ORYZON receives European Medicines Agency approval to initiate the HOPE-2 Phase II study of vafidemstat for the treatment of Phelan-McDermid Syndrome (PMS)

Oryzon Genomics, S.A. , a clinical-stage biopharmaceutical company and a global leader in epigenetics, today announced that the European Medicines Agency (EMA) has authorized its Clinical Trial Application (CTA) to initiate a Phase II study to evaluate vafidemstat for the treatment of Phelan-McDermid Syndrome (PMS).

The study, named HOPE-2, is a single-center, single-arm, open-label Phase IIa study that will enroll 12 adult patients with Phelan-McDermid Syndrome, a genetic disease associated with autism spectrum disorder (ASD). The primary objective of the study is to evaluate the safety and tolerability of vafidemstat. Secondary objectives include assessing the effect of vafidemstat on anger and aggression, measured by the Aberrant Behavior Checklist (ABC) Irritability Subscale and the Clinical Global Impression of Severity - Anger and Aggression (CGI-S A/A), as well as the efficacy of vafidemstat in the treatment of overall disease in adults with PMS, measured by the Repetitive Behavior Scale-Revised (RBS-R), the Phelan-McDermid Syndrome Assessment of Severity (PMSA-S), and the ABC Subscales: Stereotypic Behaviour, Hyperactivity/Non compliance, Inappropriate Speech, and Social Withdrawal. Vafidemstat will be administered for 12 weeks. After the first 12 weeks of treatment, the Investigator will assess whether the participant may continue treatment through week 24 based on clinical benefit.

PMS is a highly disabling neurodevelopmental disorder caused by deletions or pathogenic mutations in the SHANK3 gene. It is characterized by varying degrees of developmental delay, intellectual disability, delayed or absent speech, and autism spectrum disorder or symptoms of autism. Despite the high prevalence and substantial burden of aggression in PMS, there are no approved pharmacologic treatments for PMS or 1 specifically targeting aggression in PMS. As a result, aggression is often managed off-label with medications that have limited efficacy and significant safety concerns.

"The initiation of the HOPE-2 study bolsters our strategy to expand the applicability of vafidemstat in CNS indications," said Rolando Gutierrez-Esteinou, MD, Oryzon's Chief Medical Officer for CNS. "Vafidemstat is the only LSD1 inhibitor in clinical development for Central Nervous System disorders, with a potent and unique mechanism of action that modulates transcriptional programs involved in neural plasticity, neuroinflammation and neuronal excitability. LSD1 inhibition has been shown to trigger a 'reset' of neuronal transcription and reverse social behavior and aggression phenotypes in ASD genetic models, including SHANK3-deficient mice. These preclinical findings and the clinical results observed in the REIMAGINE Phase IIa trial in ASD patients lead us to believe vafidemstat has unique potential to provide a promising treatment option for Phelan-McDermid Syndrome."

Oryzon will collaborate with the Spanish Phelan-McDermid Syndrome Association to support the identification of potential participants for the HOPE-2 study.

"The approval of the HOPE-2 study is very important news for our families. Knowing that a potential treatment is being investigated to help manage agitation or aggressive behavior gives us great hope. We would like to thank the Oryzon team for involving us in this process from the outset. For us, it is essential to feel that we are part of these advances and to be able to contribute, drawing on our experience, to help research continue moving forward. We hope this study will bring us closer to new options that can improve the quality of life of our children," said Norma Alhambra, President of the Spanish Phelan-McDermid Syndrome Association.

The HOPE-2 study will be conducted in Spain, as part of Oryzon's VANDAM project. VANDAM, which is part of the Med4Cure Important Project of Common European Interest (IPCEI) on Health, has received funding from the Spanish Ministry of Science, Innovation and Universities and the Centre for the Development of Industrial Technology and Innovation (CDTI), under the Recovery, Transformation and Resilience Plan, funded by the European Union - NextGenerationEU.