Final data from a phase 2 proof-of-concept trial investigating the oral drug NNZ-2566 as a treatment for Rett syndrome showed it was well tolerated and active. No approved treatments are available for Rett syndrome, a progressive neurodevelopment disorder found almost exclusively in girls. More than 20,000 females in the United States have Rett syndrome. The disorder causes slow head growth; frequent erratic hand movements; and severe impairment in speech, social interaction, and motor skills. It is also associated with breathing problems, seizures, gastrointestinal disturbances, autonomic dysfunction, irritability, and spasticity. Patients with late-stage Rett syndrome have diminished muscle strength and mobility and possible loss of speech.
Most cases of Rett syndrome are caused by a mutation in the methyl CpG binding protein 2 (MECP2
, prounced "meck-pea-two") gene located on the X chromosome. The mutation occurs spontaneously in 99% of patients and impairs synthesis of proteins essential for brain development. Severity of the syndrome depends on the percentage of cells that express normal MECP2
. Girls have two X chromosomes, making them more susceptible to developing Rett syndrome but also allowing them to produce enough cells with normal MECP2
to survive the disease's devastating effects. Boys, who have only one X chromosome, are unable to compensate for the mutated gene and usually die in early infancy.
The randomized, double-blind, placebo-controlled study enrolled 53 females aged 16 to 45 years with late-stage Rett syndrome. Participants in the 28-day trial were randomly assigned to receive 35 or 70 mg/kg twice daily of NNZ-2566 or placebo. Safety was the primary endpoint. Results have yet to be published, but in a press release, Neuren Pharmaceuticals said both doses of NNZ-2566 "were well tolerated after 28 days and no safety concerns were identified."
Study investigators also evaluated 6 core measures of efficacy across 4 domains, with clinical benefit defined as improvement in at least 2 core outcome measures from 2 different domains and no significant deterioration in any other core outcome. They found response was dose-dependent, with the 70 mg/kg twice daily dose of NNZ-2566 associated with improvement in more areas. For patients in the 70 mg/kg arm, mean improvement was observed in scores for the Motor-Behavior Assessment Change Index, Clinical Global Impression of Improvement, and Caregiver Top 3 Concern instruments. When they looked at efficacy on an individual basis across all 6 core outcomes, the higher NNZ-2566 dose was more effective than placebo and showed no worsening in any endpoint. Although improvement occurred with the lower dose relative to placebo, it did not meet the targets described in the study protocol.
Dr Alan Percy, Professor of Pediatrics, Neurology, Neurobiology, Genetics, and Psychology at the University of Alabama in Birmingham, was an investigator for the study. In an interview with Rare Disease Report
, he said:
"We believe that this short-term treatment provided evidence of improved communication, awareness, and motor performance that was supported by an improvement in quality of life [as reported] by the parents."
He cautioned that although the results are encouraging, "It is essential to conduct longer term studies in adults as well as conduct similar studies in younger individuals." Dr Percy said the investigators hope to begin additional studies in the coming year. They expect to publish results of the completed trial early in 2015.
NNZ-2566 is a synthetic analogue of a peptide derived from insulin-like growth factor 1 (IGF-1). The natural peptide, known as IGF-1[1-03], has neuroprotective effects, reducing levels of damaging cytokines and neuroinflammatory markers in response to brain injury. In preclinical studies, NNZ-2566 decreased the activity of microglial cells, which signal an immune response when brain tissue is damaged or infected. It also reduced levels of important inflammatory cytokines and normalized Akt and ERK activation.
A trial of NNZ-2566 is ongoing for patients with fragile X syndrome, another disease caused by a mutation of the X chromosome. Like Rett syndrome, fragile X syndrome produces neuroinflammation and alters synaptic connectivity. NNZ-2566 is also being evaluated in a government-sponsored phase 2 trial of patients with moderate to severe traumatic brain injury.
For more information about Rett syndrome and how it is diagnosed, visit Rettsyndrome.org, which sponsors research on Rett syndrome and helped fund the current trial.