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

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.

Start Date26 Apr 2022

Sponsor / Collaborator

EspeRare Foundation

[+2]

NCT01992289

/ Active, not recruitingNot Applicable

Extension Study of XLHED-Affected Male Subjects Treated With EDI200 in Protocol ECP-002

The goal of the ECP-002e extension study is to continue the evaluation of all EDI200-treated ECP-002 subjects up to age 10 yrs. No additional study drug administration is planned. The efficacy evaluations will incorporate growth and development parameters, frequency of infections and hospitalizations, and age-appropriate assessments of ectoderm-derived organ function. The safety evaluations will include physical examinations, adverse events and concomitant medication documentation, and laboratory testing. Funding Source - FDA OOPD

Start Date01 Mar 2014

Sponsor / Collaborator

Edimer Pharmaceuticals, Inc.

NCT01775462

/ CompletedPhase 2

A Phase 2 Open-label, Dose-escalation Study to Evaluate the Safety, Pharmacokinetics, Immunogenicity and Pharmacodynamics/Efficacy of EDI200, an EDA-A1 Replacement Protein, Administered to Male Infants With X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

This Phase 2 first-in-neonate EDI200 study will enroll treatment-naïve, XLHED-affected male newborns in the first two weeks of life. All subjects will meet entry criteria including documentation of an Ectodysplasin (EDA) mutation associated with XLHED. Following Baseline evaluations, EDI200 dosing will be initiated between day-of-life 2 and 14, with each study subject receiving 2 doses/week for a total of 5 doses. The study will enroll subjects in two cohorts with subjects in cohort 1 dosed at 3 mg/kg/dose, associated with partial efficacy, and cohort 2 dosed at 10 mg/kg/dose where enhanced efficacy was demonstrated in the most relevant preclinical model. Given the challenge of identifying families where the subject is yet to be born, it is expected that cohort size and time for recruitment will be variable.

Start Date01 Apr 2013

Sponsor / Collaborator

Edimer Pharmaceuticals, Inc.

100 Clinical Results associated with Efsudenermin alfa

100 Translational Medicine associated with Efsudenermin alfa

100 Patents (Medical) associated with Efsudenermin alfa

Literatures (Medical) associated with Efsudenermin alfa

01 Oct 2020·British Journal of Clinical PharmacologyQ2 · MEDICINE

Safety and immunogenicity of Fc‐EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects

Q2 · MEDICINE

Article

Author: Clarke, Angus ; Maitz, Silvia ; Huttner, Kenneth ; Durand, Caroline ; Körber, Iris ; Faschingbauer, Florian ; Morhart, Patrick ; Klein, Ophir D. ; Schneider, Holm ; Kirby, Neil ; Bodemer, Christine ; Grange, Dorothy K.

In X‐linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X‐linked hypohidrotic ectodermal dysplasia patients may lead to life‐threatening hyperthermia, especially during hot weather or febrile illness. Fc‐EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc‐EDA and efficacy if applied prenatally. Anti‐drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc‐EDA was delivered intra‐amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc‐EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.

01 Sep 2019·The Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Prenatal Treatment of X-Linked Hypohidrotic Ectodermal Dysplasia Using Recombinant Ectodysplasin in a Canine Model

Q3 · MEDICINE

Article

Author: Schneider, Holm ; Houser, Timothy P ; Casal, Margret L ; Grove, Gary L ; Wildman, Lee ; Margolis, Carol A ; Schneider, Pascal ; Kirby, Neil ; Huttner, Kenneth

X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.

