Edimer Pharmaceuticals is developing EDI200, a fully humanized recombinant protein, as a novel therapy for patients with XLHED. XLHED is a rare genetic disorder of ectoderm (prevalence of 1-10 per 100,000 male births) associated with an elevated mortality risk of 2-27% due to diminished or absent sweat glands leading to severe hyperthermia, and diminished secretory gland function predisposing to abnormal mucous and clinically significant pneumonias. Other XLHED characteristics are missing and misshapen teeth, and sparse or missing hair. XLHED is caused by mutations in the ectodysplasin gene (EDA) that disrupt the synthesis of the signaling molecule EDA-A1. Early neonatal treatment of XLHED affected mice and dogs with the EDA-A1 replacement molecule EDI200 activates these latent developmental pathways, resulting in a safe, significant and sustained correction of the phenotype. Following a 2012 Phase 1 safety study in XLHED-affected adults, a safety/pharmacodynamics study (ECP-002) was begun in XLHED-affected neonates to demonstrate safety and tolerability in this vulnerable population and to assess early signs of bioactivity that may be predictive of clinical efficacy (currently enrolling, treatment initiated). The proposed extension study ECP-002e will monitor all ECP-002 patients with the important goals of demonstrating a clinically-significant and sustained correction of the XLHED phenotype along with ongoing documentation of long-term safety. The investigators will perform yearly safety and age-appropriate pharmacodynamic/efficacy evaluations of overall growth and development, fever, heat tolerance, dentition, sweat gland density, hair growth, skin, pulmonary and ocular health as well as craniofacial development and exercise thermoregulation. Immunogenicity testing will also be performed at 2 years of age. The information generated, being the first multi-year assessment of EDI200 treatment in XLHED-affected neonates, will provide options for subsequent studies in either the antenatal setting (Phase 2) or a pivotal Phase 3 study in neonates. Demonstration of the safety and efficacy of EDI200 treatment in the proposed extension study ECP-002e addresses a critical barrier to progress in the field by providing a replacement therapy option to a patient population whose current treatment is restricted to palliative steps such as keeping cool, monitoring for infections including painful skin conditions such as eczema, painful surgical fitting for dentures as early as ages 2 to 3 years and monitoring for sufficient nutrition intake.
The goal of the research pertaining to this application is the correction of symptoms of a genetic disorder that according to the FDA and the European Medicines Agency (EMA) is a significant unmet medical need, namely, an X-linked form of hypohidrotic ectodermal dysplasia (XLHED or Christ-Siemens-Touraine syndrome; OMIM 305100), that without treatment typically results in diminished or absent sweat and secretory gland function, craniofacial anomalies resulting in psychosocial problems, missing and misshapen teeth, and sparse or missing hair in 1-10 per 100,000 male births (3,10). Chronically debilitating and life-threatening symptoms emerge in the first years of life as hyperthermia secondary to hypohidrosis, sparse hair, a predisposition to respiratory infections, and marked oligodontia (1,3,4,6,12,14). There currently exists no preventative/ replacement therapy for this disease such as the one proposed in this application; instead patients are restricted to palliative steps to keep cool (wear cooling vests, spray themselves with water, limit physical activity, etc.), are monitored closely for infections including painful skin conditions such as eczema, wear dentures as early as ages 2-3 or undergo many difficult surgeries to receive dental implants (9), and are monitored for sufficient nutrition intake.
