Study Result

Jan 3, 2019

Press Release

Ladies and gentlemen, good day and welcome to the BioXcel Therapeutics DXCL501 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, and thank you all for joining us today. With me on the call are Vinho Mehta, Chief Executive Officer Vincent O'Neill, Chief Medical Officer Frank Yerka, Chief Scientific Officer Robert Reisinger, Chief Clinical Development Chetan LaFayette, SPT and Head of Translational Medicine and Sheldon Pressborn, a member of our Clinical Advisory Board. Before we begin, I would just like to remind everyone that certain items 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, biocathherapeutics. Com or sec.gov. Please note the company is under no obligation to update any forward looking statements made today, and 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 BioCell Therapeutics' Chief Executive Officer, Techno Mometa. Namo? Thank you. Good morning and thank you all for joining us today to discuss the results of our Phase 1 IV Dex study medicated as Alzheimer's patients and development plan for BXCL701 in 2019. Earlier today, we announced positive human proof of onset data on a study of IV Dex in Alzheimer's disease patients. These 3 met primary endpoints with a clinical candidate observed in 7 of the 10 patients in the treatment arm. The results of this study help to further establish proof of concept of BXCL501 in elevated patients, and we have now demonstrated the ability of BX to produce an arousal 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 IVFECT study in both Alzheimer's disease and schizophrenia and provide an update on the 2019 government plan for our lead neuroscience program. Following our prepared remarks, we will be happy to answer any questions you may have. With that, I would like to turn the call over to our Chief Scientific Officer, Doctor. Sainte Yohtar to provide an overview of the VXCL501 program. Thank you, Vamil. Good morning, everyone. Education, 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 $40,000,000,000 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 is a clear need for a safer drug that can be given on an as needed basis. So in looking at these unmet needs, what we decided to do was use our analytic platform, our AI platform and currently came up with a drug BXCL501 that we believe meets the needs not only in the psychiatric patients but also of the neurological and the dementia patients. It has a novel mechanism of action. We believe it targets a causal pathway that produces agitation through norepinephrine. It's non invasive in its label sent form, makes it easy to administer and has a more rapid onset of effect. Mitigation 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 of the need for an appropriate pharmacological intervention. Any psychotics 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 Parkinson's disease. The approach that we are taking with BXCL501, which is a sublingual thin film of exmedetomidine, 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 5, we show the highlights of the pill as well as our active ingredient dexmedetomidine, which is called dex. This is a drug that's been on the market since 1999 and used as a set of 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 clinical 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 out of the point of agitation we are looking at doses that are below the 0.5 microgram per kilogram loading dose. The sublingual plate of film is manufactured, multiple dose rates ranging from 10 to 15 micrograms for clinical studies are delayed. The properties of this film, it has a new procedure which allows it to stick to the bottom of the cell and it produces an immediate release of the drug. It has a proprietary technology of Golto that allows it to deliver low dose ranges. This slide, which is Slide 6, 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 methotomidine does is interact with the neurons that contain norepinephrine, they shut down the release of norepinephrine. Micro arousal is a phenomenon that should that is an actual breeder of agitation and it can be found in situations in all of these diseases that are located that are mentioned here such as schizophrenia, bipolar disease, dementia, ovarian and opioid withdrawal. This slide shows the molecular interaction of dexmedetomidine in comparison to 2 other Alpha-two receptor agonist drugs that are marketed. It compares dexmedetomidine to clonidine and leflectodine. And what this shows basically is that the antagonist, leflectivity and potency have an interaction with the ULTA-two receptor that's been transfected cells shows that dexmedetomidine has the highest potency and the rates in transient activity. What this means to us is that the pharmacology effect metotomidine may translate into a greater clinical efficacy. We want to develop DxCL501 along the lines of a precision medicine approach. And to do that, we will be using EEG or 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, the use of 501 in our study. We already know that that metacomidine elicited the 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 TNF effect and time for the course of recovery in agitated patients. The WIC Act has