An Open-Label Study of Oral NNZ-2591 in Pitt Hopkins Syndrome (PTHS-001)

Phase 2

Completed

• Conditions: Pitt Hopkins Syndrome
• Interventions: Drug: NNZ-2591

• Registration Number: NCT05025332
• 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 Pitt Hopkins 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 Pitt Hopkins 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: 2022-10-14
• Primary Completion: 2024-02-27
• Study Completion: 2024-05-03
• Results First Submitted: 2025-01-08
• Status Verified: 2025-05
• Results First Submitted QC: 2025-05-04
• Last Update Submitted: 2025-05-04
• Results First Posted: 2025-05-18
• Last Update Posted: 2025-05-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

1. Clinical diagnosis of PTHS with a documented disease-causing genetic etiology for the disorder.
2. Males or females aged 3-17 years.
3. Body weight of 12kg 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, 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 - Typical AUC24 of 30 kg Child	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 pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose at Weeks 2, 6, and 13. The overall exposure parameters for NNZ-2591, such as maximum concentration (Cmax) and area under the curve over 24 hours (AUC24), were derived using population PK modeling. Additionally, the dataset and subsequent model were supplemented with healthy volunteer and Phase 2 data from other studies. Subject-level concentration-time profiles were simulated to estimate individual PK exposure parameters (e.g., Cmax and AUC). The PK results represent model-derived exposure values.
Pharmacokinetic - Typical t1/2 in 30 kg Child	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 pre-dose, 1-3 hours post-dose, and/or 4-7 hours post-dose at Weeks 2, 6, and 13. The overall exposure parameters for NNZ-2591, such as maximum concentration (Cmax) and area under the curve over 24 hours (AUC24), were derived using population PK modeling. Additionally, the dataset and subsequent model were supplemented with healthy volunteer and Phase 2 data from other studies. Subject-level concentration-time profiles were simulated to estimate individual PK exposure parameters (e.g., Cmax and AUC). The PK results represent model-derived exposure values.

Secondary Outcome Measures

Name	Time	Method
Pitt Hopkins Syndrome-specific Clinical Global Impression Scale (CGI-I) - Overall Improvement	CGI-I was assessed at weeks 6, 13/EOT & 15. Overall improvement scores relate to week 13/EOT visit.	Pitt Hopkins Syndrome-specific Clinical Global Impression Scale (CGI-I) - Overall Improvement. Score on a Likert scale (1-7) where lower scores are better.
Caregiver Impression of Improvement: Overall Score	CIC was assessed at Week13/EOT	Caregiver Impression of Improvement: Overall Score. Measured on a 7 point Likert scale (1-7) where lower scores are better.
Pitt Hopkins Syndrome-specific Clinical Global Impression Scale - Severity (CGI-S) - Overall Score	Change in score assessed from baseline (visit 3, week 0) to visit 16 (week 13/EOT).	Pitt Hopkins syndrome-specific Clinical Global Impression Scale - Severity (CGI-S) - Change from baselines on overall Score based on a 7 point Likert scale (1-7) where lower scores are better.
Caregiver Top 3 Concerns	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in average concern severity.	Caregiver Top 3 Concerns: Change from baseline in Average Concern Severity. The average concern severity defined as the average of the severity scores for the three concerns evaluated at a given visit, and was calculated as long as at least one concern was useable for analysis at the visit. Scores range from 0 - 10 with higher scores indicating greater concern severity. A negative change from baseline indicates improvement.
MacArthur-Bates Communicative Development Inventory (MB-CDI)	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13).	MacArthur-Bates Communicative Development Inventory (MB-CDI): Words Understood Domain. Scores ranges from 0-396, with higher scores indicating greater language ability. A positive change from baseline indicates improvement.
Observer-Reported Communication Ability (ORCA)	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in Total Score.	Observer-Reported Communication Ability (ORCA): Change from baseline in Modified t-score. The ORCA measures an individual's communication abilities based on observations made by caregivers, parents, or other relevant observers, and is based on 4 domains: Expressive Communication, Receptive Communication, Social Communication, and Pragmatic Language Skills.; Scores range from 25.8 - 83.8, with higher scores indicating greater communication ability. A positive change from baseline indicates improvement. A T-score standardizes the individual's performance relative to a normative sample. It typically has a mean of 50 and a standard deviation of 10.; T score = 50 + 10 × (X-µ)/σ Where: X is the individual's raw score μ is the population mean σ is the standard deviation
Aberrant Behavior Checklist-2 (ABC-2)	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in total score.	Aberrant Behavior Checklist-2 (ABC-2): Change from baseline in Total Score. Range of scores is 0-174, with higher scores indicating more behavioral issues. A negative change from baseline indicates improvement.
CSHQ	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in total score.	Child Sleep Habits Questionnaire (CSHQ). Total Score. Change from baseline. Range of scores was (33-99) with higher scores being worse.
GIHQ	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in total frequency score.	Gastrointestinal Health Questionnaire (GIHQ). Change from baseline in total frequency score. Range of scores was (0-197) with higher scores being worse.
Vineland Adaptive Behavior Scales-3, Interview Version	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in composite standard score.	Vineland Adaptive Behavior Scales-3 (VABS-3), Interview version, Change from baseline in Adaptive Behavior Composite Standard Score. Scores range from 20 - 140 with higher scores indicating greater functional abilities. A positive change from baseline indicates improvement.
Modified Two-minute Walk Test	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in distance travelled on two minute walk test.	Modified two-minute walk test. Change from baseline in distance travelled (m) on 2 minute walk test. The test was only administered for participants who were ambulatory and able to complete the assessment. A positive score on change from baseline indicates improvement in distance walked.
QI-Disability	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in overall score score.	Quality of Life Inventory-Disability (QI-Disability). Overall Score change from baseline. Scores range from 0 - 100 with higher scores indicating better quality of life. A positive change from baseline indicates improvement.
ICND	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in overall quality of life rating score.	Impact of Childhood Neurological Disability (ICND)-Overall quality of life rating, change from baseline. Score ranges from 1 - 6, with a higher score indicating better quality of life. A positive change from baseline indicates improvement.
Behavior Problems Inventory - Short Form	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in Total Frequency score.	Change from baseline in Behavior Problems Inventory - Short Form Total Frequency Score. Scores range from 0-120, with higher scores indicating greater frequency in behavior problems. A negative change from baseline indicates improvement.
Bayley Scales of Infant Development (BSID-4): Non Verbal Development Quotient (NVDQ)	Change from baseline (visit 3, week 0) to visit 16/EOT (week 13) in NVDQ score.	Change from baseline in Non Verbal Development Quotient (NVDQ). Scores range from 40 - 160, with higher scores indicating greater development. A positive change from baseline indicates improvement.

Trial Locations

Locations (5)

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

University of California at San Francisco; 🇺🇸 San Francisco, California, United States

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

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

UT Southwestern; 🇺🇸 Dallas, Texas, United States