Ladies and gentlemen, good day, welcome to the BioXcel Therapeutics BXCL501 Clinical Study Results conference call. Today's conference is being recorded. At this time, I would like to turn the conference over to Lee Roth with The Ruth Group. Please go ahead, sir.
Thanks, Abby, thank you all for joining us today. With me on the call are Vimal Mehta, Chief Executive Officer; Vincent O'Neill, Chief Medical Officer; Frank Yocca, Chief Scientific Officer; Robert Risinger, the Chief of Clinical Development; Chetan Lathia, SVP and Head of Translational Medicine; and Sheldon Preskorn, a member of our clinical advisory board. Before we begin, I would just like to remind everyone that certain matters discussed on today's call or answers that may be given to questions asked include forward-looking statements that are subject to risks and uncertainties relating to future events and/or the future performance of the company. Our actual results could differ materially from those anticipated in such forward-looking statements. The risk factors that may affect results are detailed in the company's most recent public filings with the U.S. Securities and Exchange Commission, which can be found on our website, bioxceltherapeutics.com, or sec.gov.
Please note the company is under no obligation to update any forward-looking statements made today, investors are cautioned not to place any undue reliance on these statements. With that, it's now my pleasure to turn the call over to BioXcel Therapeutics Chief Executive Officer, Dr. Vimal Mehta. Vimal?
Thanks, Lee. Good morning, thank you all for joining us today to discuss the results of our phase I IV dex study in agitated Alzheimer's patients and development plans for BXCL501 in 2019. Earlier today, we announced positive human proof-of-concept data from a study of IV dex in Alzheimer's disease patients. The study met its primary endpoint with a clinical benefit observed in seven of the 10 patients in the treatment arm. The results of this study help to further establish proof of concept for BXCL501 in agitated patients, we have now demonstrated the ability of dex to produce an arousable sedation in patients suffering from agitation associated with Alzheimer's disease, schizophrenia, and delirium, as well as healthy volunteers.
On today's call, we will provide an overview of the BXCL501 program, review the results of our IV dex study in both Alzheimer's disease and schizophrenia, and provide an update on the 2019 development plan for our lead neuroscience program. Following our prepared remarks, we'll be happy to answer any questions you may have. With that, I would like to turn the call over to our Chief Scientific Officer, Dr. Frank Yocca, to provide an overview of the BXCL501 program.
Thank you, Vimal. Good morning, everyone. Agitation, which is defined as excessive motor and verbal activity, is frequently observed in psychiatric patients and is common among patients with Alzheimer's disease and dementia. There's a strong tendency for agitation to lead to violent behavior, and that can put patients as well as caregivers at risk. There's also an economic impact of agitation, which is highlighted by the $40 billion disease burden. There's a clear need for improved pharmacological interventions to either prevent or treat agitation. Different disorders have different needs. For example, in psychiatry, there's a need for a non-injectable that does not produce excessive sedation, has a more rapid onset of effect to target mild to moderate agitated patients. These are the cooperative patients that psychiatrists can work with. For dementia, there's a clear need for a safer drug that can be given on an as-needed basis.
In looking at these unmet needs, what we decided to do was use our analytic platform, our AI platform, and we came up with a drug, BXCL501, that we believe meets the needs not only of the psychiatric patient but also of the neurological and the dementia patient. It has a novel mechanism of action. We believe it targets the causal pathway that produces agitation through norepinephrine. It's non-invasive in its sublingual thin film form, makes it easy to administer, and has a more rapid onset of effect. Agitation and aggression are highly prevalent in patients with dementia. Since all approaches to modify the disease process have failed, controlling these problematic symptoms has become a focal point for the need for an appropriate pharmacological intervention. Antipsychotics have shown benefit for Alzheimer's disease related psychosis and is currently being prescribed to actually treat agitation as well.
Their use is associated with excess mortality, excess sedation, cognitive impairment, metabolic syndrome, tardive dyskinesia, and parkinsonism. The approach that we are taking with BXCL501, which is a sublingual thin film of dexmedetomidine, a drug that has a long track record of safety, we believe will offer new hope to produce an effective treatment of dementia-related agitation. On slide five, we show the highlights of the pill as well as of our active ingredient, dexmedetomidine, or called dex. This is a drug that's been on the market since 1999 and used as a sedative anesthetic. It has a long track record of safety. It's been prescribed to millions of patients. It's been studied in many clinical trials to try to take advantage of its activity with regard to calming and with regard to analgesia. It's been hard to do because the drug is only in parenteral administration.
