ER004 for Hypohidrotic Ectodermal Dysplasia

(EDELIFE Trial)

Recruiting at 10 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether ER004 (Ectodysplasin 1 protein replacement therapy) can help unborn boys with a rare genetic condition called XLHED. XLHED can cause fewer teeth, reduced sweat, and issues with hair and skin. The trial aims to assess the safety and effectiveness of ER004 when administered before birth. It seeks pregnant women who carry the EDA gene mutation and have an unborn male diagnosed with XLHED. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

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

Is there any evidence suggesting that ER004 is likely to be safe for humans?

Research has shown that ER004, a treatment for X-linked hypohidrotic ectodermal dysplasia (XLHED), is promising in terms of safety. ER004 is a protein replacement therapy that mimics the natural protein missing in individuals with this condition. In earlier trials, newborns with XLHED received ER004, and no serious safety issues emerged.

Although ER004 is not yet approved, the current Phase 2 trial is evaluating both its safety and effectiveness. Being in Phase 2 indicates that earlier studies have generally found ER004 to be safe for humans. However, as with any clinical trial, side effects or risks may still occur. Researchers closely monitor participants to ensure their safety throughout the study. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard of care for Hypohidrotic Ectodermal Dysplasia, which typically involves symptomatic treatments like dental care, skin moisturizers, and cooling strategies, ER004 offers a novel approach by addressing the condition at a molecular level. ER004 is unique because it uses a fusion protein that combines a human immunoglobulin G1 constant region with the human ectodysplasin-A1 receptor binding domain. This innovative mechanism targets the underlying cause of the disorder rather than just managing symptoms, which is why researchers are excited about its potential to offer more effective, long-term benefits for patients.

What evidence suggests that ER004 might be an effective treatment for Hypohidrotic Ectodermal Dysplasia?

Research has shown that ER004, the treatment under study in this trial, is a promising option for X-linked Hypohidrotic Ectodermal Dysplasia (XLHED). This condition often causes issues like reduced sweating, which can lead to dangerous overheating. ER004 replaces a missing protein called Ectodysplasin 1 (EDA1), crucial for normal sweat gland development. Early results suggest that ER004 can help restore the function of these glands. Studies indicate that the treatment is safe and has the potential to greatly improve the quality of life for those with XLHED. ^{4 6 7 8 9}

Who Is on the Research Team?

Holm Schneider, MD

Principal Investigator

University Erlangen-Nürnberg Erlangen, Germany

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36672894/

Protocol for the Phase 2 EDELIFE Trial Investigating ... A prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration.

2. esperare.org esperare.org/en/er-004-programme-x-linked-hypohidrotic-ectodermal-dysplasia-xlhed

ER-004 Programme in X-Linked Hypohidrotic Ectodermal ... ER-004 is a pioneering protein replacement therapy. ER-004 acts as a substitute for endogenous Ectodysplasin 1 protein, EDA1.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9858920/

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

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04980638

NCT04980638 | Intraamniotic Administrations of ER004 to ... The aim of this prospective, open-label, genotype-match controlled, multicenter Phase 2 trial is to confirm the efficacy and safety results for ER004 ...

5. klein.ucsf.edu klein.ucsf.edu/sites/kleinlab.ucsf.edu/files/2020_korber_br_j_clin_pharmacol.pdf

Safety and immunogenicity of Fc‐EDA, a recombinant ... The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7495278/

Safety and immunogenicity of Fc‐EDA, a recombinant ... The severe hypohidrosis common to X‐linked hypohidrotic ectodermal dysplasia patients may lead to life‐threatening hyperthermia, especially during hot weather ...

7. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bcp.14301

Safety and immunogenicity of Fc‐EDA, a recombinant ... The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01775462

NCT01775462 | Phase 2 Study to Evaluate Safety, ... This Phase 2 first-in-neonate EDI200 study will enroll treatment-naïve, XLHED-affected male newborns in the first two weeks of life.

9. edinetwork.org edinetwork.org/wp-content/uploads/2023/03/Schneider-et-al_Genes-2023-1.pdf

Protocol for the Phase 2 EDELIFE Trial Investigating the ... This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls. Keywords: ectodermal dysplasia; ...