Trial Outcomes & Findings for An Open-Label Study of Oral NNZ-2591 in Phelan-McDermid Syndrome (PMS-001) (NCT NCT05025241)

NCT ID: NCT05025241

Last Updated: 2025-06-03

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

18 participants

Primary outcome timeframe

13 weeks

Results posted on

2025-06-03

Participant Flow

Participants were recruited based on physician referral at 4 academic medical centers between August 2022 and June 2023. The first participant entered screening on 08 August 2022, and the last participant entered screening on 22 June 2023. Of 23 consented participants, 18 met eligibility criteria and were enrolled into the study. Enrolled participants received NNZ2591 12 mg/kg by liquid oral dose twice daily

Following consent, participants underwent 4 weeks of screening for eligibility. If successful, participants were enrolled and commenced open-label active treatment.

Participant milestones

Participant milestones
Measure
NNZ-2591
All enrolled participants
Screening
STARTED
23
Screening
COMPLETED
18
Screening
NOT COMPLETED
5
Treatment and Follow Up
STARTED
18
Treatment and Follow Up
COMPLETED
15
Treatment and Follow Up
NOT COMPLETED
3

Reasons for withdrawal

Reasons for withdrawal
Measure
NNZ-2591
All enrolled participants
Screening
Failed Screening
5
Treatment and Follow Up
Adverse Event
3

Baseline Characteristics

Only 2 participants recorded seizures at enrollment

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
NNZ-2591
n=18 Participants
All enrolled participants
Age, Continuous
8.6 years
STANDARD_DEVIATION 2.7 • n=18 Participants
Sex: Female, Male
Female
6 Participants
n=18 Participants
Sex: Female, Male
Male
12 Participants
n=18 Participants
Race/Ethnicity, Customized
Race : White
16 Participants
n=18 Participants
Race/Ethnicity, Customized
Race : Black or African American
1 Participants
n=18 Participants
Race/Ethnicity, Customized
Race : Asian
0 Participants
n=18 Participants
Race/Ethnicity, Customized
Race : Native Hawaiian or other Pacific Islander
0 Participants
n=18 Participants
Race/Ethnicity, Customized
Race : American Indian or Alaska Native
0 Participants
n=18 Participants
Race/Ethnicity, Customized
Race : Multi Racial
1 Participants
n=18 Participants
Race/Ethnicity, Customized
Race : Other
0 Participants
n=18 Participants
Race/Ethnicity, Customized
Ethnicity : Hispanic or Latino
3 Participants
n=18 Participants
Race/Ethnicity, Customized
Ethnicity : Not Hispanic or Latino
15 Participants
n=18 Participants
Height (cm)
130.6 cm
STANDARD_DEVIATION 15.15 • n=18 Participants
Weight (kg)
30.4 kg
STANDARD_DEVIATION 10.75 • n=18 Participants
BMI (kg/m^2)
17.4 kg/m^2
STANDARD_DEVIATION 3.48 • n=18 Participants
PMS Genotype
Terminal Deletion - Class I
7 Participants
n=18 Participants
PMS Genotype
Terminal Deletion - Class II
3 Participants
n=18 Participants
PMS Genotype
Ring 22
0 Participants
n=18 Participants
PMS Genotype
Unbalanced Translocation
0 Participants
n=18 Participants
PMS Genotype
Interstitial Deletion
1 Participants
n=18 Participants
PMS Genotype
SHANK 3 variant/mutation
6 Participants
n=18 Participants
PMS Genotype
Other
1 Participants
n=18 Participants
History of regression
Yes
11 Participants
n=18 Participants
History of regression
No
7 Participants
n=18 Participants
Autism Mental Status Exam
7.8 score on a scale
STANDARD_DEVIATION 2.05 • n=18 Participants
Seizure Types
Simple Partial
0 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Complex Partial
1 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Atonic
1 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Tonic
1 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Clonic
0 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Tonic-Clonic
1 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Myoclonic
0 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Absence/Atypical Absence
0 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Not Actual Seizure/Spells
0 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Types
Other
1 Participants
n=2 Participants • Only 2 participants recorded seizures at enrollment
Seizure Characteristics at baseline
Change in awareness
2 participants
n=18 Participants
Seizure Characteristics at baseline
Loss of urine or bowel control
0 participants
n=18 Participants
Seizure Characteristics at baseline
Loss of ability to communicate
2 participants
n=18 Participants
Seizure Characteristics at baseline
Automatic repeated movements
0 participants
n=18 Participants
Seizure Characteristics at baseline
Rhythmic jerking muscle
2 participants
n=18 Participants
Seizure Characteristics at baseline
Falls if sitting or standing
0 participants
n=18 Participants
Seizure Characteristics at baseline
Head drops
1 participants
n=18 Participants
Seizure Characteristics at baseline
Warning before seizure occurred
0 participants
n=18 Participants
Seizure Characteristics at baseline
Common triggers
0 participants
n=18 Participants
Seizure Characteristics at baseline
Muscle stiffness
1 participants
n=18 Participants
Seizure Characteristics at baseline
Muscle twitch
1 participants
n=18 Participants
Seizure Characteristics at baseline
Other
1 participants
n=18 Participants
Stanford-Binet Intelligence Scale (NVIQ) Standard Score
47.7 score on a scale
STANDARD_DEVIATION 5.39 • n=9 Participants • Participants who could not be assessed on the Stanford-Binet Intelligence (SB-5) due to their developmental level were assessed using the Mullen Scales of Early Learning instead.
Stanford-Binet Intelligence Scale (NVIQ) z deviation score
40.9 score on a scale
STANDARD_DEVIATION 17.2 • n=9 Participants • Participants who could not be assessed on the Stanford-Binet Intelligence (SB-5) due to their developmental level were assessed using the Mullen Scales of Early Learning instead.
Mullen Scales of Early Learning Non-Verbal Developmental Quotient Score
15.7 score on a scale
STANDARD_DEVIATION 7.25 • n=8 Participants • Includes only participants who were unable to be assessed on the Stanford-Binet Intelligence (SB-5) due to their developmental level.
Presence of co-morbid psychiatric disorders
Autism Spectrum Disorder (ASD)
14 participants
n=18 Participants
Presence of co-morbid psychiatric disorders
BiPolar Disorders
0 participants
n=18 Participants
Presence of co-morbid psychiatric disorders
Attention Deficit Disorder
5 participants
n=18 Participants
Presence of co-morbid psychiatric disorders
Obsessive Compulsive Disorder
0 participants
n=18 Participants
Presence of co-morbid psychiatric disorders
Other
1 participants
n=18 Participants

