The role of dupilumab in the treatment of eosinophilic esophagitis

Abstract

Dupilumab has been approved to treat a variety of atopic disorders and was the first US FDA-approved medication for the treatment of eosinophilic esophagitis (EoE), initially approved in May 2022, with expansion in use to patients as young as 1 year of age weighing at least 15 kg in January 2024. It is a fully human monoclonal antibody that inhibits both IL-4 and IL-13 signaling, suppressing TH2-mediated proinflammatory cytokines, chemokines and IgE implicated in EoE pathogenesis. Phase II and III trials in EoE have demonstrated histologic, endoscopic and symptomatic improvement in disease activity with an overall favorable safety profile. This article will review the available clinical trial data and real-world efficacy of dupilumab in EoE.

Plain Language Summary

Dupilumab is a biologic medication used for the treatment of eosinophilic esophagitis. Clinical trials have shown that this medication is effective in treating both inflammation in the esophagus and symptoms associated with eosinophilic esophagitis in a high proportion of patients. Dupilumab was well tolerated by the majority of clinical trial patients, though side effects such as injection site redness and swelling have been reported. More serious side effects are overall rare.

Plain language summary

Article highlights.

Background

• Dupilumab is a fully humanized monoclonal antibody. It acts on the IL-4α subunit shared by both IL-4 and IL-13 receptors. By blocking these receptors, dupilumab inhibits both IL-4 and IL-13 signaling, suppressing TH2-mediated proinflammatory cytokines, chemokines and IgE that are involved in many atopic conditions.

• Dupilumab has been approved to treat a variety of atopic disorders, including atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, prurigo nodularis and eosinophilic esophagitis (EoE).

• Dupilumab is administered subcutaneously. Dosing and interval of administration depends in part on age, weight and indication, ranging from 200 mg monthly to 300 mg weekly.

Clinical efficacy

• The LIBERTY EoE TREET study, the Phase III clinical trial looking at efficacy and safety of dupilumab in patients 12 years and older with active EoE demonstrated 60% of participants receiving weekly dupilumab achieved histologic remission as compared with 5% with placebo (p < 0.001) at 24 weeks.

• EoE KIDS Phase III clinical trial evaluating efficacy of dupilumab in children ages 1–11 years demonstrated that 68% of patients receiving higher-exposure dupilumab achieved histologic remission (defined as <6 eos/hpf), along with significant improvements in histologic, endoscopic and transcriptomic measures as compared with placebo at 16 weeks, with similar improvements seen up to 52 weeks.

Safety & tolerability

• Dupilumab has a favorable long-term safety and adverse effect profile. The most common reported adverse event for dupilumab is injection site reaction (18%). Other common adverse events included nasopharyngitis, exacerbation of atopic dermatitis, upper respiratory tract infections oral herpes, conjunctivitis and headaches.

1. Background

Eosinophilic esophagitis (EoE) is a chronic, antigen driven, TH2-mediated inflammatory disorder of the esophagus. EoE has a prevalence estimated to be 1 in 2000 with a male predominance with male-to-female ratio of 3:1 [1]. Presenting symptoms vary with age. Infants and children can present with vomiting and failure to thrive, while adolescent and adults often present with heartburn, abdominal pain, dysphagia and food impactions. When left untreated, EoE can lead to long term complications, including fibrostenotic disease and esophageal impactions requiring esophageal dilation [2]. Histologically, EoE is diagnosed by marked eosinophilic inflammation within the esophagus (≥15 eosinophils per high powered field [eos/hpf]) [3]. Evaluation of proton pump inhibitor (PPI) response is no longer part of the criteria required for EoE diagnosis, but PPIs remain an effective treatment in a subset of patients [3].

EoE is a non-IgE-mediated allergic process known to be caused by one or more food triggers in the diet and is highly associated with multiple atopic disorders, including atopic dermatitis (AD), immediate-type food allergies, allergic rhinitis and asthma. Dietary treatment strategies have historically involved removal of food antigen triggers, either with amino acid-based formulas, empiric elimination diets or specific food elimination diets [4]. Pharmacologic therapy until recently has mainly been limited to PPIs, effectiveness in approximately 50% of patients [5] and swallowed topical corticosteroids (STC), effective in approximately 60–80% of patients depending on medication formulation [6–8]. Budesonide oral suspension, Eohilia™ (Takeda, Osaka, Japan, Cambridge, MA, United States), is currently the only US FDA-approved swallowed topical steroid formulation in the US Budesonide oral disintegrating tablet, Jorveza^® (AVIR Pharma Inc, Blainville, QC, Canada), has been authorized by the EMA. All other STC formulations used in EoE are currently used off label.

