An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome

Study Overview
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Brief Summary
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A study of the safety, tolerability and pharmacokinetics of NNZ-2591 and measures of efficacy in children and adolescents with Angelman syndrome

Detailed Description
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The primary purpose of this study is to investigate the safety, tolerability and pharmacokinetics of treatment with NNZ-2591 oral solution, 50mg/L, in children and adolescents with Angelman syndrome. The secondary purpose is to investigate measures of efficacy of subjects will receive treatment of 50mg/mL orally administered NNZ-2591 for a total of 13 weeks

Official Title
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An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome

Conditions
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Angelman Syndrome

Intervention / Treatment
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* Drug: NNZ-2591


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of AS with a documented disease-causing genetic etiology known to impact maternally derived UBE3A expression in brain. Males or females aged 3-17 years Body Weight of >12Kg Subjects with a Clinical Global Impression - Severity (CGI-S) score of 3 or greater Not actively undergoing regression or loss of skills, defined as no persistent loss of previously acquired developmental skills for a period within 3 months of the Screening visit Each subject must be able to swallow the study medication provided as a liquid solution. Caregiver(s) must have sufficient English language skills. Exclusion Criteria: Mosaicism for disease-causing mutation. Clinically Significant abnormalities in safety laboratory testing or vital signs at screening Abnormal QTcF interval or prolongation at Screening. Positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and previous COVID 19 infection with last 12 months that required hospitalization. Unstable or changes to Psychotropic treatment 2 weeks prior to screening . Excluded concomitant treatments Actively undergoing regression or loss of skills. Unstable seizure profile. Current clinically significant renal conditions and abnormalities Current clinically significant cardiovascular, hepatic, gastrointestinal, respiratory, endocrine disease, or clinically significant organ impairment. Current clinically significant hypo or hyperthyroidism, Type 1 or Type 2 diabetes mellitus requiring insulin (whether well controlled or uncontrolled), or uncontrolled Type 1 or Type 2 diabetes. Has planned surgery during the study. History of, or current, cerebrovascular disease or brain trauma. History of, or current catatonia or catatonia-like symptoms. History of, or current, malignancy. Current major or persistent depressive disorder (including bipolar depression). Significant, uncorrected visual or uncorrected hearing impairment. Allergy to strawberry. Positive pregnancy test Subject is judged by the Investigator or Medical Monitor to be inappropriate for the study

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NNZ-2591<br>NNZ-2591 oral solution (50mg/mL) to be administered twice daily dose for 13 weeks. | Drug: NNZ-2591<br>* NNZ-2591 oral solution (50mg/mL) to be administered twice daily for 13 weeks.<br>* Other names: Cyclo-L-Glycyl-L-2-Allylproline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | To examine the incidence, severity and frequency of adverse events (AEs), including serious adverse events (SAEs) during treatment with NNZ-2591. | 13 weeks | 
| Pharmacokinetic - Measurement of Cmax | Maximum observed concentration (Cmax) of NNZ-2591 | 13 weeks | 
| Pharmacokinetic - Measurement of AUC | Area under the concentration-time curve of NNZ-2591 | 13 weeks | 
| Pharmacokinetic - Measurement of time to Cmax | Time to Cmax of NNZ-2591 | 13 weeks | 
| Pharmacokinetic - Measurement of t1/2 | Apparent terminal elimination half-life of NNZ-2591 | 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exploratory efficacy measurement | Assessed by Angelman syndrome-specific Clinical Global Impression Scale-Overall Improvement (CGI-I) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Caregiver Impression of Change | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Angelman syndrome-specific Clinical Global Impression Scales-Domain Improvement | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Angelman syndrome-specific Clinical Global Impression Scale-Severity (CGI-S)-Overall and Domain | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Angelman syndrome Clinician Domain Specific Rating Scale (AS-DSRS) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Caregiver Top 3 Concerns Likert Scale | 13 weeks | 
| Exploratory efficacy measurement | Assessed by MacArthur-Bates Communicative Development Inventory (MB-CDI) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Observer-Reported Communication Ability (ORCA) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Aberrant Behavior Checklist-2 (ABC-2) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Child Sleep Habits Questionnaire (CSHQ) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Gastrointestinal Health Questionnaire (GIHQ) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Vineland Adaptive Behavior Scales-3, Interview version | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Bayley Scales of Infant Development-4, Vineland Motor subscales | 13 weeks | 
| Exploratory efficacy measurement | Caregiver Diaries | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Quality of Life Inventory-Disability (QI-Disability) | 13 weeks | 
| Exploratory efficacy measurement | Assessed by Impact of Childhood Neurological Disability (ICND)-Overall quality of life rating | 13 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angelman Syndrome