01 Dec 2014·Journal of Investigative DermatologyQ1 · MEDICINE

Prenatal Therapy in Developmental Disorders: Drug Targeting via Intra-Amniotic Injection to Treat X-Linked Hypohidrotic Ectodermal Dysplasia

Q1 · MEDICINE

Letter

Author: Krieg, Peter ; Schneider, Holm ; Huttner, Kenneth ; Hermes, Katharina ; Schneider, Pascal ; Dang, AnhThu

TO THE EDITOR Pathologies associated with genodermatoses and other genetic disorders can irremediably affect fetuses, making early-stage therapies desirable.Prenatal maternal drug administration, however, exposes mothers to potential drug toxicity and is limited by the variability in transplacental drug delivery.Alternative approaches to fetal treatment should entail low-risk drug delivery with reproducible pharmacokinetics.X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common inherited disorder of ectoderm development, is caused by a lack of the signaling mol. ectodysplasin A1 (EDA1), which is essential for ectodermal placode formation and subsequent development of various skin appendages, glands, and teeth (Mikkola, 2009).Patients with XLHED have less hair, fewer or no eccrine sweat, sebaceous and meibomian glands, and malformed or absent teeth.Insufficient thermoregulation can lead to perilous hyperthermic episodes during infancy (Bluschke et al., 2010) and remains an important issue throughout life (Hammersen et al., 2011).Many affected individuals suffer from recurrent airway and eye problems (Dietz et al., 2013).To date, only symptomatic treatment is available for these patients.Causative therapeutic approaches to such disorders are expected to be most effective if applied already in utero, with the addnl. benefit that immune tolerance of a replacement protein may be induced, facilitating postnatal reapplication (Schneider et al., 2002; Waddington et al., 2003).In the Tabby mouse, a well-characterized animal model of XLHED (Falconer, 1952), prenatal exposure to EDA1 via serial i.v. administrations to the dam corrected developmental abnormalities to a far greater extent compared with postnatal administration (Gaide and Schneider, 2003).This approach may, however, be suboptimal for achieving reproducible therapeutic drug concentrations in human fetuses, and would expose the mother to high serum levels of an exogenous mol.We hypothesized that EDI200, an EDA1 replacement protein consisting of the receptor-binding domain of EDA1 and the Fc part of IgG1, may enter the fetal circulation also after injection into the amniotic fluid (AF), because the fetus swallows AF regularly and the neonatal Fc receptor, which is present in rodent and human fetal intestine (Shah et al., 2003), may facilitate intestinal absorption of Fc-containing proteins.AF could thus serve as a drug reservoir and provide for continuous drug uptake.Here, we report striking reversal of the XLHED phenotype of Tabby mice following a single intra-amniotic injection of EDI200.Long-term stability of this recombinant protein in AF, i.e. the retention of binding to its cognate receptor, was confirmed in vitro under various conditions (Supplementary Figure S1 online).Pharmacokinetics following intra-amniotic injection of 35 μg EDI200 per amniotic sac (=100 μg g^-1 of estimated fetal body weight) was studied in wild-type mice at day 15 of gestation (E15).All maternal animals and 93% of the treated fetuses survived the procedure.EDI200 serum levels were measured at different time points after injection both in treated and untreated fetuses as well as in the dams.Intra-amniotic injection of EDI200 resulted in mean fetal serum levels of 9.0 and 1.2 μg ml^-1 at 6 and 96 h, resp.After 6 h, this corresponds to 180 ng of EDI200 per fetus or 0.5% of the injected protein, assuming a total serum volume of approx. 20 μl in an E15 mouse fetus.Interestingly, there was a low level of EDI200 transfer into the circulation of untreated siblings and that of the pregnant dam (Figure 1).The drug was partially and slowly redistributed from treated fetuses, in which EDI200 concentration diminished over time, to untreated siblings that witnessed a parallel increase in the serum levels (up to 0.57 μg ml^-1).Maternal EDI200 serum levels remained <0.1 μg ml^-1 at the time points investigated.Thus, intra-amniotic administration of EDI200 at E15 resulted in substantial fetal uptake with minimal maternal exposure.This approach was then evaluated in pregnant Tabby mice with doses of 100, 10, and 1 μg g^-1 of estimated fetal body weightThe surgical procedure was conducted under isofluran anesthesia plus perioperative analgesia with metamizole and was approved by the local government authorities.All treated Tabby mouse fetuses of the high and intermediate dose cohorts survived the E15 intra-amniotic injection and were born without complications.They were easily distinguishable from native Tabby mice already in the second week after birth.Later, normal eye opening, retro-auricular and guard hair as in wild-type mice, and a normally shaped tail tip (Figure 2a and b) were evident.Starch-iodine tests revealed regular sweat production at the paws (Figure 2c-e).Normal eccrine sweat glands (Figure 2f-h) were detected in footpads of these animals.In addition, size and shape of the molars resembled those of wild-type mice (Figure 2i-k).Thus, in contrast to a single maternal i.v. injection of 400 μg of EDI200 in pregnant Tabby mice at E15, which corrected the XLHED phenotype in the offspring only partially (unpublished own data), a single intra-amniotic dose of 3.5 μg or above resulted in complete phenotypic correction.No adverse effects were observedAll treated Tabby mice survived to adulthood and showed normal behavior and fertility.The lower dose of 1 μg g^-1 body weight yielded only a partial restoration of normal ectoderm development, with less guard and/or tail hair and fewer sweat glands present (Supplementary Table S1 online).Interestingly, but less relevant to human singleton gestations, a dose-dependent correction was also observed for untreated littermates (Supplementary Table S1 online)-explained by partial leakage of the drug to neighboring fetuses.As expected from previous studies (Gaide and Schneider, 2003), the maternal Tabby phenotype was not visibly altered by EDI200 administration, regardless of the dose.All dams remained fertile and no adverse effects of the treatment could be detected during an observation period of 6-9 mo.The EDA1 signaling pathway is well conserved among vertebrates (Pantalacci et al., 2008) and findings in animal models should therefore be transferable to human XLHED patients.Early corrective treatment would increase their life expectancy, would have a high impact on the quality of life, and substantially reduce medical expenses.Intra-amniotic drug delivery might be most beneficial if attempted during mid-gestation, when sweat gland development is not yet completed (Ersch and Stallmach, 1999).This approach is likely to have a good benefit/risk ratio, supported by the broad experience with amniocentesis, and may represent a novel paradigm for treatment of disorders in early human development.