2. Introduction to the compound/mechanism

Recent studies elucidating the molecular mechanisms underlying EoE have led to novel potential targeted therapies for EoE. Genome-wide association studies have implicated several genes (TSLP, STAT6, CAPN14, FLG) in the development of EoE [9]. TSLP is an epithelial-derived factor which induces dendritic cells to drive TH2 differentiation of naive T-cells, leading to production of several TH2 cytokines, including IL-4, IL-5 and IL-13. Rothenberg and colleagues have identified the EoE transcriptome, which is markedly upregulated in active EoE, as well as by IL-13 [10,11]. These observations have led to the development of biologic agents that can act as targeted therapies for TH2-mediated disorders like EoE. Dupilumab is a fully human monoclonal antibody. It acts on the IL-4α subunit shared by both IL-4 and IL-13 receptors. By blocking these receptors, dupilumab inhibits both IL-4 and IL-13 signaling, suppressing TH2-mediated proinflammatory cytokines, chemokines and IgE that are instrumental in the pathways involved in many atopic conditions, including EoE [12,13].

3. Pharmacology

Dupilumab has been approved to treat a variety of atopic disorders, including AD, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), prurigo nodularis and EoE. Dupilumab is the first FDA-approved medication for the treatment of EoE, initially approved in May 2022, with expansion in use down to patients as young as 1 year of age weighing at least 15 kg in January 2024.

Dupilumab is administered subcutaneously. Dosing and interval of administration depends in part on age, weight and indication, ranging from 200 mg monthly to 300 mg weekly [14]. Serum concentrations of dupilumab achieve maximum levels at 3–7 days after administration and achieve steady state concentrations by week 16. The bioavailability of dupilumab following a subcutaneous dose is similar between AD, asthma, CRSwNP, prurigo nodularis and EoE subjects, ranging between 61% and 64% [14].

4. Clinical efficacy

The initial Phase II randomized, double-blind, placebo-controlled clinical trial of dupilumab in adults with EoE (n = 47) demonstrated encouraging results (Table 1). A significant reduction in dysphagia symptoms, peak esophageal eosinophil count, histologic severity score (EoE-HSS) and endoscopic reference score (EREFS), along with improved esophageal distensibility was seen after treatment with weekly dupilumab 300 mg over a period of 12 weeks [15].

Table 1.

Dupilumab clinical trials in eosinophilic esophagitis.

