Intrauterine therapy showed promise in XLHED

Intra-amniotic therapy with a novel recombinant protein enabled three patients with X-linked hypohidrotic ectodermal dysplasia (XLHED) to sweat normally, researchers reported.

For up to 22 months of postnatal follow-up, patients had no hyperthermia and were not hospitalized for respiratory reasons, reported Holm Schneider, MD, of the University of Erlangen-Nürnberg, Erlangen, Germany, and his associates. Treatment may have induced premature delivery at 33 weeks of a pair of twins, although most twins are born preterm, they noted. “Combined with the ability to identify affected fetuses through noninvasive sonographic prenatal screening, the approach we describe here represents a new means of protein-replacement therapy to correct XLHED,” they wrote online April 25 in the New England Journal of Medicine.

XLHED is caused by loss-of-function variants of the gene encoding ectodysplasin A (EDA). The investigational recombinant fusion protein Fc-EDA (EDI200) developed by Edimer Pharmaceuticals, which contains the receptor-binding domain of EDA and the Fc domain of human immunoglobulin G1, has shown no signs of toxicity in nonhuman primates. In prior studies, its intra-amniotic infusion prevented XLHED in EDA-deficient murine fetuses, while human postnatal Fc-EDA therapy was ineffective (NCT01775462).

Based on these data, University Hospital Erlangan approved a parental request for compassionate use of Fc-EDA in male twin fetuses with genetic deficiency of EDA. Treatment (100 mg/kg estimated fetal body weight) occurred at gestational weeks 26 and 31. Despite premature delivery at 33 weeks, 5-minute Apgar scores were 9 for one twin and 10 for the other. Cord blood testing detected Fc-EDA, suggesting its continuous uptake into fetal blood. The twins both had normal sweat-duct density, sweated as much as healthy controls, salivated normally, and had 8-10 tooth germs; their 5-year-old brother with XLHED had only three teeth and one tooth germ.

Parents of another EDA-deficient fetus also requested compassionate use of Fc-EDA, which was administrated as a single dose (because of limited supply) at gestational week 26. Birth occurred at week 39 and Apgar scores all were 10s. Sweat pore density was slightly low, compared with healthy controls, and by age 4 months, the patient had developed moderate urticaria pigmentosa.

In all cases, maternal circulation showed no trace of Fc-EDA within 24 hours of treatment.

Funders included Edimer Pharmaceuticals, Deutsche Forschungsgemeinschaft, Swiss National Science Foundation, the German-Swiss-Austrian ectodermal dysplasia patient organization, and the National Foundation for Ectodermal Dysplasias. Three of the investigators have either patents issued or patents pending related to the treatment, one is an employee of Edimer Pharmaceuticals, and two have grants from some of the abovementioned companies or organizations.
 

SOURCE: Schneider H et al. N Engl J Med. 2018 Apr 25. doi: 10.1056/NEJMoa1714322.

Intra-amniotic therapy with a novel recombinant protein enabled three patients with X-linked hypohidrotic ectodermal dysplasia (XLHED) to sweat normally, researchers reported.

For up to 22 months of postnatal follow-up, patients had no hyperthermia and were not hospitalized for respiratory reasons, reported Holm Schneider, MD, of the University of Erlangen-Nürnberg, Erlangen, Germany, and his associates. Treatment may have induced premature delivery at 33 weeks of a pair of twins, although most twins are born preterm, they noted. “Combined with the ability to identify affected fetuses through noninvasive sonographic prenatal screening, the approach we describe here represents a new means of protein-replacement therapy to correct XLHED,” they wrote online April 25 in the New England Journal of Medicine.

XLHED is caused by loss-of-function variants of the gene encoding ectodysplasin A (EDA). The investigational recombinant fusion protein Fc-EDA (EDI200) developed by Edimer Pharmaceuticals, which contains the receptor-binding domain of EDA and the Fc domain of human immunoglobulin G1, has shown no signs of toxicity in nonhuman primates. In prior studies, its intra-amniotic infusion prevented XLHED in EDA-deficient murine fetuses, while human postnatal Fc-EDA therapy was ineffective (NCT01775462).

