As a reminder, this call is being recorded, and a replay will be made available on the Reviva website following the conclusion of the event. I'd now like to turn the call over to Dr. Lax Bhat, Founder, President, and Chief Executive Officer of Reviva Pharmaceuticals. Please go ahead, Lax.
Thank you, Tara. Good morning, everyone. My name is Lax Bhat. I am the Founder, President, and CEO of Reviva Pharmaceuticals. Before I begin the presentation, I would like all the viewers to see the forward-looking statement displayed here. Reviva is a late-stage pharmaceutical company focused on developing next-generation therapies for the central nervous system, respiratory, and metabolic diseases. We use chemical genomics-driven technologies to develop novel drug candidates. We currently have two proprietary platform therapies in development, as announced in today's press release. We are going to present the phase III RECOVER open-label extension trial, long-term safety, tolerability, and efficacy results of brilaroxazine in schizophrenia. The key opinion leaders present here, Dr. Marder and Dr. Ereshefsky, will be presenting the clinical results. On behalf of Reviva, I welcome you all to this webinar. The agenda for today's webinar is highlighted here.
They begin with the introduction of key opinion leaders, and then the key opinion leaders present here. Dr. Marder will be presenting the efficacy results, and Dr. Ereshefsky will be presenting safety, tolerability, biomarker data, and then compliance. Then, right after that, we'll open the session for questions and answers. See, I'd like to introduce key opinion leaders. The key opinion leaders, Dr. Stephen R. Marder. Dr. Marder is the Daniel X. Freedman Professor of Psychiatry, the Vice Chair of Education, and the Director of the Section on Psychosis at the University of California Los Angeles, Semel Institute for Neuroscience and Human Behavior. He is also Director of the Veterans Integrated Service Network, VISN, 22 Mental Illness Research Education Clinical Center for the Department of Veterans Affairs. Dr. Marder's research has focused on improving the lives of individuals with psychotic disorders, particularly schizophrenia.
His research, supported by the Veterans, the Brain and Behavior Research Foundation, and the National Institute of Mental Health, has focused on the development of pharmacological, psychosocial, and rehabilitation approaches for improving functioning and quality of life. He led the National Institute of Mental Health Metrics Initiative, which provided guidance for the development of pharmacologic agents to improve cognition and motivation in schizophrenia. He also led the National Institute of Mental Health Network for trials of medications for improving cognition in schizophrenia. From 2016- 2018, he was the President of the International Society of CNS Clinical Trials and Methodology. He is considered an expert on clinical trials and methods for complex CNS disorders, particularly schizophrenia. Dr.
Marder has received the Exemplary Psychiatrist Award from the National Alliance on Mental Illness, the Stanley Dean Research Award of the American College of Psychiatry, the Alexander Gralnick Award from the American Psychiatric Association, the Kempf Award from the American Psychiatric Association, the American Psychiatric Association Award for Research, the Wayne Fenton Award for Outstanding Clinical Care from Schizophrenia Bulletin, and the Lieber Prize for Schizophrenia Research. The next KOL speaker, Dr. Larry Ereshefsky. Dr. Ereshefsky is a retired Professor of Psychiatry, Pharmacology, and Psychiatry at the University of Texas. He's also Chief Scientific Officer, Owner of Follow the Molecule LLC. Dr. Ereshefsky has over 45 years of career. He applies his experience as a clinician, scientist, and investigator to develop treatments and innovate clinical methodologies to make a difference in the lives of patients with neurodegenerative and psychiatric disorders.
He has contributed significantly to several drug approvals spanning neurology and psychiatry. He has designed, implemented, supervised, and conducted over 125 CNS and clinical pharmacology trials ranging from first-in-the-patient through proof-of-concept implements, patient bridging studies, and has overseen large global phase III registration trials. Dr. Ereshefsky's contributions from a unique perspective of a clinical scientist have supported clinical development, planning, pharmacokinetics, and pharmacodynamic evaluations, translational strategies, and methodological innovation for schizophrenia, depression, bipolar disorder, and Parkinson's disease, Alzheimer's disease, and pain indication. He currently focuses on strategies to de-risk early development through proof-of-concept. Currently, he is the Chief Scientific Officer and owner of Follow the Molecule, providing consultancy services to pharma CROs and technology vendors. He is also CSO for clinical sciences by CenExel Research. He is a retired Regents Professor of Pharmacy, Psychiatry, and Pharmacology from the University of Texas.
As co-head of the Advanced Pharmacology and Evaluation Lab at the University of Texas, his team made pioneering contributions to understand the relationship of pharmacogenetics, drug interactions, and the environment upon the pharmacokinetics and pharmacodynamics of drugs. He served twice on the FDA Psychopharmacological Drugs Advisory Committee. His PharmD and residency in Psychopharmacology and Clinical Pharmacy were at the University of Southern California and LA County Medical Center. He is board-certified in clinical psychopharmacy. Before I hand over the presentation of clinical data, I would like to take a moment and then quickly highlight a high-level summary of the development made on the schizophrenia program. I'm pleased to announce the phase III RECOVER trial long-term efficacy, safety, compliance, and schizophrenia. The study successfully met the endpoints and objectives. We have announced the phase III RECOVER double-blind study results.
