ORYZON Announces Topline Results from Phase IIb PORTICO study of vafidemstat in Borderline Personality Disorder (BPD)

MADRID, SPAIN and BOSTON, MA, UNITED STATES, January 5^th, 2024 - Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with a strong unmet medical need, today announced topline results from the Phase IIb PORTICO trial, evaluating the efficacy and safety of vafidemstat in Borderline Personality Disorder (BPD).

Webcast/Conference Call Information

ORYZON will host a conference call and webcast on January 7, 2024 at 5:30 pm Pacific Time to discuss PORTICO Phase IIb results. To register for the event please click here. A replay of the webcast will be available on the company’s website after the event and will be archived for approximately one month.

Summary of Efficacy Data

A mixed model repeated measures (MMRM) completed on the multiple independent primary endpoints for overall disease as measured by the Borderline Personality Disorder Checklist (BPDCL) and for agitation and aggression by the Clinical Global Impression-Severity focused on Agitation/Aggression (CGI-S A/A) across weeks 8-12 showed for both endpoints a consistent reduction over the values in the placebo group throughout the treatment, which did not reach statistical significance (p = 0.41 and p = 0.25, respectively).

However, statistically significant overall disease improvement was achieved on the secondary endpoint Borderline Evaluation of Severity (BEST) across weeks 8-12 (p = 0.042). The BEST scale was designed to measure BPD symptom severity and adaptive coping responses including negative behaviors and actions such as injuring oneself, thoughts and feelings including mood reactivity, identity disturbance, unstable relationships, paranoia, emptiness, and suicidal thinking, and positive behaviors such as avoidance of self-destructive and/or self-defeating behaviors. The relative reduction observed in the vafidemstat-treated group over the placebo group was consistent throughout the treatment and reached a maximum of 38% at week 10.

Additionally, statistically significant improvement in agitation and aggression as measured by the STAXI-2, Trait Anger (p = 0.026) was also demonstrated across weeks 8-12. The Trait Anger scale (10 items) measures the disposition to experience angry feelings as a personality-like trait over time. The relative reduction observed in the vafidemstat-treated group over the placebo group was consistent throughout the treatment and reached a maximum of 80% at week 10.

It was also encouraging to note that all results favored vafidemstat treatment over placebo across the multiple independent primary and secondary efficacy endpoints. Furthermore, the Global Statistical Test (GST p-values) confirms a strong trend effect across all efficacy endpoints. GST is designed to globally address whether a treatment is efficacious across different aspects of a condition. The GST efficiently summarizes a global treatment’s effect when the disease is complex and multifactorial.

Summary of Safety and Tolerability Data

Vafidemstat was safe and well-tolerated. Adverse events (AEs) were generally consistent with the safety profile of vafidemstat seen to date, with no new safety findings. The number of subjects with Treatment-Emergent Adverse Events (TEAEs) was slightly lower for those receiving vafidemstat (57.5%) vs placebo (65.4%). Treatment-Related TEAEs were similar between groups (34.0% of subjects in the vafidemstat arm vs 31.7% in placebo). Those TEAEs leading to Study Discontinuation, Study Drug Withdrawal, or Study Drug Interruption were low overall. Regarding TEAE Severity, the majority were independently assessed by the investigators as Mild (48.1% of subjects in vafidemstat versus 57.7% in placebo) or Moderate (27.4% in vafidemstat versus 33.7% in placebo), with low numbers in both groups experiencing a Severe AE (4.7% in vafidemstat versus 3.8% in placebo). The majority of TEAEs Recovered/Resolved by the end of the trial. There were no deaths in PORTICO, and the only TEAE with sequelae was on placebo.

Dr. Michael Ropacki, Chief Medical Officer, Head of CNS Clinical Development stated, “The results provide support and a path forward for vafidemstat’s future clinical development as a potentially promising treatment for overall BPD disease and agitation and aggression. PORTICO’s results are highly encouraging given that vafidemstat improved overall BPD severity as reflected by the BEST Total score (p = 0.042), all efficacy results favoring vafidemstat over placebo, and the GST analysis. Likewise, the data continue to highlight vafidemstat’s promise to reduce agitation and aggression as reflected on the STAXI-2 Trait Anger (p = 0.026). To contextualize these findings, the observation that all eleven primary and secondary efficacy endpoints favored vafidemstat over placebo provides consistent support for a positive treatment effect, and indicates that further clinical development of this compound should be pursued. Finally, in a disease with no ‘gold standard’ measure, PORTICO achieved an important milestone by helping determine what endpoints should be carried forward, as well as establishing the effect size needed to design a well-powered future Phase III BPD clinical trial.”

Dr. Douglas V. Faller, Global CMO at Oryzon said “Vafidemstat is the only LSD1 inhibitor in clinical development for CNS indications and induces the expression of genes involved in neuronal plasticity. Vafidemstat also improves sociability, reduces aggression, and improves memory in models of neuropsychiatric diseases. LSD1 inhibition restores NMDR functionality in preclinical models. NMDR dysfunction is one of the proposed causes of BPD. Both our prior pilot study in BPD and now the current PORTICO study results showed consistent signals on reduction in both BPD severity and agitation/aggression (albeit assessed by different scales). Our next steps will be to meet with the FDA to discuss our findings from this study and plan with them a registrational trial. The information we have obtained in this study regarding suitable clinical endpoints in BPD, in which a gold-standard endpoint has not yet been established, will be critical in this planning.”

Dr. Carlos Buesa, CEO of Oryzon said “First of all, we would like to thank PORTICO participants, the sites, the investigators, and the teams that helped us achieve this major milestone. Although we have not met the primary endpoints of the study, we still consider the trial results to be very positive and promising. This is the first time, to the best of our knowledge, that a large, randomized Phase II trial in BPD had two secondary endpoints that met statistical significance reflecting clinically meaningful improvements in overall BPD severity and in agitation/aggression. In a disease with currently no approved drugs, and no well-established regulatory endpoints yet, PORTICO’s results across these important two endpoints are paving the way to define a registrational Phase III trial, based for the first time on a well-controlled study that has enrolled a truly representative real-world BPD population. We are also excited about our ongoing trial with vafidemstat in schizophrenia, where we are studying improvements in negative and cognitive symptoms.”

The company will present the comprehensive and full data package at a psychiatric conference and in a peer-reviewed journal publication.

PORTICO (EudraCT No.: 2020-003469-20, ClinicalTrials.gov Identifier NCT04932291) is a global double-blind, randomized, placebo-controlled, adaptive 14-week Phase IIb trial evaluating the efficacy and safety of vafidemstat at 1.2 mg/day in a BPD population. The study recruited a total of 210 patients, randomized 1:1 in two arms. The trial had two independent primary endpoints: reduction of agitation and aggression and overall disease improvement in BPD severity. As independent multiple primary endpoints, appropriate adjustments for multiplicity were made to ensure that statistical significance in either one is sufficient to declare success in the trial. In the absence of a well-established regulatory endpoint, the trial investigated several secondary and exploratory endpoints to determine overall improvements in the severity of the disease, as well as reductions in levels of agitation-aggression, anxiety, depression, and cognitive impairment. The trial also investigated the impact on suicidal ideation and explored several correlative biomarkers. An important aim of PORTICO was to learn what potential endpoints would be important to leverage in a future Phase III registrational trial. PORTICO included a total of 27 clinical sites, 14 in the U.S. and 13 in Europe (Germany, Spain, Bulgaria, and Serbia).