Good afternoon and welcome to the Oryzon Genomics Virtual KOL event. At this time all attendees are in a listen only mode. A question and answer session will follow the formal presentations and fireside chat. As a reminder, this call is being recorded and a replay will be made available on the Oryzon website following the conclusion of the event. I'd now like to turn the call over to Michael Ropacki, Chief Medical Officer of Oryzon Genomics. Please go ahead Michael.
Thank you, Tara. I'd like to also thank our distinguished panelists and our audience of which we had almost 80 or more attendees register for this event today. The purpose is to discuss the potential FDA approved treatment for agitation and aggression as well as the overall treatment of BPD. Vafidemstat is an orally active brain penetrant LSD1 inhibitor which in the Phase II-B PORTICO trial showed promise in treating agitation and aggression. In Q2 of this year, the PORTICO 2 protocol and statistical analysis plan were submitted to the FDA. At this time I'm going to turn this over to one of our esteemed panelists, Dr. Fineberg.
Good, I guess. Afternoon on the East Coast, morning elsewhere. I'm glad to be here to talk a little bit about the importance of Borderline Personality Disorder as a psychiatric target. BPD affects 1- 2 out of 100 people around the world and it arises from a gene by environment interaction where people have an inborn sensitivity that interacts with their early childhood environment to yield severe interpersonal problems that take the form of feeling easily hurt, shamed, disappointed, and terrified of being left by other people. These problems can lead to dramatic efforts to solve those upsets through internal experiences of severe agitation and externally manifested experiences of aggression, including strong anger, verbal and physical destructive acts. Also, people can turn this kind of violence against themselves and unfortunately, as many as 10% of people who have Borderline Personality Disorder go on to die by suicide.
We are currently in a state lacking appropriate treatments for Borderline Personality Disorder. There are no approved drugs anywhere in the world for this and there are no FDA approved drugs for BPD. Importantly, drugs are prescribed because patients are asking for help and providers are wanting to help. Drugs are often used off-label but without really good evidence for efficacy for any specific symptom or for the whole syndrome. This leads to ongoing efforts to seek healthcare that are unsuccessful. Agitation and aggression has marked impacts on the ability of patients to benefit from healthcare. Imagine if someone is in a primary care office, they're trying to get treatment for their heart disease and they scream at their provider or they scream at the receptionist and can't get rescheduled.
This gets in the way of having a full medical treatment and a full life and leads to extraordinary economic and societal burden. Many people with BPD cannot work in the general workforce, cannot participate in full family life. This is really getting in the way and therefore we really see that from a safety perspective, from a societal citizenship perspective, and from an individual well-being perspective. Borderline Personality Disorder needs better treatments and they're currently not available.
Thank you, Sarah, for very well laying out and setting the table on how important this disorder is and how much need there is for treatments that are efficacious. Just to further set the table, I'm going to remind the audience of where we were with the Phase II-B program and then an update on where we are before we turn it over to our esteemed panelists for the Q&A session of this program. As a reminder, PORTICO was a global Phase II-B randomized double-blind placebo-controlled trial, and as a Phase II-B, one of the things you were attempting to do is to learn what endpoints to carry over into Phase III. We had a number of endpoints that we had as primary and secondary endpoints, and to note, we had multiple primary, not co-primaries.
We had multiple primary endpoints, including the measurement of agitation with the CGI severity focused on agitation and aggression, and then overall improvement on the Borderline Personality Disorder Checklist. Secondarily, secondary endpoints, rather, to measure overall disease, we had the Borderline Evaluation of Severity Over Time and the STAXI-2 Trait Anger Expression Inventory as seen here. On the left, we did not have statistical significance on the CGI-S focused on agitation and aggression overall in the trial, although we had a 12.2% reduction as compared to placebo on the secondary endpoint measuring the same symptom. However, we did have statistical significance with the p value overall of p of 0.0071 and a 58.6% reduction of symptoms as compared to placebo. Moving on to overall disease, what you see on the left is the primary endpoint, the BPDCL.
Similar story, not statistically significant, but an 11.2% reduction of symptoms as compared to placebo over weeks 8 through 12, and on the right, what you see is on a similar measure, the BEST, we did have statistical significance of a p value of 0.02 with a decrease of over 30% of overall disease symptomatology as compared to placebo. This is a forest plot, and what is unique here in my experience of over 20 years of drug development is that all of the data favored the drug over the placebo. Even trials that I've run that were positive, there usually is at least some endpoints that are favoring placebo. To put this in perspective for the audience, this is like flipping a coin over 20 times and getting heads every time. Mathematically, yes, it is possible. The probability of such event, however, is very low. Where are we now?
The FDA's feedback? We've had robust discussions with them back and forth out of the end of Phase II meeting. We've had three data packets that we've submitted to the FDA. The FDA has acknowledged that agitation and aggression is a possible therapeutic indication, as is seen in other diseases where there are approved therapies. The STAXI-2 Trait Anger as a primary efficacy measure was complemented in the Phase III protocol with the OASM as a key secondary endpoint. We'll get into more of that later on the call today. The Phase III protocol and the statistical analysis plan was submitted to the agency, and the qualitative research and the psychometric analysis that were requested by the agency have also been submitted, as well as our plans to do so in Phase III as well. We're expecting the FDA's response in the fourth quarter of this year.
