Vafidemstat emerges as a promising treatment for Borderline Personality Disorder

Oryzon Genomics, is developing vafidemstat, an oral, brain-penetrant inhibitor of the histone lysine demethylase LSD1, as a treatment for psychiatric conditions like Borderline Personality Disorder (BPD). BPD is one of the most complex, functionally debilitating, and costly psychiatric illnesses for health care systems, with an estimated prevalence in the general adult population between 0.5% and 5.9%, and higher in clinical settings. Despite its significant disease burden, there are currently no approved pharmacological treatments for BPD. Patients are often prescribed off-label antipsychotics, which come with numerous side-effects. Vafidemstat, with its unique epigenetic mechanism of action, aims to address this unmet need.

Vafidemstat has shown promise as a potential treatment for BPD in preclinical models and in clinical trials, where it reduced aggressive behavior and improved overall disease severity. Recently, Oryzon presented the final results of vafidemstat’s PORTICO Phase IIb trial at the European College of Neuropsycopharmacology (ECNP) Congress, held in Milan, Italy, on September 21-24. PORTICO was a global, double-blind, randomized, placebo-controlled Phase IIb trial which evaluated the efficacy and safety of vafidemstat in BPD patients. The trial had two independent primary endpoints: reduction of agitation and aggression and overall disease improvement in BPD severity. In the absence of a well-established regulatory endpoint, the trial also included two secondary endpoints also exploring the reduction of agitation and aggression and overall disease improvement in BPD severity by different scales. PORTICO enrolled a total of 211 patients across the USA and several European countries, randomized 1:1 in two arms.

The final data from PORTICO show a significant overall improvement compared to preliminary top-line data released in January. The agitation and aggression of patients, as measured by the secondary endpoint STAXI-2 Trait Anger scale, showed a substantial, statistically significant and clinically meaningful reduction in the vafidemstat arm compared to placebo, with a p-value now of 0.0071 across Weeks 8–12 (previously p = 0.0259). The relative reduction in the vafidemstat group over placebo reached a maximum of 92.1% at Week 10, with an average reduction of 58.6% across Weeks 8–12. Additionally, another secondary endpoint, the Borderline Evaluation of Severity (BEST), an overall measure of BPD severity, also showed an improvement with regard to topline data, with nominal statistical significance now of p = 0.0260 at Weeks 8–12 (previously p = 0.0423). 

Vafidemstat continued to show favorable results over placebo across all primary and secondary efficacy endpoints, as demonstrated by T-Forest plot analysis. The Global Statistical Test (GST) confirmed a global treatment effect favoring vafidemstat, with the GST p-value showing now a statistical significance, particularly when considering global improvement in the severity of the disease and in agitation/aggression (p = 0.0362). Interestingly, vafidemstat-treated patients showed a reduced inclination towards self-harm, with only 1 patient in the vafidemstat group versus 6 patients in the placebo group. Consistent with previous clinical studies, vafidemstat was safe and well-tolerated.

Dr. Carlos Buesa, CEO of Oryzon said: “PORTICO marks a significant milestone in BPD research, as this is the first time, to our knowledge, that statistical significance has been achieved in a large, randomized Phase IIb trial in BPD. Our study demonstrated meaningful improvements, and vafidemstat seems to produce a holistic effect in the disease. In a recent End-of-Phase II meeting with the FDA we had the opportunity to discuss these results and a potential registrational Phase III study for the treatment of BPD. A positive response from the FDA would trigger immediate preparations for our PORTICO-2 Phase III trial, and would make Oryzon the first, and only, company with a drug in Phase III clinical development in BPD.”

Further boosting the commercial potential of vafidemstat are the recent decision-to-grant communications from several patent offices, including in Europe, Japan, Korea, Australia and Mexico, in two important patent families relating to the use of vafidemstat for the treatment of BPD and aggression and social withdrawal, respectively. These patents, once granted, will extend until at least 2038-2040 (excluding any potential patent term extensions that may provide additional protection), significantly strengthening Oryzon's patent portfolio and enhancing vafidemstat’s commercial life in large market indications like BPD. 

Beyond BPD, Oryzon is also investigating vafidemstat for other neuropsychiatric conditions, including schizophrenia, with the ongoing Phase IIb EVOLUTION trial, which is actively recruiting patients.

As the global psychiatric drug market is poised for growth, vafidemstat’s emergence as a potential BPD treatment offers a unique opportunity for both patients and investors. The lack of approved medications specifically for BPD and Oryzon’s potential to bring the first drug into Phase III in BPD places the company at the forefront of innovation in the field. With a robust pipeline and expanding patent portfolio, Oryzon is well positioned to make a significant impact in the treatment landscape for BPD and other psychiatric disorders.