Oryzon Says Study on Phelan-McDermid Syndrome Sets Stage for Clinical Trial of Precision Treatment

Rare Daily Staff

Oryzon Genomics said that the final results of an observational clinical study that psychometrically characterizes individuals with the rare neurodevelopmental condition Phelan-McDermid syndrome sets the stage for a future precision psychiatry clinical trial of its experimental therapy vafidemstat as a treatment.

The study, published online in the journal Frontiers in Psychiatry, sought to clinically characterize 30 people with Phelan-McDermid syndrome (PMS) who had deletions or pathogenic variants in SHANK3. People with the condition suffer from developmental delays, intellectual disability, speech impairments, and may also have autism spectrum disorder. Agitation and aggression are key components of PMS.

The analysis provides new data on the best potential endpoints for a future clinical study exploring vafidemstat for people with SHANK3-associated psychiatric disorders

Vafidemstat has demonstrated efficacy in reducing agitation and aggression in a basket trial involving patients with autism spectrum disorder, attention deficit hyperactivity disorder, and borderline personality disorder. The company said the characterization of PMS in the study paves the way for addressing these symptoms in a subset of PMS patients.

Vafidemstat is an oral, CNS-optimized LSD1 inhibitor. The molecule reduces cognitive impairment, including memory loss and neuroinflammation, and at the same time has neuroprotective effects.

In animal studies vafidemstat not only restores memory but reduces the exacerbated aggressiveness of SAMP8 mice, a model for accelerated aging and Alzheimer’s disease, to normal levels and also reduces social avoidance and enhances sociability in murine models. In addition, vafidemstat exhibits fast, strong, and durable efficacy in several preclinical models of multiple sclerosis.

Oryzon has performed two phase 2a clinical trials in aggressiveness in patients with different psychiatric disorders and in aggressive/agitated patients with moderate or severe AD with positive clinical results reported in both. Additional finalized phase 2a clinical trials with vafidemstat include the ETHERAL trial in patients with mild to moderate AD, where a significant reduction of the inflammatory biomarker YKL40 was observed after 6 and 12 months of treatment, and the pilot, small-scale SATEEN trial in Relapse-Remitting and Secondary Progressive MS, where anti-inflammatory activity was also observed.

The company has announced plans to move forward with a phase 3 trial in agitation/aggression in borderline personality disorder. Vafidemstat is also being investigated in a double-blind, randomized, placebo-controlled phase 2b trial in negative symptoms of schizophrenia. The company is also deploying a CNS precision medicine approach with vafidemstat in genetically-defined patient subpopulations of certain CNS disorders and is evaluating a clinical trial in Kabuki Syndrome patients. The company is also exploring the clinical development of vafidemstat in other neurodevelopmental syndromes.

“There is currently no treatment approved specifically for Phelan-McDermid syndrome,” said Julian Nevado, first author of the study and head of structural and functional genomics at Instituto de Genética Médica y Molecular in Madrid. “This study is a proof of concept that highlights the importance of patient stratification in PMS. Selecting PMS patients for a clinical trial based on their distinctive clinical and genetic characteristics will be essential in the era of personalized precision medicine.”