Oryzon Genomics has submitted a Phase III clinical trial protocol to the FDA for PORTICO-2, a registrational study evaluating vafidemstat in patients with borderline personality disorder (BPD). The submission represents a significant milestone in addressing an urgent unmet medical need, as no FDA-approved medications currently exist specifically for treating BPD.
The PORTICO-2 trial builds upon encouraging results from the previous PORTICO Phase IIb study, where vafidemstat demonstrated significant and clinically meaningful reductions in secondary endpoints measuring aggression and overall BPD improvement. Vafidemstat is an orally active LSD1 inhibitor with a novel epigenetic mechanism of action that has shown a favorable safety and tolerability profile across multiple clinical studies.
Trial Design and Endpoints
PORTICO-2 will be a randomized, double-blind, placebo-controlled, multi-center study aiming to randomize 350 patients. The trial employs two clinical outcome measures for aggression: the STAXI-2 Trait Anger scale (patient-reported) as the primary endpoint, and the Overt Aggression Scale-Modified (OAS-M) (clinician-rated) as the key secondary endpoint. Additional secondary endpoints will evaluate broader clinical improvements in BPD symptomatology and quality of life.
The Phase III protocol was developed through multiple interactions and constructive exchanges with the FDA, with final design refinements incorporating scientific contributions from internationally recognized psychiatric experts, including Dr. Alan Schatzberg (Stanford University), Dr. Eric Hollander (Albert Einstein Medical School), Dr. Emil Coccaro (Ohio State University Wexner Medical Center), and Dr. Sarah Fineberg (Yale University).
Addressing Critical Medical Need
BPD affects approximately 1-2% of the general population and is characterized by pervasive emotional instability, impulsivity, interpersonal dysfunction, unstable self-image and frequent episodes of aggression and self-harm. The disorder carries devastating statistics: more than 75% of BPD patients attempt suicide, and the rate of completed suicide has been estimated to be approximately 10%, which is 50-times higher than in the general population.
"Borderline Personality Disorder is a highly disabling condition with no approved pharmacological treatments," said Carlos Buesa, Chief Executive Officer of Oryzon. "With its novel epigenetic mechanism, vafidemstat has the potential to become the first targeted therapy specifically addressing aggression and overall improvement in BPD, offering real hope for patients and clinicians confronting this serious disorder."
Broader Therapeutic Potential
Additional exploratory data from earlier Phase IIa studies suggest that vafidemstat may also reduce aggression in other patient populations, including Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and Alzheimer's Disease (AD). The company is planning to explore this further in a new trial in aggression in ASD to be conducted within the activities of the Med4Cure IPCEI-EU Grant.
Vafidemstat's Clinical Development
Vafidemstat (ORY-2001) is an oral, CNS-optimized LSD1 inhibitor that acts on multiple levels: it reduces cognitive impairment, including memory loss and neuroinflammation, while providing 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.
Oryzon has performed two Phase IIa clinical trials in aggressiveness in patients with different psychiatric disorders (REIMAGINE) and in aggressive/agitated patients with moderate or severe AD (REIMAGINE-AD), with positive clinical results reported in both. Additional finalized Phase IIa 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.
Company Background
Founded in 2000 in Barcelona, Spain, Oryzon is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. The company has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS (Phase III-ready) and iadademstat in oncology (Phase II).
A dedicated Key Opinion Leader webinar is planned in the coming weeks to discuss the PORTICO-2 study design, the substantial unmet medical need in BPD, and the role of aggression as a clinical target.