They are on our website, and then web links are given on this slide below. To our knowledge, based on the multiple trials conducted and then treated to date, close to 1,000 patients, we believe that brilaroxazine has a differentiated clinical profile. With respect to efficacy, it is a strong efficacy both in acute schizophrenia and stable schizophrenia with durable multi-domain efficacy across the patient population. We have seen improved safety and tolerability compared to historical data of the standard of care. High adherence as well. To our knowledge, the data generated today shows over a 50% better adherence outcome. Both efficacy and safety data are further supported by multiple biomarkers. Some of the biomarkers data, even in the long-term treatment, we'll be presenting today. Here is the summary of the trials conducted.
We have completed multiple trials, that is, including from phase I, phase II-b , and the clinical pharmacology studies required for supporting NDA application. A large phase II study in 234 patients met primary and then secondary endpoints. Large pivotal phase III registration trial in 411 patients as well met primary and then secondary endpoint. Today, this morning, we announced the full data set for long-term safety and efficacy data for brilaroxazine. It's an open-label extension trial of RECOVER double-blind study, and then as well as some new patients enrolled in the study. Besides these clinical trials, we completed required NDA-enabling safety pharmacology, toxicology, carcinogenicity study that typically required for submitting an NDA. With this background, I would like to invite Dr. Marder for presenting the efficacy data of the long-term extension trial. Dr. Marder.
Thank you very much, Dr. Bhat. It's a pleasure to present this very interesting data from an exciting new compound. As I think most people in this audience know, schizophrenia is a relatively common disorder. It affects about 1% of the world population and about 3.5 million people in the United States. There are major sort of gaps in the treatment of schizophrenia that include tolerability and efficacy. If you look at the figure on the right, it focuses on the major symptom domains of schizophrenia and sort of demonstrates that impairments in these domains are related to dysfunctional serotonin and dopamine signaling. The different domains include the cognitive impairments of schizophrenia, negative symptoms, the sort of lack of drive and motivation that's common, mood symptoms including excitement and depression, as well as the cardinal symptoms of schizophrenia, which include positive symptoms such as hallucinations and delusions.
Antipsychotic drugs, up until recently, demonstrated their effectiveness largely in the positive symptom domain. There are major sort of unmet needs in the areas such as negative symptoms and cognitive deficits. We'll talk about that more as we look over this very interesting data on brilaroxazine. Just a review of the pharmacology of brilaroxazine. It's a serotonin-dopamine signaling modulator. It has affinity for a number of dopamine and serotonin receptors, but it seems to differentiate in a number, in a couple of areas. It has a substantial D4 dopamine activity. If you look at the affinities, and again, for affinities, a low number is greater affinity. It has a particular affinity for 5-HT2B receptors, which may explain some of its unique clinical effects. This may include its effects in addressing the inflammatory and immune dysfunctions in schizophrenia, which really is an unmet need.
This slide lists some of the other pharmacological targets, but a particular characteristic of brilaroxazine is that it has very little activity off-target. What I'm going to talk about is largely the open-label extension study. For context, this study followed a double-blind trial that compared brilaroxazine 15 mgs, 50 mgs, and placebo in hospitalized patients with acute schizophrenia. This was a four-week trial. Following the trial, the open-label extension included two populations. One, individuals who rolled over from the double-blind trial, as well as new patients who were added to the trial. Again, the open-label extension included patients who were relatively stable, and I'll discuss that when we look at the baseline characteristics. The primary endpoint in the double-blind phase of the study was reduction in total PANSS over the four-week period.
For the safety study, we'll look at sort of both clinical efficacy as well as labs and body weight. That safety data will be presented largely by Dr. Ereshefsky. My focus will be on the efficacy data that we've learned from the open-label extension. Just to serve a reminder from the double-blind safety part, the effects of brilaroxazine were really quite substantial. If you look at the effect sizes for total PANSS, they were very large. For context, many studies in schizophrenia and major depression are able to come with effect sizes of about 0.4. The large effect sizes for PANSS total and positive symptoms, I think, kind of demonstrate the efficacy of brilaroxazine. Moreover, the discontinuation rates during the acute trial were very, very low, only 16% on brilaroxazine versus 22% on placebo.
If you look at the right, it gives another hint about the efficacy of brilaroxazine on negative symptoms. This occurred from a study of digital biomarkers, mostly revolving around voice recordings. This was able to distinguish a population of individuals who, by the biomarker, had prominent negative symptoms. As I mentioned before, negative symptoms represent really an important unmet need in the treatment of schizophrenia. Much of the long-term disability related to the illness comes from the lack of motivation and drive and the apathy that is a major problem. What you'll notice is that if you take the patients who demonstrated prominent negative symptoms, you find much larger effect sizes. For PANSS total, it's about 0.9. For the Marder Negative Symptom F actor, this is from a factor analysis of the PANSS that I did several years ago. It's again 0.6, 0.8 for PANSS.
Social cognition, for the personal and social performance, which is a measure of functioning, again, there's a large effect size of 0.6. You'll also see during the talk by Dr. Ereshefsky that there were interesting effects of brilaroxazine on markers of inflammation, as well as hormones such as prolactin and thyroid T3. Oops, let me go back one. This is the baseline data from the brilaroxazine studies. What you could see is it includes the double-blind phase as well as the pooled data. You see this is a population slightly biased towards men, which is common in schizophrenia because the illness has men seem to develop the illness earlier than women. The age was about 39 on average. These are people who had been ill on the average for more than a decade. Baseline PANSS score for the open-label extension were about 70.