At this point, I'm going to turn over the call to our esteemed panelists and start the Q&A session. We're going to start out first with Dr. Alan Schatzberg. Dr. Schatzberg, from your perspective, what do you think were the key factors that led to the FDA to recognize agitation and aggression as a clinically meaningful and approvable target in Borderline Personality Disorder?
Seventy percent of patients with borderline personality disorder have aggressive feelings and behaviors and agitation as part of their clinical picture. This often brings patients into emergency rooms because of interpersonal kind of difficulties. As Sarah Fineberg has pointed out, it causes problems at work for many of these folks and they're unable to really work with other people. It is a pretty well known set of symptoms that characterize the disorder and certainly characterize what clinicians have to deal with frequently when treating such patients. The idea that the FDA would go
for Targeting specific symptoms within a disorder for indications is not new. We've seen this with aggressive behaviors in autism spectrum disorder. We've seen it in companies looking for drugs that improve cognition in depression or in schizophrenia. We see it in anhedonia being a target in depression and other disorders, so it is pretty well known that these important symptoms can in fact be targeted. One of the things that helps is that there are objective measures that companies have already used and have been vetted, if you will, for assessing agitation and aggression. I think the other thing to keep in mind is that these symptoms like agitation, aggression probably have their own biologies. You know, when we're dealing with a lot of these disorders, they're heterogeneous or they have complex genetics, they have multiple biologies that are involved, multiple circuits, multiple neurochemicals.
Each of these may in fact encode for a particular type of behavior. Certainly aggressive behavior could be one of those that could be in fact targeted with very, very specific kinds of medications. All of these, I think, have led to the FDA really buying into looking at agitation and aggression as targets for treatment development in borderline personality disorder.
Excuse me.
Thank you for your perspective on that. That is very well received and appreciated. I'm going to advance this next slide as I move into a question for Dr. Fineberg. What and how would a targeted agitation aggression drug change in your clinical practice?
Yeah, I thought that we could look. Thanks for the slide. I thought that we could look a little closely at how we're going to measure this and think about what it's like for people. I'm thinking about a patient that I've had in the last few years in my practice who is desperate for care. She feels uncared for, she feels hurt, she feels angry. This is getting in the way of something that matters immensely to her, which is effective parenting of her school age child. Yet she finds that she's so quickly moved to anger. Here we have this item that we're going to be asking.
I have a fiery temper and when she gets angry, she's so nasty to her friends who would otherwise help her out with things, her child's school administrators who are trying to maintain his school scholarship, and her clinician here at the mental health center that she can't get the support she needs to address the most important things in her life. I think the STAXI-2 Trait Anger here is going to help us assess change for someone like this. This is the kind of person who we know can and will benefit from treatment if they can participate. The ongoing anger and aggression gets in the way of participating. Even a reduction enough that she could tolerate 10 minutes of setting with her clinician, even a reduction enough that she could get through a three minute phone call with the administrators at her child's school.
You could see how transformative those kinds of things would be for this kind of patient.
Yes, that sounds like a very dire need for this individual given how it impacts her daily life functioning. Thank you for sharing that with us from your real world practice. In terms of Dr. Hollander, Dr. Hollander, why is an epigenetic approach particularly attractive for agitation and aggression?
First of all, agitation and aggression really can be thought of as a transdiagnostic symptom domain that cuts across a broad range of different conditions. For example, in my research and clinical practice, I've been very interested in agitation and aggression that is prominent in borderline personality disorder, but cuts across developmental disorders like autism spectrum disorder, other conditions like intermittent explosive disorder, and rare conditions like Prader Willi syndrome, where this is a prominent symptom domain that cuts across different disorders. An epigenetic approach is very exciting because rather than just blocking, let's say, dopamine or serotonin receptors, for example, the LSD1 or the lysine-specific histone demethylation can regulate gene expression and brain circuitry that's much more upstream than the receptors that we often deal with with current treatments like the atypical antipsychotics.
By affecting things upstream, we can have more potent effects and more selective effects for the genes and for the brain circuits that are associated with this symptom domain. We can avoid a lot of the burden that we see associated with other treatments, the severe metabolic problems, for example, weight gain, type 2 diabetes that's associated with things like the atypical antipsychotics. Also, an epigenetic approach will affect underlying mechanisms like neuroinflammation or glutamate excitation that can often drive the agitation and lead to aggression in these conditions. It's a much more specific and targeted approach than currently available treatments.
Excellent. Thank you for sharing your perspectives on that. I'm going to move to asking Dr. Emil Coccaro a question. Dr. Coccaro, in your opinion, how does this tandem of primary and secondary endpoints de-risk the regulatory success? Especially considering there's a robust correlation between the STAXI-2 and in the OASM?
