2024-08-28 Neurocrine Q3 Update（Q&A）
Q1
As it relates to the nonlinear dose response, can you share any information you have on exposure across doses in both the periphery and the CN's?
And is there any plateaune exposure or anything that might explain why some of these higher doses are not separating? Or at the very least, your null hypothesis might be that they're not any better than 20. And then I guess, just like taking a step back.
Certainly nonlinear dose responses have been seen in psych, but we haven't seen this for the Muscarina class specifically, what gives you the conviction here that the truth and the effect size for this compound isn't somewhere in between what you're seeing with 20 and the other doses as you go into a bigger study?
Thank you.
Hey, Paul, thanks for the question.
Look, we're aware that a nonlinear dose response curve is something that is offseen, as I've said in my opening remarks, and there can be a number of reasons why that is the case. And you're right, it hasn't been seen in the muscarinic class before.
The other two that came before us, particularly KarXT, has been in developer for 30 years. Many doses have been studied over that 30 years. They had a real good idea of where they were going to see efficacy after 30 years of trials. So I don't think that this was anything that couldn't have been, if not anticipated, but maybe predicted in advance.
This was a study that had several goals, one of which was to find an efficacious dose and elucidated safety profile.
An elucidated safety profile by going multiple doses higher. And in that regard, it was very effective. We may never know why in this particular molecule, this particular mechanism that we're using here, why we saw this, but what is absolutely clear, and it is not, is that the 20 milligram dose is a real dose.
The effects we see with this, because of the way we pounded the data, we've looked at it every which way. You see that it holds up all the way through, through every analysis we can put it through, meaning that you are seeing a reproducible response here. That's on the primary endpoint.
You're seeing it start to separate from placebo. Even as early as week one, you see statistical significance between week three week four, week five and week six. You also see that on the other endpoints that we studied, it's positive throughout that it all hangs together, and with a very nice effect size, which I think is really the great equalizer. So in that stepping back and taking a look at this, will we or any others ever have satisfying answers to these kinds of dose response curves and psychiatry? Maybe, maybe not.
It's going to be from drug to drug, but it's certainly been seen. What really matters is, do you have a dose that we have high conviction of in going forward?
I'll let Iree take the first part of your question.
Yeah, I think it's pretty straightforward, Paul.
We do not see a plateauing in exposure in terms of the pharmacokinetics.
And what I will say is both in terms of peripheral exposure and central exposure from both our pre clinical and phase one data, we had confidence that the 20 milligram dose that we started the study with was going to be a potentially efficacious exposure in patients.
As Kevin said, with respect to the dose response, it's really not uncommon to see lack of traditional dose response in these types of trials. Was very encouraging to us, though, was the tolerability and safety at the higher doses that we saw, which we believe gives us a really clear path for the 20 milligrams into phase three.
Q2
So is there something about 568 being a direct agonist that could fully degrade the m four receptor versus a PANSS like cerebellar drug that could explain that dose response, or at least lack?
We didn't see the same effect with KarXT.
And now that you have the data in hand, are there plans to explore 568 in Alzheimer's psychosis or are there other molecules that you're more excited about in that indication?
Thank you so much.
So what I would say is, do we have any evidence that there could be an accommodation that takes place here, a desensitization that takes place here?
No, we don't have any pre clinical or clinical evidence that would suggest any of that is taking place. So whereas can't close the book completely on any explanation, there's really no evidence that we have in hand that would suggest that would be an explanation for this.
As far as other indications that we're going for, that we're going to be going forward with. We have several others, m one preferring agonist that m one, m four balanced. The highest conviction we have, however, is five, six, eight in m four. And we're going to be.
Q3
Hey guys, thanks so much for taking the question.
Just looking at slide nine, it seems like you had an increasing treatment effect at 20 mig dose over time out to week five. But then the 20 mg kind of maybe regressed a little bit, lost two points on PANSS.
Can you explain what happened between week four, five and six?
Or is that kind of just law of kind of sample size?
How do we think about that?
Yeah, it's kind of in noise.
Is our view right here that this is something you see.
What I would say is that what is most important here is the overall shape of the curve.
Again repeating that weeks three through six are all statistically significant.
