Intraamniotic Administrations of ER004 to Male Subjects With X-linked Hypohidrotic Ectodermal Dysplasia

Study Overview
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Brief Summary
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This is an open-label, prospective, genotype-match controlled for primary estimand, non randomized, multicenter, international Phase 2 clinical trial designed to investigate the efficacy and safety of ER004 administered intraamniotically as a treatment for unborn XLHED male subjects.

Detailed Description
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X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare developmental disease affecting body parts derived from the embryonal ectoderm. It is caused by a broad spectrum of mutations in the ectodysplasin A gene (EDA). The main symptoms of XLHED are hypo- or anhidrosis, oligo- or anodontia, and hypotrichosis. Current treatment options are limited to the management of disease symptoms and prevention of complications. Effective corrective treatment for XLHED remains a high unmet medical need. ER004 represents a first-in-class signaling protein replacement molecule designed for specific, high affinity binding to the endogenous EDA1 receptor (EDAR). The proposed mechanism of action of ER004 is the replacement of the missing EDA1 protein in patients with XLHED. The aim of this prospective, open-label, genotype-match controlled, multicenter Phase 2 trial is to confirm the efficacy and safety results for ER004 administered intra-amniotically in a larger cohort of subjects. The target population will consist of male XLHED fetuses/subjects with EDA mutation confirmed by genetic diagnosis of a mutation in one of the maternal EDA alleles and ultrasonographic diagnosis of a significantly reduced number of fetal tooth germs, or by documented direct genetic diagnosis of a hemizygous EDA mutation. In the main study phase, efficacy and safety of the treated subjects will be assessed up to 6 months of age and safety of the mothers will be assessed up to 1 month after delivery of the child. In long-term follow-up phase, efficacy and safety of the treated subjects will be assessed up to 5 years of age. Treated subjects sweating ability will be compared to an untreated relative from his family, when available, or from a matched controlled subject from a previous natural history.

Official Title
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A Prospective, Open-label, Genotype-match Controlled, Multicenter Clinical Trial to Investigate the Efficacy and Safety of Intra-amniotic ER004 as a Prenatal Treatment for Male Subjects With XLHED

Conditions
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X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

Intervention / Treatment
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* Biological: ER004


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For mother: adult mother with confirmed pregnancy no later than week 23+6 and genetically confirmed as carrier of an EDA mutation For fetal subject : male fetal subject with confirmed diagnosis of XLHED For untreated relative: untreated male relative subject aged between 6 months and 75 years with the same EDA mutation as the treated subject 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. 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. 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. Any condition other than XLHED that is likely to have an impact on the number of tooth germs. 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. For untreated relative: carrier of an hypomorphic EDA mutation. Known hypersensitivity to pilocarpine or pilocarpine-like muscarinic agonists. Presence of an implanted device (e.g., defibrillator, neurostimulator, pacemaker). Previous treatment with the study intervention by any route of administration prior to study start.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open-label, single-arm, genotype-match controlled for primary estimand, non randomized study. The primary efficacy outcome will be compared to genotype matched untreated male relatives with XLHED or to genotype-matched controls from an external XLHED database (clinical and natural history studies from which untreated genotype-matched controls will be identified).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ER004<br>Human immunoglobulin G1 constant region - human ectodysplasin-A1 receptor binding domain fusion protein. | Biological: ER004<br>* Intra-amniotic route 100 mg/kg of estimated fetal weight per injection. 3 injections, approximately 3 weeks apart starting from gestational week 26<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean sweat volume | For treated subject, mean sweat volume is collected on both forearms after local stimulation with pilocarpine (pilocarpine-induced sweating) | at 6 months of age (corrected age for subjects born at < 37 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean sweat pore density (number/cm2) | Mean sweat pore density (number/cm2) determined by direct visualization with a VivaScope® at 2 different sites on the sole/soles of the foot/feet (up to 12 months) or at 2 different sites on the sole/soles of the foot/feet and/or palm/palms of the hand/hands (>12 months) | at 6 months of age (key secondary) and other timepoints : 3, 12, 18, 24, 36, 48 and 60 months of age (secondary) | 
| Dental development | Dental development evaluated by the number of erupted teeth and tooth germs (palpable alveolar structures in the alveolar ridge) as determined by dental examination | at 6 months of age (key secondary) and other timepoints : 12, 18, 24, 36, 48 and 60 months of age (secondary) | 
| Mean sweat volume | For treated subject, mean sweat volume is collected on both forearms after local stimulation with pilocarpine (pilocarpine-induced sweating) | At 3, 12, 18, 24, 36, 48, 60 months of age | 
| Number of Meibomian glands | Number of Meibomian glands in the lower eyelids determined by Meibography | At 6 and 60 months of age | 
| Ocular surface assessment | Ocular surface assessment (normal, keratitis superficialis punctate) by eye using fluorescein | At 24, 48 and 60 months of age | 
| Tear film break-up time | Tear film break-up time (seconds) determined using fluorescein | At 24, 48 and 60 months of age | 
| Ocular Surface Disease Index (OSDI) score | Score assessed on a scale of 0 to 100 through the OSDI questionnaire. Higher scores mean a worse outcome | At 60 months of age | 
| Salivation | Saliva (volume and flow rate) assessed with Quantisal oral fluid collection device | At 60 months of age | 
| XLHED-related hospitalizations | XLHED-related hospitalisation because of hyperthermia or because of unexplained fever, respiratory, skin, eye or ear infections | Up to 60 months of age | 
| Assessment of eczema | Eczema will be assessed using the EASI score | At different timepoints from 6 to 60 months of age | 
| Incidence of TEAEs (treatment-emergent adverse events) | Number of subjets with TEAEs | Up to 60 months of age | 
| Incidence of TESAEs (treatment-emergent serious adverse events) | Number of subjects with TESAEs | Up to 60 months of age | 
| Incidence of TEAEs (treatment-emergent adverse events) leading to treatment discontinuation | Number of subjects with TEAEs leading to treatment discontinuation | Up to 60 months of age |