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Oral Trofinetide Treats Core Symptoms of Rett Syndrome: Presented at EAN

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June 24th, 2015

Tags: Conference Dispatch
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By Chris Berrie

BERLIN -- June 24, 2015 -- Patients with the neurodevelopmental disorder known as Rett syndrome may experience significant benefits in core symptoms with oral trofinetide, according to results of a phase 2 study presented here on June 21 at the First Congress of the European Academy of Neurology (EAN).

Trofinetide, a synthetic analogue of the terminal tripeptide of insulin-like growth factor-1, also appears to be safe and well tolerated in this population.

Children with Rett syndrome -- caused mainly (95%) by a mutation in the MECP2gene on the X chromosome -- appear to undergo initial normal development, until a period of regression characterised by systemic and neurological signs, particularly the loss of spoken communication and purposeful use of the hands, stereotypic hand movements during wakefulness, and abnormal gait.

This study provides initial evidence that trofinetide may be an effective drug for treating the clinical features of Rett syndrome, stated Daniel Glaze, MD, Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas.

Dr. Glaze and colleagues randomised 56 adolescent and adult females with Rett syndrome and MECP2 gene mutation to either placebo (n = 20), trofinetide at 35 mg/kg twice daily orally (n = 18), or trofinetide at 70 mg/kg twice daily orally (n = 17), for 14 or 28 days.

Mean baseline characteristics were similar across these 3 treatment groups: age 25.3 years, Rett Clinical Severity Scale (CSS) score 23.9, and Clinical Global Impression (CGI)-Severity score 5.1.

The potential benefits of trofinetide treatment were determined according to 4 efficacy domains: clinician-completed syndrome-specific measures (Rett syndrome Motor Behaviour Assessment [MBA], Rett CSS) and global measures (CGI of Improvement [CGI-I]); caretaker-completed syndrome-specific and general measures (Caretaker Top 3 Concerns and Aberrant Behaviour Checklist); and physiologic measures (modified Apnoea Index).

For the modified intention-to-treat patient group (n = 55), the researchers observed evidence of efficacy with the higher trofinetide dose of 70 mg/kg twice daily, according to prespecified criteria for the core efficacy measures, as the least squares mean changes from baseline to Day 26.

Trofinetide at 70 mg/kg twice daily promoted significant improvements in change from baseline for MBA change index (-0.6 vs -2.0; P< .05), Caretaker Top 3 Concerns change (-23 vs -62; P< .05), and subject-level efficacy score change (1.5 vs 2.7; P< .05). The absolute CGI-I score also improved, although as it was not measured at baseline, the absolute measure was given (3.64 vs 3.25; P< .05).

The Aberrant Behaviour Checklist, CSS, and modified Apnoea Index did not meet the improvement criteria compared with placebo, but met prespecified criteria for no clinically significant worsening.

For the safety analysis, based on adverse events, parent reports, electrocardiograms, physical examinations and laboratory analyses, Dr. Glazer said, “[Trofinetide] at both doses was well tolerated, without any significant adverse side effects -- neither dose-related, nor time-related.”

Funding for this study was provided by Neuren Pharmaceuticals, Camberwell, Victoria, Australia.

[Presentation title: The Treatment of Rett Syndrome with NNZ-2566. Abstract O2107]