You're not seeing that we don't have an effect through week five.
And then you get finally a downtick in week six that would show you a statistically significant. That's not what we saw. So honestly, I believe it's just the noise of the system, the noise of these kind of trials.
Do you guys have anything else to add?
Yeah, just add.
I totally agree with that.
I mean, this is an interview scale that has a lot of variability in it from patient to patient and week to week.
And so I think we believe that's within normal.
Q4
Wanted to ask you about difficulty in comparing across trials, especially with more and more known about muscarinic programs.
So on a placebo adjusted basis, the pan score clearly doesn't look as impressive as the earlier studies run by Karuna and Cerebell.
But then when looking at absolute PANSS reductions and effect size, it's more in line. So just curious how you interpret the read across from.
From your study to others that are out there.
Thank you.
You know, it's always difficult to make cross trial comparisons, but you make a very good point.
And again, this is why we have a high level of confidence in what we're seeing at the 20 milligram dose here.
If you look at the absolute PANSS reduction here of 18.2 at the primary endpoint, we believe that's highly compelling from an efficacy point of view.
And we were also really pleased with the degree of placebo response that we saw because we think it's much more indicative of what we might actually end up seeing in phase.
And there's several reasons why that might be.
You know, this was a somewhat different trial design being adaptive.
It also had more centers than some of the previous studies that had been done.
And obviously, being the third in a class, we believe that the expectation bias out there was likely that this was going to be a positive trial.
And so I think we were very pleased to see that placebo response.
And as a result, that, you know, you do get a 7.5.
Q5
Your press release and the prior suicide data on the compound reference cv effects, but they weren't in your adverse event table, and there's not a lot of detail on those.
Could you go into a bit more detail?
What are the cv effects of 5.68?
How severe are they and how long lasting?
Thanks.
Yeah, I can take that.
I mean, they're not in the adverse event table, because we really didn't see anything, and I think that was very encouraging for us.
Across all the doses tested in this trial, in particular, we didn't see a signal of hypertension that was clinically relevant or meaningful, and neither did we see an issue regarding orthostatic hypotension, which we know has been seen before.
So overall, from a CV safety profile, we were very encouraged by all doses.
Q6
In looking at the 20 mg dose, it does look like there were a few more dropouts in that dose relative to the others.
I was wondering if you could maybe tell us a little bit more about the reasons for the dropout and describe how the PANSS data were imputed for those patients.
And then secondarily, I'm curious if you had any patients allocated to the 40 milligram QD arm who weren't able to titrate up and stayed at 20 milligrams and how did those patients do on PANSS?
Improvement.
Thanks.
No, actually, all patients were able to titrate to the dose that was the assigned dose level with respect to the dropouts.
I mean, obviously this is a small study, and if you look across groups, you would expect a little bit of difference in the dropout rate across the groups.
The definition of when people dropped out is they had to actually have at least one post baseline assessment in the study.
And so when we actually look, though, at the impact of both dropouts, at that.
Q7
Thanks for taking the questions.
So I guess the 40 milligram dose arm had the initial 20 milligram lead in for a week. And you did see a separation in the 20 milligram dose arm at a week.
So for the 40 milligram patients who started at 20 milligrams, did you see any clinical benefit over that one week period?
And then second, Kyle is the incoming CEO.
Love to get your impressions on the data.
Yeah, I can answer the first one and then obviously hand it over to my upcoming new boss.
The reality is these are relatively small sample sizes.
We said in terms of the number of patients that were looked at in the first interim analysis, and looking at week one, they're comparable in terms of the effect that we saw.
And as I said then, all of that group went to the 40 milligrams dose level because of the good tolerability.
And, Josh, just for me, I think for Neurocrine, we think about the muscarinics alone or either with Nxera. We've been working in this space for over a dozen years, and there are a couple reasons for this that today is so rewarding.
One is, if you think about Ingrezza and tardive dyskinesia, here's a medicine that treats a disease that's caused by the long term use of antipsychotics.
And we've always had a long term vision here at Neurocrine to offer patients that we serve today an alternative medicine that may be void of tardive dyskinesia in the same patient population.
And we think we have that opportunity with the muscarinics and starting here with 568.
