Efficacy and Safety Evaluation of TEV-53408 in Adults with Celiac Disease Undergoing Oral Gluten Challenge: A Phase 2a Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2024-517081-42-00
Protocol: TV53408-IMM-20042
Sponsor: Teva Branded Pharmaceutical Products R&D LLC

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Diseases & Conditions

Coeliac disease

Objectives

The primary objective of this trial is to evaluate the efficacy and safety of a single dose of **TEV-53408** administered subcutaneously in adults with **Celiac Disease**. The primary efficacy objective is to assess the ability of TEV-53408 to attenuate gluten-induced enteropathy, which is clinically relevant as it addresses the core pathological process in celiac disease. The primary safety objective is to evaluate the safety profile of TEV-53408 up to week 28, ensuring that the treatment does not pose undue risk to participants.

The secondary objective is to further assess the efficacy of a single dose of TEV-53408 in this patient population, providing additional insights into its potential therapeutic benefits.

Participants

The clinical trial involves a total of **35 participants** diagnosed with **celiac disease**. The study population includes both male and female subjects, aged between 18 and 64 years. Participants were selected based on their ability to provide informed consent and their willingness to comply with trial procedures, including maintaining a gluten-free diet for at least 12 months prior to screening. The trial population is characterized by a body mass index ranging from 18.5 to 40 kg/m². Participants must have minimal enteropathy and no moderate or severe gastrointestinal symptoms attributable to celiac disease at screening. The study includes individuals who are positive for HLA DQ2 or HLA DQ8. Women of childbearing potential are required to have a negative pregnancy test and adhere to effective birth control methods, while male participants with partners of childbearing potential must use condoms and agree not to donate sperm during the trial. The trial does not include pregnant or lactating women, and participants must not plan pregnancy during the trial period. The sponsor has not provided information regarding any specific lifestyle considerations such as physical activity or other habits.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, Phase 2a study to evaluate the efficacy and safety of TEV-53408 in adults diagnosed with **celiac disease**. The trial aims to assess the ability of a single subcutaneous dose of TEV-53408 to mitigate gluten-induced enteropathy and to evaluate its safety profile over a period extending up to 28 weeks. The trial is expected to commence recruitment on June 3, 2025, and conclude by September 28, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of celiac disease, adherence to a gluten-free diet, and absence of moderate or severe gastrointestinal symptoms. The screening will also involve a duodenal biopsy to assess minimal enteropathy and confirm positive HLA DQ2 or HLA DQ8 status. Following successful screening, participants will be randomized to receive either TEV-53408 or a placebo via subcutaneous injection.

Subsequent follow-up visits will occur at regular intervals to monitor the participants' health, assess the primary and secondary endpoints, and ensure compliance with the gluten challenge. The primary endpoints include changes in villous atrophy and the incidence of treatment-emergent adverse events, while secondary endpoints focus on changes in intraepithelial lymphocyte density and a composite measure of villous crypt intraepithelial lymphocytes. The end-of-study visit will mark the completion of the trial, where final assessments will be conducted.

Participant involvement is expected to last up to 28 weeks, with conditions for early termination including the occurrence of adverse events or non-compliance with trial procedures. The trial's design ensures rigorous monitoring and evaluation to maintain participant safety and data integrity throughout the study duration.

Treatment

The clinical trial involves the administration of **TEV-53408**, an investigational medication formulated as a **solution for injection**. This experimental drug is designed for subcutaneous administration. The primary objective is to evaluate its efficacy and safety in adults with **celiac disease**. The active substance, TEV-53408, is a protein-based compound developed by TEVA Branded Pharmaceutical Products R&D, Inc. Participants will receive a single dose of TEV-53408, with the dosing schedule and administration closely monitored to ensure compliance and safety throughout the study period.

In addition to the experimental treatment, a **placebo** is utilized as a comparator to match TEV-53408. The placebo is designed to mimic the appearance and administration route of the investigational drug, ensuring the study remains double-blind. The placebo is administered subcutaneously, similar to TEV-53408, to maintain consistency in the trial's methodology. The use of a placebo allows for a controlled assessment of TEV-53408's effects, providing a baseline for evaluating its efficacy and safety in the context of gluten-induced enteropathy in celiac disease patients.

Efficacy

The efficacy of TEV-53408 in the treatment of **celiac disease** will be assessed through a series of predefined primary and secondary endpoints. The primary efficacy endpoint is the change from baseline in villous atrophy, as measured by the villous height to crypt depth ratio (Vh:Cd), at week 8. This measurement will be obtained through duodenal biopsy, which is a standard procedure for evaluating intestinal damage in celiac disease. Secondary efficacy endpoints include the change from baseline in intraepithelial lymphocyte (IEL) density and a composite measure of villous height and IEL density (VCIEL) at week 8. These assessments will provide a comprehensive evaluation of the intestinal response to gluten exposure and the potential protective effect of TEV-53408.