This is a population of people who would be kind of in clinical settings, such as my clinic where we treat schizophrenia. At baseline, they had a burden of both still positive symptoms and negative symptoms at baseline. The efficacy evaluation included a number of instruments. As I mentioned, the total PANSS, which I think is the most commonly used scale for measuring psychopathology in schizophrenia. We looked at both PANSS positive and negative, as well as social cognition factors. Also about positive symptoms and agitation. As I mentioned, the personal and social performance, which is a measure of daily function and quality of life, and the clinical global impression, which looks globally as a clinician would look at a patient.
The study was very carefully implemented with state-of-the-art methods for assuring the quality of the data, which included the rater training and calibration, as well as recalibration, independent review of video coded assessments to verify that the PANSS scores were valid, and blinded data analytics to monitor and reduce potential sources of noise and random error. In other words, it used state-of-the-art methods for assuring data quality. Oops. Sorry. This graphic looks at the overall total PANSS score over the one-year trial. To recall, if you look at the first four weeks, this was the double-blind phase, followed by the initial three groups during the open-label extension. What you'll see during the open-label extension, starting at four weeks, there were continuing and sustained decreases in psychopathology. This means that the positive clinical effects of brilaroxazine are sustained over a one-year period.
You could also see that the amount of improvement, looking at the rollover patients starting at the zero baseline, is substantial, about 46.1 point decrease in those who were originally assigned to 15 mgs and 49.6 in those on 50 mgs. I neglected to mention that during the open-label extension, the clinicians determined the dose of brilaroxazine. This looks at positive symptom scores over a six-month period and the 12-month period. You could see that there were substantial and large decreases in both the six-month and 12-month trial. It was a five-point decrease at 12 months for the open-label extension and a substantially larger amount if we take patients from the original baseline and include the rollover patients. You'll see similar findings for other dimensions. This is for PANSS negative symptoms.
You'll see again that the patients in both the rollover patients and those started continued to show improvements in negative symptoms over both six months and 12 months during the trial. This is important because although this isn't the ideal place to study negative symptoms, improvements in negative symptoms over the course of 12 months provide a suggestion that this drug has particular effects on negative symptoms that aren't secondary to the improvements in psychosis. These slides look at both the Marder factors at six months and 12 months, and you could see the very large improvements at both times. Looking at depression and anxiety symptoms, and again, at both six months and 12 months, you could see continuing improvements on brilaroxazine. Depression and anxiety, I didn't mention it before, but those are particularly important.
A lot of the suffering of individuals with schizophrenia are related to the common dysphorias that are associated with the illness. This looks at social cognition. Now, a lot of the disability of patients in schizophrenia is related to their inability to sort of function in a social world where being able to recognize social signals and to be able to react in an appropriate manner is severely impaired. This can lead to isolation, a feeling of failure. Medications that address these impairments of social cognition are really an important unmet need. At both six months and 12 months, you could see continuing improvement in the open-label extension on brilaroxazine. If one looks again at agitation and excitement symptoms, one sees the same thing, both improvement at six and 12 months.
General psychopathology gives you sort of a larger picture of some of the pathological symptoms, both somatic symptoms and other symptoms that relate to kind of the dysphorias that are associated with schizophrenia, and perhaps give you a hint about the tolerability of the drug and how acceptable it's going to be in routine clinical settings, such as the clinic that I run at UCLA for psychotic patients. Again, you see substantial and sustained decreases in psychopathology. At six months, it's about 4.7 points during the open-label extension, 8.7 at 12 months. It looks at the open-label extension that starts at baseline and goes through the 12-month period. You could see substantially greater improvements. Again, it's indicating that this is a medication related to substantial and sustained efficacy.
The personal and social performance scale gives you an idea about how the drug performs on sort of the functioning of the patients, both related to symptoms, but more related to functioning, their ability to sort of react in a social world, vocational improvements, improvements in sort of independent living, which are important in schizophrenia. You could see during the open-label extension, sustained improvement at six months as well as 12 months. I think the 12-month data really stares out at you, the amount of improvement over this period. You could see in the one looks at the rollover patients where you could look at the entire 12-month period, you see 31.9 point improvement at 15 mgs and 33.7 points on the 50 mgs. Again, very large improvements. The CGI-S is sort of a global measure of how a clinician views the patient.
You could see for all of the patients on the CGI-S, which sort of asks how the patient has improved since baseline. You could see substantial improvements at six months as well as 12 months. If you look at the proportion of patients who showed a greater than one point improvement in CGI-S on the rollover patients, it's 100% of the population, again, indicating sustained efficacy that's meaningful. This sort of provides a look at significant improvement over the entire sort of reviews the trial. I want to draw your attention to the treatment discontinuations over the open-label extension, which was only 35%, which shows that this seems to be an agent that's really acceptable to the patient population. Again, as you listen to Dr.
Ereshefsky's talk, you'll see other hints of the tolerability of the drug, which may explain the fact that there's high treatment adherence, as well as its effect on neurotrophins like brain-derived neurotrophic factor, which may be related to cortical plasticity. It's related on cytokines, inflammatory markers, as well as hormones. In conclusion, the open-label extension, together with the double-blind phase, demonstrates that brilaroxazine is an agent with a wide spectrum of efficacy that includes both positive and negative symptoms, dysphorias related to agitation and mood. There are suggestions that it improves social cognition and general psychopathology, and it seems to have positive effects on measures of functioning and quality of life. The studies that were done were of high quality with careful data monitoring. The efficacy was demonstrated by rather substantial effect sizes during the double-blind phase that, as you'll see from Dr.
