Here this morning at the Citizens Life Science Conference. Excited to be joined next by Reviva Pharmaceuticals. Reviva is a company focused on novel treatments for neuropsychiatric diseases. Really glad to be joined by the company's CEO, Laxminarayan Bhat. Lax, thank you for being here. Lax is going to run through a few slides, and then we'll jump into Q&A.
Yep. Thanks. Thanks, Jason. Thanks for having me here. I really appreciate the opportunity. Good afternoon, everyone. Reviva is a clinical stage pharmaceutical company focused on developing novel therapies for diseases of neuro target. That's our focus and strength as well. This is our pipeline. We have 2 molecules in development. Brilaroxazine is the most advanced molecule currently in the phase III studies for schizophrenia. We have treated now close to 1,000 patients, a little over 1,000 patients in schizophrenia. We have completed one phase III study, and then long-term safety study is going to complete. In fact, enrollment completed in the next 2 to 4r weeks. We are expecting a full data readout. Based on the available data, we believe Brilaroxazine can be developed beyond schizophrenia to other indications highlighted here: bipolar, major depressive disorder, and ADHD, and then also the inflammatory conditions.
That's kind of unique to our product. There is a strong relationship, pharmacological basis for neuroinflammation between neuropsychiatric conditions and some of the indications highlighted here, especially skin disease, psoriasis. It's around one third of neuropsychiatric patients suffer from skin disease. We have great data in the translational models. We intend to develop our drug for these inflammatory conditions as well. Today I focus on only the schizophrenia indication. Quickly, before I present data, I just would like to highlight a few points here. Schizophrenia is not a single disease. Rather, it is a mix of multiple symptom domains. Major symptom domains are highlighted here: positive symptom, negative, mood, and cognitive. Most approved antipsychotics address positive symptom, but they have suboptimal efficacy to treat other symptom domains. That's where the major unmet need with respect to efficacy. Of course, the currently available treatments have various side effects.
Now, if you summarize, what's the top 2 unmet need? Possibly the ability to treat negative symptoms and treatment adherence. These 2 are the top 2 unmet needs. Another thing in the last 5 to 6 years being paid increasing attention is neuroinflammation. Neuroinflammation is a part of this disease, possibly play a major role. Also, the longer these patients suffer, we expect these patients will have multiple neuroinflammation or immune-related conditions. Over the years, 14 drugs got approved as antipsychotics. Despite having 14 drugs, around 30% of patients do not respond to treatment or partially respond to the currently available treatment. That speaks a lot about unmet need in the space. Now, quickly coming to the mechanism of action, our drug directly modulates dopamine serotonin receptors. That's the primary mechanism pathway. Also, it has potent activity for neuroinflammatory targets.
I'll show you some of the dates when I walk through the clinical data. Now, quickly coming to the phase II data, this is the phase III primary endpoint. We have put 2 doses in the phase III. There's a good dose response from low dose to high dose. High dose showed statistically significant efficacy within a week and then continued to improve at week 4. The net of placebo is 10-point separation. How good is 10-point separation compared to other widely used standards of care? The highest being in similar trial for olanzapine, 8-point, and then lowest being Intra-Cellular Therapies drug, Caplyta. It's a 3.5-4-point separation. Here, 10-point separation makes this drug have the most robust efficacy for schizophrenia. This is about approving criteria. Now, the most important thing is a long-term outcome, treatment outcome. Often we see very much related to the secondary endpoints.
They are negative symptom. That's very as important as primary endpoint. If you look at the secondary endpoint, our drug has robust activity for negative symptom. It's hard to find significant efficacy for negative symptom. Out of 14 drugs got approved, only 6 to 7 drugs showed efficacy in both the confirmatory trial for negative symptom. The remaining 8 drugs have either no efficacy for negative symptom or mixed efficacy. Another important aspect of our data is we put biomarkers, blood biomarkers, as well as digital biomarkers. Digital biomarker data, if you look at it on the right-hand side. What it does is a specialty of this digital biomarker. It is independent of physicians' assessed outcome. Digital biomarker is especially the vocal biomarker is a signature in negative symptom patients.
By using digital biomarker, we were able to see how many patients in the total patients enrolled have a high degree of negative symptom. We enrolled 411 patients. Out of that, 229 patients had a high degree of negative symptom, maybe in a 1 to 10 scale, maybe around 8. In real world, there is no such thing called pure negative symptom. Always there is an overlapping of other symptom domains associated with schizophrenia. Using this biomarker approach, in the negative symptom patients, we were able to see almost double the efficacy of what we have seen in total patients. That means the drug is working for negative symptom. That's what the take-home message is. I mentioned about at the beginning another one, neuroinflammation. This is the first time an antipsychotic showed in the total ITT patient population statistically significant outcome on 2 significant biomarkers.
