The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.
The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.
The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.
“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.
However, another expert urged prudence when interpreting the findings.
“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.
The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
Little Evidence Available
“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.
In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.
“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.
REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients’ daily life.
Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.
In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.
Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.
Significantly Improved Scores
Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).
Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.
Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).
Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.
In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).
“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.
Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”
First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).
“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.
In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.
There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.
Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.
Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”
That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.
For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”
The study was funded by Oryzon Genomics, SA. Bullock and the other investigators are employees of Oryzon Genomics, SA.
European Psychiatric Association (EPA) 2020 Congress: Abstract EPP0681, presented July 6, 2020.