Hey, everyone. I'm Matthew Hershenhorn, one of the biotech research analysts here at Oppenheimer. Welcome to our 35th Annual Healthcare Conference. It's my pleasure to introduce Dr. Laxminarayan Bhat from Reviva Pharmaceuticals. Laxminarayan will be giving a presentation today, followed by some questions. If you'd like to submit a question so that we could answer it, please do so in the Q&A function. Without further ado, Laxminarayan, if you'd like to get started, we really appreciate the time.
Sure. Thanks, Matt. Thanks for having me here. Good afternoon, everyone. Before I begin my presentation, I would like you all to take a look at our forward-looking statements displayed here. Reviva is a clinically late-stage pharmaceutical company focused on developing novel therapies for diseases of narrow target. That's our core strength and then current focus as well. We have two molecules in development. brilaroxazine is the most advanced molecule currently in the phase three development for schizophrenia. We have completed two large randomized trial studies at both primary as well as secondary endpoints. We also completed a long-term safety study last month. In last December, we announced top-line data. Sometime by end of next month or early April, we expect to give full data readout for the long-term study as well.
Based on the available data and the profile of brilaroxazine, we believe our drug can be developed for beyond schizophrenia to additional neuropsychiatric conditions highlighted here: bipolar disorder, major depressive disorder, and ADHD that we intend to develop in the due course. Besides this, the drug has also shown good anti-inflammatory effects. Some of these conditions highlighted here are also comorbidity. Our neuropsychiatric patients are predisposed to develop these conditions. In a translational model, we have great data, efficacy data reported, and publications are on our website. Before I present clinical data, I would like to take a minute to talk about schizophrenia so that I can relate the data and to address unmet need. Schizophrenia is not a single disease. Rather, it is a mix of multiple symptom domains. The major symptoms are highlighted here: positive symptom, negative symptom, mood, and cognitive function dysfunction.
Schizophrenia is primarily caused by dysfunctional dopamine serotonin signaling system in the brain. The key receptors responsible for dopamine serotonin signaling cascades are highlighted here. Our drug has potent activity and selectivity for these receptors. If you look at on the left-hand side, a few points are highlighted. It's a large indication. Around 1% of the global population suffers from schizophrenia. Globally, around 24 million people suffer from schizophrenia. U.S. alone, close to 4 million. Despite having multiple treatment options available, around 30% of patients, they partially respond or do not respond to currently available treatment that you can imagine the magnitude of unmet need.
If you ask me what are the top two unmet needs in the treatment of schizophrenia, based on the profile of various drugs and unmet needs reported in the literature, negative symptoms, to treat negative symptoms, and non-adherence to treatment, these two are the top two unmet needs in the treatment of schizophrenia. To summarize what I said, if you had to compare all the approved antipsychotics currently in the market, if you would like to use a single criteria to kind of make an assessment or a comparative analysis, if you would like to make possibly, you can select the discontinuation rate or non-adherence to the treatment as a single criteria that can be applied to all the antipsychotics, regardless of the mechanism. The ultimate outcome is whether patients are taking medication or not.
If they are taking medication, not taking medication, and then why they are not taking medication, possibly suboptimal efficacy, one reason. Another reason is poor tolerability and side effects. Our drug in all the randomized trials in acute schizophrenia showed around 12%-16% discontinuation. In the long run, one-year treatment, around 35% discontinuation. This discontinuation rate, whether it is an acute or a long-term treatment, is 50% less than other antipsychotics reported in similar trials. That has to be derived from, we believe, superior efficacy and safety associated with our drug. Just to walk through the pharmacology of the drug, again, I would not go into detail unless you have questions. Our drug addresses or targets key dopamine serotonin receptors implicated in the pathophysiology of schizophrenia.
It also targets downstream targets, the dysfunctional dopamine serotonin, also known to imbalance some of the other neurotransmitters highlighted here, as well as inflammatory markers. Our drug also targets these markers as well. Overall, the broad-spectrum activity, it's reflected in broad-spectrum efficacy in treatment of schizophrenia. That's what we look for as a differentiated product. Now, directly coming to the phase three data, in a pivotal trial, we have treated 411 patients. With the two doses, high dose showed robust efficacy differentiated with statistically significant in a week time and then continued to improve, decrease symptom. With the net of placebo, it's a 10-point separation. Low dose took a week to catch up. The efficacy started separating from placebo. You expect to see the low dose slightly slower in action because they are acutely ill hospitalized patients. This is what we expect.
Overall, if you would like to compare 10-point separation, how good is this efficacy compared to other standard of care currently in the market? To my knowledge, in similar trials, the antipsychotics reported anywhere around 3.5-8-point separation. Having 10-point separation, depending upon which drug you would like to compare, this may be anywhere around 20%-50% better. This is about approval criteria. In schizophrenia, secondary endpoints play a very critical role in assessing long-term outcome or an overall treatment outcome. What are those secondary endpoints? To my knowledge, after the primary endpoint, this is an approval criteria. Negative symptom is the most important secondary endpoint.
