Neuren Pharmaceuticals announced top-line results from its Phase 2 clinical trial of NNZ-2591 in children with Pitt Hopkins syndrome (PTHS). Statistically significant improvement from baseline was observed by both clinicians and caregivers from treatment, across all 4 efficacy measures that were specifically designed to assess the core characteristics of PTHS. There are no approved treatments for PTHS despite its severely debilitating impact on the lives of patients, as well as their parents and siblings.

The open label Phase 2 trial in 16 children aged 3 to 17 years (mean age 9 years) at five hospitals in the United States examined safety, tolerability, pharmacokinetics and efficacy over 13 weeks of treatment with NNZ-2591. 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 define 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. The primary endpoints of this first trial in children with PTHS were safety, tolerability and pharmacokinetics. Secondary endpoints included four efficacy measures specifically designed for PTHS assessed by clinicians and by caregivers, as well as ten efficacy measures that were not designed for use in PTHS but have been used in other neurodevelopmental conditions.

NNZ-2591 was well tolerated and demonstrated a good safety profile. All Treatment Emergent Adverse Events (TEAEs) were mild to moderate and most were considered not related to study drug. There were no Serious TEAEs and no meaningful trends in laboratory values, electrocardiogram (ECG) or other safety parameters were observed during treatment.

11 subjects completed the trial. One subject discontinued because they were unable to complete the safety monitoring procedures required by the study protocol. Four subjects discontinued due to TEAEs, all of which resolved.

For two of those subjects the TEAEs (COVID-19 and mild vomiting/diarrhea/lethargy) were considered not related to study drug and for two subjects the TEAEs (moderate constipation/self-injury/abdominal distention/fatigue and mild sleep disorder/constipation) were considered related to study drug. The mean improvement from baseline was statistically significant (Wilcoxon signed rank test p<0.05) for each of the four efficacy measures that were specifically designed for Pitt Hopkins syndrome, whether calculated for the subjects that completed the study (n=11), or including discontinued subjects (n=15). Changes from baseline were not statistically significant for the efficacy measures that were not designed for use in PTHS but have been used in other neurodevelopmental conditions.

The results for the global measures rated by both clinicians and caregivers showed a level of improvement considered clinically meaningful. 9 out of 11 children that completed the trial showed improvement measured by the PTHS 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 2.6. Five children received a score of either 1 ("very much improved") or 2 ("much improved").

8 out of 11 children that completed the trial showed improvement measured by the PTHS 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 3.0. Four children received a score of 2 ("much improved"). out of 11 children that completed the trial showed improvement measured by the PTHS Clinical Global Impression of Severity (CGI-S), an assessment by the clinician of the child's overall severity of illness, compared with the assessment at baseline.

The CGI-S score improved from 6 to 5 for 3 children and from 5 to 4 for 3 children. 8 out of 11 children that completed the trial showed improvement measured by the Caregiver Top 3 Concerns overall score, an individualised assessment by the caregiver of their child's most concerning symptoms. Language/Communication was the most commonly chosen concern.