our value to give you an overview of the program, I would like to turn the call over to our Chief Medical Officer, Doctor. Vincent O'Neill, to review the results of the recently completed Alzheimer's trial and BXCL501 development plan. Vince? Thanks, Frank, and good morning, everyone. So over the last several months, Tylenol Xel Therapeutics has generated proof of concept data using the IV formulation of X 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 educated delirium. In other words, we have positive results from about 90 patients with IV Dex across a range of pathologies, so agitation plays a significant role. I'll now hand over to Carl Doctor. Rob Derisenar to discuss some of the details of these studies. Thank you, Vince. Before I describe the results and outcomes, I'm going to describe the study we announced the top line for in November. This is a study of education associated with schizophrenia. And in this trial we used the Richmond agitation for patient scale or RASP as a surrogate for a calming effect. The RASP is a 10 point scale. It ranges from plus 4 for a combative agitated patient to minus 5 for an unallowable state of sebation akin to what you would have for surgical anesthesia. Our target in these clinical trials has been achieving a RAS4 of -one, which on the RAS describes a patient that is either alert and calm 0 or -one being subject mildly drowsy, for example, easily able to be aroused by verbal interaction or prompting, something as simple as our yield weight. So these are proof of concept designs. These are a precision medicine approach. In the Alzheimer's trial similar to this trial for the refraining subjects were blinded, they were randomized. In this trial 4 patients with schizophrenia received IV placebo and received IV Dex. Infusions were started initially at a very low dose and the rate was gradually increased over the course of the 2 hour experiment until the endpoint of calming was observed as defined by a measurement of minus 1 on the RAS. The RAS was therefore I'm sorry, the rate was therefore adjusted for each individual subject such that they received the dose to achieve the endpoint throughout the presentation. In this study, 9 of 10 patients who were treated with CECI achieved a RAS of -one. However, it's not shown on the left, none of the placebo groups achieved a RAS of -one. In the study of agitation associated with Cirapheta, we also use the PEC. PEC stands for the positive and negative symptom scale excited for a component or PEC. It's a 5 item scale that measures symptoms Of course, these projects are also receiving a range of antipsychotic medications that are typically prescribed to schizophrenia and as vital signs are monitored throughout, there are no clinically relevant cardiovascular changes, no changes in cardiac conduction for example and no adverse events occurring. If you look on the right hand side, 9 of 10 subjects achieved a PEC score of 7 or below, which is a clinically relevant decline in education. And there was a reduction in Pex Score. If you look at 40 to 60 minutes, this reduction in Pex 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 achieved a RASM-one or were easily arousable for drowsiness. So it appears that we have a good dose range, the drug appears to drop the agitation into the apnea as measured by the tax before there's a robust effect on sedation where they achieved a RAS of -one. So let's move now to the Alzheimer's study. This is another proof of concept trial and in Altamax just the Alzheimer's type. Alzheimer's patient population was treated similarly to the proof of concept in schizophrenia where the patients were given IV infusion, 4 were randomized to placebo, 10 were randomized to treatment. And as you can see, 7 of the 10 patients randomized the treatment with IVFAT, which started at a very low dose, in fact, a lower dose in this study than patients with schizophrenia, 7 of the 10 nonetheless were able to achieve a reduction in the RAS score down to a level of -one. Of note, only one of the sore placebo patients with Alzheimer's achieved a LAP-four of -one. And in the Section of 10, we now have clear pharmacologic data that shows plasma levels related to the clinical effect of decreasing education. Have other common medical conditions, cardiovascular monitoring reveals no clinically meaningful cardiovascular effects, including no changes in cardiac conduction. The class of concentrations that we observed in this are very comparable to our prior study we conducted in healthy surgery subjects. So the plasma concentrations in the endpoint of -one were achieved at a fraction of the dose and exposures required for surgical sedation. And this study, therefore, allows us with some confidence in targeting a dose range to optimize BXCL501 dose and delivery via the cell. So before I describe our clinical development plans for GAK11, I'd like to review an independent published trial of ipadetomidine in elderly patients who became delirious after cardiac surgery. In a study by Carrasco et al, subjects who became delirious were treated in ICU and found to be refractory to the standard of care IV haloperidol were initiated on IV Dexmedetomidine. After 2 hours, we can see