It can be considered as an assessor for how good is the drug to treat broad-spectrum symptom associated with this because negative symptom linked to other chronic conditions, such as mood symptom as well as cognitive function, they are very hard to treat as well. Now, if you look at negative symptom data here, we use two scales. One is a left-hand side scale is kind of to some extent comprised of cognitive impairment as well as mood. Broader scale, it's very hard to find efficacy. In one month, we have seen statistically significant outcome. The second one is Marder factor. That's a core negative symptom focused on five factors. So this is a really, again, consistent efficacy. Within a week, we have seen robust efficacy. This is very hard to see within a week if you look at the data for other approved drugs currently in the market.
The bottom line is robust efficacy for negative symptom is a marker for quick recovery. To a great extent, it's a marker for preventing relapse. Patients are on the right path to recover. Another scale we use, CGI scale. CGI is complementary to primary endpoint you can consider. Over one-point reduction can be considered almost equal to the primary endpoint, as you can see on the right-hand side. 78% patients showed statistically significant outcome with over one-point reduction in CGI score, while other antipsychotics currently in the market in similar trials showed acute symptom trials showed over 30% dropout. This is the kind of differentiation we have, not only with the efficacy as well as treatment adherence as well. Here is the data for biomarker data. This is a neuroinflammation data.
What we know in the recent clinical literature, schizophrenia patients have significant amount of inflammation or diseases associated with significant amount of neuroinflammation. How do we evaluate neuroinflammation? There are biomarkers we call pro-inflammatory biomarkers highlighted here. Drug has reduced a number of pro-inflammatory biomarkers. Shown here are two markers. IL-8 is a highly expressed biomarker in schizophrenia. We have seen statistically significant decrease from both doses. Another marker is MIP-1. This is a chemokine, again, highly expressed in schizophrenia patients. To my knowledge, this is the first drug ever shown statistically significant outcome in a pivotal trial in a large patient population. There are some isolated reports in a small number of isolated or cherry-picked patient population just to show that it reduces as the treatment works. The patients may have reduced inflammation.
In a large trial, this is a first time ever reported for statistically significant outcome. We feel very good about the translation of this or effect of this anti-inflammatory or addressing the systemic inflammation. We believe has significant impact on efficacy as well as a safety outcome. That's what it reflected in the outcome. Now, to summarize here what I said, I made three columns here in the middle column, as you can see, primary endpoint as key secondary endpoint, pre-specified secondary endpoint, every single secondary endpoint met with statistically significant outcome. Lastly, if you look at the bottom, there's 16% discontinuation for the efficacious dose versus 22% discontinuation in placebo. Again, to reiterate, other antipsychotics currently in the market reported higher than placebo discontinuation, anywhere around 30%-45% in similar trial.
Our drug has shown less than discontinuation, less than placebo, as well as almost 50% less than other antipsychotics showed in similar trial discontinuation. This is really overall, we believe, a reflection of overall broad-spectrum good efficacy and then tolerance. Now, if you look at the biomarkers, they further support the efficacy. Like left-hand side shown here are key blood-based biomarkers. Prolactin is one of the key, as well as thyroid hormone, are known to imbalance with the currently available treatment, as well as organic cause of the disease. Our drug has shown good response to that reduction in prolactin and then increase in thyroid T3 hormone you expect to see. These are most schizophrenia patients show hypothyroidism. This is really good data.
Similarly, reduction in inflammation as reflected by reduction in pro-inflammatory markers as well as increase in BDNF is also a reflection of a good neuroplasticity as well as an improvement or a decrease in neuroinflammation. On the right-hand side shown is a digital biomarker. This is specifically pointing to negative symptom. Schizophrenia patients in general, in particular, negative symptom patients have kind of signature vocal biomarker. The way they speak is unique compared to other general population. If we use that once a biomarker in the total patient population, you can identify the patients with a significantly higher negative symptom. We use a criteria significantly higher negative symptom, around 70% enriched negative symptom patients. There are 220 patients. Remaining 180 patients had negative symptoms as well as other symptoms as well, much higher in heterogenic patient population.
The bottom line here is if a drug has to work for negative symptom, we expect to see the patients had a high degree of negative symptom, much higher efficacy. That's what exactly we saw. If you look at the primary endpoint, the total population, 411 patients, 10-point separation from placebo, the patients with high negative symptom showed 15-point reduction. That is unheard of in the treatment of schizophrenia. Similarly, negative symptom and other endpoint, especially negative symptom, if you look at the total patient population, 2-point separation from placebo with a statistically significant outcome. In the negative symptom enriched patient, it's almost double. That means drug is working very well, efficacious to treat negative symptom. This is the safety study. The slide is on our website. It's comparable to placebo. There is a very compared to other antipsychotics, you can consider a much cleaner profile.
