Prader-Willi syndrome (PWS) is a rare genetic condition caused by loss of function in the 15q11-q13 region on the paternal copy of chromosome 15. Approximately 70% of cases are caused by deletion of a segment of the paternal copy of chromosome 15 and approximately 25% by duplication of the maternal copy of chromosome 15. PWS affects both males and females and can affect individuals of any ethnic or racial background, with an estimated incidence of between 1:10,000 and 1:30,000. PWS is associated with a constellation of symptoms that significantly negatively impact upon quality of life for affected individuals and their families.
PWS is characterised by early failure to thrive followed by the onset of insatiable hunger, which frequently results in obesity, type 2 diabetes, and metabolic syndrome. Additional characteristics include multiple endocrine abnormalities, hypotonia, hypogonadism, sleep disturbances, a challenging neurobehavioral phenotype, self-injurious behavior, mild to moderate intellectual and learning disabilities, and distinctive facial features. Growth hormone deficiency is reported to occur in 40-100% of patients and dysregulation of the growth hormone-IGF-1 axis is considered to be universal, with sub-normal serum IGF-1 levels.
NNZ-2591 was tested in the Magel2-null mouse model, which mimic the behavior and metabolic profile of Prader-Willi syndrome in humans. The study compared normal mice ("wild type") and Magel2-null mice. In the Magel2-null mice, treatment with NNZ-2591 for 6 weeks normalised all behavioral deficits. After treatment with the high dose of NNZ-2591 the fat mass, insulin levels and circulating IGF-1 levels of the Magel2-null mice were indistinguishable from wild type mice. The Magel2-null mice treated with the low dose of NNZ-2591 showed partial reversion to normal levels.
Neuren has been granted Orphan Drug designation by the US Food and Drug Administration (FDA) for NNZ-2591 to treat PWS and is preparing for a Phase 2 clinical trial.