ORYZON announces submission of Phase III protocol to FDA to initiate PORTICO-2 trial of vafidemstat in Borderline Personality Disorder (BPD) patients

Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company and a European leader in epigenetics, announced today that it has submitted the clinical trial protocol for its Phase III PORTICO-2 trial to the U.S. Food and Drug Administration (FDA) to initiate a registrational trial to evaluate vafidemstat in patients with Borderline Personality Disorder (BPD). The PORTICO-2 trial builds upon the encouraging results observed in the previous PORTICO Phase IIb study, where vafidemstat demonstrated significant and clinically meaningful reductions in secondary endpoints measuring aggression and overall BPD improvement. Aggression is a key symptom domain in BPD that currently represents a major unmet medical need and will be the primary endpoint in PORTICO-2. Vafidemstat, an orally active LSD1 inhibitor with a novel epigenetic mechanism of action, has shown a favorable safety and tolerability profile across multiple clinical studies.

"The submission of PORTICO-2 to the FDA marks a major step forward for Oryzon and for the field of neuropsychiatry of personality disorders," said Carlos Buesa, Chief Executive Officer of Oryzon. "Borderline Personality Disorder is a highly disabling condition with no approved pharmacological treatments. 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. Vafidemstat has also the potential to manage aggression in other neurodevelopmental and neurodegenerative disorders, and we are planning to explore it in a new trial in aggression in ASD."

The Phase III protocol was developed through multiple interactions and constructive exchanges with the FDA. Its final design was further refined with the scientific contribution of 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).

PORTICO-2 will employ 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) (clinicianrated) as key secondary endpoint. Additional secondary endpoints will evaluate broader clinical improvements in BPD symptomatology and quality of life.

A dedicated Key Opinion Leader (KOL) 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. Details will be announced in a further communication.

PORTICO-2 will be a randomized, double-blind, placebo-controlled, multi-center study to assess both the efficacy and safety of vafidemstat in BPD patients, and aims to randomize 350 patients.

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. More than 75% of BPD patients attempt suicide, and the rate of completed suicide has been estimated to be approximately 10%, 50-times higher than in the general population. Currently, there are no FDA-approved medications specifically indicated for the treatment of BPD, underscoring the urgent need for novel therapeutic approaches.

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 IPCEIEU Grant.

About Oryzon

Founded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS (Phase III-ready) and iadademstat in oncology (Phase II). The company has other pipeline assets directed against other epigenetic targets like HDAC-6 where a clinical candidate, ORY- 4001, has been nominated for its possible development in CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com

About Vafidemstat

Vafidemstat (ORY-2001) is an oral, CNS-optimized LSD1 inhibitor. The molecule acts on several levels: it reduces cognitive impairment, including memory loss and neuroinflammation, and at the same time has 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 (AD), to normal levels and also reduces social avoidance and enhances sociability in murine models. In addition, vafidemstat exhibits fast, strong, and durable efficacy in several preclinical models of multiple sclerosis (MS). Oryzon has performed two Phase IIa clinical trials in aggressiveness in patients with different psychiatric disorders (REIMAGINE, see Ferrer et al, Psychiatry & Clin Neurosci, 2025, doi.org/10.1111/pcn.13800) 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, and the pilot, small-scale SATEEN trial in Relapse-Remitting and Secondary Progressive MS, where anti-inflammatory activity was also observed. Vafidemstat has also been tested in a Phase II in severe Covid-19 patients (ESCAPE) assessing the capability of the drug to prevent ARDS, one of the most severe complications of the viral infection, where it showed significant anti-inflammatory effects in severe Covid-19 patients. Vafidemstat is currently advancing as a Phase III-ready asset in Borderline Personality disorder (BPD) following completion of the global, randomized, double blind Phase IIb PORTICO trial (final data presented at ECNP-2024). Following receipt of the minutes from the End-of-Phase II meeting with the FDA to discuss PORTICO’s results, the company announced plans to move forward with a Phase III PORTICO- 2 trial in agitation/aggression in BPD (PhIII protocol submitted to FDA). Vafidemstat is also being investigated in a double-blind, randomized, placebo-controlled Phase IIb trial in negative symptoms of schizophrenia (EVOLUTION trial, recruitment ongoing). The company is also deploying a CNS precision medicine approach with vafidemstat in genetically defined patient subpopulations of certain CNS disorders, as well as in neurodevelopmental syndromes, and is evaluating the feasibility of conducting clinical trials in autistic conditions like Fragile X syndrome and Phelan-McDermid syndrome.