Trial Outcomes & Findings for An Open-Label Study of Oral NNZ-2591 in Pitt Hopkins Syndrome (PTHS-001) (NCT NCT05025332)

Participants were recruited based on physician referral at 5 academic medical centers between August 2022 and December 2023

Following completion of informed consent, participants (28) underwent 4 weeks of baselining/screening. During this process 12 participants failed screening. The remaining 16 participants commenced treatment.

Participants who could not be assessed on the Stanford-Binet Intelligence (SB-5) due to their developmental level were assessed using the Bayley Scales of Infant Development instead.

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.