NNZ-2591 / Neuren, Acadia Pharma - LARVOL DELTA

Neuren receives US FDA meeting feedback for NNZ-2591 clinical development in HIE and PTHS (Neuren Pharma Press Release) - "Neuren requested a Type B pre-Investigational New Drug (IND) meeting for HIE and a Type C meeting for Pitt Hopkins syndrome. FDA determined that both meetings would be conducted as Written Responses Only (WRO)...FDA requested that Neuren provides additional juvenile animal study data to support NNZ-2591 dosing in neonatal participants prior to initiating the clinical study...Neuren plans to generate this data before submitting the IND application and commencing the clinical study later in 2026...The FDA feedback regarding PTHS indicated that in a controlled trial to demonstrate efficacy of NNZ2591, a PTHS-specific clinical global impression (CGI) scale may be used as a co-primary endpoint if it is accompanied by an observer-reported functional outcome measure....Neuren still intends to initiate the next trial in 2026."

FDA event • IND • New trial • CNS Disorders • Developmental Disorders

NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results. (PubMed, Neurol Genet) - P2 | "Submitted August 24, 2021. First participant enrolled on August 8, 2022."

Journal • P2 data • CNS Disorders • Developmental Disorders • Psychiatry • IGF1

Neuren Pharmaceuticals…announced that Health Canada has approved its Clinical Trial Application (CTA) for the Koala Phase 3 clinical trial evaluating NNZ-2591 for the treatment of Phelan-McDermid syndrome (PMS) in children aged 3 to 12 years (Neuren Pharma Press Release) - "Approval of the CTA enables the potential initiation of clinical trial sites in Canada. The Koala Phase 3 clinical trial previously received Investigational New Drug (IND) approval from the US Food and Drug Administration (FDA) and enrolment is ongoing....A second US site has now been activated and is enrolling in California."

Trial status • Developmental Disorders • Genetic Disorders

A Study of NNZ-2591 in Pediatric Participants With Phelan-McDermid Syndrome (clinicaltrials.gov) - P3 | N=160 | Recruiting | Sponsor: Neuren Pharmaceuticals Limited

New P3 trial • Pediatrics

Fast Track granted by FDA for NNZ-2591 in Phelan-McDermid syndrome (Neuren Pharma Press Release) - "Neuren recently initiated 'Koala', a Phase 3 randomized double-blind placebo-controlled clinical trial evaluating NNZ-2591 treatment in children aged 3 to 12 years with PMS."

Fast track • Trial status • Genetic Disorders

An Open-Label Study of Oral NNZ-2591 in Pitt Hopkins Syndrome (PTHS-001) (clinicaltrials.gov) - P2 | N=28 | Completed | Sponsor: Neuren Pharmaceuticals Limited | N=16 ➔ 28

Enrollment change

Neuren receives FDA minutes and re-confirms primary endpoints for Phase 3 trial (Neuren Pharma Press Release) - "Neuren Pharmaceuticals...confirmed that it has received the official minutes of its Type C Meeting with the US Food and Drug Administration (FDA), held on 8 April to discuss efficacy endpoints for its upcoming Phase 3 clinical trial of NNZ-2591 to treat Phelan-McDermid syndrome...As announced last month by Neuren following the Meeting, the co-primary endpoints for the single Phase 3 pivotal trial will be the change from baseline in the Receptive Communication sub-domain of the Vineland Adaptive Behavior Scales, Third Edition (VABS-3 Receptive-Raw Score) and the overall score in the Phelan-McDermid Syndrome Assessment of Change (PMSA-C, previously referred to as CGI-I in Neuren’s Phase 2 trial)...Neuren remains on-track to commence the Phase 3 trial mid-year 2025, subject to FDA review of the final version of the trial protocol."

