Company to host Conference Call and live Webcast on
An executive summary of the data to be presented at the 7th Sachs Annual
- Results across all efficacy endpoints consistently favored vafidemstat over placebo. Global Statistical Test (GST p-values) confirms consistent trend across efficacy endpoints
- The primary endpoints, improvement in Borderline Personality Disorder Checklist (BPDCL) and in agitation/aggression by the Clinical Global Impression – Severity Agitation/Aggression (CGI-S A/A), did not reach statistical significance
- Nominal statistical significance was achieved on the secondary endpoint Borderline Evaluation of Severity (BEST), an overall measure of BPD disease severity, at weeks 8-12 (p = 0.042)
- Nominal statistical significance was also achieved on the secondary endpoint State-Trait Anger Expression Inventory 2 (STAXI-2) Trait Anger, a measure of agitation and aggression, at weeks 8-12 (p = 0.026)
- Vafidemstat was safe and well tolerated, consistent with the overall safety profile to date
- Based on the efficacy and safety results, Oryzon intends to request an FDA end-of-Phase II meeting to discuss a registrational Phase III study for the treatment of BPD
Webcast/Conference Call Information
ORYZON will host a conference call and webcast on
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
Dr.
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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
About Oryzon
Founded in 2000 in
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) 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 has been 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 has also been 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. Currently, vafidemstat is in two Phase IIb trials in borderline personality disorder (PORTICO) and in schizophrenia patients (EVOLUTION). The company is also deploying a CNS precision medicine approach with vafidemstat in genetically-defined patient subpopulations of certain CNS disorders and is preparing a clinical trial in Kabuki Syndrome patients. The company is also exploring the clinical development of vafidemstat in other neurodevelopmental syndromes.
About Borderline Personality Disorder
Borderline Personality Disorder (BPD) is one of the most complex, functionally debilitating and costly psychiatric illnesses for healthcare systems, affecting between 0.5 and 1.6% of the general population. BPD patients often experience emotional instability, impulsivity, irrational beliefs and distorted perception, and intense but unstable relationships with others. Up to 10% of those affected die by suicide. Psychotherapy is the first-line treatment and while medications may be prescribed to treat specific symptoms, there is no FDA-approved treatment for BPD patients. It is estimated that around 1.4 million BPD patients in the
FORWARD-LOOKING STATEMENTS
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