The important thing is to be able to measure a behavior. Even if you have one measure that reflects that behavior, there are going to be other pieces of that behavior that are not reflected by it. Having two or more outcome measures that focus on the behavior in question is going to give you greater power and greater certainty that you're getting an effect. The STAXI-2 is a sort of a personality measure of anger, and it's actually how angry do you feel more in general over a certain period of time. There's also a state version of it, but that's how you're feeling at this moment, not very variable. The other thing is looking at the actual behaviors, and that's what the Overt Aggression Scale-Modified for outpatient use does.
The OAS was created by Stuart Yudofsky, but it was really created for inpatient studies of serious mental illness and aggression there. What would happen is patients would be observed and every eight hours for a shift, the nurses would rate if something had happened, and then if something had happened, they would rate exactly what happened. You can't do that in outpatient studies. You actually have to ask all of the kinds of items for a particular outpost, and that's what we do with the OASM. We developed the OASM in preparation for study with fluoxetine, which was one of the first studies to look at aggression in personality disorders. Many of the subjects, borderlines, many of them had intermittent explosive disorders.
What we clearly showed was that over a 12-week period of time, you had a very nice reduction in aggressive behaviors and against a quantitative thing as opposed to simply feelings. That plan has separated out placebo from drug in a number of other studies involving fluoxetine and other kinds of drugs. Also, studies that I did with a colleague of mine, Mike McCluskey, where we did an anger management program, two different studies, same effect, decreased aggression compared to control. The most exciting result actually is recently from the Peter Fonagy group in England, which showed that when you look at aggressive individuals who were on parole, their mindfulness study reduced aggressiveness with the OASM far more than just in the control treatment. There are many studies that show that the OASM works in terms of looking at the ability to reduce aggression and the like.
The important thing also is that the STAXI-2 Trait Anger and the OASM are highly correlated, 0.7, 0.75, but that accounts for only 50% of each. So 50% of the STAXI-2 Trait Anger relates to 50% of the OASM. They overlap, but not so much so that you could use one instead of the other. This is really, I think, the best way to do it. It's something that we actually did in our studies where we had a questionnaire sort of like the STAXI-2 Trait Anger except we had a different one, and the OASM. The OASM always gets you effects. Again, the OASM is looking at actual behavior that the patient reports as opposed to how they feel because sometimes they may actually get less aggressive but may not feel like they're really that much better. In fact, they are, and that's why you really need both.
That's your wealth of experience with the OASM and the research that you did on the STAXI-2 Trait Anger with the OASM gives us a lot of assurance about the use of these endpoints. Thank you for providing your perspective on that. Before we move into some more questions, I just want to re-emphasize to the audience that Oryzon Genomics has had continued dialogues with the FDA starting in August of last year. Three data packages delivered in the first two quarters of this year, culminating in the press release around the submission of the protocol and the statistical analysis plan June 20th. Based on their feedback, we have added the OASM as a key secondary endpoint.
We added a psychometric analysis plan for Phase III and submitted our qualitative research protocols and discussion guides to further validate and demonstrate the content validity and the clinical meaningfulness of the STAXI-2 Trait Anger as well as the OASM. We've put in place a number of things to ensure the signal in our trial is tight, the variance is tight, like central reviews and some different rater training and digital compliance. We are very optimistic that this will give us an approval to proceed with Phase III. Where we're sitting right now is that we are waiting by Q4 of this year to have the feedback from them and anticipate the top-line readout from PORTICO 2 to be somewhere in the second half of 2028. With that, now I'd like to again move into more of a roundtable. Going back to Dr.
Schatzberg, drawing on your extensive experience of FDA interactions discussing different drugs, what precedents should investors keep in mind when they're evaluating behavior-focused endpoints like agitation and aggression in BPD? Dr. Schatzberg, you're on mute.
Thank you. There are a few things obviously that are important. I think as you heard from Drs. Coccaro and Eric Hollander, there are actually commonly used scales, both self-report as well as objective report, that can be used to measure both the degree of aggression, degree of agitation as well as measure change. They're sensitive to change, and they can be used to look at primary and secondary endpoints. I think that they're well validated. You heard that from Dr. Coccaro, who's done an unbelievable amount of work, and Dr. Hollander on the OASM. I think there's real reason to have some comfort that this is a manageable target that can be assessed.
Excellent. Thank you for that perspective. Dr. Fineberg, given your experience, frontline experience with BPD and thinking about the scales we're focusing on, and specifically the STAXI-2 Trait Anger, what makes this a strong choice for the primary outcome measure?
Yeah, thanks. I mean, I think that we talked a little bit about the STAXI-2 Trait Anger earlier and the very relevant questions that are part of it to help us understand this core issue, which is as you try to get better from BPD and, you know, despite a lot of stigmatizing information in the world, in the scientific and in the healthcare communities, there's strong evidence that people with BPD do get better and get better faster with effective treatment. You know, we really want to target some of the things that are getting in the way of patients being able to get better and providers being able to work with them to do so.
Being able to assess where someone is right now with anger and where someone is changing over time, which the STAXI-2 allows us to do effectively and importantly efficiently, will allow us to know if someone is getting better over the course of the trial and in ways that are highly relevant to the clinical work with BPD. We want to decrease aggression as the treatment, but we also want to decrease aggression in order to allow ongoing augmentation treatments, for example, psychotherapies over time, that kind of thing. There's a concern that given this patient presentation, patients might not do well in these trials. However, those of us experienced with the trials in my setting, I think in Dr. Coccaro's setting and also at Oryzon , have found that these patients are eager to be in trials.
