ER004 for Hypohidrotic Ectodermal Dysplasia

(EDELIFE Trial)

Recruiting at 8 trial locations

Overseen By Agnes Jaulent

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: EspeRare Foundation

Must not be taking: Pilocarpine

Disqualifiers: HIV, Preterm birth risk, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to delivery

20 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What data supports the effectiveness of the drug ER004 for treating hypohidrotic ectodermal dysplasia?

Research shows that the drug ER004, when administered before birth, can potentially help develop normal skin, hair, and sweat glands in patients with hypohidrotic ectodermal dysplasia. Animal studies and early human trials suggest that replacing the missing protein EDA1 can correct key symptoms of the disorder. ^{1 2 3 4 5}

Is ER004 (also known as Fc-EDA or Ectodysplasin 1 protein replacement therapy) safe for humans?

Research shows that ER004, tested as Fc-EDA, is generally safe in humans, with no significant immune response detected in newborns treated in the womb or after birth. Some adults developed anti-drug antibodies, but this was not observed in pregnant women or infants. ^{1 2 3 5 6}

How is the drug ER004 different from other treatments for hypohidrotic ectodermal dysplasia?

ER004 is unique because it is a first-of-its-kind protein replacement therapy designed to be administered prenatally, replacing the missing EDA1 protein in unborn babies to help develop normal skin, hair, and sweat glands. Unlike other treatments, it specifically targets the EDA1 receptor to activate a pathway crucial for tissue development, offering a potential long-term solution for this condition. ^{1 2 4 7 8}

Research Team

Holm Schneider, MD

Principal Investigator

University Erlangen-Nürnberg Erlangen, Germany

Eligibility Criteria

This trial is for unborn male babies with X-linked Hypohidrotic Ectodermal Dysplasia (XLHED), diagnosed via genetic testing. The mother must be an adult, confirmed pregnant up to week 23+6, and a carrier of the EDA mutation. Relatives aged 6 months to 75 years with XLHED can also join. Exclusions include other serious medical conditions, maternal infections or conditions increasing preterm birth risk, known hypersensitivity to certain drugs, significant additional fetal anomalies, and previous treatment with ER004.

Inclusion Criteria

My unborn son has been diagnosed with XLHED.

I am pregnant, not past 23 weeks and 6 days, and carry an EDA mutation.

I am a male relative with the same genetic mutation, aged between 6 months and 75 years, and have not been treated.

Exclusion Criteria

You are allergic to pilocarpine or similar medications that work like pilocarpine.

I do not have conditions affecting my tooth development other than XLHED.

You have an ongoing infection that could harm the baby during pregnancy or after birth.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

ER004 is administered intra-amniotically to male fetuses with XLHED

Up to delivery

Initial Follow-up

Efficacy and safety of treated subjects assessed up to 6 months of age; safety of mothers assessed up to 1 month after delivery

6 months

Long-term Follow-up

Efficacy and safety of treated subjects assessed up to 5 years of age

5 years

Treatment Details

Interventions

• ER004

Trial Overview The trial tests the safety and effectiveness of ER004 given intraamniotically (into the amniotic fluid) as a potential treatment for XLHED in unborn males. It's an open-label Phase 2 study without randomization but includes genotype-matched controls for primary estimand evaluation across multiple international centers.

Participant Groups

Group I: ER004 Experimental Treatment 1 Intervention

Human immunoglobulin G1 constant region - human ectodysplasin-A1 receptor binding domain fusion protein.

Who Is Running the Clinical Trial?

EspeRare Foundation

Lead Sponsor

Trials

2

Recruited

40+

Iqvia Pty Ltd

Industry Sponsor

Trials

120

Recruited

177,000+

Ari Bousbib

Iqvia Pty Ltd

Chief Executive Officer since 2016

MBA from Columbia University, Master of Science in Mathematics and Mechanical Engineering from Ecole Superieure des Travaux Publics, Paris

Jeffrey Spaeder

Iqvia Pty Ltd

Chief Medical Officer

MD

IQVIA (clinical CRO)

Collaborator

Trials

1

Recruited

20+

Pierre Fabre Medicament (co-sponsor)

Collaborator

Trials

1

Recruited

20+

Pierre Fabre Medicament

Industry Sponsor

Trials

83

Recruited

90,400+

Marie-Andrée Gamache

Pierre Fabre Medicament

Chief Executive Officer

MBA from HEC Montréal

Dr. Núria Perez-Cullell

Pierre Fabre Medicament

Chief Medical Officer since 2022

PhD in Pharmacy from the University of Barcelona

Findings from Research

Fc-EDA, an EDA1 replacement protein, has shown a favorable safety profile in clinical trials involving adults and neonates, supporting its potential use in treating X-linked hypohidrotic ectodermal dysplasia.