Authors	Study type and patient population	Drug regimen	Histologic response	Endoscopic response	Symptomatic response	Ref.
Hirano et al., 2020	Phase II RCT (NCT02379052) Adults (18–65 years) with EoE (n = 47)	600 mg dupilumab loading dose followed by 300 mg dupilumab weekly versus placebo.	Peak esophageal eosinophil count reduced by a mean 86.8 eos/hpf (p < 0.0001 vs. placebo) at 12 weeks.	EREFS score reduced by 1.6 (p = 0.0006 vs. placebo).	SDI PRO score reduced by mean value of 3.0 at week 10 (vs. 1.3 in placebo, p = 0.0304).	[15]
Dellon et al., 2022	Phase III RCT (LIBERTY EoE TREET, NCT03633617) Adults and adolescents (12–65 years) with EoE (n = 321)	Part A: 300 mg dupilumab weekly versus placebo Part B: 300 mg dupilumab weekly vs. every other week vs. placebo	Histologic remission (≤6 eos/hpf) in 60% (part A) and 59% (part B) for weekly dosing, 60% (part B) for every other week dosing at 24 weeks.	Reduction in EREFS score with least-squares mean difference of -2.9 points (part A) and -3.8 (part B) for weekly dosing vs. placebo. Least squares mean difference of -3.9 points for every other week dosing vs. placebo at 24 weeks.	DSQ score reduction of 12.32 (part A) and 9.92 (part B) for weekly dosing vs. placebo (both p < 0.001). DSQ score reduction not clinically significant for every other week dosing vs. placebo at 24 weeks.	[16]
Rothenberg et al., 2023	Phase III RCT Extension study of LIBERTY EOE TREET Adults and adolescents (12–65 years) with EoE (n = 227)	300 mg dupilumab weekly versus every other week	Histologic remission (≤6 eos/hpf) in 85% for weekly dosing, 74% for every other week dosing at 52 weeks.	Mean change in EREFS score was -5·4 points for weekly dosing and -5.2 points for every other week dosing at 52 weeks.	Mean absolute change in DSQ score was -30.3 points for weekly dosing and -20.9 points for every other week dosing at 52 weeks	[17]
Chehade et al., 2024	Phase III RCT (EoE KIDS, NCT04394351) Children (1–11 years) with EoE (n = 102)	Tiered weight-based dosing vs. placebo	Histologic remission (≤6 eos/hpf) in 68% at 16 weeks, 63% at 52 weeks in higher-exposure dupilumab group.	Least-squares mean difference in EREFS was -3.6 points at 16 weeks.	Greater decrease in the proportion of days with 1 or more signs of EoE (based on PESQ-C) with dupilumab treatment vs. placebo at 16 weeks.	[19]

DSQ: Dysphagia Symptom Questionnaire; EoE: Eosinophilic esophagitis; EREFS: Endoscopic reference score; SDI PRO: Straumann Dysphagia Instrument patient-reported outcome.

This led to a Phase III clinical trial looking at efficacy and safety of dupilumab in patients 12 years and older with active EoE (Table 1) [16]. The LIBERTY EoE TREET study was done in three parts – patients were either randomized 1:1 to weekly dupilumab 300 mg or placebo (part A) or randomized 1:1:1 to weekly dupilumab 300 mg, every other week dupilumab 300 mg or placebo (part B). Those who completed Parts A or B then moved on to part C in which all patients received dupilumab 300 mg either weekly or every other week. The primary outcomes of this study were histologic remission (defined as ≤6 eos/hpf) and reduction in dysphagia symptoms as measured by change in Dysphagia Symptom Questionnaire (DSQ) score at 24 weeks. For part A of this study, 60% of participants receiving weekly dupilumab achieved histologic remission as compared with 5% with placebo (p < 0.001). In part B, histologic remission rates in those receiving weekly and every other week dupilumab were similar (59% and 60%, respectively) and significantly higher than the 6% receiving placebo (p < 0.001).

In terms of symptomatic improvement, DSQ scores improved with weekly dupilumab as compared with placebo in both parts A and B (p < 0.001) but a significant improvement in DSQ was not seen in those receiving dupilumab every other week as compared with placebo. Therefore, while dupilumab 300 mg both once weekly and every other week was effective in achieving histologic remission, once weekly dosing was needed to also achieve significant improvement in DSQ scores. Additionally, a significantly higher proportion of those receiving either once weekly (64.3% in part A, 82.5% in part B) or every other week dupilumab (79%) achieved histologic response with peak eosinophil count of <15 eos/hpf, as compared with those receiving placebo (7.7% in part A, 7.6% in part B). A significant reduction in baseline in the EoE-HSS grade and stage score was also seen in those who received either weekly or every other week dupilumab as compared with placebo.

As an expansion of the above study, Rothenberg and colleagues examined the larger cohort of patients (n = 227) initially treated with dupilumab for 24 weeks (part B of the LIBERTY EoE TREET study) in an additional 28-week extension study (part B–C) to evaluate the long-term efficacy and safety of dupilumab (Table 1) [17]. Histologic improvements seen at 24 weeks of weekly dupilumab treatment were either maintained or continued to improve at 52 weeks, with the percentage of patients achieving histologic remission (≤6 eos/hpf) on weekly dupilumab increasing from 65% at week 24–85% at week 52 and those on every other week dupilumab increasing from 63% at week 24–74% at week 52. A total of 89% of participants on weekly dupilumab had a peak eosinophil count of <15 eos/hpf at 24 weeks, which increased to 100% at 52 weeks. After switching from placebo to weekly dupilumab similar improvements were seen both histologically and symptomatically. Dupilumab every other week improved EoE-HSS grade and stage score, EREFS and transcriptomic outcomes to a similar extent as weekly dupilumab when evaluated at 52 weeks. Extent of improvement in EoE symptoms, as measured by DSQ score, was noted to be smaller in those receiving dupilumab every other week as compared with those receiving dupilumab weekly.