Then similarly, this is the data, what we topline data we announced in last December. We treated three different doses, almost 150 patients each, altogether close to 450 patients. With the 113 patients completed one year, this is the topline data. As you can see, the drug is very well tolerated over one-year treatment. FDA NDA approval criteria is we need to have 100 patients completed for one year. This is what the topline data for that. Again, 35% discontinuation in the long-term treatment. This is the lowest reported to my knowledge. Most drugs currently in the market showed anywhere 60%-70% dropout rate in similar trial. This is very well reflected and translated what we have seen in the double-blind to long-term treatment. That means sustainable efficacy and then safety profile.
When I say sustainable efficacy, as you can see here, I put three efficacy endpoints here. Total PANSS is a primary endpoint used in the double-blind study. Again, sustained efficacy, very good separation, positive symptom and negative symptom. These are also equally important to maintain throughout the course of the treatment. Otherwise, patients get relapse, and then they end up in hospital. This is really a good efficacy. Now, if you would like to see over a course of the treatment one year, every month, how did this patient perform with respect to efficacy? As you can see, very consistent efficacy gradually decreased. The patients who enrolled in the double-blind study and then rolled over to one-year treatment, 86% patients had over 30-point reduction in efficacy or a PANSS score. And then over 65% patients had 40-point, around one-third patients had a 50.
Over 30-point reduction can be considered as almost remission, or they are very near remission. Fifty, you can consider as almost remission. This is overall good efficacy in a sustained efficacy. That's what we look for. This is the comparative data for phase two and then phase three. As you can see, primary endpoint and key secondary endpoint and adherence to the treatment or a discontinuation rate, they are comparable. Lastly, these are the summary what I mentioned here. We have completed large two-arm and randomized trial, identical results, and then large long-term safety study as well as completed great data we have. The full data readout will be available in the next four to six weeks around that time. We are in the process of initiating the second study. That is a four-week trial. It takes about one year to complete.
Otherwise, for NDA, we have completed most all other requirement of non-clinical studies required for NDA. We remain very optimistic and confident to drive this one to NDA sometime in Q2 2026. This is the comparative data with the generator with widely used antipsychotics currently in the market. Purple bar is for our drug, brilaroxazine. Blue bar, dark blue bar, is for other drugs widely used. As you can see, efficacy-wise, it's a very good efficacy compared to other antipsychotics. On the right-hand side, if we compare our data with aripiprazole, not only for the primary endpoint, total PANSS, but also the key secondary endpoints, again, drug showed robust efficacy compared to one of the widely used drugs for both in the acute as well as the long-term treatment. This is about the overall data.
Again, thank you for attending this presentation and happy to answer any questions you may have.
Absolutely. Thank you so much for that, Laxminarayan . Really comprehensive overview and definitely appreciate it. I did have some questions, and we have received a few just to address a couple at once of the questions we've received. Just in terms of initiating that phase three trial that you plan to do in the first half of this year, could you just talk about maybe a little more granularly to the extent you can the process of doing that initiation, the work you're doing with sites? Just curious, I guess, if you could give any color on the timelines there and how confident you are to have the data still for Q1 next year.
Yeah. That's the great question.
Again, the couple of things matters for continuity, as well as, as you rightly mentioned, how confident we are in kind of you are alluding to replication of the data in the RECOVER-1. The site, what we are engaging or engaged already are almost 90%-95% sites are same sites where they participated in the RECOVER-1 because they are very familiar with. They just completed the long-term safety. Now they are rolling over to the last study. This is, again, the composition of sites in the U.S. and then ex-U.S., exactly similar, like almost similar like RECOVER-1. Considering that we are using almost all the sites, we are re-engaging them for the second study. The protocol is also kind of identical. If you look at here, only difference is the low dose 15 milligram will be replaced by 30 milligram.
In the long-term study, all three doses worked very well. We believe 30 milligram should work very well in the second study. That's what we are putting the 30 as a low dose. Overall, we are very confident as protocol is identical. FDA has already reviewed the protocol. We are in the process of initiating the study.
Okay. Perfect. I really appreciate that. I know that we get a lot of questions. One question that I had was just in terms of the differentiation versus Cobenfy, aka KarXT. There's a lot of attention on the muscarinic class as the new entrant for antipsychotics. It is really good to see some innovation here since there hasn't been anything too new in a very long time.
Just curious, I guess, how Brilaroxazine compares to the muscarinic classes and any differentiation versus Cobenfy and to the extent that it could help for BMY to pave a new pathway for a new drug. Just curious if there's any benefits there as well.