It has a wide therapeutic index and from the point of agitation, we are looking at doses that are below the 0.5 μg per kilogram loading dose. The sublingual thin film is manufactured, multiple dose strengths ranging from 10 to 50 μg for clinical studies have been made. The properties of this film, it has a mucoadhesive, which allows it to stick to the bottom of the tongue, and it produces an immediate release of the drug. It has a proprietary technology also that allows it to deliver low dose ranges. This slide, which is slide six, shows you the mechanism of action of dexmedetomidine. What we are targeting here is hyperarousal. Hyperarousal occurs from excess norepinephrine being released into the brain. What dexmedetomidine does is interact with the neurons that contain norepinephrine to shut down the release of norepinephrine.
Hyperarousal is a phenomenon that is an actual breeder of agitation, and it can be found in situations in all of these diseases that are mentioned here, such as schizophrenia, bipolar disease, dementia, delirium, and opiate withdrawal. This slide shows the molecular interaction of dexmedetomidine in comparison to two other alpha-2 receptor agonist drugs that are marketed. It compares dexmedetomidine to clonidine and moxonidine. What this shows basically is that the agonist activity and potency have an interaction with a human alpha-2 receptor that's been transfected into cells, shows that dexmedetomidine has the highest potency and the greatest intrinsic activity. What this means to us is that the pharmacology of dexmedetomidine may translate into a greater clinical efficacy. Now, we want to develop BXCL501 along the lines of a precision medicine approach.
To do that, we will be using EEG, which is a characteristic technique to identify drugs that are active in the brain to come up with a number of different facts around the use of dexmedetomidine and the use of 501 in our study. We already know that dexmedetomidine elicits a characteristic change in EEG. We plan to use this to demonstrate CNS activity that determines the therapeutic window. We can determine the lowest dose with CNS activity, the highest dose that produces efficacy without excessive drowsiness or other side effects, and determine the onset of CNS effect and time for the course of recovery in agitated patients.
With that as our prelude to give you an overview of the program, I would like to turn the call over to our Chief Medical Officer, Dr. Vincent O'Neill, to review the results of the recently completed Alzheimer's trial and BXCL501's development plan. Vince?
Thanks, Frank, Good morning, everyone. Over the last several months, BioXcel Therapeutics has generated proof of concept data using the IV formulation of dex in Alzheimer's patients, in schizophrenia patients, and in healthy volunteers. In addition, there are previously published data from the Carrasco group using dex in agitated delirium. In other words, we have positive results from about 90 patients with IV dex across a range of pathologies where agitation plays a significant role. I'll now hand over to my colleague, Dr. Rob Risinger, to discuss some of the details of these studies.
Thank you, Vince. Before I describe the results in Alzheimer's, I'm going to describe the study we announced the top line for in November. This is a study of agitation associated with schizophrenia. In this trial, we used the Richmond Agitation Sedation Scale, or RASS, as a surrogate for a calming effect. The RASS is a 10-point scale. It ranges from +4 for a combative, agitated patient to -5 for an unarousable state of sedation akin to what you would have for surgical anesthesia. Our target in these clinical trials has been achieving a RASS score of -1, which on the RASS describes a patient that is either alert and calm at 0 or -1 being a subject that's mildly drowsy. For example, easily able to be aroused by verbal interaction or prompting.
Something as simple as, "Are you awake?" These are proof of concept designs. These are a precision medicine approach. In the Alzheimer's trial, similar to this trial in schizophrenia, subjects were blinded, they were randomized. In this trial, four patients with schizophrenia received IV placebo, 10 received IV dex. Infusions were started initially at a very low dose, the rate would gradually increase over the course of the two-hour experiment until the endpoint of calming was observed, as defined by a measurement of -1 on the RASS. The rate was therefore adjusted for each individual subject such that they received the dose to achieve the endpoint for arousal and sedation. In this study, nine of 10 patients who were treated achieved a RASS of -1.