Ereshefsky's talk, which is to follow, the side effect profile seems like it'll lead to acceptability in clinical settings. Again, this may be an agent which will be effective in both acute settings as well as in clinics that treat chronic schizophrenia. With that, I will complete my talk, and I'll turn it over to my friend and colleague, Larry Ereshefsky. Thank you.
Thank you very much, Steve, for Dr. Marder. We go back many decades, and we have worked on the first-generation antipsychotics, and I know both really happy to see our patients do so much better on second-generation drugs. We're now looking for, if you will, the next wave of drugs that improve outcomes beyond symptom control of acute psychosis. I will mention that at the University of Texas, I ran a state psychiatric hospital research unit.
I worked with the most ill patients, going back to long-acting injectables, through clozapine, through many of the treatments, and have had the pleasure of working very closely with Steve, with Dr. Martin, for decades. He truly is one of the great leaders in our field. It is a great honor to be part of this presentation with him. Taking a look at that past, we've come a long way, but there's a lot more that we need to do. The current generation of drugs certainly do better than the early drugs where we were literally plagued with severe extrapyramidal symptoms of movement disorders, akathisia, tardive dyskinesia, and discontinuation rates in the real world were well over 50%-70%. The greatest challenge we had was keeping patients on medications.
The current medications in the second-plus generation, although better than that, still have issues with long-term tolerability. Recovery and remission are still the exception to the rule, and that really ultimately is our goal. Even relapse prevention, which is a more basic requirement of a medication for schizophrenia, is less than 50% by the second year. What that results in in the clinic is polypharmacy, combining multiple medications, multiple antipsychotics, multiple medications to treat side effects, runs the risk of high levels of drug-drug interactions, including those cytochrome P450s. Ultimately, you get a high rate of discontinuation and a poor quality of life. Of the current generation of drugs, we see metabolic side effects, especially the metabolic syndrome, which includes weight gain, diabetes type two, dyslipidemia, hypertension. We still have side effects tied to prolactin and thyroid that contribute to sexual dysfunction.
We have a long way to go, and we already have heard about the wide array of symptoms that need to be addressed to make these drugs truly effective. There is a growing area that I will explore that I'm excited about in neuroinflammation that may be a driver for improvement of negative symptoms and cognitive impairment, as well as the fact there's immune dysfunction associated with these chronic psychiatric illnesses. An illustration of both chronicity of the illness and why relapse prevention is so critical is you're looking at level of functioning against your age. Schizophrenia typically afflicts people in the late teens, early 20s. What you can see here is it's the prodrome. These folks are not, if you will, completely normal clinical high-risk youth that are identified that progress to schizophrenia and other psychosis.
However, with first episode and there is brain damage, there's progressive brain tissue loss. The inset is showing ventricular atrophy, the enlargements of the open space, meaning the cells are being reduced in number. This is progressive. First episode of psychotic relapse, second episode, third episode. Into the fourth episode, there is accruing damage. Beyond that phase, at some point, you're into a more chronic relapsing illness. Treatment resistance can develop. Part of this is this progression in brain tissue loss. Part of it is the devastating symptoms of the illness and impoverishment in the social domains, accruing negative symptoms. It's multifactorial as to what's happening here. If we can reduce the rates of exacerbation and relapse, we may be able to modify how much damage is done and how quickly. Looking at first the four-week data, and then we'll go into the open label.
This is a very busy slide, but it's giving you at a shotgun level of the adverse events, the treatment emergent events for brilaroxazine 15, 50 randomized with placebo, as shown. You can see that at the overarching level of just total numbers of adverse events, there really is no difference across the three treatments. The discontinuation rate shows very low discontinuation in the 16-18% range. Remember that these are acutely psychotic individuals being treated. That's giving you a sense of tolerability and control of symptoms against the placebo discontinuation rate, closer to 22%. The most common side effects are really benign. Those occurring in more than 5% of participants are somnolence, basically sleepiness, and headache. That's remarkable.
In the good old days, you would have dystonic reactions, pseudoparkinsonism, akathisia, and on and on, things that were really difficult to both manage for the long term and to keep people on their drugs. I will be focusing more on the metabolic changes in the open label because these are where the current generation of drugs still have some challenges. Here we saw in the short four-week trial, there was some weight gain against placebo. One has to remember we're taking acutely exacerbated folks who may not have been eating well, may have been sleeping on the street, may have been in crisis in a variety of settings, putting them into a clinic, providing them with three meals a day and snacks, and not surprising to see some shifting in weight as your symptoms improve. Cholesterol is a marker against metabolic syndrome as well.
You can see that there were reductions in these key cholesterol LDL measures against placebo. Then looking at extrapyramidal, there are a lot of zeros and tiny numbers, meaning almost no effect in this area, which is a great improvement. I guess I'll click twice. There it goes. Did it skip a slide? Hold on. Here we go. Here's the 52-week trial. I should mention to you, I'm at 83 degrees north of latitude, about 1,000 miles or less from the North Pole on an expedition ship. I guess thanks to Starlink, so far, so good. Anyway, to move into the 52-week data, as you can see here, same type of construction of the data across three dose levels. There is no placebo, of course. That always is going to temper some of what we can interpret from this data.
Looking across the line here at treatment emergent adverse effects, remarkably low for an effective drug over a year long. You can see the discontinuation rate, how low it is due to an adverse effect. That is why we believe there is an impact on adherence. Remember that the acute study is in clinic. This is now outpatient. There is a lot less supervision about taking medications. We are talking about a remarkably durable response here. The treatment adverse events shown here now, greater than 2%, headache, insomnia, some sleep disturbance, tremor, mild, are really all benign and very low numbers. The metabolic changes are noteworthy in that they are far lower over a year than they were over the four weeks. I am going to focus on those in a minute. The extrapyramidal symptoms basically stay benign.
