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

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

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

Study Overview

• Status: Completed
• Conditions: Phelan-McDermid 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 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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

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 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 dose for 13 weeks.	Drug: NNZ-2591; NNZ-2591 oral solution (50mg/mL) to be administered twice daily dose 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 - Mean AUC24	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.	Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.
Pharmacokinetic - t1/2	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.	Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.

Secondary Outcome Measures

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2022
• Primary Completion (Actual): November 1, 2023
• Study Completion (Actual): November 17, 2023

Study Registration Dates

• First Submitted: August 24, 2021
• First Submitted That Met QC Criteria: August 24, 2021
• First Posted (Actual): August 27, 2021

Study Record Updates

• Last Update Posted (Actual): June 3, 2025
• Last Update Submitted That Met QC Criteria: June 1, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Phelan-McDermid Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Disease; Congenital Abnormalities; Chromosome Aberrations; Monosomy; Aneuploidy; Syndrome; Chromosome Disorders; Chromosome Deletion
• Other Study ID Numbers: NEU-2591-PMS-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