They're eager to join trials, they're eager to participate to benefit themselves, but they're also really eager to give back to others. These people feel so isolated. Imagine feeling so angry that the people around you don't want to interact with you. You burn so many bridges so quickly. Being able to give back to the world is such a core part of being able to feel better. We've found that the STAXI-2 and trials like this one that have really novel approaches are rare. Doing a good job, being able to measure something that matters with a novel mechanism that might actually make change for people with BPD is, I think, going to be not only feasible, I think it has really promise to change the landscape for treatment.
Thank you for providing that perspective. As a quick reminder to the audience, PORTICO and PORTICO 2 have been designed to be the most real world trials done in BPD to date. What do I mean by real world? We allowed people with comorbidities that were typically excluded in other trials. We allowed people to be on other medications that were excluded in other trials. When these trials are done in a clean, vacuumous environment like a laboratory setting, you wonder where did these people come from? These don't really exist in the real world. Following on that, Dr. Fineberg, do you think the STAXI-2 Trait Anger would reflect real world improvements in aggression? If so, do you think this would make a shift in prescribing behavior?
Yeah. I mean, as I was thinking again about these questions and I think we had them on the screen earlier. You'll recall one of the questions was I have a really fiery temper. How much is that true for you? Right. Another question was I have verbal outbursts in response to, oh, thanks. Yeah, when I get mad, I say nasty things. Right. You can see how a small number of questions like this can really help us assess how someone is doing with respect to those real world problematic behaviors and critically treatment interfering behaviors. The things that get in the way of getting the medical care that keeps you alive. The things that get in the way of making a positive psychotherapeutic relationship that keeps you from completing suicide. The kind of things that keep you from having positive social relationships. We should really care.
I think the trial can, using this measure, measure those things that really get in the way as far as whether clinicians would prescribe more a medication like this. I think patients and clinicians join in desperation for something that would allow them to be able to work together more effectively. Even this year I had the opportunity to speak to a large group of clinicians who were and patients and families. Sorry, just checking my power here. I need a power problem with my computer. I'm just going to switch ports. I'm so sorry, the power source on my computer has become unreliable. I'll just say briefly, I think it's be transformative.
Excellent. Dr. Hollander, should Vafidemstat demonstrate positive results in BPD, do you see a viable path forward to treating agitations in other conditions such as ASD?
Absolutely. First, you know, following up on this idea of agitation and aggression as a transdiagnostic concept, Oryzon Genomics has also conducted some studies like the Reimagine trial where they looked at individuals with borderline personality disorder, attention deficit hyperactivity disorder, and ASD and found significant improvement in agitation and aggression using a range of different kinds of scales as outcome measures. In autism in particular, there's a clear pathway towards FDA approval, and I'd like to remind people that both Abilify and Risperidone received FDA approval for the treatment of agitation and aggression in individuals with autism spectrum disorder, so pediatric autism individuals, so they understand that, you know, in these complex conditions, really what we're looking at is improving core or associated symptom domains within that condition.
They've already approved medicines for this sort of domain in a condition like autism spectrum disorder, so they're comfortable with this approach. I think that the outcome measures that were chosen for this particular study are valid and appropriate outcome measures in borderline personality disorder. The other thing that's kind of exciting about this epigenetic mechanism is that the preclinical studies with Vafidemstat have suggested that you can get substantial benefit in animal models or in human studies and that you can get really durable or long-lasting benefits as well, again without a lot of the adverse events that are associated with some of the other medicines they use to treat individuals with this symptom domain. I think there's a clear-cut pathway.
I also think that in the rare conditions where there's significant agitation and aggression, there would be an important pathway in terms of orphan drug approval for the symptom domain as well.
Excellent. Thank you for sharing your perspective. Dr. Coccaro, considering you are the author of the OASM, which is a PORTICO key secondary endpoint, in your opinion, what makes this a strong choice as a key secondary clinician reported outcome?
What makes it a strong choice is its very strong face validity. I mean, you're asking people about outbursts they've had in the past week, and then you go through the outbursts and you check to see how much of verbal behavior is involved or behavior directed at other objects or other people. There's also a rater question where they do sort of a zero to five global thing on anger and also aggression. It all correlates with other things that it should correlate with. It correlates with life history of aggression, again about 0.5. In this study in particular, it correlates nicely with STAXI-2, but again, not so much that you can use one versus the other.
The fact that it does move, it can move down or up depending on what's happening with a person's behavior, that's what makes it a very, very strong measure for this kind of study.
I'm just going to put this out there for anyone on the roundtable here to address. Maybe more than one of you would like to tackle this. Do you see a meaningful unmet need, clinical need for managing emotional dysregulation and reactive aggression in psychiatric disorders such as borderline personality disorder? How well do the current off-label treatments address these symptoms? Finally, in your opinion, does Vafidemstat meaningfully address this gap in treatment of emotional dysregulation and aggression?
