WASHINGTON, DC—A new investigational drug for Rett syndrome is well tolerated and may provide clinical benefit, according to a presentation at the 67th Annual Meeting of the American Academy of Neurology. Currently, no therapy is approved for the treatment of Rett syndrome, a genetic disorder involving neurodevelopmental impairment and dysfunction of the autonomic and central nervous systems.
Daniel Glaze, MD, Medical Director of the Blue Bird Circle Rett Center at the Baylor College of Medicine in Houston, described results of a Phase II, randomized, double-blind, placebo-controlled, dose-escalation study of NNZ-2566 in two cohorts of females between ages 16 and 45 with late-stage Rett syndrome. NNZ-2566 is a synthetic analog of a terminal tripeptide derived from insulin-like growth factor 1 (IGF-1) that has demonstrated neuroprotective and neurorestorative effects in a wide range of animal models, including brain injury and Fragile X syndrome. In an animal model study of Rett syndrome (MECP2-knockout mouse), NNZ-2566 restored the loss of long-term potentiation in the hippocampus, enhanced dendritic growth, and improved longevity, thus supporting the potential application of the drug to treat patients with Rett syndrome.
A total of 56 participants in the current trial were randomized to receive either 35 mg/kg (ie, a low dose) of NNZ-2566, 70 mg/kg (ie, a high dose) of NNZ-2566, or placebo twice daily for 28 days. Clinical efficacy was determined using a combination of clinician and caregiver scores in six core measures across four efficacy domains. Improvement in at least two core measures from two different domains, without any worsening demonstrated in other core measures, was required to establish efficacy for group analysis. Subject-specific scores also were used to measure individual improvements. Efficacy on the subject level analysis was shown if the mean of individual scores for the treatment group was greater than that of the placebo group. Overall efficacy for the study was demonstrated if improvement was shown on at least the group or subject level analysis according to the above criteria, and if the other analysis showed at least numerical superiority of treatment over placebo.
“The higher dose exceeded the prespecified criteria for improvement in core efficacy measures, demonstrating clinical benefit in three of six core areas of measurement,” Dr. Glaze reported. The 70-mg/kg dose was associated with mean improvement in core measurement scores for the Motor-Behavior Assessment Change Index, the Clinical Global Impression of Improvement, and the Caregiver Top 3 Concern instruments, which was better than placebo. The higher NNZ-2566 dose also showed no worsening in any core measurement end point. Clinical benefit also was demonstrated in the subject-level analysis.
“Although improvement occurred with the lower dose, relative to placebo, it did not meet the targets described in the study statistical analysis plan,” Dr. Glaze said. Both doses were well tolerated. No significant adverse events related to the drug occurred during the treatment phase. These findings support further study of NNZ-2566 for the treatment of Rett syndrome, Dr. Glaze concluded, adding that if approved, the drug would become the first treatment available for this disease.