FDA event • Developmental Disorders • Genetic Disorders

Neuren confirms primary endpoints for Phase 3 trial of NNZ-2591 in PMS (Neuren Pharma Press Release) - "Neuren Pharmaceuticals...announced that the primary endpoints for its planned single Phase 3 pivotal clinical trial of NNZ-2591 in Phelan-McDermid syndrome (PMS) have been confirmed at a productive Type C Meeting with the US Food and Drug Administration (FDA)....The co-primary endpoints in the double-blind placebo-controlled study of treatment for 13 weeks will be the change from baseline in the Receptive Communication sub-domain of the Vineland Adaptive Behavior Scales, Third Edition (VABS-3 Receptive-Raw Score) and the overall score in the Phelan McDermid Syndrome Assessment of Change (PMSA-C, previously referred to as CGI-I in Neuren’s Phase 2 trial).... Neuren remains on-track to commence the Phase 3 trial mid-year 2025, subject to FDA review of the final version of the trial protocol."

FDA event • New P3 trial • Developmental Disorders • Genetic Disorders

Neuren initiates development of NNZ-2591 to treat HIE in newborns (Neuren Pharma Press Release) - "Neuren Pharmaceuticals...announced the initiation of development of NNZ-2591 to treat hypoxic-ischemic encephalopathy (HIE)....Based on its therapeutic properties and compelling data from preclinical models...Neuren anticipates that NNZ-2591 in HIE will qualify for Orphan Drug and Rare Pediatric disease designations from the US Food and Drug Administration (FDA). Leveraging the platform of clinical, nonclinical and manufacturing data that Neuren has built for NNZ-2591, a pre-IND meeting with the FDA is targeted in Q4 2025 before initiating a clinical trial in HIE patients."

FDA event • Pipeline update • CNS Disorders

Neuren receives Rare Pediatric Disease Designation from FDA (Neuren Pharma Press Release) - "Neuren Pharmaceuticals...has received Rare Pediatric Disease Designation from the US Food and Drug Administration (FDA) for NNZ-2591 in each of Pitt Hopkins syndrome (PTHS) and Angelman syndrome (AS). Neuren has also previously received Rare Pediatric Disease Designation from the FDA for NNZ-2591 in Phelan-McDermid syndrome (PMS). With this designation in place for PMS, PTHS and AS, Neuren may be awarded a priority review voucher (PRV) if the Rare Pediatric Disease PRV program is reauthorized by the US Congress and NNZ-2591 receives marketing authorization for any of these indications."

FDA event • Developmental Disorders • Genetic Disorders

Fast Track granted by FDA for NNZ-2591 in Pitt Hopkins syndrome (Neuren Pharma Press Release) - "Neuren Pharmaceuticals...announced that the US Food and Drug Administration (FDA) has granted Fast Track designation for NNZ-2591 for the treatment of Pitt Hopkins syndrome (PTHS)...In Neuren’s Phase 2 clinical trial of NNZ-2591 in children with PTHS, 82% of participants showed improvement, including communication, social interaction, cognition and motor abilities"

Fast track • Genetic Disorders

Neuren Presentations at the ACMG Annual Clinical Genetics Meeting 2025 (Neuren Pharma Press Release) - "Neuren Pharmaceuticals...announced the acceptance of three abstracts for presentation at the 2025 American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting, being held on 18–22 March 2025, in Los Angeles....'The presentations address the evolving diagnostic landscape in Phelan-McDermid syndrome, and the encouraging results achieved in our Phase 2 trials'."

Clinical • P2 data • Developmental Disorders • Genetic Disorders

An Open-Label Study of Oral NNZ-2591 in Prader-Willi Syndrome (PWS-001) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Neuren Pharmaceuticals Limited | N=20 ➔ 0 | Suspended ➔ Withdrawn

Enrollment change • Trial withdrawal • Prader–Willi syndrome

Safety, Efficacy, and Exposure-Response of NNZ-2591, a Synthetic Analog of Cyclic Glycine-Proline (cGP), an IGF-1 Metabolite, for the Treatment of Phelan-Mcdermid Syndrome in Children and Adolescents (AACAP 2024) - "NNZ-2591 appeared safe and well tolerated in children and adolescents with PMS. Both clinicians and caregivers observed improvements in clinically important aspects of PMS, including communication, behavior, cognition/learning, and socialization. The efficacy of NNZ-2591 is supported by exposure-response modeling that shows that the target minimum exposure can be achieved with the evaluated dosage.ND, PKS, OLT"