the 120 minutes, they were treated or randomized. In fact, IV dexmedetomidine, IV halvold was discontinued. And we can see in these 46 subjects, they responded and achieved a RAS score of 0 and eventually REDD at 1. Of note, there was no respiratory or cardiac conduction disturbances. In the published literature, you can see that achieved a greater time and satisfactory formation with greater stability, cultivation and the stability population. And so it's an independent demonstration of the ability of teprotumabine to calm and have an anti agitation effect in the elderly. So currently we have an ongoing trial of the ACL-five zero one. We are studying the cytokinetic spatial and tolerability of the subbingual 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. We expect the dose to be completed in the Q1 of 2019. And this is a bigger picture. So in terms of our development plans, we have data from the PKM safety study of BXCL501. Data readout is expected in the first half of this year. We then expect to embark on a registration trial later this year. We're using a pathway that has been established or paved for us essentially by Adafu, which has been approved for the treatment of acute agitation associated with bipolar disorder or spodecilia. They conducted 2 trials. In fact, they used 2 doses. Each trial was in the separate indication and they considered about 300 patients, 1 in each indication. And their primary endpoint was the PEC reduction based on it. As you can see, we're considering other options. We have an array of indications now. And we do believe that our NDA submission, our first NDA submission will be filed in 2020 as these are relatively rapid trials to conduct. So this is the summary of our data thus far. We have demonstrated what logos are producing clinically measurable anti agitation effects. We are clearly on track to initiate a registration trial for an indication with EXCL501 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 that published and in our own hands, we have multiple indications for potential use of DxM-five zero one in terms of anti agitation because it has these properties across different disease pathologies, potentially due to a mechanism which I earlier described. And so with that, I'll hand it over to our CEO, Vimal. Thanks, Rob. And some RYZ data we have announced today is highly encouraging, and we remain firmly on track to initiate a registration trial for BHCL501 this year. Following the data readout from our PK study in the first half, this time saver would position us to potentially file it today in 2020. We believe that GXCL501's anti education capabilities, which seem to be independent of underlying disease pathologies due to product broad market potential, and we are well capitalized to reach multiple inflection points throughout 2019, not only with DxCL501, but our leading oncology program, DxCL701 as well. That concludes our prepared remarks. We would now like to open the line for questions. Operator? 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 questions. For VCSEL-five zero one, how many doses are you exploring in the Phase 1 study? So I'll answer this question. How many doses are we giving? We're giving 4 doses. We have 4 different doses of BXCL501 that we're testing in the Phase 1 study. This is in healthy volunteers with the standard kind of design. I think the best way to describe it is that we are once we have our dose selection and full data in hand, we make a decision that what is the best strategy to move it into registration trial 505(2) approval process. So it is very common to go from after the election of the dose to Phase II, Phase III trial. But I think we will know that until we have the data from the film on our end, but this strategy will be, and we should be in a position to outline that in next several months for the history. Okay, great. And just one more follow-up. One of the key things people continue to struggle with is how to frame the commercial opportunity for BXCL501 and the cost structure aren't appropriate. Is there other commercial work you've done to better delineate the opportunity for agitation in your commercial And who will be the champion in driving the appropriate adoption appropriate institutions? That's a great question. We continue to work with our internal clinical advisory board as well as external key senior leaders to do deeper market research to understand how this opportunity is. We all know that in terms of the pharma economic burden, it's a very large burden on the system and results from primarily from the neuroscience division. In terms of our work, we believe that schizophrenia and bipolar, there are about 600,000 patients who will need these treatments and they need about a dozen times every day when they enter the emergency room. So depending on what the reimbursement strategies in terms of the AdiHealth, reimbursement at $150 per episode. So for our team, we should be able to easily get that. It becomes a pretty large opportunity just for schizophrenia and bipolar. And in dementia, that time saving 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 the cells. Some of them need chronic treatment and a lot of them need more or less