Highlights: 

• Significant improvement was assessed by both clinicians and caregivers across multiple efficacy measures  
• Improvements were consistently seen across clinically important aspects of Phelan-McDermid syndrome, including communication, behaviour, cognition/learning and socialisation 
• Clinician and caregiver global efficacy measures showed a level of improvement typically considered clinically meaningful:

- Clinical Global Impression of Improvement (CGI-I) - mean score of 2.4, with 16 out of 18 children showing improvement assessed by clinicians

- Caregiver Overall Impression of Change (CIC) – mean score of 2.7, with 15 out of 18 children showing improvement assessed by caregivers

• For 10 out of 14 efficacy endpoints, improvement from baseline on overall/total scores was statistically significant (Wilcoxon signed rank test p<0.05)  
• NNZ-2591 was safe and well tolerated, with no clinically significant changes in laboratory values or other safety parameters during treatment 

Neuren CEO Jon Pilcher commented "The strength and consistency of these results has exceeded our expectations and gives us high confidence as we strive to accelerate the development of a potential first therapy to address the overwhelming unmet medical need of PMS.  We are very grateful to all the people at the trial sites in the United States and in the PMS community who enabled this groundbreaking trial to be completed successfully." 

Elizabeth Berry-Kravis, MD, PhD, Professor Department of Pediatrics at Rush University Medical Center in Chicago and an Investigator in the study, commented: "Although the Phase 2 trial was an open label study, I am very encouraged that both clinicians and caregivers observed pervasive improvements across multiple, clinically important features of PMS including communication, cognition, learning, socialisation and behaviour.  Improvements typically considered clinically meaningful were achieved in the clinician rated CGI-I as well as the caregiver rated CIC. I look forward to seeing this program advance to the next stage of development for the PMS community". 

Study design
The open label Phase 2 trial in up to 20 children aged 3 to 12 years at four hospitals in the United States examined safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ2591. NNZ-2591 was administered to all subjects as an oral liquid dose twice daily, with escalation in two stages up to the target dose of 12 mg/kg during the first 6 weeks of treatment, subject to independent review of safety and tolerability data. The study commenced with at least 4 weeks of screening and observation to thoroughly examine baseline characteristics prior to treatment, followed by the treatment period of 13 weeks. A follow-up assessment was made 2 weeks after the end of treatment. 23 children were screened, 5 failed screening and 18 entered the study. The mean age was 8.6 years.

The primary endpoints of this first trial in children were safety, tolerability and pharmacokinetics. Secondary endpoints included 14 efficacy measures assessed by clinicians and by caregivers. Efficacy measures included global measures assessing overall change, measures assessing specific symptom areas and measures assessing quality of life. 

Safety and tolerability
NNZ-2591 was well tolerated and demonstrated a good safety profile. Most Treatment Emergent Adverse Events (TEAEs) were mild to moderate. There was only one Serious TEAE (gastroenteritis), which was not related to study drug and occurred during the safety follow-up period after end of treatment. Three subjects discontinued due to TEAEs, two testing positive for COVID-19 and one due to seizures that were not related to study drug. No clinically significant changes in laboratory values, electrocardiogram (ECG) or other safety parameters were observed during treatment.

Efficacy
Improvement from baseline on overall/total scores was statistically significant (Wilcoxon signed rank test p<0.05) for 10 out of 14 efficacy endpoints. 

The results for the global measures rated by both clinicians and caregivers showed a level of improvement typically considered clinically meaningful. 16 out of 18 children showed improvement measured by the Clinical Global Impression of Improvement (CGI-I), an assessment by the clinician of the child's overall status compared with baseline. The mean CGI-I score was 2.4. 10 children received a score of either 1 ("very much improved") or 2 ("much improved").

15 out of 18 children showed improvement measured by the Caregiver Overall Impression of Change (CIC), an assessment by the caregiver of the child's overall status compared with baseline. The mean CIC score was 2.7.  Seven children received a score of either 1 ("very much improved") or 2 ("much improved").

Other ongoing Phase 2 trials of NNZ-2591
Neuren is also conducting Phase 2 clinical trials of NNZ-2591 in children with three other neurodevelopmental disorders – Pitt Hopkins syndrome, Angelman syndrome and Prader-Willi syndrome. Top-line results from the Pitt Hopkins syndrome trial are expected in Q2 2024. All four programs have been granted Orphan Drug designation by the US Food and Drug Administration (FDA) and are being developed under Investigational New Drug (IND) applications. Each syndrome is a seriously debilitating neurological disorder that emerges in early childhood and has no or limited approved treatment options.