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

Holm Schneider, Smail Hadj-Rabia, Florian Faschingbauer, Christine Bodemer, Dorothy K Grange, Mary E Norton, Riccardo Cavalli, Gianluca Tadini, Holger Stepan, Angus Clarke, Encarna Guillén-Navarro, Sigrun Maier-Wohlfart, Athmane Bouroubi, Florence Porte, Holm Schneider, Smail Hadj-Rabia, Florian Faschingbauer, Christine Bodemer, Dorothy K Grange, Mary E Norton, Riccardo Cavalli, Gianluca Tadini, Holger Stepan, Angus Clarke, Encarna Guillén-Navarro, Sigrun Maier-Wohlfart, Athmane Bouroubi, Florence Porte

Abstract

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls.

Keywords: anhidrosis; clinical trial; ectodermal dysplasia; ectodysplasin A; fetal therapy; protein replacement; sweat glands.

Conflict of interest statement

Holm Schneider is inventor on a patent related to the prenatal treatment of XLHED. He signed, however, a Remuneration Waiver Agreement with the Free State of Bavaria to relinquish any personal financial gain from this invention. A.B. is an employee of Pierre Fabre Médicament, F.P. is an employee of the Esperare Foundation. The other authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Ultrasound-guided injection of the study drug into the amniotic cavity. Advancement of the needle must be continuously visualised. In this image, the needle tip (white) is located correctly in the amniotic fluid (black) underneath the placenta.

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Source: PubMed

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