A total of 74% of participants in part A and 70% in part B had history of prior STC use [18]. A subgroup analysis evaluating the impact of prior STC use on the results of the LIBERTY EoE TREET study demonstrated that histologic remission rate, reduction in DSQ score, improvement in EREFS score and improvement in EoE-HSS grade and stage score at both 24 and 52 weeks was unaffected by history of prior STC use or inadequate response, intolerance or contraindication to STC.

In January 2024, dupilumab received FDA approval for use in children with EoE down to 1 year of age weighing at least 15 kg. FDA approved dosing is weight based, with recommended dose of 200 mg every 2 weeks for children 15 kg up to 30 kg, 300 mg every 2 weeks for patients 30 kg up to 40 kg and adult dosing of 300 mg weekly for patients 40 kg and up [14]. In part A of the EoE KIDS Phase III RCT, patients aged 1 through 12 years received tiered weight-based dosing of dupilumab (200 mg every 2 weeks for patients 15 kg to <30 kg, 300 mg every 2 weeks for patients 30–60 kg) or placebo (Table 1) [19]. At week 16, 68% of patients receiving higher-exposure dupilumab achieved histologic remission (defined as ≤6 eos/hpf) as compared with 3.4% receiving placebo. Part B of the study demonstrated that 63% of patients on dupilumab from the start of the study were in remission at week 52 and 53% who transitioned from placebo to higher-exposure dupilumab at week 16 achieved remission at week 52. Rates of histologic response were higher when using <15 eos/hpf as a cut off, with 84% histologic response rate at 12 weeks and 86% at 52 weeks. Endoscopic and symptomatic improvement was similarly noted at both week 16 and 52.

5. Real-world evidence

While clinical trials provide substantial data to support dupilumab’s use in uncomplicated EoE, less is known regarding its effectiveness in patients with more complicated disease, as the LIBERTY EoE TREET trial excluded patients with an esophageal stricture that could not be passed with a standard endoscope and patients who required esophageal dilation at initial study screening. A retrospective study looked to determine the real-world efficacy of dupilumab in patients with severe, treatment-refractory and fibrostenotic EoE [20]. All patients included in this study (N = 46) were either treatment-refractory to standard modalities (PPI, STC, dietary elimination) or had lost prior response to one or more of these treatments and 85% of patients had undergone one or more esophageal dilation prior to dupilumab initiation (average 9.0 ± 7.0 dilations). A total of 30 patients (65%) received 300 mg dupilumab once weekly and 16 (35%) received 300 mg every other week. When comparing response to dupilumab to either the worst prior esophagogastroduodenoscopy (EGD) or the EGD just prior to dupilumab initiation, histologic, endoscopic and symptomatic improvement was seen. After initiation of dupilumab, 80% of patients achieved a peak eosinophil count of <15 eos/hpf as compared with 11% pre-dupilumab (p < 0.001) and 57% with peak eosinophil count ≤6 eos/hpf as compared with 9% pre-dupilumab (p < 0.001). Endoscopic features were also noted to improve, with drop in total EREFS score to 1.89 as compared with 5.01 pre-dupilumab (p < 0.001). While the esophageal diameter improved with dupilumab as compared with pre-dupilumab EGD (13.9 ± 3.2 vs 16.0 ± 3.0; p < 0.001), the percentage of patients with strictures did not change; 91% of patients reported symptomatic improvement at the time of repeat EGD as compared with 17% reporting symptomatic improvement at time of EGD pre-dupilumab. No comparison of weekly dosing versus every other week dosing was completed.

