Dupilumab as Add-On Therapy for Hypereosinophilic Syndrome With Partial Clinical Response to Eosinophil-Depleting Biologic Agents

Study Description:

The purpose of this study is to evaluate the efficacy and tolerability of dupilumab in reducing clinical manifestations in patients with hypereosinophilic syndrome (HES) and persistent eosinophil-related pulmonary, skin, gastrointestinal, or sinus symptoms despite eosinophil reduction in response to eosinophil-lowering biologic therapy. Patients who meet criteria for HES and are currently receiving mepolizumab, reslizumab or benralizumab with persistent symptoms (as above) despite absolute eosinophil count (AEC)<0.5x10^9/L will be eligible to enroll. Participants will be treated with dupilumab at the US Food and Drug Administration (FDA)-approved doses for asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyposis (CRSwNP), or eosinophilic esophagitis (EoE) depending on their residual symptoms Participants will have clinical evaluations and AEC measured every 4 weeks for 24 weeks. Participants who remain in clinical remission and have an AEC<0.5x10^9/L will be eligible to continue dupilumab therapy for an additional 24 weeks with tapering of background therapy (other than the eosinophil-lowering biologic) as clinically tolerated.

Objectives:

Primary Objective: To assess the efficacy of add-on dupilumab therapy in reducing residual pulmonary, skin, esophageal, and sinus symptoms in patients with HES in complete hematologic and partial clinical remission on eosinophil-lowering biologics

Secondary Objective: To determine the effect of eosinophil-lowering therapy on dupilumab-induced blood eosinophilia and eosinophil-associated AEs

Endpoints:

Primary Endpoint: Clinical improvement on dupilumab therapy at 24 weeks, as assessed by HES-Most Bothersome Symptom (HES-MBS) and HES-Symptom Inventory (HES-SI)

Secondary Endpoints:

• Incidence of new or worsening symptoms or signs attributable to eosinophilia requiring therapeutic intervention through week 24
• Peripheral blood AEC at 4, 12, and 24 weeks.
• Proportion of patients who maintain an eosinophil count below 0.5x10^9/L at 4, 12 and 24 weeks.

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet all the following criteria:

• Age >=18 years
• Documented diagnosis of HES with historic AEC>1.5x10^9/L on two occasions, no secondary etiology for the eosinophilia despite careful clinical evaluation, and evidence of end organ damage (histologic evidence of tissue infiltration by eosinophils and/or objective evidence of clinical pathology in any organ system that is temporally associated with eosinophilia and not clearly attributable to another cause)
• Currently receiving treatment with an eosinophil-lowering biologic (mepolizumab, reslizumab, or benralizumab) for a minimum of 24 weeks
• AEC<0.5x10^9/L
• Residual symptoms after a minimum of 24 weeks of eosinophil-lowering biologic therapy with at least 1 most bothersome symptom of moderate severity (HES-SI score >=2) consistent with >=1 of the following diagnoses:

a. asthma, defined as physician-documented asthma requiring medium to high dose inhaled corticosteroids + long-acting beta agonist b. atopic dermatitis, defined as physician-documented chronic or recurrent inflammatory skin disease

c. CRSwNP, defined as evidence of rhinosinusitis and nasal polyposis on physical examination or imaging

d. EoE, defined as biopsy-proven esophageal eosinophilia >15 eosinophils/high power field

• For participants who can become pregnant: sexual abstinence or use of highly effective contraception (i.e., partner vasectomy, bilateral tubal ligation, IUD, progestin implants, and other hormonal methods) starting 4 weeks prior to study drug initiation and agreement to use such a method during study participation and for an additional 12 weeks after the end of study drug administration
• Participation in NIH protocol 94-I-0079 (Activation and function of eosinophils in conditions with blood or tissue eosinophilia)
• Ability of subject to understand and the willingness to sign a written informed consent document

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Pregnancy or lactation
• Known allergic reaction to dupilumab or any of the excipients in Dupixent(TM)
• Febrile illness within 7 days of enrollment
• Treatment with an investigational drug or other intervention other than mepolizumab, reslizumab, or benralizumab within 12 weeks or 4 half-lives of the investigational agent (whichever is longer).
• Known or suspected acquired or inborn immunodeficiency disorder, including HIV infection
• Known diagnosis of eosinophilic granulomatosis with polyangiitis
• Change in eosinophil-active therapy within the past 6 weeks, including but not limited to topical corticosteroids, leukotriene inhibitors, initiation or change of a food-elimination diet regimen or re-introduction of a previously eliminated food (in patients with gastrointestinal involvement), and proton pump inhibitors (in patients with gastrointestinal involvement)
• Planned or anticipated major surgical procedure during the study
• Active parasitic infection
• History of malignancy within 5 years, excluding completely treated in situ carcinoma of the cervix, or squamous or basal cell carcinoma of the skin
• Any condition that, in the investigator s opinion, places the patient at undue risk by participating in the study

For patients with eosinophilic gastrointestinal disease only:

• Active infection with Helicobacter pylori
• History of achalasia, Crohn s disease, ulcerative colitis, celiac disease, or prior esophageal surgery
• Any esophageal stricture unable to be passed with a standard, diagnostic, 9 to 10 mm upper endoscope