Oryzon secures EMA approval to start HOPE-2 vafidemstat trial in PMS

Oryzon Genomics has received authorisation from the European Medicines Agency to initiate HOPE-2, a Phase IIa clinical study evaluating its lead CNS candidate vafidemstat in adults with Phelan-McDermid Syndrome (PMS). The Barcelona-based epigenetics company described the approval as a key step in its strategy to broaden vafidemstat's reach across neurodevelopmental conditions.

PMS is a rare genetic disorder caused by deletions or pathogenic mutations in the SHANK3 gene. It presents with varying degrees of intellectual disability, delayed or absent speech, and autism spectrum disorder. US prevalence is estimated at approximately one in 7,300 people. There are currently no approved pharmacological treatments for the condition, with aggression and agitation typically managed off-label using drugs that carry significant safety concerns and limited evidence of benefit.

The study design

HOPE-2 is a single-centre, single-arm, open-label trial that will enrol 12 adult PMS patients in Spain. Its primary objective is to assess the safety and tolerability of vafidemstat over 12 weeks, with secondary endpoints covering measures of anger, aggression, stereotypic behaviour, hyperactivity, inappropriate speech, and social withdrawal, evaluated using validated scales including the Aberrant Behavior Checklist and the Clinical Global Impression of Severity. Investigators will determine after the initial 12-week period whether patients show sufficient clinical benefit to continue through week 24.

The study is being conducted in collaboration with the Spanish Phelan-McDermid Syndrome Association, which will support participant identification. Partial funding comes through Oryzon's VANDAM project under Med4Cure, an Important Project of Common European Interest on Health, backed by the Spanish Ministry of Science and the EU's NextGenerationEU recovery fund.

Rolando Gutierrez-Esteinou, Oryzon's Chief Medical Officer for CNS, noted that vafidemstat is the only LSD1 inhibitor currently in clinical development for central nervous system disorders: "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."

Market and competitive context

The rare neurodevelopmental disease space is attracting growing attention from both biotech developers and patient advocacy groups, though most programmes remain in early-stage or investigational work. The absence of any approved therapy for PMS makes even a small open-label safety study clinically significant as a proof-of-concept step.

Vafidemstat's broader clinical programme gives Oryzon an unusual degree of human data to draw on. The company has reported positive results in the REIMAGINE trials of aggression in psychiatric patients, and vafidemstat is described as Phase III-ready in borderline personality disorder following completion of the PORTICO Phase IIb study. An ongoing Phase IIb trial, EVOLUTION, is evaluating the drug in negative symptoms of schizophrenia. This portfolio of CNS data, built around a single LSD1 inhibitor, positions Oryzon as a specialist in epigenetic modulation of neuropsychiatric disease, a niche that few companies currently occupy.

The HOPE-2 readout will be watched for safety signals and early efficacy signals on the behavioural endpoints, which could inform whether a larger, controlled study is warranted in this genetically defined population.