Data on efficacy in the pediatric population is more limited than what is known in adults. There are a number of case reports and case series that highlight the real-world efficacy of dupilumab in pediatric patients [21–23]. One such retrospective study looked at 45 pediatric patients (mean age 15.31 + 3.46 years) with EoE who had been prescribed dupilumab for the indication of AD, asthma or nasal polyps, dosed according to FDA approved indication [21]. Of the 26 patients who had pre- and post-dupilumab histology available for analysis, 22 had histologically active EoE (>15 eos/hpf) on pre-dupilumab EGD. Post-dupilumab initiation, 22 of 26 patients demonstrated a peak eosinophil count of <6 eos/hpf on follow-up EGD, done on average 23.4 weeks after starting dupilumab (range: 16–40 weeks). EREFS score was also noted to drop from a total score of 5.8 ± 3.6 pre-dupilumab to 0.5 ± 0.9 post-dupilumab (p < 0.001) and pediatric EoE symptom score significantly improved from 36.2 + 11.5 pre-dupilumab to 6.1 + 10.3 post-dupilumab (p < 0.001). A total of 29 patients were also reported to have been able to reduce or wean off EoE treatment medications or dietary restrictions, though not all patients had repeat EGDs completed so the authors were unable to comment on the histologic response to these changes.

To better guide clinicians in their use of dupilumab in EoE in patients 12 and older, clinical guidance was published by a group of experts in 2022 [24]. In this publication, multiple clinical scenarios were reviewed in which a clinician might consider initiation of dupilumab for EoE. It was suggested that first line use should be considered when patients have multiple comorbid atopic conditions, including difficult to control asthma, AD or CRSwNP or in patients with a strong preference to avoid dietary restrictions or STCs. Dupilumab can also be considered a step-up therapy in those who have difficult to treat EoE, patients refractory to or with adverse effects to current EoE therapy, patients whose growth and weight is impacted by EoE or require a severely restricted diet or patients who require frequent “rescue therapies” such as esophageal dilation and systemic steroids.

6. Safety & tolerability

Dupilumab has a favorable long-term safety and adverse effect profile. In randomized controlled clinical trials of dupilumab to treat asthma, AD and EoE, injection site reaction was the most common reported adverse event [25]. Other adverse events included nasopharyngitis, exacerbation of AD, upper respiratory tract infections oral herpes, conjunctivitis and headaches [26].

6.1. Ocular complications

Tzui-Yi-Lin et al. conducted a systematic review of all RCT involving dupilumab and did a meta-analysis to determine whether there is an association between dupilumab use and conjunctivitis. They found that dupilumab was associated with a higher incidence of conjunctivitis than placebo users, but only among patients with AD [27]. The average time of onset for ocular adverse events is 3–4 months. Other reported ocular side effects included dry eyes, conjunctivitis, blepharitis, keratitis and ocular pruritus (1–10%). Oro-facial herpes simplex infection was also reported in 1–10% of patients. These ocular adverse events were not significantly reported in patients treated with dupilumab for asthma or EoE [28–30].

6.2. Malignancy

There was no association found between treatment with dupilumab and short term malignancy risk in an analysis of patients taking dupilumab for AD [31] with the exception of a small case series of possible cutaneous T-cell lymphoma that worsened after dupilumab therapy [32].

6.3. Hypereosinophilia

Several different dupilumab clinical trials observed a transient increase in absolute eosinophil count in a subset of patients after treatment initiation, though has not been reported in clinical trials for the EoE patient population [28,33,34]. However, the blood eosinophil counts eventually decreased to below study baseline counts by week 72. Most of these patients did not have associated clinical symptoms and did not require interruption of their treatment. In addition to the gradual reduction in peripheral eosinophilia, long-term dupilumab exposure in asthma patients demonstrated reduction in serum total IgE concentrations. It has been suggested that dupilumab gradually suppresses B-cell class switching and IgE production [35].