episodic. So we will have a leachable market from the Alzheimer's. So those are the 2 areas where our currency focus, presenting with the Delirium and OSAT 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 PKPD 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? So I'll address your last portion of the question. There was a range of ways in the Alzheimer's study, but we haven't analyzed the pharmacokinetic parameters with respect to their BMI, for example, that would be provided in a scientific venue, either a poster or permutation? I think I can invite Chandan Prascon, who is our clinical advisor. He can let us comment on inter individual that he has been associated right from the beginning with the healthy oriented business to the design of the Alzheimer's child. Sheldon? Thank you, Vimal. There is inter individual variability. We presented a poster on the healthy elderly volunteers in the ACMP meeting at 2018. But it's a manageable issue, and we have a strategy for how to approach that. So I'll leave it at that. Great. Thank you. And just to follow-up, were there any common underlying characteristics for the 3 non responders that were treated with 501? Not that we've been able to define. It was a fairly homogenous group. They were on for example, they did have concomitant illness, as you would expect, and that was really hypertension, for example, and we're on concomitant medications. So we need to drill down in that. I would caution you, however, it's a small number. So we will report this, but I would be surprised if we identify more than one subject or 2 that might have anything that would be related to non response. And as you know, with any type of drug based medication, you always find non responses. And if you find the drug that works in the majority of patients has an excellent size, and that's what we've demonstrated, the majority of patients respond. We will take our next question from Sumant Kulkarni with Canaccord Genuity. Please go ahead. Thanks for taking my questions. I'm sorry if I missed this, but did you say what the baseline RAS characteristics were for patients in the Alzheimer study and the schizophrenia study? The baseline RAS and the Alzheimer study very high treatment group. The rapid baseline in the placebo arm, I believe, was 1, and the RAF was slightly greater than that in the treatment group. That was simple by chance. And in the I don't recall what the baseline lab was in the schizophrenia trial, but they were comparable across placebo and retrieval groups. 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. And it is clearly a greater effect in the treatment groups than placebo groups, whether you're talking about defining a proof of concept for the Alzheimer's proof of concept. And it looks like it took a longer time to G RAS of minus 1 in the AD versus schizophrenia in particular groups. Is that simply a function of dosing or is it something else? And even on the sedative effect, can you comment on that? Can you comment on the sedative effect, please, in KD patients? Because in schizophrenia, you showed that the effect lasted 1.52 hours, what was potentially level driven for Alzheimer's in that case? So we believe that the delay, if you will, in percent of patients achieving a RAS of -one in Alzheimer's, we'd like to do a little lower dose that we initiated at for all time. And that was obviously for safety purposes. We were concerned that they may be overly sensitive to the drug. That proves not to be the case. So we actually have a very comparable dose range for the 2 populations that we've studied in terms of schizophrenia and Alzheimer's. The dementia population that's been published, I believe, has a similar concentration range. I'm sorry, telerium, in the elderly telerium, the Corastor Without publication shows a very similar dosing than in comparison to what we have. So, Sumant, this is Ramal. We are finding that across these disease pathologies, we have a very good handle on what the good range is. As Rob said, we started with a lower in the Alzheimer's estimate, take a little longer. But the goal was how many patients we achieved, that minus 1. Here, we are not trying to assess the onset of action because we are titrating starting with very low growth 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 U. S. Like the options for Q1 as a potential source of non dilutive financing? That's again a great question. I think, as you know, we hired CEO Business Development like in November of the year last year. And we believe that sometimes in the second half of twenty nineteen will be the right time to bring on a partner who can help us expand this into Japan and help us develop that over there because our capabilities allow us to develop better in U. S. And Europe. And with no further questions, I would like to turn the call back to Vimalanta for any additional or closing remarks. We would like to thank you again for participating in this call and for your continued support of IQOS Theravutics. We look forward to providing further update to our lead neuroscience candidate, the ACL-five zero one, as well as other clinical and preclinical program from our GI 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.