IL-8 is a major pro-inflammatory biomarker found in almost every single schizophrenia patient. We have shown statistically significant outcome. With the chemokine, these 2 are major inflammatory cytokines. To summarize the data here, as you can see, the middle column shows the primary and then secondary endpoints. Discontinuation rate 16% is kind of the lowest compared to any other antipsychotics approved to date. Approved antipsychotics to date, they are in the range of anywhere 30%-45% discontinuation rate in the acute schizophrenia patients. We have shown 16% discontinuation. This is consistent within the phase 2 data as well. The efficacy data here is further supported by both blood-based biomarkers as well as a digital biomarker. That makes the data much more stronger and a reliable outcome. Quickly coming to the safety data, there is nothing concerned about the safety. Very clean profile compared.
They are comparable to placebo. Good thing is we haven't seen hardly any movement disorder in this patient population. I will show you in the one-year treatment data, top-line data. It is much better than this. This is the one-year data. In the top-line data, we are going to release the full data readout in the next 2 to 4 weeks. That will have full biomarker data as well and then as secondary endpoints. Most important things to read out here in the one-year data, if you look at, there is no clinically meaningful movement disorder like akathisia, EPS you see with other standard of care. Most importantly, over one year of treatment, we don't see any drug-related serious adverse events. Lastly, the treatment adherence, this is very important. This speaks a lot about safety, efficacy, and long-term outcome. We have seen 35% discontinuation.
If you would like to compare this data with other standard of care currently in the market, in similar trials, showed anywhere around 60%-70% discontinuation. Again, consistently with what we generated in the double-blind trial, it's around 50% less discontinuation compared to other antipsychotics. This is the long-term efficacy data. As you can see, very consistent data. All 3 doses showed dose-dependent efficacy. There is no unusual activity here. Sustained efficacy, that's very important. Often in the schizophrenia trial, you see kind of an unusual pattern, even though the drug showed at the endpoint is statistically significant. During the course, you see something not normal, sustained efficacy. Here, we have seen sustained efficacy. That speaks a lot about both efficacy, safety, and tolerability. Now, lastly, this is the phase II and then phase III comparison.
Very consistent data, primary endpoint and secondary endpoint, as well as a discontinuation rate. Lastly, comparison of our data, efficacy data with other antipsychotics widely used currently in the market. As you can see, our data is very robust in the primary endpoint as well as key secondary endpoints compared to other approved antipsychotics. As I mentioned, we are expecting full data readout, long-term safety data in the next 2 to 4 weeks. We remain very optimistic about this one, taking this drug to NDA approval in the next 18 to 24 months. I pause here. Happy to answer any questions you may have.
Great. Thank you, Lax. Why don't we jump into some questions? I think it's really important to start with mechanism. The drug has a different mechanism to most any antipsychotic. Can you just maybe frame for us a little bit more detail what the differences are and why they matter?
Yeah. So when it comes to mechanism, schizophrenia is primarily caused by dysfunctional dopamine serotonin signaling casket. And there may be multiple approaches to balance that one. But historically, in the mechanism perspective, what we have seen, if a drug has decent safety and then if directly modulates, that often we see translation, kind of you can see the dose proportional. So our drug acts on dopamine serotonin, but it differentiates from other drugs currently in the market, as I mentioned. Neuroinflammation is another key element contributing to schizophrenia. 5-HT2B activity are the most important activity. And then another 2 receptors differentiates activity differentiates from other antipsychotics are 5-HT7 and D4. They are highly expressed in frontal cortex and then involved in chronic conditions, negative symptom mode, and cognition. So bottom line, the key differentiation is 5-HT2B activity.
We believe that neuroinflammation, anti-inflammatory effect not only enhanced the efficacy, but also mitigated the side effect, especially motor side effect. Even if you're treating a one-year, we haven't seen really any motor side effect in this patient population. Often some of the standard of care currently in the market. In the short-term study, we may see around 5%-6%. In the long run, it's over 10%. In the one-year study, we haven't seen really hardly any patients showed motor side effect.
I guess, balance for us, to what extent does efficacy matter on the differentiation side versus safety and tolerability?
Yeah. First of all, often when we talk about new drug, we only talk about the mechanism. Yes, efficacy is very important for a quick effect to see. Of course, in the long-term side, this is a lifelong treatment in most patients. Even though the efficacy is good, if the long-term safety is not good, patients will not take medication. When it comes to efficacy, the key thing is to address negative symptom. Every single drug currently in the market addresses positive symptom despite varying degree of side effects. They do have efficacy for positive symptom, stabilize patients, and then patients are good to go out of the hospital.