Here is a look more closely at body weight change. You have the 15 and 50 mg doses of brilaroxazine, which, of course, is what was randomized in the four-week trial. In the open label, there was a flexible dose between 15 and 50. One can see from this data at both the six-month and 12-month time points that the highest dose of 50 mgs in one year has a weight gain of 1.2, 1.3 kilos. That is indicating that there really is a very, very modest, if any, effect on weight in the long term where it matters.
If you look at the body weight change in the rollover patients, the third of the subjects who rolled over, and then 21 are on 50 mgs in the original randomization, you can see the weight gain is 1.2 kilos now over 13 months of treatment. Lipid profile, again, in the open label is shown here across both the doses and the pool data. The pool data is probably the most important. Notice that the 50 mg, the highest dose, seems to have a beneficial effect, a reduction in cholesterol and LDL that then holds up as a group effect across all dose levels. You can see changes from baseline in the bottom text for both the LDL and the cholesterol.
We are talking about a medication that is reducing lipids, certainly not increasing them, and having a nearly weight-neutral effect over 13 months. Here are the changes now portrayed for the acute and stables back to back or side to side, if you will. Again, cholesterol and LDL, the reductions are more robust the longer you're on the drug, which also means that the effect of the drug is not having a negative effect on dyslipidemia or on the metabolic risk profile that we are concerned about with other atypical second-generation antipsychotics. You can see both the placebo from the original acute trials, and then you can see the doses across the three dose levels. The numbers are basically all negative reductions in lipids occur with this drug, both acutely and chronically. Now we'll get into some of the hormonal effects.
This is looking at prolactin in the open label trial over 12 months of time. It's important, first off, to note that hyperprolactinemia is very common in our patients. Many of our current generation of drugs elevate prolactin two- to tenfold above the normal range. This is a serious problem for our patients for a number of reasons. This includes both patients with schizophrenia and other psychiatric disorders like bipolar, where antipsychotics are used. First off, prolactin elevations can be associated with immunologic disease such as MS. Elevated prolactins chronically are a health concern in a general sense. In a specific sense, the hyperprolactinemia is associated with weight gain and type two diabetes.
There certainly is breast tenderness and gynecomastia and galactorrhea, meaning that you can have, when the prolactins are exceedingly high, as occurs with D2 blocking drugs, you can certainly see milk expression even in males, which is not only embarrassing but is extremely disconcerting and will lead to discontinuation of medications. A more important insidious effect, perhaps, is that hyperprolactinemia can lead to sexual dysfunction. That can be lack of libido in men and women, also erectile dysfunction in men. When you take a look now at the data in the graphs, you can see that across the dose levels and the pooled group data, there is a substantial reduction in prolactin. In fact, the prolactin levels on average are now within the normal range or slightly above normal versus being well above normal previous to this.
This, to me, is a very important improvement over the older D2 blocking drugs. Remember that this drug is a D2, D3, D4 partial agonist antagonist. It is not a straight-on D2 blocker. It has agonist effects which mitigate the prolactin elevations you see with some of the older medications. Now we're looking at thyroid, something that's less closely looked at over the years, frankly. First off, there are reports that hypothyroidism, lower T3 hormone, lower T4, are reported in patients with schizophrenia, especially those with negative symptoms. We know that low thyroid is associated with mood disorders, especially depression. Elevation of thyroid hormone from low levels is of health benefit for a variety of reasons. Hypothyroidism can certainly lead to obesity, immunologic disorders. Thyroid hormones are implicit in cell signaling and important for modulation of a variety of neurotransmitters, dopamine, serotonin, glutamate, and GABA.
These are all integral to our treatment of psychiatric illness. The increases shown here, especially if one looks at the 50 mg group and then the pooled data, are increases in T3, the most potent thyroid hormone. There is a resultant decrease in TSH, thyroid stimulating hormone, which is the brain's way of activating the thyroid gland when it feels there is a deficit in thyroid. A decrease in TSH is exactly what you expect to see when you treat hypothyroidism with thyroid supplement. You are basically seeing that to a little bit of a degree here. The direction of change adds perhaps an additional dimension to this drug's effect on a variety of symptoms. As I mentioned, the prolactin and thyroid effects very well can contribute to sexual dysfunction. In fact, the data here is quite compelling in looking at the sexuality functional scale.
There is improvement in both males and females. This CSFQ is a standardized scale used in many clinical trials. What we are looking at in general is sexual dysfunction in schizophrenia is above 55%-60%. That is linked to negative symptoms, poor adherence. If you're not functioning, this is going to affect self-esteem and your social skills and everything else tied with having a healthy sense of self. This dysfunction does impact quality of life, is a leading cause of poor adherence, and can lead to secondary depression and worse. Here we see the functional scales for males and females increasing, which is a reduction in dysfunction at a significant level at both six months and 12 months.
It is important to note that, if anything, the effect is increasing over time, which is exactly what we see with many of the symptoms that we observe with Dr. Marder's report. These are the inflammatory biomarkers. I do have to say that to me, this data is, in some ways, it's the most exciting because it's new. You do not see biomarker data of neuroinflammation for basically drugs during clinical development. We already heard about BDNF, brain-derived neurotrophic factor. Indeed, this is, if you will, one of the good guys. It reduces neuroinflammation. It improves neuronal signaling. Plasticity means you can recover better from damage. You have better memory. A host of things can improve when BDNF increases.