Data collection will occur at specific timepoints, with the primary focus on week 8 for efficacy assessments. The trial will also monitor the incidence of treatment-emergent adverse events, serious adverse events, and adverse events leading to early discontinuation up to week 28. These safety parameters will be crucial in determining the overall benefit-risk profile of TEV-53408. The trial is designed as a multicenter, randomized, double-blind, placebo-controlled, Phase 2a study, ensuring rigorous evaluation of both efficacy and safety in adults with celiac disease undergoing oral gluten exposure.

Inclusion and Exclusion Criteria

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Inclusion Criteria

a. Male or female (assigned sex at birth) ≥18 to <65 years of age, inclusive, at the time of signing the informed consent.
b. Diagnosis of celiac disease at least 12 months prior to screening (documentation required at screening): − Participant has documentation of EGD confirming celiac disease and positive antibodies, or − If the participant is <30 years of age and a biopsy was not performed at the time of the celiac diagnosis, the participant had met the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) criteria for diagnosis.
c. On a gluten-free diet for at least 12 months prior to screening, as determined by the investigator through participant interview.
d. tTg IgA - <5 U/mL for participants being screened with the EliA™ Celikey IgA (Celikey) assay used at sites in the EU
e. Minimal enteropathy as determined by Vh:Cd ≥2.0 on a duodenal biopsy (EGD) performed during screening period.
f. No moderate or severe gastrointestinal symptoms attributable to celiac disease at Screening (visit 1) based on the Symptom Screening Tool.
g. Positive at screening for HLA DQ2 or HLA DQ8.
h. Body mass index >18.5 to 40 kg/m2 (inclusive).
i. Women of non-childbearing potential should be: − congenitally or surgically sterile (documented hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) as assessed by a physician, or − 1-year postmenopausal (no menses for at least 12 months without an alternative medical cause, plus either a concentration of follicle-stimulating hormone [FSH] within the postmenopausal range [an increased concentration of FSH of more than 35 IU/L] in women not using hormonal contraception/hormonal replacement therapy [HRT], or medical documentation of menopause for women on HRT).
j. Women of childbearing potential (WOCBP) must have a negative β-human chorionic gonadotropin (HCG) test result and practice a highly effective method of birth control prior to IMP administration and for the duration of trial participation, or for 5 half-lives of TEV-53408 (28 weeks) after IMP administration, whichever is longer.
k. Women must not be pregnant, lactating, breastfeeding, or planning pregnancy during the trial period.
l. Male participants (including vasectomized) with WOCBP partners (whether pregnant or not) must use condoms and also agree not to donate sperm after IMP administration and for the duration of trial participation, or for 5 half-lives of TEV-53408 (28 weeks) after IMP administration, whichever is longer.
m. Participants should be capable of giving signed informed consent, and willing and able to comply with trial procedures, including duodenal biopsy both during screening and at week 8, maintaining the gluten challenge, and other restrictions.

