An Open-Label Study of Oral NNZ-2591 in Phelan-McDermid Syndrome (PMS-001)

Phase 2

Completed

• Conditions: Phelan-McDermid Syndrome
• Interventions: Drug: NNZ-2591

• Registration Number: NCT05025241
• Lead Sponsor: Neuren Pharmaceuticals Limited

Brief Summary

A study of the safety, tolerability and pharmacokinetics of NNZ-2591 and measures of efficacy in children and adolescents with Phelan-McDermid Syndrome.

Detailed Description

The primary purpose of this study is to investigate the safety, tolerability and pharmacokinetics of treatment with NNZ-2591 oral solution in children and adolescents with Phelan-McDermid Syndrome. The secondary purpose is to investigate measures of efficacy. Subjects will receive treatment with NNZ-2591 oral solution (50 mg/mL) doses for a total of 13 weeks.

Study Timeline

• Study First Submitted: 2021-08-24
• Study First Submitted QC: 2021-08-24
• Study First Posted: 2021-08-27
• Study Start: 2022-08-08
• Primary Completion: 2023-11-01
• Study Completion: 2023-11-17
• Disposition First Submitted: 2024-10-31
• Results First Submitted: 2024-12-11
• Results First Submitted QC: 2025-05-28
• Results First Posted: 2025-05-30
• Disposition First Posted: 2025-05-30
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-01
• Last Update Posted: 2025-06-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

1. Clinical diagnosis of PMS with a documented disease-causing genetic abnormality of SHANK3.
2. Males or females aged 3-12 years.
3. Body weight of 12 kg or higher at Screening.
4. Subjects with a Clinical Global Impression - Severity (CGI-S) score of 4 or greater at the Screening visit.
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. Body weight < 12kg at screening
2. Clinically significant abnormalities in safety laboratory tests and vital signs at Screening.
3. Abnormal QTcF interval or prolongation at Screening.
4. Any other clinically significant finding on ECG at the Screening visit.
5. Positive for severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) and previous COVID 19 infection with last 12 months that required hospitalization
6. Unstable or changes Psychotropic treatment 2 weeks prior to screening .
7. Excluded concomitant treatments.
8. Actively undergoing regression or loss of skills.
9. Unstable seizure profile.
10. Current clinically significant renal conditions and abnormalities
11. Current clinically significant cardiovascular, renal, hepatic, gastrointestinal, respiratory, endocrine disease, or clinically significant organ impairment.
12. 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.
13. Has planned surgery during the study.
14. History of, or current, cerebrovascular disease or brain trauma.
15. History of, or current catatonia or catatonia-like symptoms.
16. History of, or current, malignancy.
17. Current major or persistent depressive disorder (including bipolar depression).
18. Significant, uncorrected visual or uncorrected hearing impairment.
19. Allergy to strawberry.
20. Positive pregnancy test
21. Subject is judged by the Investigator or Medical Monitor to be inappropriate for the study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
NNZ-2591	NNZ-2591	NNZ-2591 oral solution (50mg/mL) to be administered twice daily dose for 13 weeks.

Primary Outcome Measures

Name	Time	Method
Safety and Tolerability	13 weeks	To examine the incidence, severity and frequency of adverse events (AEs), including serious adverse events (SAEs) during treatment with NNZ-2591.
Pharmacokinetic - Mean AUC24	Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.	Approximately nine sparse pharmacokinetic (PK) samples were collected from each participant under steady-state conditions. These samples were taken at pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose during Weeks 2, 6, and 13. The individual pharmacokinetic parameters for NNZ-2591, including half-life (t1/2) and area under the curve over 24 hours (AUC24), were derived using subject-level concentration-time profiles from the study population model.
Pharmacokinetic - t1/2	Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.	Approximately nine sparse pharmacokinetic (PK) samples were collected from each participant under steady-state conditions. These samples were taken at pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose during Weeks 2, 6, and 13. The individual pharmacokinetic parameters for NNZ-2591, including half-life (t1/2) and area under the curve over 24 hours (AUC24), were derived using subject-level concentration-time profiles from the study population model.

Secondary Outcome Measures

Name	Time	Method
CIC	CIC was assessed at Week13/EOT	Caregiver Impression of Improvement: Measured on a 7 point Likert scale (1-7) where lower scores are better.
CGI-I	CGI-I was assessed at Weeks 6, 13/EOT & 15. Overall improvement scores relate to Week 13/EOT visit.	Phelan-McDermid Syndrome-specific Clinical Global Impression of Improvement Scale (CGI-I) - Overall Improvement Score on a 7 point Likert scale (1-7) where lower scores are better.
Top 3 Concerns	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall improvement score.	Caregiver Top 3 Concerns - Total Concerns Severity: Change from baseline. The range of scores was (0-30) for total concerns, with higher scores being worse
MB-CDI	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16).	MacArthur-Bates Communicative Development Inventory (MB-CDI) - change from baseline. Range of scores was (0-792) with higher scores being better.
CGI-S	Change in score assessed from baseline (visit 3, week 0) to visit 16 (week 13/EOT).	Phelan-McDermid 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 a lower score is better.
ORCA	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in Total Score.	Observer-Reported Communication Ability (ORCA) - Change from baseline in Total Score. Range of Scores was (25.8-83.8) with higher scores being better
ABC-2	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score.	Aberrant Behavior Checklist-2 (ABC-2) - Total score: Change from baseline. Range of scores was (0-174) with higher scores being worse
CSHQ	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score.	Child Sleep Habits Questionnaire (CSHQ) - Change from baseline in Total Score. Range of scores was (33-99) with higher scores being worse.
GIHQ	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score.	Gastrointestinal Health Questionnaire (GIHQ) - Total Frequency Score: Change from Baseline. Range of scores was (0-212) with higher scores being worse.
VABS-3	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in composite standard score.	Vineland Adaptive Behavior Scales-3, Change from baseline in Composite Standard Score. Range of scores was (20-140) with higher scores being better.
QL-Disability	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall score score.	Quality of Life Inventory-Disability (QL-Disability) Overall Score - change from baseline. Range of scores was (0-100) with higher scores being better.
ICND	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall quality of life rating score.	Impact of Childhood Neurological Disability (ICND) - Change from baseline in overall quality of life rating. Range of (1- 6) for quality of life rating, with higher scores indicating greater impact.
PMS-DSRS	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall severity score.	PMS Clinician Domain Specific Rating Scale - Change from baseline in overall severity score. Range of Scores Was (0-20) With Higher Scores Being Worse.
Behavior Problems Inventory - Short Form	Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score.	Total Frequency Score - Change from Baseline. Range of scores was (0-4) for each of 30 behaviors, total range (0-120), with lower scores being better.

Trial Locations

Locations (4)

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Texas Children's Hospital; 🇺🇸 Houston, Texas, United States