BDNF then drives a number of these cytokines, which are, if you will, the damaging chemicals in the brain, the peptides that can cause neuronal loss, inflammation, and a variety of illnesses beyond schizophrenia and depression. You have the interleukins. Almost all of them are indeed significantly reduced over the 12 months. Another important one that has been studied for decades across many illnesses is TNF, tumor necrosis factor alpha. That has a dramatic decrease. TNF alpha is one of the other key signaling systems in the brain, along with BDNF, that drive a lot of the negative neuroinflammatory change that occurs. This is also consistent beyond the interleukin stories, the ILs, with a new group of drugs called the chemokines. These are small proteins, and they play a role in immune response by signaling other immunologic cells.
MIP and MCP also have reductions. This is a very broad effect across a host of inflammatory markers. How much this contributes to improvement in schizophrenia is an important question to answer. We do know from other illnesses, such as Parkinson's, where I did some of the earliest work in neuroinflammatory markers and severity of motor dysfunction in Parkinson's, the higher the interleukin inflammatory cytokines, the more impaired the patient with Parkinson's was in terms of motor symptoms. There was a correlation to staging of Parkinson's illness and the interleukin shown here. The same neuroinflammatory markers are being looked at in other neurodegenerative disorders. There are treatments that target the inflammatory system for Alzheimer's and other illnesses in that degenerative space. There is something here that I think is quite important. It does require more study.
It does require some analyses to correlate these changes against the symptoms themselves. But this, to me, represents potentially another gear for our antipsychotic drugs to treat schizophrenia. And so this is exciting data. And you're looking at the changes over 12 months of time. So it is a sustained effect. And I really hope to see more about this as this drug proceeds in development. To summarize, the drug is certainly well tolerated over the year or the 13 months when you take the double-blind trial, and then a third of the patients did roll over. Common treatment emergent adverse events are all minor, if you will. There are no serious adverse events which might lead to hospitalization or an emergency room visit. As we also mentioned, there's a 35% total discontinuation rate, which over a year suggests a high rate of adherence or compliance to therapy.
There are no meaningful extrapyramidal motor symptoms such as akathisia or, again, dystonic reactions or pseudoparkinsons. That is a major part of tolerability for a patient as well as quality of life. The metabolic side effects are among the greatest concern with current atypical antipsychotics such as olanzapine, quetiapine. Here we are seeing mild weight gain in the pool data. The weight gain is not dose-dependent. The highest dose has the least weight gain. There are some positive signals on lipids, cholesterol, and LDL. These are all very important for long-term treatment benefit. Also pointed out that prolactin elevation is not going to occur with this drug. Prolactins will be reduced from prior therapies typically into the normal range, which can lead to then improvements in sexual function as well as a reduction of risk for other illnesses.
Lastly, in a long-term study, especially, it's important to note there is no detection of significant cardiovascular disease, gastrointestinal side effects, nor any incidents of drug-induced injury. At this point, thank you for your attention. I'm going to turn it over to Tara for Q&A.
Great. Thank you so much, Dr. Ereshefsky. At this time, we'll be conducting a question-and-answer session with our speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Ram Selvaraju at H.C. Wainwright. Please go ahead, Ram.
Thanks very much for taking my questions. Maybe we could start with Dr. Marder. I think it would be helpful if you could characterize the efficacy profile of brilaroxazine in the context of other widely used marketed atypical antipsychotics.
In particular, if you could comment on whether you think it's more important the effect on positive symptoms in terms of its magnitude, comparatively speaking, or if you would classify the impact of brilaroxazine on negative symptoms as being the primary differentiating factor versus existing atypicals.
That is a great question. It is really hard to compare the efficacy on positive symptoms without a direct comparison trial. I think one can look at the effect sizes in acute schizophrenia to get an idea that it certainly seems to have excellent efficacy against positive symptoms, probably comparable to other antipsychotics. Regarding negative symptoms, and again, I think that is particularly important, I think these trials really provide evidence, but I think we will need to see in clinical settings how that sort of manifests itself in sort of improvements in negative symptoms and apathy.
I think one of the most attractive features of the drug from what we can see now seems to be that negative symptom efficacy, which seems to be vigorous and sustained. Dr. Bhat may want to add something to this answer.
See, again, Ram, for the positive symptom, every single drug up to date showed good efficacy on positive symptoms because without positive symptom efficacy, we can't have total path reduction. That's been the trend we have seen. However, not all antipsychotics up to date showed good efficacy on negative symptoms, especially on more than one trial. We have seen in the phase II and the phase III, including the long-term treatment, a sustained efficacy for negative symptoms. We believe this efficacy for negative symptoms is really robust. That's going to make change in patients' life if it's approved. Thank you.
Great.
Just very quickly for Dr. Ereshefsky, I had a couple of questions regarding the safety data from the OLE. In particular, again, from a comparative standpoint, if you look at, for example, the impact on thyroid function, thyroid hormone levels, to what extent is what we see with brilaroxazine unprecedented relative to existing atypical antipsychotics? Do we have data indicating that that's pretty much what a lot of the other marketed atypical antipsychotics also do? With respect to the metabolic profile, I was wondering if, specifically drilling down into the weight gain aspect, if there's really any data that was collected during the OLE that would indicate that, in effect, not only is the weight gain magnitude itself not particularly clinically meaningful or significant, but maybe there were body composition changes that were, in effect, positive.
