Evaluation of Intra-Amniotic ER004 for Efficacy and Safety in Male Patients with X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

Trial ID: 2024-512632-30-00
Protocol: EDELIFE
Sponsor: Fondation EspeRare

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Diseases & Conditions

Congenital ectodermal dysplasia

Objectives

The primary objective of this clinical trial is to evaluate the **efficacy** of intra-amniotic administrations of ER004 on the **sweating ability** in male subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) who have a null mutation in the EDA gene, at 6 months of age. This is compared to untreated matched control subjects. The clinical relevance of this objective lies in addressing the impaired sweating ability, a significant symptom of XLHED, which can lead to life-threatening hyperthermia.

Secondary objectives include:

Assessing the efficacy of ER004 on **sweat pore density** and **dentition** in male subjects with XLHED at 6 months of age.
Evaluating the efficacy of ER004 in male subjects with XLHED up to 5 years of age.
Assessing the **safety** of ER004 in male subjects with XLHED up to 6 months of age and in mothers up to 1 month after delivery.
Evaluating the long-term safety of ER004 in male subjects with XLHED up to 5 years of age.
Assessing safety parameters in untreated relatives (controls).

These secondary objectives aim to provide a comprehensive understanding of both the short-term and long-term effects of ER004, as well as its safety profile, which is crucial for the potential therapeutic management of XLHED.

Participants

The clinical trial involves a total of **7 participants** and focuses on male subjects diagnosed with **X-linked hypohidrotic ectodermal dysplasia (XLHED)**. The study population includes male fetal subjects with a confirmed diagnosis of XLHED and untreated male relatives aged between 6 months and 75 years, all possessing a null mutation in the EDA gene. The trial specifically excludes female subjects, as the study is designed to assess the efficacy of intra-amniotic administrations of ER004 on sweating ability in male XLHED subjects. Participants were selected based on genetic confirmation of the EDA mutation, with the trial including a vulnerable population due to the involvement of fetal subjects. The trial does not provide specific information regarding lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of intra-amniotic administrations of ER004, a **solution for injection**, in male subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED). This is a prospective, open-label, genotype-match controlled, multicenter Phase 2 trial. The primary objective is to assess the impact of ER004 on sweating ability in male XLHED subjects with a null mutation in EDA at 6 months of age, compared to untreated matched control subjects. The trial is expected to conclude by January 6, 2030, with recruitment having commenced on January 6, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility. Key inclusion criteria include an adult mother with a confirmed pregnancy no later than week 23+6 days, genetically confirmed as a carrier of an EDA mutation, and a male fetal subject with a confirmed diagnosis of XLHED. An untreated male relative with the same EDA mutation, aged between 6 months and 75 years, will also be included as a control. There are no specified exclusion criteria.

Following the screening, participants will receive intra-amniotic administrations of ER004, with the maximum treatment period being 3 months. The primary endpoint is the mean sweat volume collected on both forearms after local stimulation with pilocarpine. Secondary endpoints include mean sweat pore density, dental development, and assessments of dry eye, salivation, and eczema, among others. Safety and tolerability, as well as health-related quality of life, will also be evaluated.

Participants are expected to remain in the study until the end-of-study visit, which will occur at 6 months of age for the treated subjects. Conditions that may lead to early termination from the study include adverse reactions to the treatment or withdrawal of consent. The trial will ensure rigorous monitoring to maintain participant safety and data integrity throughout its duration.

Treatment

The clinical trial involves the administration of the experimental medication **ER004**, which is a **solution for injection**. The active substance in ER004 is a **human immunoglobulin G1 constant region - human ectodysplasin-A1 receptor-binding domain fusion protein**. This protein is classified as a "Protein - Other" and is specifically designed for intra-amniotic use. The medication is administered with a maximum daily dose of 100 mg/kg and a total maximum dose of 300 mg/kg over a treatment period of up to 3 weeks. The pharmaceutical form of ER004 is a solution for injection, and it is not a pediatric formulation. The medication is designated as an orphan drug, indicating its use in treating a rare condition.

In this study, ER004 is being evaluated for its efficacy and safety as a prenatal treatment for male subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED). The primary objective is to assess the impact of ER004 on the sweating ability of these subjects at 6 months of age, compared to untreated matched control subjects. The trial is open-label and genotype-match controlled, conducted across multiple centers. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the study protocol. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

Efficacy

The efficacy of the clinical trial investigating the prenatal treatment of male subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) using intra-amniotic ER004 will be assessed through several primary and secondary endpoints. The primary endpoint is the mean sweat volume collected on both forearms after local stimulation with pilocarpine, known as pilocarpine-induced sweating. This measurement will be used to evaluate the improvement in sweating ability at 6 months of age compared to untreated matched control subjects.

Secondary endpoints include the mean sweat pore density, determined by direct visualization with a VivaScope® at 6 months of age at two different sites on the soles of the feet, and dental development, evaluated by the number of erupted teeth and tooth buds through oral examination at the same age. Additional secondary endpoints encompass assessments of mean sweat volume and sweat pore density at other timepoints, dentition, dry eye, salivation, number of XLHED-related hospitalizations, eczema, safety and tolerability, and health-related quality of life.

Inclusion and Exclusion Criteria

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Inclusion Criteria

For mother : Adult mother with confirmed pregnancy no later than week 23+6 days and genetically confirmed as carrier of an EDA mutation
For fetus subject: Male Fetal subject with confirmed diagnosis of XLHED
Untreated relative : Untreated male relative subject ages between 6 months and 75 years with the same EDA mutation as the treated subject

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Exclusion Criteria

For mother: Any evidence of active maternal infection associated with a risk of preterm birth and/or congenital anomalies of prenatal and postnatal risk to the child. Documented maternal HIV infection.
For mother: Any pre-existing maternal medical condition that increases the risk of preterm birth or increases the risk of a serious untoward event occurring to the mother during pregnancy.
For mother: Any pregnancy disorder associated with an increased risk of preterm birth, and/or maternal, fetal or neonatal morbidity/mortality
For fetal subject: Second major anatomic anomaly (not related to the underlying XLHED) that contributes to a significant morbidity or mortality risk, or echocardiogram or ultrasonography or other findings that indicate a high risk of fetal demise or risk of preterm birth
For fetal subject: Any condition other than XLHED (i.e., other forms of ectodermal dysplasia, large orofacial clefts) that is likely to have an impact on the number of tooth germs.
For fetal subject: Any other medical condition which in the opinion of the investigator would not allow for safe conduct of the study for the subject, or that would interfere with efficacy assessments (e.g., any disorders that lead to reduced fetal swallowing).
For Untreated Relative: Carrier of an hypomorphic EDA mutation.
For Untreated Relative: Known hypersensitivity to pilocarpine or pilocarpine-like muscarinic agonists.
For Untreated Relative: Presence of an implanted device (e.g., defibrillator, neurostimulator, pacemaker).
For Untreated Relative: Previous treatment with the study intervention by any route of administration prior to study start.