News (Medical) associated with Efsudenermin alfa

07 Jul 2024

·esperare.org

EspeRare renews hope for children suffering from a disabling skin disease

EspeRare is currently looking to re-launch the development of ER004 (formerly known as EDI200) as a treatment for babies affected by X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED). XLHED is a serious rare disease that is life-threatening, ... Read More EspeRare is currently looking to re-launch the development of ER004 (formerly known as EDI200) as a treatment for babies affected by X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED). XLHED is a serious rare disease that is life-threatening, particularly in the first years of life. Infants affected by this genetic disorder cannot sweat and are at risk of sudden death due to hyperthermia and severe respiratory issues. See here for more information on the disease. ER004 is the first and only therapy for this disease. ER004 was developed until 2015 by Edimer Pharmaceuticals (US). Unfortunately its development was stalled following a clinical setback as the treatment, when administered to newborn babies, did not seem to provide therapeutic benefits. In the meantime, Prof. Holm Schneider, a German medical expert, renewed hope for XLHED patients. When he administered ER004 in-utero to 3 babies (including Maarten & Linus, the babies in the picture), he could show that these patients were subsequently able to sweat normally. These results highlight the strong potential for this therapy, when administered during pregnancy, to address the most debilitating aspects of XLHED. See here for more information on Maarten and Linus. Using Prof. Holm Schneider’s promising new in-utero approach, EspeRare is now restarting the development of this promesing therapy. Currently, the main hurdle to overcome is to find the right regulatory and funding path forward. Once those challenges are addressed, clinical development in Europe is set to restart as early 2018. Importantly and in-line with our patient-centered approach, EspeRare is partnering with XLHED patient associations, such as the American organisation NFED, to better understand the patients needs and their expectations from a therapy. See here for news from NFED. Together with our partners, we are working very hard to ensure a way forward for this ground-breaking treatment. We hope to be able to share more exciting news on this program soon!