There's nothing really out there for emotional dysregulation in the first place. I mean, some of the work that I've done and Eric's done and Alan, actually Alan, I forgot, did a study before, you mind, where they gave fluoxetine to borderlines to see, you know, what it did for them. It actually worked. The SSRIs are very helpful, but they're not a magic bullet and they don't work for everybody. In fact, from some data that I have, the worse your serotonergic system is, meaning the worse, more dysfunctional, the less likely the SSRIs are going to be able to work. That's because if the system is really dysfunctional and the drug works directly on serotonin receptors, and receptors aren't working very well, then that drug's not going to do much. We don't really have drugs that do it.
This drug, of course, is a totally different mechanism of action. I think what's exciting about this drug is what's happening is it's becoming clearer and clearer that pathology, psychopathology has a lot to do with problems with connectivity between different areas of the brain. This drug will probably work to increase the connectivity of various areas of the brain. That's going to be a very novel way to try to treat somebody, but also can give us a lot more bang for our buck in terms of treating aggressive agitation, the like, because again, as Eric said, it's an upstream effect and will affect a whole lot of things downstream.
Excellent. You mentioned Dr. Schatzberg and Dr. Hollander have done some research in this space. If you'd like to touch on the unmet need for managing this emotional regulation and how current treatments address these or how Vafidemstat will address these, please chime in as well.
Yeah, I think the current treatments are kind of wanting in terms of really attacking these kind of core symptoms. You get some mild relief in patients, but the patients often have quite residual symptoms even when you treat them. I just want to give an example for the people in the audience. Because some people might say, oh, this is, you know, it's kind of a nuisance, but it's not. Not much of a disorder. We started doing these studies years and years ago, as Eric pointed out, as Emil pointed out. I just want to give you one example. We were doing a study with Thioridazine and Scott Aronson, who's gone on to do great things with brain stimulation down at Shepherd Pratt, was my postdoc and my resident.
We put ads in the paper looking for people who were kind of aggressive and had borderline symptoms, et cetera. We get a response one day to call back, and we call back the patient, and it turned out the patient hadn't responded. It was one of the people at work who couldn't stand how agitated and aggressive the person was that called in for her. It has a huge impact on people's adjustment. As Sarah pointed out, it really makes some of these people unfit to work because they can't fit in with their fellow workers. It's a serious problem that needs treatment. The current drugs, I think, are pretty weak.
Yeah.
I would agree with what Alan and Sarah and Emil have said. You know, agitation and aggression leading to violence is really the problem of our time right now in society. Our emergency rooms are clogged up with people who have done violent, agitated, and aggressive kind of things. In our hospitals, we have patients who are attacking other patients or patients who are attacking staff. There are large direct and indirect costs associated with that. Agitation and aggression, as we've heard, impacts relationships and leads to divorce. It's associated with high rates of suicide, for example. It's associated with people being arrested and clogging up our legal system as well. The current available treatments, whether they're atypical antipsychotics or anticonvulsants or SSRIs, clearly are not doing the job and are associated with significant burden in terms of adverse events.
This timely approach with an interesting mechanism of action, borderline personality disorder, is really an unmet need. We don't have approvals here. You've heard from Sarah how it impacts so many different aspects of functioning and leads to disability. This is very timely.
I'd like to add two anecdotes, one of which is touching and the other one's funny. In some of our studies, we had a patient who didn't get better on the study drug. He turned out to be on placebo. When the study was over, we put him on fluoxetine. What we heard later from his family was that the daughter said it was a young kid, said, oh, now we have our daddy back. Because he was very angry. He would blow up. Then he just settled down. That's the touching one. The funny one was we had somebody who also responded, who did respond to fluoxetine. He called me up one day and said, I think the pharmacy has made a mistake and they've given me generic Prozac. This is at the end of Prozac's patent life.
You know, it's possible that, you know, there was a generic version available. There wasn't yet. I said, there is no generic Prozac. What does the label on your pill bottle say? He runs back, he gets it and says, Prilosec. I said, oh, I bet you don't have any heartburn. He says, oh, actually, no, I don't. That's because it's a heartburn drug. So I've heard of a script for Prozac. He took it and within a week or two, he's back where he was in the study. No, he was out of the study by that point. Not only do these drugs work, but they clearly affect their personal lives.
Excellent. Thank you all for those insights. We have about 15 minutes left. I'd like to turn this back over to Tara for audience Q&A.
Great. Thank you so much, Michael. Please hold for a brief moment while we pull for questions. Our first question comes from Shan Hama at Jefferies. Please go ahead, Shan.
Hi there.
Thank you for taking my question. Very useful. Thank you so much for all of that information. What do you view as an ideal timeline for a patient to rehabilitate? Whether that's defined by having better relationships with family, going to work, overall better quality of life on a medication like Vafidemstat, and how is that compared to current off-label treatments? Thank you.
I could start and then maybe others could weigh in. Thank you for this question. It's really important to think about the sort of burden that treatment imposes on people and the burden treatment imposes on the system. One thing that we've not yet raised today is that the standard of care for personality disorders in general and borderline personality disorder in particular is currently very high intensity psychotherapy.