Although it's not shown, on the left, none of the placebo group achieved a RASS of -1. In the study of agitation associated with schizophrenia, we also used the PEC. The PEC stands for the Positive and Negative Syndrome Scale-Excited Component, or PEC. It's a five-item scale that measures symptoms of agitation in schizophrenia, with each item rated from one, which is absent, to seven, which is extreme. Of course, these subjects were also receiving a range of antipsychotic medications that were typically prescribed for schizophrenia. Those vital signs were monitored throughout. There were no clinically relevant cardiovascular changes, no changes in cardiac conduction, for example, No adverse events reported. If you look on the right-hand side, nine of 10 subjects achieved a PEC score of seven or below, which is a clinically relevant decline in agitation.
There was a reduction in the PEC score if you look at 40 to 60 minutes. This reduction in PEC score began with the onset of infusion and continued out past 40 minutes. At 40 minutes, you'll note that there were only 2 or 20% of subjects who achieved a RASS of -1 or were easily arousable if drowsy. It appears that we have a clear dose range. The drug appears to drop the agitation in schizophrenia as measured by the PEC. Before, there was a robust effect on sedation, where they achieved a RASS of -1. Let's move now to the Alzheimer's study. This is another proof-of-concept trial in mild dementia of the Alzheimer's type. This Alzheimer's patient population was treated similarly to the proof of concept in schizophrenia, where the patients were given IV infusion.
Four were randomized to placebo, 10 were randomized to treatment. As you can see, 7 of the 10 patients randomized to treatment with IV dex, which started at a very low dose, in fact, a lower dose in this study than the patients with schizophrenia. 7 of the 10, nonetheless, were able to achieve a reduction in their RASS score down to a level of -1. Of note, only 1 of the 4 placebo patients with Alzheimer's achieved a RASS score of -1. In those 7 of 10, we now have clear pharmacologic data that shows plasma levels related to the clinical effect of decreasing agitation. These subjects did have other common medical conditions. Cardiovascular monitoring revealed no clinically meaningful cardiovascular effects, including no changes in cardiac conduction.
The plasma concentrations that we observed in this were very comparable to a prior study we conducted in healthy elderly subjects. The plasma concentrations and the endpoint of -1 were achieved at a fraction of the dose and exposures required for surgical sedation. This study therefore allows us with some confidence in targeting a dose range to optimize BXCL501 dose and delivery via the film. Before I describe our clinical development plans for BXCL501, I'd like to review an independent published trial of dexmedetomidine in elderly patients who became delirious after cardiac surgery. In a study by Carrasco et al., subjects who became delirious were treated in an ICU and found to be refractory to the standard of care, IV haloperidol, were initiated on IV dexmedetomidine. After 2 hours, we can see at 120 minutes, they were treated or randomized.
In fact, the IV dexmedetomidine, IV haloperidol was discontinued. We can see in these 46 subjects, they responded and achieved a RASS score of 0 and eventually -1. Of note, there was no respiratory or cardiac conduction disturbances. In the published literature, you can see that it achieved a greater time in satisfactory sedation. There was greater stability and sedation in this elderly population. It's an independent demonstration of the ability of dexmedetomidine to calm and have an anti-agitation effect in the elderly. Currently, we have an ongoing trial of BXCL501. We are studying the pharmacokinetic, safety, and tolerability of the sublingual film. Dosing has initiated. In fact, last month in December. We are continuing to accrue subjects in the trial with periodic reviews and dose escalation. I would expect the dosing to be completed in the first quarter of 2019.
This is the bigger picture. In terms of our development plans, we have data from this PK and safety study of BXCL501. Data readout is expected in the first half of this year. We expect to embark on a registration trial later this year. We're using the pathway that has been established or paved for us, essentially, by ADASUVE, which has been approved for the treatment of acute agitation associated with bipolar disorder or schizophrenia. They conducted two trials. In fact, they used two doses, each trial was in a separate indication, and they consisted of about 300 patients, one in each indication. Their primary endpoint was the PEC reduction from baseline. As you can see, we're considering other options. We have an array of indications now.
