Therapy
Recent years have witnessed significant developments in the pursuit of
safe and effective treatment options for those with FA.59-61 (Table 1 ). Landmark studies
demonstrating the safety, efficacy of desensitization, and improvements
in patient quality of life with oral immunotherapy (OIT) for food
allergens led to the approval of peanut (Arachis hypogaea )
Allergen Powder-dnfp, the first oral peanut agent approved by the FDA
and EMA for use in FA8,19,29,60,62-70. Durability of
desensitization following therapy, however, is still under question. The
IMPACT study demonstrated that peanut OIT is safe in children 1-3 years
of age, inducing desensitization up to 5000 mg of peanut protein in 71%
of patients71. Remission rates were highly enriched in
younger patients, suggesting that desensitization within a critical
window may lead to more permanent immune changes. Similarly, the POISED
study, a long-term trial of peanut OIT in patients aged 7-55 years
highlights that SU is only achievable in less than 35% of those who are
successfully desensitized, and SU through the course of a year is even
less (13%)19.
Despite the efficacy of OIT in desensitization, the daily consumption of
allergenic foods can be burdensome, stressful, and marked with
dose-related AEs, making continued compliance challenging. Designed to
counter some of these difficulties, epicutaneous immunotherapy (EPIT)
employs a skin patch system for continuous, non-invasive delivery of the
food allergen. Initial results have demonstrated modest success, with
peanut EPIT providing improvements in quality of life and improving
threshold sensitivity to one peanut (300 mg protein) in 35.3% after 12
months of therapy (PEPITES)72 and to 444 mg peanut
protein in 21.7% of patients after 130 weeks of
desensitization73. Rates of adherence with EPIT are
high (96%) and although reactions are common (77.6%), they are mild
and local. 73-75. Although EPIT achieves lower
sensitivity thresholds than OIT initially, threshold sensitivity appears
to improve over time. In addition to EPIT, sublingual immunotherapy
(SLIT) is another alternative to OIT which has proven to be safe and
effective76,77. Peanut SLIT induced desensitization in
25% and SU in 20.8% of patients after 3-5 years of
treatment78. Other alternatives to oral exposure are
currently under investigation, including a Phase I clinical trial
assessing the safety and feasibility of INT301, a toothpaste containing
peanut protein, targeting peanut concentrations between SLIT and OIT.
Despite oral delivery, INT301 is hoped to elicit fewer systemic side
effects compared to OIT as the majority of the agent is expelled after
brushing, minimizing gastrointestinal (GI) contact with the allergen.
Growing data supports the link between the microbiota and immune system
and modulation of gut microbiota through the introduction of new
bacterial species or manipulation of existing microbes via specific
probiotic supplementation has been proposed as treatment for
FA79-81. In a phase II study of peanut OIT with
adjunct Lactobacillus rhamnosus GG ATCC 53103, adjuvant probiotic
therapy slightly, but significantly, reduced the exposure-adjusted
incidence of AEs by about 8% in comparison to OIT with placebo
probiotic; with a more notable (24%) reduction in exposure-adjusted
incidence of AEs in children 1-5 years of age82.
Further research into the use of an alternative probiotic,Bifidobacterium bifidum TMC3115, in infants aged 0.5 to 12 months
of age with cow’s milk allergy found reduced allergic symptom scores in
the GI tract (p = 0.001), respiratory tract (p = 0.002), and skin (p =
0.011) compared to placebo after 6 months of supplementation, with
decreased serum levels of TNFα, IL-1β, and IL-6 (p ≤
0.001)83.
In addition to studies investigation single bacterial strains as
adjunctive treatment for FA, other clinical trials investigating the
broader modulation of the microbiome in those with FA are underway. A
phase I/II study, is currently evaluating the use of an orally
administered combination of dormant commensal bacteria (VE416) prior to
or in combination with peanut OIT, with or without pretreatment with
vancomycin, in those with PA (NCT03936998). Another study is evaluating
the efficacy of encapsulated fecal microbiota transplantation delivered
orally with or without pretreatment with antibiotics in those with PA
(NCT02960074). By attempting to augment or replace the microbiome with
that of those without FA, the approach may display an advantage over
strategies limited to a single strain. The relationship between the
microbiome and the immune system is complex and further research is
needed before we can leverage the microbiome for treatment of FA.
