FDA Minutes Confirm Trial Design, But Phase 3 Success Remains Uncertain

• FDA confirms co-primary endpoints for NNZ-2591 Phase 3 trial
• Endpoints focus on VABS-3 Receptive Communication and PMSA-C scores
• Phase 2 results showed clinically meaningful improvements in 16 of 18 children
• Phase 3 trial expected to start mid-2025, no additional funding needed
• Phelan-McDermid syndrome remains an area of high unmet medical need

Regulatory Alignment on Trial Design

Neuren Pharmaceuticals, the Melbourne-based biotech, has taken a significant step forward in its quest to develop a treatment for Phelan-McDermid syndrome (PMS). The company announced it has received the official minutes from its recent Type C meeting with the US Food and Drug Administration (FDA), confirming the primary efficacy endpoints for its upcoming Phase 3 clinical trial of NNZ-2591.

This regulatory clarity is critical for Neuren as it prepares to launch what it hopes will be a pivotal study to demonstrate the drug’s effectiveness in a rare and challenging neurodevelopmental disorder. The FDA’s endorsement of the co-primary endpoints, the change from baseline in the Vineland Adaptive Behavior Scales, Third Edition (VABS-3) Receptive Communication sub-domain, and the Phelan-McDermid Syndrome Assessment of Change (PMSA-C), provides a clear framework for measuring clinical benefit.

Building on Promising Phase 2 Data

Neuren’s Phase 2 open-label trial delivered encouraging results, with 16 out of 18 children showing improvement in both the VABS-3 Receptive-Raw Score and PMSA-C assessments. The mean improvement in receptive communication was 7.5 points from a baseline of 29, a statistically significant change that suggests meaningful gains in a domain often severely affected in PMS patients.

These findings underpin the company’s confidence as it moves into the larger, more rigorous Phase 3 trial. The trial’s design, now aligned with FDA expectations, aims to confirm these benefits in a broader patient population, potentially paving the way for regulatory approval and commercialisation.

Addressing a Critical Unmet Need

Phelan-McDermid syndrome is a rare genetic disorder caused by deletions or mutations affecting the SHANK3 gene, leading to severe developmental delays, intellectual disability, and a range of neurological symptoms. Currently, no approved treatments specifically target PMS, leaving families with limited options.

Neuren’s NNZ-2591, with orphan drug designation in the US, represents one of the few hopeful candidates aiming to fill this therapeutic void. The company’s ongoing commitment to advancing treatments for rare neurodevelopmental disorders highlights the broader challenge and opportunity in this space.

Financial and Operational Outlook

Importantly, Neuren confirmed that it has sufficient financial resources to execute the Phase 3 trial without seeking additional funding. The trial is on track to commence mid-2025, pending final FDA review of the trial protocol. This financial stability reduces execution risk and allows the company to focus on delivering robust clinical data.

CEO Jon Pilcher’s leadership will be closely watched as Neuren navigates this critical phase. The company’s progress with NNZ-2591 could not only impact the lives of those affected by PMS but also serve as a bellwether for the viability of treatments targeting rare neurological conditions.

Bottom Line?

Neuren’s FDA-aligned Phase 3 trial sets the stage for a potential breakthrough in treating Phelan-McDermid syndrome, but the path to approval still hinges on upcoming trial outcomes.

Questions in the middle?

• Will the Phase 3 trial replicate the strong efficacy signals seen in Phase 2?
• How will Neuren manage recruitment given the rarity of Phelan-McDermid syndrome?
• What are the timelines and expectations for FDA’s final protocol approval?