Q3 2022 Orchard Therapeutics PLC Earnings Call
[music].
[music].
[music].
[music].
[music].
[music].
Good morning, My name is Audrey and I will be your conference operator today at this time I would like to welcome everyone to the Stoke Therapeutics interim analysis a S. T 001 for the treatment of Dravet syndrome.
All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session. If you would like to ask a question. During this time simply press the star key followed by the number one on your telephone keypad. If you would like to withdraw your question Press Star one again.
At this time I'd like to turn the conference over to Eric Rojas head of Investor Relations. Please go ahead.
Thanks, Arthur and good morning.
Eric Rojas head of Investor Relations of Stone Therapeutics.
Today's call, we will discuss results from the interim analysis of the phase one two clinical studies of our investigational medicine. SDK is there is there are one or two.
Treatment of Dravet syndrome.
Because today are Dr. Edward Kaye.
Dr. Barry Chico Stokes Chief Medical Officer.
You listen to this call we recommend that you access the webcast slides in the investors section on our website.
The call is being recorded and a replay will also be available on the Stoke website later today.
We will make forward looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the SEC.
These statements, including without limitation those regarding Stoke store base syndrome program are based on management's current intentions beliefs and assumptions.
Actual outcomes and events could differ materially.
Sept as required by law, we assume no obligation to update any such forward looking statements. After the date of this presentation or to conform. These forward looking statements to actual results.
I'll now turn the call over to Dr. Quay, Thanks, Eric and good morning, everyone.
We're pleased to share with you today the positive interim results from our ongoing phase one two clinical studies of SDK Zero Star one.
And to have frequent and prolonged seizures patients experienced significant non seizure comorbidities. What you will see today is new evidence that S E T.
<unk> continues to be well tolerated and is reducing seizures in children and adolescence would drive a syndrome <unk>.
Importantly, these improvements are on top of the best available anti seizure medicines with more than half of the patients taking <unk> for me.
Today, we are also sharing very preliminary evidence of the drugs effect on non seizure comorbidities.
Together these results give us confidence that we are honing in on an effective dose level and dose frequency. We look forward to sharing additional data in 2023 that will inform our plans for pivotal studies.
Before Barry walks you through the specifics of the data I'd like to share a bit of background on the disease and patient population.
<unk> syndrome is a severe and progressive genetic epilepsy, it's caused by a happier with sufficiency, which resulted in half of the normal lab 1.1 protein expression one out of 16000 babies around the world are born with this devastating disease and it is not concentrated in any particular geographic.
Yeah.
There is a real and urgent need for better medicines that treat seizures.
And the myriad of Nazis or Comorbidities.
The non seizure aspects of this disease some of which are listed on slide six significantly impact quality of life for patients.
Caregivers the combination of anti seizure medicines that make up the current standard of care are burdensome do not control seizures for the vast majority and come with a host of side effects.
With our butterfly observational study, we are learning more about the natural progression of <unk> syndrome, and the clinical assessments that we can use to measure changes in neuro development.
Born without symptoms. These children develop fairly normally but begin to regress with age as the disease advances the goal of treatment today is seizure management, but what are these patients need it syndrome management.
Our number one priority priority at Stoke is too advanced educators are one is potentially the first disease modifying approach for the treatment of drive a central one that will control seizures and address the non seizure comorbidities from the start we have set a high bar for success. The majority of patients enrolled in our studies.
Are taking at least three and often for anti seizure medicines. Despite this they continue to express their experience seizures and many of the debilitating effects that characterize this disease.
Based on what we're seeing in the clinic, we believe that producing a consistent and durable clinical effects for patients will require reaching a steady state of drug levels in the brain to boost and sustained normal protein levels.
Three factors play a role in this process dose level dose frequency and time on drug we expect that additional data in 2023 will answer all remaining questions and then lots of path to pivotal studies I'll now hand over the call to Barry.
Thank you Ed and good morning.
Before I get into the clinical data I'd like to quickly remind you of the science behind US the case zero, one an antisense oligonucleotide.
The cartoon on slide 10.
It was how our targeted augmentation of nuclear gene output or Tango technology aims to boost protein production.
Bridging the wild type copy of a gene to increase productive mrna levels.
The initial indications for tango or diseases caused by halfway when sufficiency, whereby a mutation and one copy of a gene results in half the normal protein production.
Dravet syndrome is typically caused by Apple and sufficiency of U S. C N one aging which results in insufficiency of NAV, one one protein expression.
<unk> is designed to address the root cause of Dravet syndrome by restoring that $1 one levels.
Okay.
Turning to slide 11.
You see schematics of our two phase <unk> studies monarch and Admiral.
These are open label studies of children and adolescence, two to 18 years of age who have an established diagnosis of Dravet syndrome.
