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The Promise of Vafidemstat for Borderline Personality Disorder (BPD)

Oryzon Genomics, a clinical-stage biopharmaceutical company, is developing vafidemstat, an oral, CNS-optimized LSD1 inhibitor, as a potential therapy for Borderline Personality Disorder (BPD). BPD is a complex mental health condition characterized by intense emotional instability, impulsivity, and distorted self-image. The neurodevelopmental disorder affects around 1.6% of the US population and is a leading cause of suicide attempts and self-injury. While current treatments for BPD, such as mood stabilizers and psychotherapy, offer limited efficacy, vafidemstat aims to address the underlying epigenetic mechanisms that contribute to the disorder.

The Science behind Vafidemstat

LSD1 is a histone demethylase enzyme that regulates gene expression through chromatin remodeling. Dysregulation of LSD1 activity has been implicated in various psychiatric and neurological disorders, including BPD. Vafidemstat acts as an inhibitor of LSD1, leading to changes in gene expression that promote neuroplasticity and reduce neuroinflammation. In preclinical studies, vafidemstat has demonstrated efficacy in reducing cognitive impairment, memory loss, and social avoidance in murine models of aging and Alzheimer's disease. Additionally, the drug has shown anti-inflammatory effects in models of multiple sclerosis and COVID-19.


The ongoing Phase IIb PORTICO trial is evaluating the safety and efficacy of vafidemstat in adult BPD patients. The multicenter, double-blind, randomized, placebo-controlled trial plans to recruit 188 patients distributed between two arms. The trial has two primary independent objectives: to reduce agitation and aggression and to produce an overall improvement in BPD severity. An independent Data Monitoring Committee (DMC) reviewed blinded aggregate safety data from the first 167 randomized patients and recommended that the trial continue without modifications until full enrollment, which is planned for early Q3 2023.

Positive Safety Data from PORTICO

The blinded aggregate safety data from the PORTICO trial reviewed by the independent DMC showed no treatment-related serious adverse events or deaths. A total of 306 adverse events affecting 98 patients treated with vafidemstat or placebo were reported, with most being mild or moderate. Only 12 were severe, leading to six treatment discontinuations or patient withdrawals. The reviewed blinded PORTICO safety data is aligned with aggregated safety data collected from seven completed vafidemstat clinical trials, in which almost 400 subjects have been treated with the drug.

Interim Analysis of PORTICO

A predefined independent interim analysis (IA) was conducted on the data of the first 90 patients that had concluded at least two-thirds of the trial. The IA assessed the signal size and futility of the trial and determined that PORTICO was not futile and should continue as it is without increasing the number of patients to be recruited. The adaptive design of the trial allows for a pre-defined interim analysis to adjust the sample size in case of excessive variability around the endpoints.

Other Clinical Trials of Vafidemstat

In addition to the PORTICO trial, vafidemstat is being evaluated in other clinical trials for various indications. The REIMAGINE trial is a Phase IIa clinical trial in aggressiveness in patients with different psychiatric disorders, while the REIMAGINE-AD trial is evaluating vafidemstat in aggressive/agitated patients with moderate or severe Alzheimer's disease. The ETHERAL trial is investigating vafidemstat in patients with mild to moderate Alzheimer's disease, while the SATEEN trial is evaluating the drug in Relapse-Remitting and Secondary Progressive Multiple Sclerosis. Vafidemstat is also in two Phase IIb trials in schizophrenia patients (EVOLUTION) and borderline personality disorder (PORTICO).

Precision Medicine Approach with Vafidemstat

Oryzon is deploying a CNS precision medicine approach with vafidemstat in genetically-defined patient subpopulations of certain CNS disorders. The company is preparing for a clinical trial in Kabuki Syndrome patients, a rare genetic disorder characterized by intellectual disability, developmental delay, and distinctive facial features. The company is also exploring the clinical development of vafidemstat in other neurodevelopmental syndromes.


The ongoing PORTICO trial provides hope for BPD patients who currently have limited treatment options for their condition. Vafidemstat, with its unique mechanism of action, has demonstrated promising results in preclinical studies and completed clinical trials for various indications. The positive safety data from the PORTICO trial and the recommendation from the independent DMC to continue the trial without modifications are encouraging signs for the potential of vafidemstat as a therapy for BPD. Oryzon's CNS precision medicine approach with vafidemstat further highlights the potential of epigenetic therapies to address the underlying mechanisms of complex neurological disorders.


  1. Oryzon Genomics Reports New Preliminary Blinded Aggregate Safety Data from Its Ongoing Phase IIb PORTICO Trial Investigating Vafidemstat in Borderline Personality Disorder. (2023, July 5). GlobeNewswire News Room.

  2. About Oryzon. Oryzon Genomics. (n.d.).

  3. About Vafidemstat. Oryzon Genomics. (n.d.).

  4. Borderline Personality Disorder. National Alliance on Mental Illness. (2021, September).

  5. Synapse: Global Drug Intelligence Database


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