The problem comes in beyond that, what in the next few weeks to a few months, the patients end up in hospital because if a drug can't address negative symptom, mood, and cognition, they are not functional. That leads to relapse of symptoms. One way to look at the efficacy is possibly the discontinuation rate. In the long-term treatment, patients discontinue because of relapse as well. Historically, if you look at the data, around 20% of patients discontinue because of relapse on treatment. Our discontinuation rate is very low. Overall discontinuation in one year, it is 35%. Relapse-related discontinuation is hardly 1%. That speaks a lot about the mechanism, not only to stabilize patients, but also addressing the chronic condition, negative symptom, possibly cognitive and mood. In the next 2 to 4 weeks, we will have full data readout.
Great. Maybe let's go back to the first phase III trial design. Can you just talk about the trial design relative to what we normally see in schizophrenia?
Most trials are conducted 6 weeks historically. In recent years, like if you look at Caplyta, all trials, acute trials are conducted in 4 weeks. There was a publication from FDA in 2019, the historical overview meta-analysis of the last 25 years' data. The FDA publication clearly indicates if a drug has to show efficacy, we will see in 3 weeks. 4 weeks may be optimal trial. If you go for longer, sometimes it is very cumbersome to do the trial as well. The bottom line is if a drug has efficacy, it will be seen in 3 to 4 weeks. Quick onset of action is very important for patients to, what do you call, acute treatment. Hospital setup is very expensive.
When you think about safety and other component of is the dropout rate, discontinuation rate, can you just talk about what you saw in the study?
In the acute trial, historical data, if you look at all the approved antipsychotics, anywhere 30%-45% in 4-6 week trial. Most patients discontinue in the first 2 weeks. That's the kind of historically what we have seen. Because if the drug is not getting into blood system quickly, we call it quick onset of action, you see the higher discontinuation. Compared to other antipsychotics, our drug becomes a quick onset of action within 5 to 6 days max. Compared to other antipsychotics, other than our drug, the Risperidone, despite having a lot of side effects, it has a quick onset of action in 4 days. That's what in the hospital setup in the acute, Risperidone is very preferred. Now discontinuation rate, 16% compared to other drug.
This is 50% less discontinuation than any other antipsychotics currently in the market, including recently approved Cobenfy showed in one trial around 22%, in second trial, 37% discontinuation.
Just you have a very positive phase III study. Can you talk us through the interactions you've had with FDA, regulatory agencies, and what the next steps are?
After the first phase II, phase III study, we submitted the data and then the protocol for the second study. We made some changes to the secondary endpoints because in the first study, the neuroinflammation was an exploratory endpoint. We also evaluated sexual side effect because most antipsychotics cause sexual side effect. In our case, we have seen statistically significant outcome improvement in sexual function, especially in female patients because there is a relevance of a prolactin hormone dysfunction with antipsychotic treatment and then sexual side effect. Having seen statistically significant improvement, we saw this is a clear benefit to patients in the long run. We made the second study protocol to have secondary endpoints in that. FDA has seen our data, phase III, first phase III data.
Now with the full data readout coming, we will reach out to FDA with something you may call it a pre-NDA meeting or kind of pre-consultation for NDA submission.
Just walk us through any changes to the second study. You said secondary endpoints, but in terms of trial conduct or anything that would increase or decrease risk of showing the same outcome.
Yeah, we believe the risk mitigation is very much embedded in the trial because almost 95% sites re-engaged in the second study. Protocol treatment duration and by and large protocol is identical to the RECOVER-1. Only difference is low dose we replace with a mid-dose of 30 mg. 30 mg equally showed good efficacy in the one-year treatment. We believe 30 mg will show good efficacy in the acute trial. That's what we replaced it. Other than that, trial design, the sites are all kind of identical to what we used in the first trial. Only difference is we introduced a few secondary endpoints with hoping to get a label claim appropriately.
Maybe fast forwarding, actually before we go there, the open label extension data, what should we expect to see and how important are these data?
Yeah. Often in the schizophrenia trial, 4 week trial or 6 week trial, people expect, okay, we need to see the long-term data because that speaks a lot about whether it is a treatment adherence or outcome. Within the next 2 to 4 weeks, we will be announcing a full data readout that will have efficacy over one year in 300 patients treated for 6 months and 159 patients treated for one year. It will also have biomarker data, biomarker data independent of clinician assess. Biomarkers, not only blood-based biomarker, we will also have digital biomarkers as well. In other words, this will be a fulsome data as a package, what you expect with this treatment over one year.