We do believe that our first NDA submission will be filed in 2020, as these are relatively rapid trials to conduct. This is the summary of our data thus far. We have demonstrated that low doses produce clinically measurable anti-agitation effects. We are clearly on track to initiate a registration trial for an indication with BXCL501 this year in 2019, and that would indicate we have a potential NDA filing in 2020. In addition, with an array of proof-of-concept trials both published and in our own hands, we have multiple indications for potential use of BXCL501 in terms of anti-agitation, because it has these properties across different disease pathologies, potentially due to a mechanism which Frank earlier described. With that, I'll hand it over to our CEO, Vimal.
Thanks, Rob. In summary, the data we have announced today is highly encouraging, and we remain firmly on track to initiate a registration trial for BXCL501 this year. Following the data readout from our PK study in the first half, this timetable would position us to potentially file an NDA in 2020. We believe that BXCL501's anti-agitation property, which seems to be independent of underlying disease pathologies, gives the product broad market potential, and we are well capitalized to reach multiple inflection points throughout 2019, not only with BXCL501, but our leading oncology program, BXCL701 as well. That concludes our prepared remarks. We would now like to open the line for questions. Operator?
Thank you. If you would like to ask a question, please signal by pressing star one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, it is star one if you would like to ask a question. Excuse me. We will take our first question from Carter Gould with UBS. Please go ahead.
Hi, this is Andrea on for Carter. Thanks for taking our question. For BXCL501, how many doses are you exploring in the phase I study? Are there other gating factors we should be thinking of in moving from phase I to pivotal? I have a follow-up.
I'll answer this question. How many doses are we giving? We're giving four doses. We have four different doses of BXCL501 that we're testing in the phase I study. This is in healthy volunteers with the standard design.
What was your follow on, sorry?
Are there any gating factors for moving from the phase I to the pivotal that we should be thinking of?
I think the best way to describe it is that once we have our dose selection and full data in hand, we'll make a decision that what is the best strategy to move it into registration trial. It's a 505(b)(2) approval process, so it is very common to go from after selection of the dose to phase II trial. I think we will know that until we have the data from the film in our hand, what the strategy will be, and we should be in a position to outline that in next several months, Q3.
Okay, great. Just one more follow-up. One of the key things people continue to struggle with is how to frame the commercial opportunity for BXCL501, given the comps and processes aren't appropriate. Is there other commercial work you've done to better delineate the opportunity for agitation in your key opinion leader census, and who will be the champion in driving the adoption in appropriate institutions?
Right. That's a great question. We continue to work with our internal clinical advisory board as well as external key opinion leaders to do deeper market research to understand how big the opportunity is. We all know that in terms of the pharmacoeconomic burden, it's a very large burden on the system, and this is primarily from the neuroscience community. In terms of our work, we believe that in schizophrenia and bipolar, there are about 600,000 patients who will need this treatment, and they need about a dozen times [heavy than Epilim when they end up in the emergency room. Depending on what the reimbursement strategy is in terms of the ADASUVE, they got reimbursement at $150 per episode. For our film, we should be able to easily get that. It becomes a pretty large opportunity just for schizophrenia and bipolar.
In dementia, that landscape is evolving fast because what we have understood that large number of dementia patients, in Alzheimer's across other dementias, are experiencing this type of agitation, and it's very episodic in nature. Some of them need chronic treatment, and lot of them need more or less episodic. We will have a reachable market from the Alzheimer's. Those are the two areas we are currently focused. We continue to explore delirium and opioid withdrawal.
Thank you.
We will take our next question from Do Kim with BMO Capital Markets. Please go ahead.
Hi, thanks for taking my questions. First, I was wondering if you observed any differences in PK/PD between the Alzheimer's and schizophrenia patients, and if there were certain factors like patient weight that determined intra-patient variability in the Alzheimer's study.
I'll address your last portion of the question. There was a range of weight in the Alzheimer's study, but we haven't analyzed pharmacokinetic parameters with respect to their BMI, for example. That will be provided in a scientific venue, either a poster or a publication.