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Exclusion Criteria

a. A diagnosis or suspicion of refractory celiac disease.
j. The participant has a history of chronic alcohol or substance abuse disorder within the previous 2 years.
k. The participant has an active infection(s) requiring treatment with intravenous (iv) anti-infectives (antibiotics, antivirals, antifungals) within 30 days prior to screening or oral anti-infectives (antibiotics, antivirals, antifungals) within 14 days prior to screening.
l. Received or intends to receive any live vaccine within 4 weeks or any non-live vaccine 2 weeks prior to IMP administration. Live vaccines include, but are not limited to, measles, mumps, rubella (MMR combined vaccine), rotavirus, smallpox, chickenpox, yellow fever, and oral polio vaccine.
m. An active infection with EBV or CMV, with a confirmed EBV or CMV PCR-based viral DNA level of ≥10000 IU/mL obtained at screening. Note: “Confirmed” is defined by a repeat positive test within 7 days of the reporting of the initial finding.
n. A clinically active infection of HPV, VZV, or HSV 1/2 at screening or baseline.
o. Active tuberculosis (TB) (as determined by the QuantiFERON® TB Gold Test) or history of untreated latent or active TB. Note: If the QuantiFERON ® TB Gold Test is indeterminate, a second test should be performed through the central laboratory or local. If the second test is positive, the participant is considered to be positive. If the second test is negative, the participant is considered to be negative.
p. Positive viral serology at screening: − Hepatitis B: hepatitis B surface antigen (HBsAg) positive or detected sensitivity on the HBV-DNA PCR qualitative test for hepatitis B core total antibody (HBcAb)/hepatitis B surface antibody (HBsAb) positive participants − Hepatitis C: HCV ribonucleic acid (RNA) detectable in any participant with positive anti-HCV antibody (HCVAb) − Human immunodeficiency virus (HIV) Types 1 or 2 Ab (confirmed positive serology test, according to 4th generation serology testing)
q. Participant has a history of opportunistic or serious infection that makes the participant an unsuitable candidate for the trial (if the infection is oral herpes simplex or palmoplantar warts, then the participant will be allowed).
r. Participant has a known genetic or acquired immune deficiency.
s. Participant has a history of disseminated herpes simplex, multidermatomal, ophthalmic, recurrent herpes zoster, or herpes encephalitis.
b. History of severe celiac-related symptoms following gluten exposure that require acute medical care or intervention of a health care professional (either inpatient or outpatient) for management, dermatitis herpetiformis, or history of neurological symptoms including ataxia after gluten exposure.
t. Any participant that has a chronic or recurrent infection that the investigator believes does not fit any of the above exclusion criteria should be discussed with the medical monitor prior to enrollment in the trial.
u. Prior treatment with systemic immune suppressants or modulators including biological agents within the past 2 years for any condition (a brief course of 7 days or less of oral or parenteral corticosteroids for an emergent transient medical condition is allowed if use was >4 weeks prior to screening; up to 2 treatment courses per year).
v. Use of angiotensin II receptor blockers (eg, losartan, olmesartan, valsartan) within 4 weeks prior to screening.
w. Use of probiotic supplements within 4 weeks prior to randomization (probiotics in food [eg, yogurt] are allowed).
x. The participant has any of the following values from laboratory testing at screening (abnormal laboratory tests at the screening visit may be repeated once during the screening period): − aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) − alanine aminotransferase (ALT) >3 × ULN − total bilirubin >1.5 × ULN (unless it is known to be secondary to Gilbert’s syndrome per the participant’s medical history) − creatine phosphokinase (CPK) >2.5 × ULN − lymphocyte count <1000 cells/μL − NK cell percentage below 4% of total lymphocytes. NK cell percentage is calculated as the ratio of CD56+ cells divided by the total lymphocyte count (CD45+ cells from T cell, B cell, and natural killer cell [TBNK] cell assay). If the total lymphocyte count is below the normal range, the denominator for the calculation will be the LLN for the lymphocyte count.
y. The participant has any other laboratory or physical examination findings or clinically significant electrocardiogram (ECG) result that might place the participant at an unacceptable risk for participation in this trial in the opinion of the investigator.
c. Any other gastrointestinal disease or condition that may interfere with the assessment of celiac disease, such as irritable bowel syndrome, lactose intolerance, uncontrolled gastroesophageal reflux disease, ulcerative colitis, Crohn’s disease, or microscopic colitis. In addition, participants who have evidence on screening endoscopy of greater than Grade A esophagitis, eosinophilic esophagitis, or active peptic ulcer are excluded.
d. Current or history of malignancy or treatment of malignancy in the last 5 years, excluding treated basal cell carcinoma.
e. Pregnant or lactating woman, or plans to become pregnant during the trial; any man who is considering fathering a child or donating sperm during the trial.
f. The participant is currently participating in, or has participated in another trial of an IMP (or a medical device) within the previous 30 days or 5 half-lives of the IMP (whichever is longer).
g. The participant has previously been randomized within this trial or has participated previously in a trial with TEV-53408 or another anti–IL-15 therapy. In addition, participants who received any other immunotherapy for celiac disease within 2 years prior to screening are excluded.
h. Known hypersensitivity or idiosyncratic reaction to the IMP, its related compounds, or to any metabolites or any compound listed as being present in a trial formulation or other IMP; history of anaphylactic reactions to protein therapeutics or known hypersensitivity to any ingredients listed in the label of the daily gluten dose that is to be consumed during the gluten challenge in this trial.
i. Donated or received any blood or blood products (eg, WBCs, platelets) within the 60 days prior to screening or has donated blood or blood products on 2 or more occasions within the 6 months prior to IMP administration, or donated plasma within 7 days before the screening visit or has planned donations during the trial. The minimum reference volume of whole blood lost or donated is 500 mL.
z. The participant is an employee of the sponsor or the site or a relative of an employee at the site conducting the trial.
aa. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious disease) illness.
bb. Legal or mental incapacitation, or inability to understand and comply with the requirements of the trial.
cc. Participants incapable of giving written informed consent.