Clinical • Gastroenterology • Gastrointestinal Disorder • IGF1

AS-001: An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Neuren Pharmaceuticals Limited | Recruiting ➔ Completed

Trial completion • UBE3A

An Open-Label Study of Oral NNZ-2591 in Prader-Willi Syndrome (PWS-001) (clinicaltrials.gov) - P2 | N=20 | Suspended | Sponsor: Neuren Pharmaceuticals Limited | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Prader–Willi syndrome

An Open-Label Study of Oral NNZ-2591 in Pitt Hopkins Syndrome (PTHS-001) (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Neuren Pharmaceuticals Limited | Recruiting ➔ Completed

Trial completion

An Open-Label Study of Oral NNZ-2591 in Phelan-McDermid Syndrome (PMS-001) (clinicaltrials.gov) - P2 | N=18 | Completed | Sponsor: Neuren Pharmaceuticals Limited | Active, not recruiting ➔ Completed

Trial completion

An Open-Label Study of Oral NNZ-2591 in Prader-Willi Syndrome (PWS-001) (clinicaltrials.gov) - P2 | N=20 | Suspended | Sponsor: Neuren Pharmaceuticals Limited | Recruiting ➔ Suspended

Trial suspension • Prader–Willi syndrome

An Open-Label Study of Oral NNZ-2591 in Prader-Willi Syndrome (PWS-001) (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Neuren Pharmaceuticals Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Prader–Willi syndrome

An Open-Label Study of Oral NNZ-2591 in Phelan-McDermid Syndrome (PMS-001) (clinicaltrials.gov) - P2 | N=20 | Active, not recruiting | Sponsor: Neuren Pharmaceuticals Limited | Recruiting ➔ Active, not recruiting

Enrollment closed

An Open-Label Study of Oral NNZ-2591 in Pitt Hopkins Syndrome (PTHS-001) (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Neuren Pharmaceuticals Limited | Trial completion date: May 2023 ➔ Apr 2024 | Trial primary completion date: May 2023 ➔ Apr 2024

Trial completion date • Trial primary completion date

An Open-Label Study of Oral NNZ-2591 in Phelan-McDermid Syndrome (PMS-001) (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Neuren Pharmaceuticals Limited | Trial completion date: May 2023 ➔ Dec 2023 | Trial primary completion date: May 2023 ➔ Dec 2023

Trial completion date • Trial primary completion date

AS-001: An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Neuren Pharmaceuticals Limited | Trial completion date: May 2023 ➔ Jun 2024 | Trial primary completion date: May 2023 ➔ Jun 2024

Trial completion date • Trial primary completion date • UBE3A

Acadia Pharmaceuticals Acquires Ex-North American Rights to Trofinetide and Global Rights to Neuren’s NNZ-2591 in Rett Syndrome and Fragile X Syndrome (Businesswire) - "Acadia Pharmaceuticals...announced that it has expanded its current licensing agreement for trofinetide with Neuren Pharmaceuticals to acquire ex-North American rights to the drug as well as global rights in Rett syndrome and Fragile X syndrome to Neuren’s development candidate NNZ-2591. In April of this year, Acadia launched trofinetide in the United States under the brand name DAYBUE as the first and only drug approved for the treatment of Rett syndrome....In addition to expanding access to trofinetide outside of North America, this agreement gives Acadia exclusive worldwide rights to NNZ-2591 in both Rett syndrome and Fragile X syndrome. NNZ-2591 is an investigational synthetic analogue of cyclo-glycyl-proline (cGP) which results from the breakdown of human insulin-like growth factor 1 (IGF-1)."

M&A • CNS Disorders • Fragile X Syndrome • Genetic Disorders • Parkinson's Disease