There are five or six different evidence-based psychotherapies and in their full evidence-based form, the least intensive one is two hours a week over a year or two years. The most intensive one is 20 hours a week plus additional outside phone coaching for the six to 12 months.
It's a job.
Yeah, that's a full time job. That's right. That's exactly what I was going to say. It's a full time job to get psychotherapy. It requires extremely well trained providers that are rarely available, especially in middle America and other parts of less resourced world. If we're able to see the kinds of benefits that were seen on the timeline of the PORTICO trial, we would be rapidly acting compared to the current standard of care. If we could maintain at those levels, we would be also achieving better tolerability. The most widespread psychotherapy for Borderline Personality Disorder is called dialectical behavior therapy or DBT. That treatment, although effective for about, I'd say, half of the people who stick it out, one third of people do not make it past the first session. They either don't go or they don't start.
In this trial we saw very good tolerability and that is a key aspect of this trial because people with BPD often can't get into the psychotherapies that would help them because of things within themselves, even if they can access them, which is rare. When people are prescribed medications for BPD, they often find that the side effects are intolerable. People with BPD seem to be more sensitive to side effects than do other patient groups. The low side effect profile in this trial is particularly remarkable and worth noting so much.
Great. Thank you for the question, Shan. We have a few questions that Jonathan Ashoff from Roth sent in, so I'm going to read them. What is the minimal treatment effect physicians want to see out of the Vafidemstat to justify recommending it for patients? Is it honestly just as simple as there's nothing else?
Sarah, do you want to take this or Emil?
Sure.
I think we've talked about this some and I'm thinking about some of the things that Alan was saying. You know, people really are suffering here. It's not that there's nothing else. There are these very intensive psychotherapies, and some people do benefit a little from these other drugs that have some big downsides and don't treat everyone well. One of the difficulties in the current treatment landscape is that people are so variable in their responses to the available treatments, and the available treatments are so hard to access and stick with. I think that doctors would want to see something that reliably treated the thing. I think you could see here that the error bars separate, meaning that the variability does not by any means overcome a signal.
I think we should feel cheered by not just the difference between drug and placebo, but the relative consistency of the response here, which means that if I, as a prescriber, reach for this medication, I can have increased confidence that it'll target more of the people that I prescribe it to. That's not something we can count on for most of the psychiatric drugs on our shelves.
If I may add on to that and from the last question as well, at week six, you saw on agitation and aggression, the endpoint separating. By week eight, you see that there was an overall reduction of over 30% between drug and placebo on agitation and aggression for the timeline. On overall disease, a similar thing at week six with the treatment of overall disease versus placebo having a reduction of 24.2% by week eight.
We're talking about two months. You know, that's really fast compared to years of psychotherapy or years of trying one drug after another after another, which are ineffective and intolerable.
Great. Thank you both. Jonathan's next question. What is the minimum treatment effect that it must show in Phase III to narrowly achieve statistical significance?
I don't know if this is one for the panel or Oryzon, so I'll take a crack at it. We saw an effect size above 0.23 in our Phase II-B PORTICO program, and we're planning to power PORTICO 2 likewise.
Great. His next question. Of the 70% of BPD patients, a panelist said, has aggression and agitation, what fraction of those patients have enough aggression and agitation to warrant prescribing it? Should Phase III hit its primary efficacy endpoint?
Well.
I think most of the patients have sufficient aggression and agitation.
You know.
To warrant treatment approaches for it. I think these are not just incidental findings. They're kind of core findings for many, many people. If they have sufficient, obviously sufficient severity, I would say probably of the 70%, probably 70% of them have sufficient agitation that you would want to target it for treatment.
To make the diagnosis, you need to have the criteria, but it has to cause significant distress and impair functioning to get the diagnosis right.
To make the criteria, to count the criteria, the behavior in that criteria has to be associated with some functional or subjective stress, not simply the overall diagnosis. The specific criteria also must be referable to problems.
To bookend this, I will add that in our PORTICO 2 Phase II trial, there were very few people that were screened that did not meet the threshold for sufficient agitation and aggression, meaning that this was widespread, as the panelists here have conveyed, in those that were screened for potential participation.
Great. Our next questions come from Jason McCarthy at Maxim Group. Given the heterogeneity of BPD, what patient profile is most likely to benefit from Vafidemstat, and how should clinicians think about patient selection?
I think the approach here is to target the agitation and aggression. I mean, that would be the likely proved indication. Any borderline patient that has sufficient agitation and aggression to be impairing would be a very good candidate.
Yes. Mortal impersonality, as Sarah can expound on, does have subtypes. You've got the more aggressive, suicidal kind of folks, but you also have people who have issues with identity. They're not sure who they are, what they should be doing for the rest of their lives, feeling empty. That group's probably not going to—I wouldn't expect those people to get better with this drug if the drug's really working on aggression. We won't know. Although I don't think many of those subjects will get in the study because you need to have some aggressiveness to get in there.