Let's talk about the market for a minute. Can you talk about how you see the drug fitting into the treatment landscape? Obviously, we have an established set of older generic drugs. We also have successful newer drugs in terms of, for example, Caplyta. You also now have new mechanisms with the muscarinic agonist. Just how do you see the drug fitting in, where the need is?
Now addressing to newer drug, new mechanism of action, of course, there's a lot of buzz in the market in the last 2 years with the new mechanism. If you look at the data and then what this new mechanism does to treat the schizophrenia, ultimately, this is the allosterically modulate dopamine and then cause efficacy. Allosteric modulation with the dopamine without having serotonin modulation, we haven't seen any efficacy for a negative symptom, real tangible negative symptom outcome. Yes, if you look at the Cobenfy in the first trial, showed statistically significant outcome. Second trial did not. What we call this one is unless you have a significant serotonin serotonergic modulation, it is not realistic to expect negative symptom outcome.
If it is a robust activity for schizophrenia, if you look at the recent trial outcome from AbbVie, Neurocrine, there's a mixed result. There is no statistically significant outcome. Even with the last announcement of add-on therapy, there is a mixed result. It did not meet the statistical significance. The bottom line here is if the new target is a disease-modifying target, we should expect to see consistent efficacy with the established mechanism that we do not see. Maybe in the coming years, we may see. At this time, at least to my knowledge, it is not convincing to me this is a treatment option that many patients and physicians would adopt. Now coming to the existing mechanism, serotonin dopamine, there's a proven mechanism, but there is room to improve it. We have done it with our drug. The data speaks a lot.
It's not just a 100 patients data. We have treated close to 1,000 patients in the multiple trial. We believe this will be a differentiated product when we wrap up the development.
Just with the last minute or so, can you talk to us about other indications? What are your plans for development beyond schizophrenia?
The key for beyond schizophrenia is if a drug has good safety profile, especially no motor side effect, and then improvement in negative symptom, that is an indication that a drug can be developed for bipolar as well as a major depressive disorder in a large market. Then having, especially with our drug, with the potent activity for 5-HT2B, we are very optimistic that this could be developed for ADHD. That's a $28 billion market. To my knowledge, currently, there is no new drug in development for ADHD. Our primary focus is to get this to approval for schizophrenia and then later on to expound to other indications.
Here this morning at the. Excited to be joined next by Reviva Pharmaceuticals. Reviva is a company focused on novel treatments for neuropsychiatric diseases. Really glad to be joined by the company's CEO, Laxminarayan Bhat. Laxminarayan, thank you for being here. Laxminarayan is going to run through a few slides and then we'll jump into Q&A.
Yep. Thanks. Thanks, Jason. Thanks for having me here. I really appreciate the opportunity. Good afternoon, everyone. Reviva is a clinical stage pharmaceutical company focused on developing novel therapies for diseases of neuro target. That's our focus and strength as well. This is our pipeline. We have 2 molecules in development. Brilaroxazine is the most advanced molecule currently in the phase III studies for schizophrenia. We have treated now close to 1,000 patients, a little over 1,000 patients in schizophrenia. We have completed one phase III study and then long-term safety study is going to complete. In fact, enrollment completed in the next 2 to 4 weeks. We are expecting a full data readout. Based on the available data, we believe Brilaroxazine can be developed beyond schizophrenia to other indications highlighted here, bipolar, major depressive disorder, and ADHD, and also the inflammatory conditions.
That's kind of unique to our product. There is a strong relationship, pharmacological basis for neuroinflammation between neuropsychiatric conditions and some of the indications highlighted here, especially skin disease, psoriasis. It's around one-third of neuropsychiatric patients suffer from skin disease. We have great data in the translational models. We intend to develop our drug for these inflammatory conditions as well. Today, I focus on only the schizophrenia indication. Now quickly, before I presenting data, I just would like to highlight a few points here. Schizophrenia is not a single disease. Rather, it is a mix of multiple symptom domains. Major symptom domains are highlighted here, positive symptom, negative, mood, and cognitive. Most approved antipsychotics address positive symptom, but they have suboptimal efficacy to treat other symptom domains. That's where the major unmet need with respect to efficacy. Of course, the currently available treatments have various side effects.
Now, if you summarize, what's the top 2 unmet need? Possibly the ability to treat negative symptoms and treatment adherence. These 2 are the top 2 unmet needs. Another thing in the last 5 to 6 years being paid increasing attention is neuroinflammation. Neuroinflammation is a part of this.