An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome (AS-001)

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

Study Overview

• Status: Completed
• Conditions: Angelman Syndrome
• Intervention / Treatment: Drug: NNZ-2591

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Centre for Clinical Trials in Rare Neurodevelopmental Disorders at Children's Health Queensland Hospital and Health Service
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 13 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Clinical diagnosis of AS with a documented disease-causing genetic etiology known to impact maternally derived UBE3A expression in brain.
2. Males or females aged 3-17 years
3. Body Weight of >12Kg
4. Subjects with a Clinical Global Impression - Severity (CGI-S) score of 3 or greater
5. 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
6. Each subject must be able to swallow the study medication provided as a liquid solution.
7. Caregiver(s) must have sufficient English language skills.

Exclusion Criteria:

1. Mosaicism for disease-causing mutation.
2. Clinically Significant abnormalities in safety laboratory testing or vital signs at screening
3. Abnormal QTcF interval or prolongation at Screening.
4. Positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and previous COVID 19 infection with last 12 months that required hospitalization.
5. Unstable or changes to Psychotropic treatment 2 weeks prior to screening .
6. Excluded concomitant treatments
7. Actively undergoing regression or loss of skills.
8. Unstable seizure profile.
9. Current clinically significant renal conditions and abnormalities
10. Current clinically significant cardiovascular, hepatic, gastrointestinal, respiratory, endocrine disease, or clinically significant organ impairment.
11. 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.
12. Has planned surgery during the study.
13. History of, or current, cerebrovascular disease or brain trauma.
14. History of, or current catatonia or catatonia-like symptoms.
15. History of, or current, malignancy.
16. Current major or persistent depressive disorder (including bipolar depression).
17. Significant, uncorrected visual or uncorrected hearing impairment.
18. Allergy to strawberry.
19. Positive pregnancy test
20. Subject is judged by the Investigator or Medical Monitor to be inappropriate for the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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 - Typical t1/2 in 30 kg Child	Apparent terminal elimination half-life of NNZ-2591	13 weeks
Pharmacokinetic - Typical AUC24 of 30kg Child	Area under the concentration-time curve of NNZ-2591 over 24 hours	13 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory efficacy measurement	Assessed by Bayley Scales of Infant Development-4, Vineland Motor subscales	13 weeks
Angelman syndrome-specific Clinical Global Impression Scale-Overall Improvement (CGI-I)	Assessed by Angelman syndrome-specific Clinical Global Impression Scale-Overall Improvement (CGI-I). Score on a Likert scale (1-7) where lower scores are better	13 weeks
Caregiver Impression of Improvement : Overall Score	Caregiver Impression of Improvement: Overall Score. Measured on a 7-point Likert scale (1-7) where lower scores are better.	13 weeks
Angelman syndrome-specific Clinical Global Impression Scale - Severity (CGI-S): Overall Score	Angelman syndrome-specific Clinical Global Impression Scale-Severity (CGI-S): Change from baseline on overall score based on a 7-point Likert scale (1-7) where lower scores are better.	13 weeks
Angelman syndrome Clinician Domain Specific Rating Scale (AS-DSRS)	Angelman syndrome Clinician Domain Specific Rating Scale (AS-DSRS). Change from baseline in total score based on a 5-point Likert scale (0-4) where lower scores are better.	13 weeks
Caregiver Top 3 Concerns	Caregiver Top 3 Concerns: Change from baseline in Average Concerns Severity.	13 weeks
MacArthur-Bates Communicative Development Inventory (MB-CDI)	MacArthur-Bates Communicative Development Inventory (MB-CDI)	13 weeks
Observer-Reported Communication Ability (ORCA)	Observer-Reported Communication Ability (ORCA). Change from baseline in modified t-score. Scores range from 25.8 - 83.8 with higher scores indicating greater communication abililty. A positive change from baseline indicates improvement	13 weeks
Aberrant Behavior Checklist-2 (ABC-2)	Aberrant Behavior Checklist-2 (ABC-2) - Change from baseline in total score. Higher scores indicate more behavioral issues. A negative change from baseline indicates improvement.	13 weeks
Child Sleep Habits Questionnaire (CSHQ)	Child Sleep Habits Questionnaire (CSHQ). Change from baseline in total score. Range of scores was (33-99) with higher scores being worse	13 weeks
Gastrointestinal Health Questionnaire (GIHQ)	Gastrointestinal Health Questionnaire (GIHQ)	13 weeks
Vineland Adaptive Behavior Scales-3, Interview version	Vineland Adaptive Behavior Scales-3, Interview version; Composite standard score	13 weeks
Quality of Life Inventory-Disability (QI-Disability)	Quality of Life Inventory-Disability (QI-Disability). Change from baseline inoverall score. Scores range from 0-100 with higher scores indicating better quality of life. A positive change indicates improvement	13 weeks
Impact of Childhood Neurological Disability (ICND)	Impact of Childhood Neurological Disability (ICND): Change from baseline in overall quality of life rating. Scores range from 1-6, with a higher score indicating better quality of life. A positive change from baseline indicates improvement	13 weeks

Collaborators and Investigators

• Sponsor: Neuren Pharmaceuticals Limited
• Investigators: Study Director: James Shaw, Neuren Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2022
• Primary Completion (Actual): May 13, 2024
• Study Completion (Actual): July 16, 2024

Study Registration Dates

• First Submitted: August 5, 2021
• First Submitted That Met QC Criteria: August 13, 2021
• First Posted (Actual): August 18, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 29, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Angelman Syndrome
• Additional Relevant MeSH Terms: Imprinting Disorders; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Genetic Diseases, Inborn; Disease; Congenital Abnormalities; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Syndrome; Angelman Syndrome
• Other Study ID Numbers: NEU-2591-AS-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No