Vafidemstat: A Potential Breakthrough in Treating Agitation and Aggression Across Different Psychiatric Populations

Agitation and aggression are common in many psychiatric disorders and neurodegenerative diseases. These symptoms significantly impair patients' daily lives, contribute to worse outcomes—such as disease progression, institutionalization, and increased mortality—and place a substantial burden on families and caregivers.

In Autism Spectrum Disorder (ASD), aggression can manifest as severe tantrums, hostility, violent outbursts, self-harm, and rage episodes, with up to 20% of individuals exhibiting these behaviors. In many cases, aggression leads to property destruction and direct violence toward caregivers, causing physical harm.

Patients with Attention-Deficit/Hyperactivity Disorder (ADHD) also exhibit agitation/aggression behavior, which can affect up to 50% of patients.

Agitation and aggression are also prominent features of Borderline Personality Disorder (BPD). Patients with BPD frequently exhibit aggressive behavior, with a one-year study reporting that 73% of individuals with BPD engaged in violent behavior. Additionally, individuals with BPD often display self-directed aggression, including self-harm and suicidal behavior, with suicide rates in BPD higher than those of any other psychiatric disorder and the general population.

Vafidemstat is an oral, brain-penetrant, epigenetic experimental drug that has demonstrated the ability to reduce aggression and enhance sociability in animal models and clinical trials.

The final data from the REIMAGINE Phase IIa basket trial, recently published in a prestigious specialized journal (M Ferrer et al, 2025), evaluated vafidemstat’s safety and efficacy in treating aggression in adults with BPD, ADHD, and ASD. The eight-week treatment led to a statistically significant reduction in agitation/aggression across all assessments (CGI-S, CGI-I, and NPI-A/A), both in the aggregated dataset (p < 0.0001) and within each individual disorder (p-values ranging from 0.0064 to 0.0175). Notably, improvements were observed as early as two weeks into treatment and were sustained throughout the trial. The positive safety and efficacy results from REIMAGINE validated the rationale for conducting controlled clinical studies targeting agitation and aggression in psychiatric disorders, including borderline personality disorder, which currently has no approved pharmacological treatment. This has been addressed in PORTICO, a global, double-blind, placebo-controlled Phase 2b trial, which enrolled 211 BPD patients in two arms. While the treatment arm did not meet the primary endpoint (CGI-S A/A), it demonstrated a strong and significant effect on the secondary endpoint STAXI-2 Trait anger, with a p-value of 0.0071 in the last month of treatment—indicating an almost 60% reduction in aggressivity compared to placebo. Furthermore, the treatment group showed a lower tendency toward self-harm (1 patient with 2 events vs. 6 patients with 10 events in the placebo group).

These findings strongly suggest vafidemstat’s efficacy in controlling agitation-aggression in BPD patients, leading the U.S. Food and Drug Administration (FDA) to allow Oryzon to submit a Phase 3 registrational trial protocol. This protocol is currently being finalized and will be submitted to the FDA in the coming weeks. 

If vafidemstat confirms its effectiveness in reducing agitation-aggression in BPD patients in Phase 3, it could become the first pharmacological treatment specifically targeting this severe symptom in a disease with no treatments approved so far. This breakthrough could also pave the way for expanding aggression management strategies across other psychiatric and neurodegenerative disorders.