The other piece that's exciting is that the efficacy that we have here at the table stakes, but with the safety tolerability, and the dosing convenience that we have here once a day, no food effect, these are all things that are going to allow us to pivot into other indications in a different patient populations that require the safety and convenience of that one.
Q8
Maybe if I could ask one more question on placebo response, was there any washout for the patient on the mats?
And that could that have affected the placebo response?
And then I completely understand your point about in real world now, with the two muscarinics working patients, placebo response could improve from here on.
But how would you think about differentiating this asset compared to, compared to two front runners a few years down the line?
Thank you.
Let me start.
So in terms of the washout.
Yes.
Subjects were off their treatment prior to entering into the study.
And so that is not uncommon in these programs.
And I think it's consistent with other acute schizophrenia studies that have performed recently.
I want to reiterate, though, we were very pleased with the placebo response that we saw in this study because it is much more reflective of what we believe happens in the broader environment regarding these types of studies.
So from a differentiation point of view, I think we believe we have a very compelling benefit risk profile here.
And really that includes both the strength of the efficacy data in terms of the PANSS reduction, both absolute and the effect size, and also the tolerability and safety profile, as Kyle alluded to.
Yeah, maybe I'll just add to that.
You know, I think what we see out there in the muscarinic class is that there are three different approaches for activating this muscarinic system.
You know, for me, being in this space for 20 plus years, I've never seen three entirely different approaches try to activate a particular pharmacology, as we see here with muscarinic today.
If you start with one approach, you've got KarXT out there that has a pan agonism approach that has off target effects in some of the muscarinic subtypes.
The solution here is to add back a pan muscarinic antagonist that blocks some of the side effects associated with this off target pharmacology.
It's not a perfect fit.
So you get some of the safety and tolerability concerns of the agonist in some of the safety and tolerability concerns of the pan antagonist.
It's also twice a day, and the elderly we've seen in different patient population, it's three times per day. So I think that the differentiation here with 568 is quite clear in terms of the efficacy, the safety, tolerability, the convenience of once a day dosing no food effect. The list goes on and on.
I think that's a very clear approach that we look at, and we'll lean on for differentiation moving forward.
In terms of the other way of activating the system, we see the alternative being an m four positive allosteric modulator. And unlike an agonist, the PANSS requires acetylcholine levels to be present in a.
Q9
I believe it was in the one Q call I asked Kevin around, sort of the capacity across the R&D franchise to fund everything.
And I think at the time there was an acknowledgement that you can't do everything, but since that time, you've both moved Ampa into phase three and now this.
So you sort of are doing everything.
Is there implied in there some sort of assumption around the priorization of the rest of the mid stage portfolio and any sort of thoughts on how we should be thinking about that R&D line in the years going forward?
Thanks.
Yeah, so I'm going to take first crack, but then we'll let the guys who have to live with us going forward take the next crack.
But what I would say is that, boy, are we beating the odds.
Right.
We've just read out here in a few weeks two very important mechanisms in order to treat psychiatric diseases, and they've both been very positive, so they absolutely deserve our investment to carry them forward.
We're constantly doing a review of prioritization.
I'm not going to fall back on the trait saying that this is a good problem to have.
We're going to have our failures as we go forward, just as we're going to have other successes as we go forward.
So nature is going to take care of some of the prioritization, but it's up to management to be diligent in our prioritization.
Yes.
So this is Matt, we're really fortunate with this data.
Q10
So, given the dose response of 568 in schizophrenia, how should we think about the doses for other indications like Alzheimer's psychosis?
And secondly, can I provide more color on the PANSS positive subscale and the negative subscale score?
And do remember any cognition related.
Thanks.
Okay, let me take that.
I'll take the first part of that and say that obviously we were very confident and very pleased with the data that we saw with the 20 milligram dose level here, and being able to take that forward in schizophrenia and given that dose, that also positions us well for other indications.
Clearly, as we think about other indications, we'll be giving more thought to that from a dosing point of view, and we'll certainly update you on that as we go forward with respect to the subscales, we reported in our press release and in our presentation the mater subscales, positive and negative, both of which were statistically significant at the primary endpoint.