And have evidence of the mutation in the <unk> AG.
The goal of these initial studies is to determine if that's the case here was you wanted to save and.
And to identify the best dose, one that maximizes efficacy and minimize as treatment frequency.
Advanced to pivotal studies.
In the U S patients and monarch are treated with either a single or multi three dose regimen up to 45 milligrams.
In the U K patients and Admiral received multiple doses up to 70 milligrams.
The multi dose regimens consist of three doses as shown here.
All patients are followed for six months after their last dose before they are eligible to enroll in one of the open label extension studies swallowed hill or long way.
Most of the data you will see today comes from a combined analysis of patients treated with multiple doses in monarch and Admiral.
In addition, I will share some very early data from the swallowtail open label extension study.
On slide 12, you'll see a summary of patient demographics.
Our safety analysis is based on 55 patients who were enrolled in monarch and Admiral and received at least one dose of the drug up to 45 milligrams.
Patients were evenly distributed by age race and sex across all dose cohorts.
Patients enrolled in the study had severe disease.
75% of the patients enrolled in the study were taking three or more anti seizure medications as maintenance therapy and more than half of the patients were taking four or more anti seizure medications.
More than half of the patients were treated with concomitant affirming.
The observed median baseline convulsive seizure rate ranged from eight to 64 by cohort over a 28 day period.
The most common convulsive seizure type was generalized tonic clock.
Looking at the safety profile on slide 13.
Single and multiple doses of <unk>, one up to 45 milligrams were well tolerated.
All adverse events related to study drug with mild to moderate in severity.
27% of patients experienced a treatment emergent adverse event that was classified as related to the study drug.
22% of patients had a treatment emergent serious adverse event.
None of these are say he's were related to <unk>.
The most common treatment emergent adverse events were vomiting, headache and seizure.
None led to study drug withdrawal.
33% of patients experienced CSF protein elevation after dosing.
To date no associated clinical manifestations of this protein increase have been reported.
Overall these safety results are very encouraging and support further clinical development of <unk>.
Turning to PK on slide 14, a dose dependent increase in study drug drug exposure was observed in plasma.
The 45 milligram levels are clearly separated from 30 milligram, although $20 30 milligram levels appear less differentiated.
On slide 15 C. S. FX exposure was measurable up to six months following single and multiple doses of <unk> 001.
Indicating sustained exposure of <unk> one in the brain.
These data continue to support a potential four to six months dosing schedule.
Turning to our modeling results on slide 16.
Based on the preclinical modeling, we anticipate that the majority of patients would achieve pharmacologically active levels in drug in the brain of drug in the brain. Following three doses of 30 milligrams.
These drug levels were conservatively defined as ones that would could result in a two fold increase in that $1 one protein in the brain.
Clinical data indicate that the majority of patients treated with three doses of 20 or 30 milligrams have achieved these pharmacologically active levels at some point during dosing.
Most importantly based on the effect that we're seeing in the 45 milligram dose groups.
Now I believe we are entering a therapeutic range that is leading to a clinical effect.
These findings are consistent with our understanding of the biology of the disease and the mechanism of SD case It was zero.
To have a clinical effect, we need to reorganize the electrical circuitry in the brain.
Which requires both getting <unk> into the brain and time to produce a clinical effect.
We will now review findings from our preliminary interim analysis of seizure frequency on slide 17.
A secondary objective of the monarch and Admiral studies this.
As to assess clinical effect as an adjunctive anti seizure medication.
These data were captured by caregivers.
Keep a daily diary of countable seizures.
Based on data available from 27 patients who were treated with three doses of <unk> zero, one at 2030 or 45 milligrams and followed for at least three months after the last visit.
20 out of 27 patients or 74% demonstrated.
<unk> reduction from baseline in convulsive seizure frequency as measured from day 29 after their first dose to three months after.
<unk> in both studies.
This is why the seizure reduction was assessed after day 29.
Median reductions from baseline in convulsive seizure frequency were observed across the multiple dose cohorts.
The 45 milligram cohort produced the most robust response, demonstrating a 55% reduction in <unk>.
Convulsive seizure frequency.
We observed a median reduction of 20% among the patients treated in the 30 milligram dose group and a median reduction of 41% among those in the 20 milligram cohort.
These benefits were observed on top.
Various anti seizure medications.
At least half of the patients were on sensor.
No clear dose response was observed between the 20 and 30 milligram multiple dose cohorts.
To understand why we looked at the underlying drug exposure levels.
As you saw in the previous slides there was no meaningful difference between the 20th 30 milligram cohorts, which we believe may account for the lack of dose response and seizure reductions observed in these cohorts.
However, we see a separation in plasma PK and CSF exposure and the 45 milligram group, which corresponds to a greater reduction in seizure frequency.