Maybe some evidence that, in fact, the weight gain is an indicator of, broadly speaking, improvement in overall patient well-being.
Let me unmute. Thank you for that question. Several difficult parts to that question I might mention. Thyroid hormone has not been adequately well studied. I do not remember off the top of my head all of the open-label trials done over the last several decades as to how many looked at change in thyroid. Nothing stands out in my memory of seeing an upward T3 signal and TSH going downward in a one-year trial. I think partly, and this gets into your second question as well, the effect on prolactin is pretty dramatic. You have a significant reduction in that. You are seeing this convergence, if you will, of a low set of adverse effects. I do think there is a small weight gain here.
I'm not sure over one year with a patient significantly doing better on positive and negative symptoms and social symptoms that there wouldn't be, if you will, a modest behavioral weight gain just from this social change. I'm not aware of the BMI data, so that is something that I will defer to Dr. Bhat about. I also want to mention that a variety of our drugs clearly have significant weight gain, changes in lipids that go up dramatically, changes in blood pressure, which do not occur here. When I look at the net effect of the metabolic and the weight signal, I'm looking at an increased risk of metabolic syndrome. There is no hypertension here. There's no cardiovascular illness of any magnitude at all. The direction is going the right way. Now, the BMI is a great question, and I'm going to defer to Dr.
Bhat for that answer.
Yep. Thanks, Dr. Ereshefsky. Yeah, in a good number, good percentile of patients in this study, we have seen where we have seen the increase in weight, their BMI at the beginning of the baseline somewhere around 16.5-18. So they are very low. They are basically, they were underweight. See, as in the clinical studies, we had to report any weight gain seen. With the weight gain by end of the study, their BMI was still below 25. That means the weight gain seen in this patient is still a healthy weight gain, possibly as Dr. Ereshefsky mentioned. See, at the beginning of his presentation, some of these patients, when they're ill, they would not eat very well. If they feel better with the treatment, they come on the normal diet. We do see some weight gain.
Most importantly, the biomarkers, what we put, they are a good indicator of measuring whether this is a mechanism-based or the diet-based. For the mechanism-based outcome, that you see, it's not possible to control. If the mechanism-based outcome is a weight gain in our study, we don't think so because if it is mechanism-based outcome, we should have seen an increase in lipid level as well that we don't see. Also, we should see some to some extent to great extent hypothyroidism because that's directly linked to binge eating in this patient population. These are reduction in thyroid and reduction in hormone prolactin and then improvement in lipid level or decrease in lipids. These are all indications that a marginal weight gain seen, it is not mechanism-based. That's a good sign.
Just very quickly, two things I wanted maybe both Doctors Marder and Ereshefsky to drill down on for us. Firstly, with respect to the impact on sexual function, maybe Doctors Marder and Ereshefsky could comment on whether from their standpoint, it is more important to have an absence of sexual side effects as opposed to improvement in sexual function. In particular, if they see any difference in terms of gender effect, for example, on female sexual dysfunction, I think it's quite unprecedented to have a drug that actually appears to improve female sexual function. Maybe you folks could weigh in on that front.
If you think that this might actually have important implications for the deployment of brilaroxazine in patients with mixed symptoms of depression and schizophrenia, since clearly a lot of antidepressants have sexual side effects, and that's considered a significant drawback in that population. Lastly, if either one of you good doctors would care to opine on what the prospects are for the deployment of brilaroxazine as a long-acting injectable, given the profile that you've seen with the drug so far as an oral, and if you think that this drug might actually, in a long-acting injectable format, potentially be considered superior to all other existing atypical long-acting injectable drugs.
I could start by in young men, sexual dysfunction is a major driver of non-adherence to antipsychotics. They appreciate it. In our clinic, we see it all of the time, and it certainly drives adherence.
I think it's less apparent with women, but I think in just the past few years, there's been data indicating that drugs that elevate prolactin are really associated with a risk for breast cancer. In my clinic, we've started to not prescribe drugs that increase prolactin for particular, well, for women, both young and old. I think some of these effects really both drive adherence and clinical decisions. I think the other questions, I think Larry Ereshefsky could probably answer better than I.
All right. Thank you for that. I do want to first comment that in women, the effect on libido and orgasm is, again, the most problematic. Prolactin indeed is part of that story. You're emulating people postpartum, and your brain is basically in a different state than it would be if prolactin's lower. It's a very interesting question about antidepressant effects.
The pharmacology of this drug suggests it would be useful for depressive symptoms, the way we see that even in schizophrenia on the Marder factors, for instance. I don't believe there's been any studies done in depression. If this medication, either standalone or as an add-on, can mitigate sexual dysfunction, that is clearly a major dissatisfaction amongst patients, both male and female. That is a given. Let me think now. There were several pieces. Oh, the long-acting injectable. I will say that I have been a strong advocate, as has Steve Marder, for use of long-acting injectables. We first worked together discussing fluphenazine decanoate, haloperidol decanoate onto the new medication.
We're talking decades of work where we believe that given challenges with adherence, also comorbid drug dependence, which is something that can derail even a treatment that someone's adherent to for other reasons, that LAIs make great sense. Whether this drug is being developed as an LAI, I'll have to defer to Dr. Bhat, but I would root for it if that was possible.