12 Oct 2023

·esperare.org

HUG to Host Innovation Day on 19th October with a Keynote from EspeRare’s co-founder, Caroline Kant

EspeRare, a pioneer in prenatal treatment advancements, announces that its co-founder and executive director, Caroline Kant, will be featured as a keynote speaker at the Geneva University Hospitals (HUG) Innovation Day on October 19, 2023. The... Read More EspeRare, a pioneer in prenatal treatment advancements, announces that its co-founder and executive director, Caroline Kant, will be featured as a keynote speaker at the Geneva University Hospitals (HUG) Innovation Day on October 19, 2023. The spotlight of Caroline’s keynote will be "EspeRare: a collaborative model at the forefront of prenatal treatment." Attendees will be given an insightful glimpse into the groundbreaking work EspeRare is undertaking, particularly surrounding ER-004 in X-Linked ectodermal dysplasia. This program, rescued and championed by EspeRare, is poised to become the first-ever treatment that addresses a genetic disease before birth, setting a groundbreaking precedent in medical innovation and offering hope for countless genetic conditions with debilitating perinatal symptoms. About HUG Innovation Day The HUG Innovation Day, now in its 17th year, is a platform that showcases innovative health projects. As an established event, it gathers innovators, allowing them to network, exchange experiences, and present transformative ideas within the healthcare sphere. Awards, including the Innovation Award, a Jury’s Favorite, and audience-driven prize, will highlight the day’s presentations. A startup award will also aim to support the ambitions of emerging healthcare entrepreneurs. For those interested in attending or learning more about the HUG Innovation Day 2023, additional details can be found at: https://www.hug.ch/centre-linnovation/journee-linnovation-2023. For more about EspeRare and ER004 in XLHED, visit ER-004 Programme in X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED) | EspeRare Foundation

02 Feb 2023

·esperare.org

Pierre Fabre and EspeRare move forward a pioneering in-utero therapy for XLHED patients

When French pharma company, Laboratoires Pierre Fabre and Swiss not-for-profit organization, EspeRare, joined forces by the end of 2020, their goal was to develop a life-changing treatment for a debilitating rare disease, X-Linked Hypohidrotic Ectodermal Dysplasia, which affects approximately 1 in 25,000 live male births every year. “Currently, there are no therapeutic options for XLHED. Only the symptoms of the disease can be alleviated” – as Caroline Kant, CEO and co-founder of EspeRare and Caroline Miklaszewski, Project Director at Pierre Fabre, jointly stated. There is no doubt that the drug development in rare diseases is highly challenging but when two patient-centric organizations combine complementary expertise, the ground-breaking research and a novel therapeutic approach can see a daylight. ER-004, a pioneering in-utero protein replacement therapy, is currently being investigated in the EDELIFE clinical trial and if approved, it will become the first therapy to address a genetic condition before birth. To read the full article, please follow the link: Discovery & Development (themedicinemaker.com)

Clinical Study

100 Deals associated with Efsudenermin alfa

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Indication	Highest Phase	Country/Location	Organization	Date
Ectodermal Dysplasia 1, Anhidrotic	NDA/BLA	Italy	Edimer Pharmaceuticals, Inc.	01 Apr 2013
Ectodermal Dysplasia 1, Anhidrotic	NDA/BLA	Germany	Edimer Pharmaceuticals, Inc.	01 Apr 2013
Ectodermal Dysplasia 1, Anhidrotic	NDA/BLA	United Kingdom	Edimer Pharmaceuticals, Inc.	01 Apr 2013
Ectodermal Dysplasia 1, Anhidrotic	NDA/BLA	France	Edimer Pharmaceuticals, Inc.	01 Apr 2013
Ectodermal Dysplasia 1, Anhidrotic	NDA/BLA	United States	Edimer Pharmaceuticals, Inc.	01 Apr 2013
Ectodermal Dysplasia	Phase 2	-	Dermelix Biotherapeutics, LLC	-
Ectodermal Dysplasia	Phase 2	-	Apoxis SA	-

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