As you can see on slide 18, the reduction in convulsive seizure frequency was also observed across age group the <unk>.
Green lines here, so that the effects were more evident at the highest dose and in younger patients, including the two patients who experienced median reductions of up to 74% in the 45 milligram treatment group.
We believe the older patients who had been living longer with this disease may benefit from longer durations of treatment at the high higher dose levels.
Turning to slide 19.
We're pleased that these interim data.
We're pleased with these interim data.
And believe we have entered a therapeutic range.
With monarch and Admiral ongoing we are gathering important information about the initial dosing regimen of SDK 001 up to 70 milligrams.
Once through their initial treatment.
<unk> are eligible to enroll in one of the two open label extension studies Swallow Taylor in the U S or long linked in the UK.
Following recent interactions with regulatory agencies, we agreed to limit chronic dosing in the extension studies.
Dosing is now ongoing and swallowed Taylor at 30 milligrams, and then long wing at 45 milligrams.
This decision was based on a review of interim chronic toxicology data from a study in nonhuman primates.
In this study the total drug administered to NH fees was higher than we would anticipate given to patients because of this we do not know why we do not know whether there is any clinical relevance to these findings.
We believe the effects seen in Hps, maybe the result of an accumulation of drug in their brain due to a longer than expected half life of XT cases zero one.
We plan to conduct a new chronic toxicology study in NH piece that will better reflect our clinical dosing plants.
Turning to slide 20, as Ed mentioned earlier today, we are pleased to be able to share very early findings from a small number of patients who have continued dosing with <unk> in our swallowtail open label extension study.
Overall, the safety profile for patients in swallowtail was similar to monarch.
Reductions from baseline in convulsive seizure frequency were maintained with multiple doses.
Preliminary results from a small cohort of patients who received 30 milligrams. During this study showed improvements in executive function as measured by the brief Pete.
Standardized ratings scale designed to measure the range of behavioral manifestations of executive function in children, such as the ability to organize thoughts and have working memory.
As shown on the right side.
A lower data points at week, 16, and 32 demonstrate improvements and executive function compared to baseline.
I want to reiterate that these results are early and based on a small number of patients.
Seen changes in non seizure aspects of the disease at this stage with somewhat unexpected.
Longer follow up as more and more patients as needed to validate these findings.
We see these data as another indication of potential clinical effect of address of addressing the underlying cause of Dravet syndrome.
Before I hand, the call back to Ed I'll summarize the key takeaways and next steps for the program on slide 21.
Multiple doses of <unk> up to 45 milligrams were well tolerated.
The majority of patients treated with multiple doses experienced a reduction in seizures, which was more evident at the highest dose and in younger patients.
These benefits were observed on top of background of standard anti seizure medications.
The very early non seizure data indicate our confidence that we are addressing the root cause of this disease.
Studies remain ongoing we are treating patients in an expanded 45 milligram multi dosing arm of monarch. We are also working to expand 70 milligram multi dose arm of Admiral pending a safety review.
We look forward to sharing these data with the scientific and medical community at the American Epilepsy Society annual meeting in December .
And to reporting additional data in 2023.
I'll now hand, the call back to Ed Thanks, Barry.
In short what we see today furthers, our confidence that we're going to be able to address the underlying cause of <unk> syndrome to change the course of this disease for patients and their families.
In addition to the effects we are seeing on seizures. The early non seizure data support the idea that we are on our way to developing a drug that will address the syndrome. In addition to the seizures. We've a lot of work to do but we're well on our way our job here. Its job is to continue to push forward into the clinic. So that we can get additional data that.
We need to be able to take SDK joser one into pivotal studies. This is not something we do have loans I'd like to thank all of the families who have trusted us and made significant sacrifices to participate in these studies.
I would also like to thank the teams of people at the clinical sites, who are at the front lines of patient care, including the investigators study coordinators and support staff.
Finally, I'd like to thank the entire team here at Stoke who continue to work tirelessly to progress our clinical studies and generate data that will continue to advance. The case those are one as potentially the first new medicine to treat the underlying cause of this devastating disease.
As someone who has spent his entire career I understand in genetics and applying insights to the development of treatments for rare diseases I understand the urgent need to move quickly to advance potential new medicines like Sdk's those are one two patients.
Operator will you. Please open the lines for questions. Please.
Thank you at this time I would like to remind everyone. I wanted to ask a question Press Star then the number one on your telephone keypad.
Yeah.
We will take our first question from Joseph Stringer at Needham <unk> Company.
Hi, good morning, Thanks for taking our questions.
Just curious if you could provide some more detail on why you think youre seeing greater seizure reduction in the younger patients.
It kind of seen this both sets of data releases here.
Is it more just the advanced nature of the deep of the disease in the older patients or is there some element of different mrna levels.
