HCPLive’s Post

Transcript

Maybe then since we're talking about the clinical side, we should move on to talk about, uh, the clinical trials to Doctor Kakar, where the emerging trials showed a significant reduction in symptoms. So how should clinicians interpret these findings in relation to current treatment options? And for which subset of schizophrenia patients would you feel most comfortable recommending this treats? Yeah. But I mean that's a really good question because it and I think that one if it goes to. Can you equate the clinical trial results to the population at large, right. And I think, I think that then becomes essential to realize how the clinical trials are done. So if I may just give a little bit of shedding a light up backward to it. So as a part of the NDA application, right, in this case, in the emerging trials, you really have to conduct these acute studies, which are these five week studies which are basically reflecting on the back. If a patient comes in with increased symptoms, you give them a drug like the cabin fee versus placebo, what would happen to them? In five weeks. And then there is the open label portion of the trial which I call the second bucket which is represents our patients out there who are going to continue taking these medications long term. Where what happens to them does he affect whereof does the safety, safety tolerable? Do people discontinue their treatment? So when I look at clinical trials, I was looking from those two buckets, right, you've got the are they effective and can the patient stay on them long term in that particular perspective. So for the immersion trials that I was a part of. So they're pivotal trials really that's what they analyzed. They looked at patients who actually baseline and scores was pretty elevated. You're looking at an average of a 98, close to 98 for the pain score, which in a case of walking a patient with quite paranoid, quite delusional, quite symptomatic, they're coming in and they're admitted to a research site or a hospital and then they're given you the cabin free or placebo and they're monitored for five weeks while inpatient. And then the the measure using a scale that I mentioned before, which is the positive and negative symptoms scale. Which is a 30 item scale, each item is 7 points. So you could have 30 all the way to 210 right as a Max for those for those particular symptom. And you're looking at A5 week point reduction. And if you look at the data, the IT showed the reduction of either a 9.4 or an 8.6 points in the two trials that were shown to the FDA that were that were provided to the FDA now statistically significant. Rishi wasn't that that was the difference between drug and placebo. Thank you Operation. Yeah, which is very significant. I'm so glad you mentioned that because that sometimes gets confused. OK. Was it a total point? No, that was a difference between the placebo and What Car XT or Cabin Phi did which is which actually is very significant on. And anyone know this of course for a long time doing these trials usually when you have a reduction of about a 20% Indian schools it's considered fairly good and you have a reduction of. About 9-8 to 9 points compared to placebo with a go and score of about 1.6, right? It lets you believe that the results are possibly very clinically meaningful as well and not just statistically significant. And I saw that in my patients. You know, of course, I'm blinded to the studies of that investigator, but you saw the patient stayed in the trials that their symptoms were reduced, right? And so that particular part as you as a question, I think Sam, your question was how does it apply to the population? Large adding my particular input on that is that that that reduction is going to definitely resonate out there with the clinicians and the patients alike and you're going to see that reflected out there in the community. And then the second bucket of those safety studies that are done, you know, FD has a requirement. You do have to submit data for up to 52 weeks in, in certain amount of patients to be able to look at the safety data. And when you look at it in large, overall the patient actually did quite well, I think over 75. Percent of the patient maintained their effect as they went to by the 52 week in the post hoc analysis. So good deal overall. Is it transportable to every patient? No, I wouldn't say that at all. There are patients who potentially wouldn't be the choice for lack of Benji. But overall just the fact that it's a fundamental new approach that the results separated from placebo and the pens are very high in the patients, discontinuation rates are low. All of that sort of gives you a global picture of what? Patient population when they take of anti might look like and of course and of course that's a couple of please jump in with that as well because I think that clinical trial part is really crucial to sort of look at it and that lens as we look at them. Yeah. I just like to exemplify a couple of points. There have been three studies done now, acute studies, emergent 1-2 and three. Emergent two and three were the so-called pivotal phase three trials. But emergent one, which is phase two had a very strong efficacy signal with effect sizes are much higher than we're used to seeing, to be honest. And then emergence 2 and 3 virtually replicated as you mentioned, effect sizes of .6, which is a high moderate. Effect size I'm used to seeing for antipsychotic medications or medicines that treat schizophrenia, effect sizes of .3 and .4. So clearly for acutely psychotic patients this was very effective. But as Rishi said, just because the drug looks safe when you take it for five weeks doesn't mean if you take it for a whole year, some other safety for signal might emerge. And the FDA really changed in the early 2000s. There was a medication they approved without long term data and then the long term. Data showed a cardiac risk. So the big news here is now we have this year long safety data with no new safety findings and that's important with a new mechanism medicine like this. Now if I could just speak to the clinical aspects, Rishi's 100% right. The results were highly clinically meaningful, not just statistically significant. And I think that the right patient might be someone who has had a partial or inadequate response, not necessarily treatment resistant, who could benefit from a new mechanism. Either as monotherapy or I think that it may be added to our traditional DID 2 blocking agents, and that's rational because they're different mechanisms. My hope, of course, is that in addition to the positive symptoms, it will show some efficacy on cognitive impairment and negative symptoms, which are the symptoms that are most impairing and not as well