Yeah, sure. This is a question often I get when I talk to investors. Happy to address that. Often what people ask me, there's a new mechanism of action. I just take 30 seconds to a minute to explain that what this mechanism really brings on table. Schizophrenia is primarily caused by dysfunctional dopamine and serotonin. That's a very critical dysfunctional. Of course, dysfunctional dopamine, serotonin, neurotransmitter also at various degrees level. Cause dysfunction in other neurotransmitters as well, such as acetylcholine. There are two receptors in that, nicotinic and muscarinic. And then GABA and then NMDA. Cobenfy targets muscarinic receptors.
The ultimate goal of the mechanism is allosterically, scientifically we call, or in a simple term, it's called indirectly, the goal is to balance dopamine. Mechanistically, to my knowledge, this mechanism is not modulating serotonin. Historical data, if you look at a drug that can modulate both dopamine and serotonin or balance dopamine, dysfunctional both dopamine, serotonin in the brain, that's the approach we need to treat schizophrenia. Having said that, the Cobenfy in their trial, in one trial, it showed significant outcome on the negative symptom. In the second trial, it did not. Overall, the approval score of total PANSS, it showed statistically significant outcome around an 8-9 point separation from placebo in five weeks. The bottom line is key differentiation. We need to have a good efficacy for negative symptom. We believe our data were presented here.
We believe we have consistent data in the phase two as well as phase three showed statistically significant outcome, both positive and negative symptom, total PANSS score, as well as a biomarker. We feel we have much robust data.
Right. That's actually a perfect segue to the next question I had, which was just about what you think are the prevailing unmet needs that these treatments have so far not addressed and what brilaroxazine could do, perhaps particularly on negative symptoms. And then just curious, I guess, if you could discuss the relevance of deploying your vocal biomarkers in the phase three program and how that could expand your understanding of negative symptoms.
Yeah. The challenge in the negative symptom is out of 14 drugs got approved, 14th drug, a new drug in the last over the last 40 years approved is Cobenfy.
Out of 14 drugs, only six drugs, to my knowledge, showed decent statistically significant outcome in both the pivotal trials. The negative symptom, as I mentioned, again, reiterating, it is critical to patients' recovery. It's critical to address for patients' recovery. Vocal biomarker data further confirms the clinician-assessed outcome with our drug negative symptom, as well as other endpoints in a much more robust efficacy seen in negative symptom-specific patients. That gives us a lot of confidence and optimism that this would be a much better treatment option for treating schizophrenia. In the second study as well, we are using vocal biomarker. As I mentioned, we use the vocal biomarker in the long-term treatment as well. We are currently analyzing the data. When we announce the full data readout, we expect to give vocal biomarker data as well.
We remain very optimistic about the negative symptom outcome in the long-term treatment as well.
Okay. Got it. That's really important and definitely looking forward to seeing those data eventually. One other question that we're getting is just in terms of your current cash runway and financing strategy. Is initiating this phase three contingent upon additional financing? Or if you could just give some color on if you could start that regardless. I'm curious about how maybe at the point of data, you could potentially raise a cash.
It is not contingent upon. We always say it is one is you can always try parallelly to rush the approval. Again, doing the trial in a right way, right endpoint, addressing the unmet needs are very key. Last December, we raised $18 million. We have cash in the Q2. It is a continuous process.
We need additional $50 million, 5-0, to complete the NDA process as well as have some runway beyond NDA submission. Considering having cash in hand, and then we remain optimistic to fund the company trial and then move forward to NDA as planned.
Okay. Perfect. That definitely captures that. I appreciate that. One question. I know we're running out of time, but I do think personally it's really interesting that you could go after multiple different indications with brilaroxazine. Just curious, I guess, how internally, perhaps once you get the next data set for the second phase three, just curious, I guess, how internally you would think longer term about which indications to prioritize and curious how you think about the relative probabilities of success for anyone.
If you look at the historic development, if a drug has shown broad spectrum activity, bipolar disorder, major depressive disorder, these are the large indications, great unmet needs. We believe the data generated, especially secondary endpoints, are predictive for going after these indications. Logically, to go after these indications, they are low-hanging fruits. The regulatory path for these indications is very well worked out. We intend to extend this one. Most importantly, having strong negative symptom data, we are also planning for down the line to have a separate study for negative symptoms because currently, no drug has a negative symptom indication label claim. Having strong data, we remain very optimistic about that.
Got it. That's perfect. Thank you so much for taking us through the story and for answering all the questions. Really do appreciate it. Thank you, everyone, for listening.
Thanks, Matthew.
Thanks for the opportunity. Thanks all, everyone, for attending this presentation. Thank you.