PRIMARY outcome

Timeframe: 13 weeks

Population: Intention to treat population

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

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
Safety and Tolerability
Participants with any AE
17 Participants
Safety and Tolerability
Participants with TEAE
17 Participants
Safety and Tolerability
Participants with Serious TEAE
1 Participants
Safety and Tolerability
Participants who discontinued due to TEAE
3 Participants
Safety and Tolerability
Participants with mild TEAE
11 Participants
Safety and Tolerability
Participants with moderate TEAE
5 Participants
Safety and Tolerability
Participants with severe TEAE
1 Participants

PRIMARY outcome

Timeframe: Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.

Population: PK Population

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.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
Pharmacokinetic - Mean AUC24
411 µg.h/mL
Standard Deviation 116

PRIMARY outcome

Timeframe: Pre-dose, 1-3 h post-dose and/or 4-7 h post-dose at Weeks 2, 6 and 13.

Population: All participants enrolled in this study who receive the study drug through to the morning dose of Week 2 (Visit 5) as a minimum, and who undergo PK sample collection at least one of the specified post-dose time point(s).

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.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
Pharmacokinetic - t1/2
8.02 hours
Standard Deviation 2.33

SECONDARY outcome

Timeframe: CGI-I was assessed at Weeks 6, 13/EOT & 15. Overall improvement scores relate to Week 13/EOT visit.

Population: Intention to treat

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.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
CGI-I
2.4 score on a scale
Standard Deviation 0.86

SECONDARY outcome

Timeframe: CIC was assessed at Week13/EOT

Population: Intention to treat population

Caregiver Impression of Improvement: Measured on a 7 point Likert scale (1-7) where lower scores are better.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
CIC
2.7 score on a scale
Standard Deviation 1.02

SECONDARY outcome

Timeframe: Change in score assessed from baseline (visit 3, week 0) to visit 16 (week 13/EOT).

Population: Intention to treat

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.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
CGI-S
-0.4 score on a scale
Standard Deviation 0.5

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall improvement score.

Population: Intention to treat population

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

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
Top 3 Concerns
-5.9 score on a scale
Standard Deviation 5.86

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16).

