer.2019.909

11. Koysombat K, McGown P, Nyunt S, Abbara A, Dhillo WS. New advances in menopause symptom management. Best Pract Res Clin Endocrinol Metab. Published online April 11, 2023. doi:10.1016/j.beem.2023.101774

12. Rance NE, Krajewski SJ, Smith MA, Cholanian M, Dacks PA. Neurokinin B and the hypothalamic regulation of reproduction. Brain Res. 2010;1364:116-128. doi:10.1016/j.brainres.2010.08.059

13. Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. Published online February 3, 2023. doi:10.1210/clinem/dgad058

14. Brisdelle^®. Prescribing information. Sebela Pharmaceuticals, Inc; 2017. Accessed June 7, 2023. http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204516s004lbl.pdf

15. Veozah^TM. Prescribing information. Astellas Pharma US, Inc; 2023. Accessed June 7, 2023. http://www.astellas.com/us/system/files/veozah_uspi.pdf

16. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401(10382):1091-1102. doi:10.1016/S0140-6736(23)00085-5

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Reviewed June 2023