The drug demonstrated efficacy when administered prenatally, with no detectable immune response in neonates, suggesting it could be a promising therapy for preventing severe symptoms associated with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects. Körber, I., Klein, OD., Morhart, P., et al.[2021]

ER004 is a first-in-class protein replacement therapy designed to treat X-linked hypohidrotic ectodermal dysplasia (XLHED) by replacing the missing ectodysplasin A1 (EDA1) protein, which is crucial for normal skin and appendage development.

The EDELIFE trial is a multicenter clinical study aimed at evaluating the safety and efficacy of administering ER004 to male fetuses with XLHED during the late second and third trimesters, following promising results from preclinical studies and named-patient use cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia. Schneider, H., Hadj-Rabia, S., Faschingbauer, F., et al.[2023]

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a genetic disorder that leads to severe health issues, including life-threatening hyperthermia and chronic respiratory problems, with no approved therapies available until now.

Recent studies using an EDA-A1 replacement protein (EDI200) in animal models have shown promising results, permanently correcting key features of XLHED, and the FDA has now approved trials to test this treatment in human patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future developments in XLHED treatment approaches. Huttner, K.[2020]

A 7-year-old boy with hypohidrotic ectodermal dysplasia (HED) exhibited symptoms such as thin hair, hypohidrosis, and seizures, linked to a partial deletion of the EDA gene identified through genome-wide CNV-seq.

The boy's mother also carried a similar microdeletion of the EDA gene but displayed milder symptoms, suggesting a genetic link and supporting the diagnosis of X-linked recessive HED in both cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phenotypic and genetic analysis of a case with hypohidrotic ectodermal dysplasia due to Xq13.1 microdeletion]. Mei, D., Mei, S., Chen, G., et al.[2021]

A 2-year-old girl with severe hypohidrotic ectodermal dysplasia (HED) exhibited significant symptoms including hair loss, missing teeth, and dry skin, linked to a novel homozygous mutation in the EDAR gene.

The identified mutation (c.84delC) leads to a complete loss of ectodysplasin-mediated NF-kB signaling, which is likely responsible for the severe clinical features observed in the patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel mutation in the EDAR gene causes severe autosomal recessive hypohidrotic ectodermal dysplasia. Henningsen, E., Svendsen, MT., Lildballe, DL., et al.[2020]

Agonist anti-EDAR monoclonal antibodies can effectively induce the formation of hair and sweat glands in EDA-deficient mice, demonstrating their potential as a treatment for X-linked hypohidrotic ectodermal dysplasia (XLHED).

These antibodies have a long half-life of about 11 days in adult mice and can revert ectodermal dysplasia features when administered in utero or at birth, suggesting they could be suitable for long-term therapeutic use across various vertebrate species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies. Kowalczyk, C., Dunkel, N., Willen, L., et al.[2021]

A novel missense mutation in the EDA1 gene was identified in a family from Yucatán, México, affecting seven men with hypohidrotic ectodermal dysplasia (HED), which is linked to the X-linked form of the disorder.

This study also uncovered new clinical signs of HED, such as short toes and plantar hyperkeratosis, which had not been previously reported, highlighting the variability of symptoms associated with this genetic condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel missense mutation in the EDA1 gene identified in a family with hypohidrotic ectodermal dysplasia. Pozo-Molina, G., Reyes-Reali, J., Mendoza-Ramos, MI., et al.[2015]

A novel mutation (c.593G>A, p. Gly198Glu) in the collagen domain of the ectodysplasin A (EDA) gene was identified as a cause of hypohidrotic ectodermal dysplasia (HED), affecting the receptor-binding activity of EDA and impairing NF-κB transcriptional activation.

Functional studies demonstrated that while the mutant EDA1 protein was secreted normally, it could not effectively bind to its receptor (EDAR), leading to the conclusion that mutations in the collagen domain of EDA disrupt critical signaling pathways involved in HED.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel mutation in the collagen domain of EDA results in hypohidrotic ectodermal dysplasia by impacting the receptor-binding capability. Liu, X., Zhao, Y., Zhu, J.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Future developments in XLHED treatment approaches. [2020]

4. China pubmed.ncbi.nlm.nih.gov

[Phenotypic and genetic analysis of a case with hypohidrotic ectodermal dysplasia due to Xq13.1 microdeletion]. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

A novel mutation in the EDAR gene causes severe autosomal recessive hypohidrotic ectodermal dysplasia. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Molecular and therapeutic characterization of anti-ectodysplasin A receptor (EDAR) agonist monoclonal antibodies. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Novel missense mutation in the EDA1 gene identified in a family with hypohidrotic ectodermal dysplasia. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

A novel mutation in the collagen domain of EDA results in hypohidrotic ectodermal dysplasia by impacting the receptor-binding capability. [2023]