Population: Intention to treat population

MacArthur-Bates Communicative Development Inventory (MB-CDI) - change from baseline. Range of scores was (0-792) with higher scores being better.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
MB-CDI
12.3 score on a scale
Standard Deviation 35.19

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in Total Score.

Population: Intention to treat population

Observer-Reported Communication Ability (ORCA) - Change from baseline in Total Score. Range of Scores was (25.8-83.8) with higher scores being better

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
ORCA
1.9 score on a scale
Standard Deviation 4.22

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score.

Population: Intention to treat population

Aberrant Behavior Checklist-2 (ABC-2) - Total score: Change from baseline. Range of scores was (0-174) with higher scores being worse

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
ABC-2
-17.2 score on a scale
Standard Deviation 19.65

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total score.

Population: Intention to treat population

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

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
CSHQ
-3.6 score on a scale
Standard Deviation 5.68

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score.

Population: Intention to treat population

Gastrointestinal Health Questionnaire (GIHQ) - Total Frequency Score: Change from Baseline. Range of scores was (0-212) with higher scores being worse.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
GIHQ
-9.6 score on a scale
Standard Deviation 10.8

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in composite standard score.

Population: Intention to treat population

Vineland Adaptive Behavior Scales-3, Change from baseline in Composite Standard Score. Range of scores was (20-140) with higher scores being better.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
VABS-3
2.8 score on a scale
Standard Deviation 7.82

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall score score.

Population: Intention to treat population

Quality of Life Inventory-Disability (QL-Disability) Overall Score - change from baseline. Range of scores was (0-100) with higher scores being better.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
QL-Disability
6.1 score on a scale
Standard Deviation 8.91

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall quality of life rating score.

Population: Intention to treat population

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.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
ICND
0.3 score on a scale
Standard Deviation 0.69

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in overall severity score.

Population: Intention to treat population

PMS Clinician Domain Specific Rating Scale - Change from baseline in overall severity score. Range of Scores Was (0-20) With Higher Scores Being Worse.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
PMS-DSRS
-0.9 score on a scale
Standard Deviation 1.69

SECONDARY outcome

Timeframe: Change from baseline (visit 3, week 0) to visit 13/EOT (week 16) in total frequency score.

Population: Intention to treat population

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.

Outcome measures

Outcome measures
Measure
NNZ-2591
n=18 Participants
All enrolled participants
Behavior Problems Inventory - Short Form
-5.1 score on a scale
Standard Deviation 9.41

Adverse Events

NNZ-2591

Serious events: 1 serious events
Other events: 17 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
NNZ-2591
n=18 participants at risk
All enrolled participants
Gastrointestinal disorders
Gastroenteritis
5.6%
1/18 • Number of events 1 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.

Other adverse events

Other adverse events
Measure
NNZ-2591
n=18 participants at risk
All enrolled participants
Gastrointestinal disorders
Constipation
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Gastrointestinal disorders
Diarrhea
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Gastrointestinal disorders
Nausea
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Gastrointestinal disorders
Vomiting
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
General disorders
Fatigue
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
General disorders
Pyrexia
16.7%
3/18 • Number of events 3 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Infections and infestations
Covid 19
16.7%
3/18 • Number of events 3 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Infections and infestations
Nasopharyngitis
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Infections and infestations
Otitis Media
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Metabolism and nutrition disorders
Decreased appetite
16.7%
3/18 • Number of events 3 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Nervous system disorders
Psychomotor Hyperactivity
22.2%
4/18 • Number of events 4 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Nervous system disorders
Somnolence
16.7%
3/18 • Number of events 3 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Psychiatric disorders
Aggression
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Psychiatric disorders
Insomnia
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.
Respiratory, thoracic and mediastinal disorders
Rhinorrhea
11.1%
2/18 • Number of events 2 • 15 weeks for each participant starting on date of first dose
Once eligibility was confirmed, subjects were dosed at a starting dose of 4 mg/kg twice daily (BID). Doses were titrated to 8 mg/kg at week 2 and to 12 mg/kg at week 6. The mg/kg dosing was based on the subject's weight at baseline. Subjects received treatment with NNZ-2591 for a total of 13 weeks.

Additional Information

Chief Medical Officer

Neuren Pharmaceuticals

Phone: +61 (3) 9092 0480

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place

Restriction type: LTE60