Yep. Thanks, Dr. Ereshefsky. Yes, we are developing brilaroxazine, a long-acting. It's in the preclinical development, intent to develop. Then based on the data generated, as you mentioned, we believe this drug would benefit in the bipolar, especially bipolar depression, and then major depressive patients as well. We intend to develop brilaroxazine for these indications as well beyond schizophrenia. Thank you.
Thank you.
Great. Thank you so much for the questions, Ram. Our next question comes from Maanasa Ramesh Sangita at Roth.
Please go ahead, Maanasa.
Thank you so much, team, for taking the questions. And congratulations on your progress. I'm calling on behalf of Bovalin. My first question is for Dr. Bhat. Given you've executed three clinical studies in the TRS patients and with the long-term safety data available for like 100 patients completing the 12 months of the treatment, and with the added advantage of the positive vocal biomarker data and the efficacy against the negative symptoms that were rarely shown in the competitor TRS clinical trials, do you think there's a chance that the FDA might allow you to file an NDA and grant an accelerated approval regardless of whether you start the RECOVER-2 study or not? We're also interested in knowing if there is any regulatory precedent for schizophrenia or other indications which are similar to this.
Thank you. See, this is a regulatory question.
It would be difficult for me to give a definite answer. Yes, the regulatory standpoint, the two well-controlled efficacy studies and a long-term safety tolerability studies are required for NDA. We have completed two randomized trials with the positive data. Today, we announced the long-term safety data as well. Based on the data generated in over 1,000 patients, we may qualify for NDA, but we are reviewing the data and exploring all the options to expedite the process. Again, as we make progress, we will update to shareholders. At this time, the regulatory standpoint, yes, we believe we may have met the criteria, but yeah.
Okay. My next question is, on the competitive landscape front, what are your thoughts on Cobenfy's higher-than-expected sales performance in the first quarter of 2025?
Yet it has failed to impress on the efficacy front as an adjunctive therapy shown in the recent clinical studies. Do you think the brilaroxazine's profile is well differentiated and superior to Cobenfy?
This is our competing drug and an approved antipsychotic. We do not have sales figures for Cobenfy. It has just been in the market for the last couple of months. We have done the historical comparison data, and then it is done in our corporate presentation. With Cobenfy, we do not have commercial data yet. Based on the data generated to date, we believe our drug has broad-spectrum efficacy and then especially differentiated safety profile, cardiac, GI safety profile, as well as overall, we believe this is a well-tolerated drug. Again, it is very hard to compare brilaroxazine with Cobenfy because Cobenfy does not have historical data in the market.
I would defer to our KOL speakers, Dr. Marder and then Dr. Ereshefsky, if they have any comments on this. I think go ahead.
Go ahead, Steve. Go ahead.
Cobenfy has a new mechanism of action. We know we have very limited data on how it compares to other drugs. I am quite enthused about its introduction, but there are limitations. I mean, a substantial number of people are unable to tolerate the drug due to its GI effects. Although I sort of welcome it as a new drug, how it will actually change the landscape, I think we will need to learn more very soon.
If I might add a little bit to that, I worked on the development of Cobenfy as well as [KarXT] and Emraclidine. There are some novel drugs with different mechanisms of action coming, which is welcome.
We cannot gauge comparative efficacy at this stage at all, of course. I will say that the side effect profile is very different. That does not mean you can say one is better than the other. Certainly, the GI symptoms, the need for dose titration are considerations, and the effects on the cholinergic system are substantial. I mean, beyond GI effects, potential urinary retention, hypertension are all potential considerations. Again, it is a complex question when you have a drug that is new, has not been compared against other drugs. I think that we are looking at an important advance with these multitude of new drugs and different mechanisms. I think that the brilaroxazine, with its profile and potentially effects on neuroinflammation, belongs in this new club of medications.
Thank you.
Great. Thank you for the questions, Manasa.
At this point, this concludes our Q&A session for today. I will now turn the call back over to Lax for closing remarks. Thanks, Tara. I would like to thank our KOL speakers for taking time to join and present the data here. Despite their busy schedule, in a short notice, they joined this call. It's truly an honor to have them in this call to present our data. Thank you, Dr. Marder and then Dr. Ereshefsky. I would like to thank the contributors for this clinical development in general and the open-label trial, Reviva employees and consultants, a number of people contributed in this, Reviva employees, consultants, as well as external agencies. I would also like to thank drug monitoring committee members. Due to confidentiality, I'm not able to name the drug monitoring committee members.
Drug monitoring committee members are internationally recognized psychiatrists, statisticians, and then other members in this. I would like to thank them, their contribution and associated with the trial, and then especially drug safety monitoring, in general, drug monitoring committee over the last three years. I'd also like to thank Clinical Research Organization. They conducted the trial. Again, this is a top-tier clinical research organization that conducted the trial. Due to confidentiality, I would not disclose their name. I would like to thank all the members at the clinical research organization who contributed to this study. I would also like to thank a number of sites, close to 40 sites involved in this trial, and the investigators and the site associates for their contribution to the trial, both double-blind as well as open-label extension.
Altogether in this trial, over 100 professionals associated with the trial, their hard work, and then I truly appreciate and thank them. Lastly, the scientific publication and communication are also part of this journey. The two organizations here, Akita Biomedical, involved in our scientific communications, as well as LifeSci Advisors, our IR and PR communications as well. Their contribution, I thank them. Overall, all the people who contributed to this program, I would like to thank. Finally, I would like to thank all the viewers who attended this webinar. I would like to thank. Thank you all. Yeah.