EMA Clears Oryzon's HOPE-2 Phase IIa Trial of Vafidemstat in Phelan-McDermid Syndrome
核心洞察
Oryzon Genomics (搜索) received EMA authorization of its Clinical Trial Application to start the HOPE-2 Phase IIa study of vafidemstat in Phelan-McDermid Syndrome (搜索).
HOPE-2 is a single-center, single-arm, open-label study enrolling 12 adults with PMS, a SHANK3 (搜索)-linked neurodevelopmental disorder with no approved pharmacologic treatment.
The primary objective is safety and tolerability, with secondary measures covering anger, aggression, repetitive behavior and overall disease severity over 12 weeks.
The European Medicines Agency (搜索) has authorized Oryzon Genomics (搜索)' Clinical Trial Application to initiate a Phase II study of vafidemstat in Phelan-McDermid Syndrome (搜索) (PMS), the Barcelona-based clinical-stage biopharmaceutical company announced on Sept. 28, 2026. The study, named HOPE-2, will evaluate the oral LSD1 (搜索) inhibitor in adults with the genetic disorder, which is associated with autism spectrum disorder (搜索) (ASD).
Trial Design and Endpoints
HOPE-2 is a single-center, single-arm, open-label Phase IIa study that will enroll 12 adult patients with PMS. The primary objective 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). Investigators will also assess efficacy in the treatment of overall disease in adults with PMS using the Repetitive Behavior Scale-Revised (RBS-R), the Phelan-McDermid Syndrome (搜索) Assessment of Severity (PMSA-S), and the ABC Subscales for 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.
Rationale in a SHANK3-Linked Disorder
PMS is a highly disabling neurodevelopmental disorder caused by deletions or pathogenic mutations in the SHANK3 (搜索) gene. It is characterized by varying degrees of developmental delay, intellectual disability, delayed or absent speech, and autism spectrum disorder (搜索) or symptoms of autism. U.S. prevalence is estimated at approximately 1 in 7,300 people.
Despite the high prevalence and substantial burden of aggression in PMS, there are no approved pharmacologic treatments for PMS or 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 (搜索) 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."
Gutierrez-Esteinou added that LSD1 (搜索) inhibition has been shown to trigger a "reset" of neuronal transcription and reverse social behavior and aggression phenotypes in ASD genetic models, including SHANK3 (搜索)-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 (搜索)," he said.
Vafidemstat's Broader CNS Program
Vafidemstat (ORY-2001) is an oral, CNS-optimized LSD1 (搜索) inhibitor designed to address neuropsychiatric disorders through epigenetic modulation. In preclinical studies it has demonstrated effects on cognition, neuroinflammation, aggression, and social behavior, as well as neuroprotective and anti-inflammatory activity across multiple CNS disease models.
Oryzon has completed several Phase II trials with vafidemstat, including REIMAGINE and REIMAGINE-AD, in aggression in patients with different psychiatric disorders and in aggressive or agitated patients with moderate or severe Alzheimer's disease, respectively, with positive clinical results reported in both. Following completion of the global randomized double-blind Phase IIb PORTICO trial in borderline personality disorder (搜索) (BPD), vafidemstat is advancing as a Phase III-ready asset for aggression in BPD, with a Phase III in preparation. The compound is also being evaluated in the ongoing double-blind, randomized, placebo-controlled Phase IIb EVOLUTION trial in negative symptoms of schizophrenia (搜索).
Oryzon's clinical portfolio is built around two LSD1 (搜索) inhibitors. Alongside vafidemstat, iadademstat is being evaluated in several ongoing Phase I and II studies in oncology and hematology and has demonstrated preliminary clinical activity in acute myeloid leukemia (搜索), including a 100% overall response rate in first-line AML. The company is also advancing a pipeline targeting other epigenetic mechanisms, including HDAC6, for which it has nominated ORY-4001 as a clinical candidate for potential development in Charcot-Marie-Tooth disease (搜索), amyotrophic lateral sclerosis (搜索), and other neurological disorders.
Patient-Organization Collaboration and Funding
Oryzon will collaborate with the Spanish Phelan-McDermid Syndrome Association (搜索) to support identification of potential participants for HOPE-2. The study will be conducted in Spain as part of Oryzon's VANDAM project.
"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," said Norma Alhambra, President of the Spanish Phelan-McDermid Syndrome Association (搜索). "We would like to thank the Oryzon team for involving us in this process from the outset."
VANDAM is part of the Med4Cure Important Project of Common European Interest (IPCEI) on Health and 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's NextGenerationEU.