We're defining aggression here as crossing symptom domains. There are nine criteria for borderline personality disorder. We've not reviewed them in detail here today, but I'll say that anger and suicidal ideation are probably the most prominent ones that are going to contribute to the agitation and aggression criterion here. However, mood lability, which you might think of initially when you hear it as increasing and decreasing depression, also includes increasing and decreasing strong emotions of anxiety, of guilt, and of anger, among others. Now we have at least three different of the nine criteria, and you only need five to meet criteria for the disorder.
You can see how, even if we just expected, which is not really the case, that symptom distributions were even across the nine symptoms, almost anyone who meets criteria for the disorder is going to have to have agitation and aggression in order to meet criteria just by symptom counts. We've heard already that 70% of people have significant agitation, agitation and aggression in the BPD group. To summarize, this is a prominent problem and the various symptoms manifest in a way that's consistent with agitation and aggression. Furthermore, the impulsivity symptoms are really, I think, best conceptualized as people making maladaptive attempts to solve problems that are upsetting. When you feel really badly, you try to get away from those problems by driving too fast, taking a drug, having sex with someone in an ill-advised way, eating too much food, et cetera, et cetera.
Those efforts are really actions consistent with an agitated and aggressive state, I might add.
Alan and Emil and I were involved in studies that sort of cut across borderline personality disorder and intermittent explosive disorder. One of the nice things about borderline personality disorder in terms of clinical trials is that the frequency of the agitation and aggression is such that you can have a more stable baseline and show greater separation. There's an advantage actually doing studies in borderline personality disorder.
Yet another argument for intervention, right.
Yeah.
Great. Thank you all. Jason at Maxim's next question. Does the COBENFY miss in the adjunctive setting for schizophrenia change the opportunity for vafi or does the company look to prioritize this indication more than it did prior?
I don't know if that's a panelist question, Tara, or more of a company question, but I think that the fact that Karuna's old KarXT drug and now COBENFY with BMS didn't get the indications that we were expecting or they were hoping for, I think does provide an opportunity for Vafidemstat more than it did in the past. I will turn it over to our clinicians if they have a different perspective here.
I think that really does come down to a decision for Oryzon, you know, from the company perspective. I do think that there are going to be lots of potential uses for this drug in other disorders that have similar symptoms, you know, I think it's likely that you'll see follow
on applications.
And I will remind the audience that Oryzon does have a Phase II trial in schizophrenia that is ongoing called Evolution, where we're focused on negative symptoms specifically and cognitive impairment associated with schizophrenia. More on that to come in the future.
Great. Thank you both. Our next question comes from Luisa Morgado at Kempen. Please go ahead, Luisa.
Hi all, thank you so much for taking my questions.
I was interested to get a bit of your thoughts on, first of all.
What is the relation exactly between agitation and aggression into suicide
Ideation, if there's any.
How do you see more specifically for the autism disorder, how do you see the Reimagine results versus or compare it to the current drug landscape. You mentioned that there are already two drugs approved. Curious to hear your thoughts here.
Maybe this is a good question for Dr. Eric Hollander.
I mentioned the Reimagine trial, which was sort of an open-label basket trial across different conditions, one of the conditions being autism spectrum disorder. There was a nice reduction in various measures of aggression that occurred relatively quickly in that population as well as the others. I know that Oryzon has also received a grant from the EU to do a Phase II study in autism spectrum disorder as well. I did mention that Abilify and Risperidone have been approved by the FDA for pediatric autism, and the target is irritability or agitation and aggression. Those medicines have a large effect size and they work relatively quickly. What we have found is, often when people are treated starting early on and over the lifespan, there's really substantial metabolic issues that are an important complicating factor. Having something that doesn't have those types of adverse events would be very helpful.
The preclinical data and the early clinical data also suggest that Vafidemstat may have some benefit in other core symptoms in autism, such as the social deficits and the repetitive behaviors, which are two of the core symptom domains in autism that really are not addressed by Risperidone or Abilify, which is sort of a proof of the irritability. It's possible that this drug, which has a better adverse event profile and epigenetic effects, may target some of the core symptom domains as well as this other associated symptom domain in that condition.
Great, thank you for the question, Luisa. Our next question comes from Joseph Hedden at Rx Securities. Please go ahead, Joseph.
Hi there.
Thanks for taking my questions. I'm just wondering if STAXI-2 Trait Anger and the OASM address self-directed aggression as well as they address outward aggression. Perhaps from Oryzon's perspective, do you balance, you know, the types of aggression that patients are experiencing across the arms of the PORTICO 2 trial.
Thanks.
The OASM has an item in it for self directed aggression, and people who are aggressive also tend to have, are more at risk for self directed aggression, but the relationship is not as strong as you might think it is. We've seen very little self directed aggression in our trials. I should say self directed aggression in terms of suicide is different than self directed aggression that's part of self injurious behavior because they're driven by two different things in terms of psychology and motivation, but also biology.
The second part of that question, can you remind me again towards the company?
Yeah, I guess. Do you balance the kind of types, we've spoken of aggression as kind of like a broader domain. Do you balance the types of aggression that patients are experiencing in the arms of the trial, or is it kind of a cruder.
