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

To examine the incidence, severity and frequency of adverse events (AEs), including serious adverse events (SAEs) during treatment with NNZ-2591.

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.

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.

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. 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) - 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 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): 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 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 in Total Score. Range of scores is 0-174, with higher scores indicating more behavioral issues. A negative change from baseline indicates improvement.

Child Sleep Habits Questionnaire (CSHQ). Total Score. Change from baseline. Range of scores was (33-99) with higher scores being worse.

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 (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 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.

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.

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.

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.

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.