The reason for doing that is that the field really generally believes that these are more clinically representative and important to understand.
But that's not.
We didn't present just that because of a lack of effect or lack of finding on the PANSS subscales.
In fact, what we saw on the PANSS subscales was a statistical.
Q11
Just maybe looking forward into the phase three trial, would you consider looking at any additional doses beyond that 20 mg once daily, or are you definitely set on doing a one to one randomized trial against placebo there?
Just curious.
As we know, AbbVie are obviously still doing some dose finding work in the what may be a series of pivotal studies there.
Thanks very much.
Thanks.
You know, we haven't made a final decision on that.
Obviously, the data are pretty fresh to us.
Still, I think we had confidence going in around the 20 milligram dose from our preclinical and phase one data that that was likely to be an efficacious dose.
Is there a possibility of considering a lower dose?
I think that's going to be part of the discussions moving forward.
And then. So I think we haven't made a final call around that.
And then. The one thing I would say, though, is obviously in the context of a phase three study, we'll be looking for as simple, as straightforward a design as possible in this, as you noted in this.
Q12
For 568, why do you think the results on efficacy fall below than mraquidine 4 in phase one b.
Does it suggest that maybe allosterics are potentially more effective than orthosterics, especially in patients where acetylcholine levels are compromised?
We don't think this is a different result in any meaningful way from what was seen for emrapladine.
I think we're very confident in the total PANSS score reduction that we saw.
The difference in the change from placebo is essentially driven by a different placebo response in this study in our minds, which was a higher placebo response, more reflective likely of what's going to be seen in other trials.
And if you look at the effect size, they're pretty much on top of one another.
Thank you.
Q13
Just wanted to follow up on the cardiovascular effects, or lack thereof, that you've seen so far.
Is the expectation then that there would not be a need for additional studies to more fully describe the cardiovascular impacts on hypertension and blood pressure and then separately just, I guess, what steps are you taking in the phase three study to minimize or reduce variability?
Any comments there that you can add in?
Thank you.
Yeah.
Regarding the cardiovascular study, I mean, we're fully expecting, given the class, that we'll be required to do that.
And, you know, at least we have the confidence going into that now based on these phase two data that, you know, that's not something that we're concerned about. But I think you would expect that we would do that given that this class of drugs has been required.
And then in terms of the kind of management of variability, I do want to give a shout out first of all to Samir Jaz and the whole clinical development team because we ran a very tight ship on this clinical study in phase two to manage variability, to understand that engaging with the sites and having a really ongoing set of work there. And we're going to continue that into phase three.
Closing Remarks by Kevin Gorman, Ph.D.
Really appreciate all the questions that you've had.
I realize, we all realize, it can be unsatisfying to not see a traditional dose response going on here.
But your questions go to the heart of the matter, and you've challenged us, and what you've seen is, in our answers, a high degree of confidence.
And the high degree of confidence is data driven in the 20 milligram dose.
We identified a very good dose here, and we identified a dose that's not, if you will, hanging on by its skin of its teeth to go forward.
Every way you can pick at this dose, every way that you can pick at the trial, and the data that goes into that 20 milligram dose, it not only holds together, it's robust. Irie said something that you probably haven't heard very often in a psychiatric trial. Boy, were we glad to see a higher placebo effect that can bring a chuckle to people's face. But it is actually, that is very gratifying when you look at this, because we have a phase two trial here, which we think is going to be indicative of what we're going to see in phase three.
There's going to be puts and calls in what will ameliorate a placebo effect into phase three from what we found in phase two. And then you're going to see things that are going to add to the placebo response in phase three over phase two.
All in all, the belief here is that, and the belief comes from members of this team who are in this study, have 30 years of experience of running these types of trials, that they're going to lead to a placebo response that's going to look much like this. And therefore, we think we're going to see effect sizes much like this in phase three, highly competitive.
What's on the market and what we see from our competitors there is every endpoint hangs to get there at every time point, it hangs together.
And I don't think you see defensiveness here on our part.
I think that what we are trying to bring across and what your questions really drew out of us is the consistency, the robustness of the efficacy, and equally important in this patient population and future patient populations that we're going to study with this drug is the safety.