Highlights:

• Statistically significant improvement from baseline assessed by both clinicians and caregivers in all four efficacy measures specifically designed for Pitt Hopkins syndrome (Wilcoxon signed rank test p<0.05)
• Clinician and caregiver global efficacy measures showed a level of improvement considered clinically meaningful:

- Clinical Global Impression of Improvement (CGI-I) - mean score of 2.6, with 9 out of 11 children showing improvement assessed by clinicians- Caregiver Overall Impression of Change (CIC) – mean score of 3.0, with 8 out of 11 children showing improvement assessed by caregivers

• Improvements were seen in clinically important aspects of Pitt Hopkins syndrome, including communication, social interaction, cognition and motor abilities
• NNZ-2591 was safe and well tolerated, with no serious or severe adverse events and no meaningful trends in laboratory values or other safety parameters during treatment
• Second positive Phase 2 trial result further strengthens confidence in NNZ-2591's potential relevance for multiple neurodevelopmental disorders

MELBOURNE, Australia, May 27, 2024 /PRNewswire/ -- Neuren Pharmaceuticals (ASX: NEU) today 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.

Neuren CEO Jon Pilcher commented "We are very excited about the results of this first clinical trial in Pitt Hopkins patients. This underserved community has such urgent unmet need and we can now continue towards our goal of developing a first approved treatment. We are very grateful to the people in the Pitt Hopkins community and at the trial sites in the United States who enabled the successful completion of this extremely challenging, but groundbreaking trial."

Elliott Sherr, M.D., Ph.D., Professor of Neurology and Pediatrics at the University of California San Francisco, and Director, Brain Development Research Program was an investigator in the trial. Dr Sherr commented: "I am optimistic about the results in the PTHS specific measures. The mechanism of action of NNZ-2591 supports this response seen in PTHS and its potential in other highly impactful neurodevelopmental disorders." 

Dr. Nancy Jones, Neuren Vice President of Clinical Development commented: "The consistent results on the PTHS specific assessments affirm the need for syndrome specific measurements in severe neurodevelopmental disorders where measures that were developed for broader populations may not be as appropriate. Neuren appreciates the collaboration of Dr. Cassandra Newsom, Associate Professor at the University of Alabama, Birmingham (an investigator in the trial), the Pitt-Hopkins Research Foundation, and others who contributed to the development of these important measures."

Study design

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.

Safety and tolerability

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.

Efficacy

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.

Results for efficacy measures specifically designed for Pitt Hopkins syndrome

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").   

6 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.

Detailed results are available in the full announcement and investor presentation:

https://announcements.asx.com.au/asxpdf/20240527/pdf/063ysycd36ykzt.pdf

https://announcements.asx.com.au/asxpdf/20240527/pdf/063ytmj3st1zr6.pdf

About Pitt Hopkins syndrome

Pitt Hopkins syndrome (PTHS) is a neurodevelopmental condition caused by the loss of one copy or a mutation of the TCF4 gene on chromosome 18. The incidence of PTHS has been estimated at between 1 in 34,000 and 1 in 41,000 people. Characteristics of PTHS are a range of developmental delay with moderate-to-severe intellectual disability and behavioral differences, hyperventilation and/or breath-holding while awake, seizures, gastrointestinal issues, lack of speech, sleep disturbance, stereotypic hand movements and distinctive facial features. Some individuals with PTHS are diagnosed with autism.  Further information about PTHS is available at: www.pitthopkins.org

About Neuren

Neuren is developing new drug therapies to treat multiple serious neurological disorders that emerge in early childhood and have no or limited approved treatment options. Recognising the urgent unmet need, all programs have been granted "orphan drug" designation in the United States. Orphan drug designation provides incentives to encourage development of therapies for rare and serious diseases.

DAYBUE™ (trofinetide) is approved by the US Food and Drug Administration (FDA) for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. Neuren has granted an exclusive worldwide licence to Acadia Pharmaceuticals Inc. for the development and commercialisation of trofinetide.

Neuren's second drug candidate, NNZ-2591, is in Phase 2 development for multiple neurodevelopmental disorders, with positive results achieved in Phase 2 clinical trials in Phelan-McDermid syndrome and Pitt Hopkins syndrome.

ASX Listing Rules informationThis announcement was authorized to be given to the ASX by the board of directors of Neuren Pharmaceuticals Limited, Suite 201, 697 Burke Road, Camberwell, VIC 3124

Forward-looking Statements

This announcement contains forward-looking statements that are subject to risks and uncertainties. Such statements involve known and unknown risks and important factors that may cause the actual results, performance or achievements of Neuren to be materially different from the statements in this announcement.