treated up till now with most of our medications. So I think it's very exciting, the potential here. Of course, we have a lot to learn. And that's a very good point that maybe future trials will show cognitive improvement and given what you've already mentioned both of you on M1 receptors possibly playing a role with that, there's a potential underlying mechanism by which that might work. So that's very exciting. So we'll see. So then maybe since we're talking about the clinical side of things, we could better understand then that how this might be applied given that the absence of the anti psychotic warnings we're called Benji. So how might this influence the clinician's decision to prescribe it over some of the other antipsychotics that are on the market? Well, if I could start with that, of course we don't have head-to-head data. So I certainly can't say this drug is going to be more effective than something else. But certainly there might be different patient types that might respond better or worse or tolerate better or worse. But what I can say is for 70 years our anti psychotic medications for schizophrenia have blocked the D2 receptor. And as I mentioned earlier, there's a lot of collateral damage or safety issues that come along with that. And so we know that those drugs. Of warnings for weight gain, metabolic disturbance, some of them have prolactin, hormonal elevation. And then the one that I'm really extremely wary of right now are drug induced movement disorders. Acute would be parking drug induced parkinsonism, akathisia, dystonia, we call that EPS. And then what I'm really worried about is the long term or tardive or chronic tardive dyskinesia, which is sort of a ticking time bomb and can show up at any time. Co Benji interestingly, does not have any. Of those warnings and in the clinical trials did not demonstrate weight gain or metabolic disruption or a signal for movement disorders. We can't conclusively say it won't cause tardive dyskinesia. That's a longer term kind of thing. But I think that also it's highly unusual in my over 30 year experience that a medication comes to the market in psychiatry without a serious bolded boxed warning. So the FDA did not look at this. It's not called an atypical antipsychotic. Pam as a matter of fact, the word nephrotic does not even show up in the label. So it's called a muscarinic agonist indicated to treat schizophrenia. And so since it's not considered atypical antipsychotic, it it did not get all of those warnings that you would see for all of the atypical anti psychotics. So I think this is very exciting for clinicians to have a new mechanism, a new way to treat schizophrenia and potentially a very different side effect. And risk profile now no drugs perfect. This drug is not without of course risks and side effects. And there are warnings and precautions in the label, especially regarding anticholinergic effects, particularly if added to other anticholinergic agents, which by the way might also impair the efficacy. There are also warnings about liver hepatic warnings, including a recommendation to get liver function tests and bilirubin before starting Copenhagen and periodically during treatment. There also are warnings regarding a heart rate elevation. Blood pressure elevation was also seen in, so it would be prudent to monitor those parameters as well. Yeah. And and, and I and I really share both the, the enthusiasm and the and the caution that Doctor Cutler mentioned quite a bit. I mean especially being a practicing psychiatrist that has seen many of these patients over the years and now conducting the research on on at Kirk Coventry and other antipsychotic, but again, not relating antipsychotic terminology to Coventry in this case, but it is. I think clinicians are just looking for another option, right? A patients in a caregivers are looking for other option in one of the things that was very important and salient that was mentioned was if you look at the life history of schizophrenia. Patients don't necessarily just not respond, but rather their adverse event burden gets so high and now you have medical conditions that are contributing to mortality and morbidity more than even schizophrenia alone as a sciatic condition. So I think looked at from that lens alone having a new differentiated mechanism that is not affecting the dopamine directly, thus so far showing not causing movement disorders or possible weight gain like that. Adler mentioned or lipid increase or prolactin increase. I see that as a win in that column that yes, we have to be wary of the other adverse events that will happen because of muscarinic effect like that the caller mentioned. But I think on Arsenal has been sold toward one side so far that I think I welcome that. I, I'm sure a lot of clinicians would welcome that at this time to be able to have an opportunity to see what that does. And again, with the caution that Doctor Cutler mentioned right as we go to the patients and clinicians need to be aware in the clinical trials, the most common side effects largely revolved around. A combination of pro and anti cholinergic side effects, which is interesting, nausea, vomiting, diarrhea are provocative and then Constipation and that may be due to this mix of a pro and anticholinergic agent. So clinicians need to be aware of this and no drug as I said is perfect. What what I want to come back to the clinical trial data too is I am very interested in the incidence of side effects. You want to of course warn your patients what to look for, what are the most common side effects, but I also want to know. Verity and to me a great measure of severity is how often did the patient stop the medicine due to a side effect. They couldn't tolerate it. I'd like to say they vote with their feet. And as Rishi said, the dropout rates in the acute studies were relatively low and similar to placebo on the basis of what we call adverse events or side effects and is Doctor Kakar said in the year long open label data that we have so far, the dropout rates were surprisingly low. Again, having experience doing many, many studies. Like this usually you're hay with a 50% retention rate or 50% dropout rate and the retention rate was quite a bit higher than 50%. So it's patients vote with their feet both maybe because of the medicine seems to be helping, but also because it's relatively well tolerated. And again the caution here, we don't have head-to-head data. I can't make any claim that this is any way better or safer than anything else. OK. Well, that's great. Those are both 2 very thorough answers covering both the potential benefits over other antipsychotics as well as some of the metrics to measure when initiating treatment, liver and heart rate and the GI side effects. So very exciting.