6.4. Safety in young children

Clinical trials of dupilumab for AD in children as young as 6 months of age show a similar favorable adverse event profile in this age group. Dupilumab was well tolerated including in patients younger than 2 years of age. A transient increase in absolute eosinophil count was again observed with dupilumab, but was not associated with clinical symptoms. Viral gastroenteritis and dental caries occurred at a higher rate in the dupilumab group than the placebo group; however, the small number of patients with these adverse events were too few to draw any conclusions. The incidence of conjunctivitis was higher in the dupilumab group than the placebo group. In addition, hand-foot-and-mouth disease was reported in nine (5%) pediatric subjects and skin papilloma was reported in four (2%) of pediatric subjects 6 months to 5 years of age treated with dupilumab for AD. These cases did not lead to study drug interruption. No serious infections were noted with dupilumab, similar to previous dupilumab clinical trials in older children and adults. Skin infection incidence was lower in the dupilumab group than the placebo group [36].

6.5. Pregnancy

An analysis of the WHO safety reporting database identified 36 reports of pregnancy-related adverse drug events in patients receiving dupilumab. There was no clear association between reported adverse outcomes and dupilumab use. Of these 35 adverse events, 58.3% were spontaneous abortion. An ongoing retrospective cohort study (Dupi PODS) seeks to identify the incidence of adverse pregnancy and infant outcomes in women who are receiving dupilumab for AD compared with those with AD not on dupilumab. The trial began enrolling patients in September 2019 and is expected to conclude in July 2027 [37].

6.6. Vaccinations

It is recommended that all age-appropriate vaccinations are completed prior to initiating treatment with dupilumab. It is unknown if administration of live vaccines during dupilumab treatment will impact the safety or effectiveness of these vaccines. In a clinical study, adult subjects with AD treated with dupilumab were subsequently immunized with Tdap and meningococcal polysaccharide vaccines. Antibody responses to both tetanus toxoid and serogroup C meningococcal polysaccharide were similar in dupilumab-treated and placebo-treated subjects [12].

7. Regulatory affairs

Dupilumab received its first global approval on 28 March 2017, in the USA, for use in the treatment of adult patients with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies [12]. The FDA approved dupilumab for the treatment of adults with moderate to severe asthma on 19 October 2018. On 11 March 2019, the FDA approved dupilumab for the treatment of adolescents with moderate-to-severe AD and on 26 May 2020, they extended approval to include children aged 6–11 years. In October 2021, the FDA expanded approval of dupilumab to include children aged 6–11 years with moderate to severe asthma. On 20 May 2022, the FDA approved dupilumab as first line treatment for EoE in adults and children aged 12 years and older. On 7 June 2022, the FDA approved dupilumab for the treatment of eczema in children aged 6 months to 5 years. On 24 January 2024 the FDA approved dupilumab for use in children with EoE down to 1 year of age weighing at least 15 kg.

8. Conclusion

Clinical trials have shown dupilumab to be an effective treatment for EoE with an overall favorable long-term safety and adverse effect profile. While improvement in histologic and endoscopic response has been demonstrated in both weekly and every other week dosing regimens in adults, significant improvement in symptoms was only demonstrated with weekly dosing, in line with the current FDA-approved weekly dosing regimen for adults with EoE. FDA approval for use in children down to 1 year of age weighing at least 15 kg was also recently granted. Real world data additionally demonstrates support for the use of dupilumab in patients with fibrostenotic disease and those with more complicated disease not responsive to other standard treatment modalities. As the only FDA approved biologic for EoE at this time, clinicians are in the unique position of weighing risks and benefits of using dupilumab as compared with other FDA approved and non-FDA approved medications which have long been considered the standard of pharmacologic care for EoE.

9. Future Perspective

In the 30 years since the identification of EoE as a distinct clinical entity, much has been learned about this condition, though until recently limited medication options have existed. The speed at which new treatment modalities are being developed for EoE is ever increasing, with a number of other potential new biologics in late-stage clinical trials at this time. Dupilumab is the first of hopefully many future effective EoE therapies, which will help to expand therapy options for this patient population.

Author contributions

All authors contributed to the conception of the work, drafting the work or reviewing it critically for important intellectual content and were involved in final approval of the version to be published.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Competing interests disclosure

The author’s institution is a study site for phase 3 trials entitled “A randomized, double-blind, placebo-controlled study to investigate the efficacy and safety of dupilumab in pediatric patients with active eosinophilic esophagitis” sponsored by Sanofi and Regeneron Pharmaceuticals. EP Syverson acted as a consultant on a medical advisory board sponsored by Sanofi. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.