Initial OIT studies were restricted to treatment of patients with a
single FA and did not address the approximately 30% and 45% of
children and adults, respectively, who are allergic to more than one
food3. In recent years, however, a growing number of
trials have demonstrated that simultaneous desensitization to multiple
food allergens can be facilitated through the concomitant use of
biologic agents. By selectively inhibiting specific mediators of the
allergic pathway, these adjunct therapies are proposed to transiently
reduce the likelihood of allergic reaction (Figure 3). The most studied
biologic, omalizumab, an anti-IgE antibody, has proven to be safe and
effective as an adjunct to multi-allergen OIT 84-86,
achieving desensitization to amounts of allergen beyond accidental
ingestion (1-2 g protein per food)87-89. Compared to
placebo, participants receiving adjunct omalizumab prior to and during
multi-food OIT experienced reductions in the severity of AEs and a lower
median per-participant percentage of their OIT doses associated with any
AE (68% vs 27%; p=0·0082), with GI events reported as the most common
AE in both groups87,90-93. Ligelizumab, another
anti-IgE agent with higher binding affinities for free IgE compared to
omalizumab, is currently under investigation for peanut allergic
patients (NCT04984876)94-96.
Despite promising data thus far, questions remain regarding the optimal
use of biologics, such as dosing, inter-patient variability in response
to therapy, and duration of pre- and concomitant
treatment85. Studies investigating these questions are
currently underway, including the BOOM and OUtMATCH studies. The BOOM
study seeks to evaluate the use of an alternative weight-based dosing
strategy for omalizumab in combination with multi-allergen OIT
(NCT04045301). In parallel, OUtMATCH, a largescale, multi-stage phase
III study sponsored by the National Institutes of Health is
investigating the use of variable-duration omalizumab therapy for
multi-food allergy, with or without multi-allergen OIT, in addition to
long-term follow-up monitoring the post-treatment transition to daily
consumption of real-food equivalents (NCT03881696).
While omalizumab has shown significant promise in promoting safe and
rapid desensitization to multiple foods through IgE suppression, other
clinical trials are focusing on broader targets in the
allergic pathway in efforts to
further minimize AEs and promote SU87,90-93.
Dupilumab, an IL-4Rα antibody, blocks downstream signaling of both IL-4
and IL-13, key mediators involved in the promotion of B cell IgE
class-switching, macrophage polarization toward the pro-inflammatory M2
phenotype, and the induction of peripheral and esophageal
eosinophilia97. With potential benefits over anti-IgE
therapy through broader inhibition of inflammatory pathways, multiple
phase II clinical trials are currently evaluating the use of dupilumab
for FA. These include trials investigating its use with and without
concomitant peanut OIT for PA, as well as the MAGIC study evaluating its
use as an adjunct to cow’s milk OIT for milk-allergic patients
(Table 1 ). In a first-of-its-kind trial, the COMBINE study, a
phase II multi-center trial, is investigating the combined use of
biologics for the first time in FA, aiming to simultaneously target
multiple allergenic pathways. In the study, the step-wise use of
omalizumab followed by dupilumab during concomitant multi-allergen OIT
will evaluate safety and efficacy related to desensitization and the
induction of SU.
Upstream of the allergic pathway, the interruption of early signaling
pathways involving an alarmin, IL-33, with etokimab has shown modest
promise in a pilot study (Table 1 ). A single dose of etokimab
improved desensitization in peanut allergic patients in a DBPCFC 15 days
after treatment (73% of patients tolerated 275mg peanut vs 0%
placebo). Beyond each of the biologics present here, trials
investigating strategies aimed at novel targets continue to emerge at a
consistent pace. Some recent examples include a co-stimulatory inhibitor
(Abatacept) and Bruton tyrosine kinase inhibitor (Acalabrutinib) (Table
1).
While the use of biologic therapies aims to selectively inhibit or
modify components of the allergic pathway with or without concomitant
allergen exposure, an alternative therapeutic strategy centers on
allergen exposure in ways that promote desensitization while avoiding
recognition by allergic mediators altogether. Studies investigating the
safety and efficacy of intravenously delivered nanoparticle-encapsulated
purified peanut extract (CNP-201) are currently underway for those with
PA (Table 1). By shielding the peanut antigen from recognition by IgE
and other mediators within a nanoparticle matrix, investigators aim to
prevent allergic reactions while the allergen is in circulation and
present allergen to naïve T cells in a tolerogenic environment in the
liver and spleen.