Based on these data, University Hospital Erlangan approved a parental request for compassionate use of Fc-EDA in male twin fetuses with genetic deficiency of EDA. Treatment (100 mg/kg estimated fetal body weight) occurred at gestational weeks 26 and 31. Despite premature delivery at 33 weeks, 5-minute Apgar scores were 9 for one twin and 10 for the other. Cord blood testing detected Fc-EDA, suggesting its continuous uptake into fetal blood. The twins both had normal sweat-duct density, sweated as much as healthy controls, salivated normally, and had 8-10 tooth germs; their 5-year-old brother with XLHED had only three teeth and one tooth germ.

Parents of another EDA-deficient fetus also requested compassionate use of Fc-EDA, which was administrated as a single dose (because of limited supply) at gestational week 26. Birth occurred at week 39 and Apgar scores all were 10s. Sweat pore density was slightly low, compared with healthy controls, and by age 4 months, the patient had developed moderate urticaria pigmentosa.

In all cases, maternal circulation showed no trace of Fc-EDA within 24 hours of treatment.

Funders included Edimer Pharmaceuticals, Deutsche Forschungsgemeinschaft, Swiss National Science Foundation, the German-Swiss-Austrian ectodermal dysplasia patient organization, and the National Foundation for Ectodermal Dysplasias. Three of the investigators have either patents issued or patents pending related to the treatment, one is an employee of Edimer Pharmaceuticals, and two have grants from some of the abovementioned companies or organizations.
 

SOURCE: Schneider H et al. N Engl J Med. 2018 Apr 25. doi: 10.1056/NEJMoa1714322.

Intra-amniotic therapy with a novel recombinant protein enabled three patients with X-linked hypohidrotic ectodermal dysplasia (XLHED) to sweat normally, researchers reported.

For up to 22 months of postnatal follow-up, patients had no hyperthermia and were not hospitalized for respiratory reasons, reported Holm Schneider, MD, of the University of Erlangen-Nürnberg, Erlangen, Germany, and his associates. Treatment may have induced premature delivery at 33 weeks of a pair of twins, although most twins are born preterm, they noted. “Combined with the ability to identify affected fetuses through noninvasive sonographic prenatal screening, the approach we describe here represents a new means of protein-replacement therapy to correct XLHED,” they wrote online April 25 in the New England Journal of Medicine.

XLHED is caused by loss-of-function variants of the gene encoding ectodysplasin A (EDA). The investigational recombinant fusion protein Fc-EDA (EDI200) developed by Edimer Pharmaceuticals, which contains the receptor-binding domain of EDA and the Fc domain of human immunoglobulin G1, has shown no signs of toxicity in nonhuman primates. In prior studies, its intra-amniotic infusion prevented XLHED in EDA-deficient murine fetuses, while human postnatal Fc-EDA therapy was ineffective (NCT01775462).

Based on these data, University Hospital Erlangan approved a parental request for compassionate use of Fc-EDA in male twin fetuses with genetic deficiency of EDA. Treatment (100 mg/kg estimated fetal body weight) occurred at gestational weeks 26 and 31. Despite premature delivery at 33 weeks, 5-minute Apgar scores were 9 for one twin and 10 for the other. Cord blood testing detected Fc-EDA, suggesting its continuous uptake into fetal blood. The twins both had normal sweat-duct density, sweated as much as healthy controls, salivated normally, and had 8-10 tooth germs; their 5-year-old brother with XLHED had only three teeth and one tooth germ.

Parents of another EDA-deficient fetus also requested compassionate use of Fc-EDA, which was administrated as a single dose (because of limited supply) at gestational week 26. Birth occurred at week 39 and Apgar scores all were 10s. Sweat pore density was slightly low, compared with healthy controls, and by age 4 months, the patient had developed moderate urticaria pigmentosa.

In all cases, maternal circulation showed no trace of Fc-EDA within 24 hours of treatment.

Funders included Edimer Pharmaceuticals, Deutsche Forschungsgemeinschaft, Swiss National Science Foundation, the German-Swiss-Austrian ectodermal dysplasia patient organization, and the National Foundation for Ectodermal Dysplasias. Three of the investigators have either patents issued or patents pending related to the treatment, one is an employee of Edimer Pharmaceuticals, and two have grants from some of the abovementioned companies or organizations.
 

SOURCE: Schneider H et al. N Engl J Med. 2018 Apr 25. doi: 10.1056/NEJMoa1714322.