I think I can invite Sheldon Preskorn, who is our clinical advisor. He can little bit comment on the inter-individual variability as he has associated right from the beginning with the healthy volunteer, with the schizophrenia to design of the Alzheimer's trial. Sheldon?
Thank you, Vimal. There is inter-individual variability. We presented a poster on the healthy elderly volunteers in the ACNP meeting at 2018. It's a manageable issue, and we have a strategy for how to approach that. I'll leave it at that.
Great. Thank you. Just to follow up, were there any common underlying characteristics for the three non-responders that were treated with 501?
Not that we've been able to discern. It was a fairly homogeneous group. For example, they did have concomitant illness, as you would expect in the elderly, hypertension, for example, and were on concomitant medication. We need to drill down in that. I would caution you, however, it's a small number. We will report this, but I would be surprised if we identify more than one subject, or two, that might have anything that would be related to non-response. As you know, with any psychotropic medication, you always find non-responders. If you find a drug that works in the majority of patients, that's an excellent sign. That's what we've demonstrated. The majority of patients respond.
Okay. Thank you for taking the questions.
Thank you, Do.
We will take our next question from Sumant Kulkarni with Canaccord Genuity. Please go ahead.
Morning. Thanks for taking my questions. I'm sorry if I missed this, but did you say what the baseline RASS characteristics were for patients in the Alzheimer's study and the schizophrenia study?
The baseline RASS in the Alzheimer's study varied by treatment group. The RASS at baseline in the placebo arm, I believe, was one, and the RASS was slightly greater than that in the treatment group. That was simply by chance. I don't recall what the baseline RASS was in the schizophrenia trial, but they were comparable across placebo and the treatment group. I'd like to add, however, that these are small proof-of-concept trials, and the placebo group in this context is really just to keep us scientifically true to form. It's not for statistical comparisons with these small numbers of subjects. It's really a proof of concept and to keep us always vigilant that the effects that we're seeing are in a majority of patients, not a minority.
It is clearly a greater effect in the treatment groups than placebo groups, whether you're talking about the schizophrenia proof of concept or the Alzheimer's proof of concept.
It looks like it took a longer time to achieve RASS of -1 in the AD versus schizophrenia in treatment groups. Is that simply a function of dosing, or is it something else? Even on the sedative effects, can you comment on that? Can you comment on the sedative effects, please, in AD patients? Because in schizophrenia, you showed that the effect lasted 1.5 to 2 hours. What was considered clinically relevant for Alzheimer's in that case?
We believe that the delay, if you will, in percent of patients achieving a RASS of -1 in Alzheimer's is likely due to the lower dose that we initiated at for the Alzheimer's patients, and that was obviously for safety purposes. We were concerned that they may be overly sensitive to the drug. That proved not to be the case. We actually have a very comparable dose range for the two populations that we studied in terms of schizophrenia and Alzheimer's. The dementia population that's been published, I believe, has a similar concentration range. Yeah, I'm sorry, delirium. In the elderly delirium patients, the Carrasco et al. publication shows a very similar dose range in comparison to what we have.
Sumant, this is Vimal. We are finding that across these disease pathologies, we have a very good handle of what the dose range is. As Rob said, we started with a lower in the Alzheimer's, that may take little longer. The goal was how many patients we'll achieve, RASS -1 . Here, we are not trying to assess the onset of action because we are titrating, starting with a very low dose and going up. Does that make sense?
Yes, it does. My last question is, at what point as a company do you think it would be optimal to start looking at US licensing options for 501 as a potential source of non-dilutive financing?
That's, again, a great question. I think, as you know, we hired a VP of business development, like an end of the year last year. We believe that sometime in the second half of 2019 will be the right time to bring on a partner who can help us expand this into Japan and help us develop the drug over there because our capabilities allow us to develop the drug in U.S., and Europe.
Thank you.
We have no further questions. I would like to turn the call back to Vimal Mehta for any additional or closing remarks.
We would like to thank you again for participating in this call and for your continued support of BioXcel Therapeutics. We look forward to providing further updates on our lead neuroscience candidate, BXCL501, as well as other clinical and pre-clinical programs from our AI platform as we move forward with their development. Thanks again.
Ladies and gentlemen, this concludes today's call, and we thank you for your participation. You may now disconnect.