Just as a reminder, as I stated earlier, the PORTICO was a very real world trial as compared to some of the other drugs like Olanzapine and as recently as Brexpiprazole. If you look at our inclusion exclusion criteria, but specifically to your question, there were no controls to try to balance besides randomization into both arms, again reflecting more of that real world nature. As long as somebody had a very basal amount of agitation and aggression, they were allowed into the trial. Despite that, we did see some very marked changes on the STAXI-2 Trait Anger. The OASM correlates between 0.7 and 0.75 with this scale, enough that it gives you comfort, but not so much that you're saying you're measuring exactly the same thing. My thoughts are that we should expect, fingers crossed, similar things out of PORTICO 2.
I think what he was also asking was if the different aspects of aggression are being measured. Certainly for the OASM they are. There's verbal aggression, aggression against objects, aggression against others, and aggression against self. The typical outcome measures are the combined score, but you can look individually at them as well.
Okay, thank you, that's very helpful.
Thanks for the questions, Joseph. Our final question comes from Arron Aatkar at Edison. Please go ahead, Arron.
Hello everyone.
First of all, we just wanted to.
Say thanks very much for putting on the event.
You know, it's great to see this
insight from the key opinion leaders in
combination with the management.
Thanks also for taking my questions. I'm curious to know how you see a potential therapy like Vafidemstat fitting into the current sort of psychotherapeutic element of the treatment for BPD.
Would it sort of complement or replace certain aspects of the treatment approach?
We complement it.
Yeah. I mean that's not being tested directly here. However, it's my thinking that we often need a way in and we need a way of. We need a first step and a bridge for people who are either not ready to do a psychotherapy, who have a job and can't afford another full time job, as we mentioned earlier, who are not in a place because of agitation and aggression to benefit from psychotherapy yet. You have to be sort of ready, you know. One of the things that we thought about in my work and that I think this drug could relate to is sort of psychotherapy readiness, you know. I think that this drug is relevant to people who are and who are not in a position to access and participate in psychotherapy.
The hope would be that in future downstream work there could be clarification of the role of this drug as a way in to help people do further more character changing work over time.
Excellent, thanks very much. My final question, I was wondering if you could touch upon the sorts of challenges you face in diagnosing BPD in the first place, I'm curious to hear your thoughts on if you think the availability of a specifically approved drug for the indication might sort of shift the landscape.
Oh, thank you so much for this. As a final question, this is a topic close to, I think, my and other people's hearts on this call. I strongly suspect that stigma is partly driven in the healthcare setting by helplessness. If you have to say to someone you have a condition that I don't fully understand and I wouldn't know how to help with, you would find yourself reasonably reluctant to disclose a diagnosis. Whereas if you have a clear understanding of what the thing is and a clear understanding of a way forward that you could actually offer, I think the reluctance to provide an accurate diagnosis and to learn how to provide an accurate diagnosis decreases.
In my view, diagnosing borderline personality disorder is not only not rocket science, it's often an enormous relief to the people who receive the diagnosis. In fact, my students talk about this tone of voice shift that they hear as they talk to people on the phone for research studies. I hear this also in the clinic. We start asking the first question and then the second question. At first the person is suspiciously saying yes or reluctantly saying yes. By the third or fourth or fifth question they say how did you know? Are you saying that this is a thing? Is it a thing that I could get help for and is it a thing that other people have? Are you saying I'm not crazy? I'm not by myself and there's a way to help.
People are disappointed it took this long to find out and so relieved to have a way forward and someone who's willing to talk about it. I very much hope that the answer to your question is yes. People will be less reluctant to diagnose, will be more willing to receive the simple educational steps to learn to diagnose, and then will be able to offer people a way forward when we have treatments that have demonstrated efficacy. We should be working hard to find out.
This has been a fantastic panelist and roundtable discussion. I want to again thank our esteemed panelists and all of those who have submitted questions and submitted them ahead of time. In closing, I'd like to ask if there is one brief closing statement from Dr. Schatzberg, Dr. Fineberg, Dr. Hollander, and Dr. Coccaro and then we can wrap up this call.
Dr. Schatzberg?
Strong unmet need that hopefully we have an interesting solution, which brings to the fore a novel mechanism of action, considerable hope for decreasing these kinds of symptoms in various disorders.
Dr. Fineberg?
We should be cheered by the positive tolerability profile of the drug and the experience of the company in working successfully with these patients in trials.
Dr. Hollander?
I'm excited that this has sort of a next generation epigenetic mechanism. I think that agitation and aggression is really a trans diagnostic concept that cuts across conditions. I think that borderline personality disorder is a great place to start in terms of investigating this.
I would agree with everything that's been said. I think this trial is actually very nicely placed to answer the questions we're posing in terms of can this drug work for agitation, aggression, can it help borderline personality disorder? If it does what I think it's going to do, it's probably going to be an interesting drug to try in other disorders where connectivity seems to be an issue, because we think that's going to be a critical thing for therapeutics as we go down the road.
Excellent. Thank you again to everyone involved. With that, Tara, I will turn it back to you.
Great. Thank you, Michael. Thank you to all of our panelists in the audience for joining. This concludes today's webinar. You may now disconnect.