And those various age groups and then.
The second question is just curious if you can comment on.
The treatment emergent adverse events.
Any dose relationship there were they higher than the 45 make cohort. Thanks.
Hi, John This is Barry thanks for the questions.
So the first one.
So we are very pleased to see that in that yard younger dose cohort of treated with 45 milligrams were seeing 74% reduction in seizure frequency which is.
Tremendous response.
As.
Yes.
No.
Okay.
Using other compensatory mechanisms.
So that has to be reversed and that takes time that re wiring.
Back to normal after we restore the sodium channels back up to normal it takes it takes a while so that's why we think in our advisors.
For the year and potentially.
The older patients will take a little bit more time to be on drug and perhaps at higher doses as well.
As far as the adverse events go we have not been seeing any dose relationship with the adverse events. So as we go to higher doses and too.
Longer treatment, we have not seen an increase in the treatment emergent adverse events and again, we have not seen any.
And this current data set we have not seen any of the serious adverse events related to study drug.
Great. Thanks for taking my questions.
Well move next to Laura Chico.
<unk> Securities.
Hey, good morning, guys. Thank you very much for taking the question I have wanted to efficacy and one on safety.
And Barry your comments were helpful. In the opening remarks here, but.
Either for barrier at realizing there's no control group in either monarch or Admiral but help us understand conceptually the expected placebo response after 120, <unk> hundred 40 day period.
Period.
What would've been the type of reduction expected in a placebo cohort for this type of population and essentially what gives you confidence that youre seeing a true signal at the 45, Meg cohort and then I have one follow up.
Yes, Hi, Laura Thanks for the question. This is Barry again.
So yes, we were very pleased with the 55% reduction that we're seeing in that 45 milligram cohort.
And to give you a.
A sense of the.
The relative levels that have been seen in other placebo controlled trials.
We have food.
Some data in the literature that show.
A variety of responses.
Other placebo controlled.
10% increase in the.
The seizure.
<unk> to somewhere around 20%.
So reduction in seizure rate.
So.
That gives you a sense it also.
That the.
The fact that it's.
It takes.
Several weeks to see.
Insert of effect, which we're seeing consistently across all the dose cohorts.
And.
Sure.
They were seeing a difference between the younger patients in the older patients and there were seeing a dose response all would indicate that this is more this is based on the mechanism of action of the drug and not just to see placebo response.
Thanks, very very helpful.
Maybe the safety question, then that I wanted to ask was.
Just with respect to the CSF protein elevations could.
Could you comment on that a little bit further.
And wondering if you could talk about it in the context of the dosing interval. So I think you've mentioned you're exploring potentially expanding the dosing interval is this something that is linked to the frequency and just how are you thinking about that going forward. Thanks.
So.
Thanks, Laura for the question.
I didn't quite hear the whole question, but I think in terms of the dosing frequency. The results that we're seeing right now in the patients.
Thank you Sir.
Operator can you hear engineers.
We can hear you announced.
It went silent for a few seconds, but I can hear you now.
Hey, sorry. This is Laura Chico, if I might try to re ask the question apologies.
Barry you had CSF protein elevations and about a third of patients just wondering if thats corresponding are related to the dosing frequency and the study if youre extending the dosing interval going forward. How would you think about that in terms of the potential impact on that adverse events. Thanks.
Yeah, Hi, this is Barry.
F protein levels that we saw above normal were not associated with any clinical manifestation.
We did see them in about a third of the patients. This is something thats known phenomenon.
Patients with epilepsy, and so some reports are showing that up to half of patients with epilepsy.
CSF protein that was above normal and in fact, we were seeing at almost 10% of the patients at baseline before dosing had elevations in CSF proteins. It's also a known phenomenon for patients for people, who have been getting into sequel antisense oligonucleotides.
And even in the spin Rozzer case as well as other.
Reported cases that have been.
30 to even 50% of the of the patients who have had elevated CSF protein levels. So this is something that we're monitoring as part of their routine monitoring that we do in this study it's not clear exactly what the etiology is it may be related to the frequent number of lumbar punctures that get done and so we're in.
Expecting perhaps that as the number of <unk>.
<unk> get spread out in our patients because right now we're doing them as you know every month and the initial studies and then were spacing it out to every four months in the open label extension study. So we'll be monitoring in the open label extension studies, what the rate of this is but at this point again, it's not causing any clinical consequence.
And with.
We're continuing to see a very favorable safety profile overall, so it's just something that we're keeping an eye on.
Thanks, guys.
We'll move next to Jessica Fye of Jpmorgan.
Good morning, everyone and thank you for taking our question.
In your prepared remarks, you noted the older patients might benefit from longer treatment can you elaborate on that comment and what it means for development plans as you think about the age groups to include in future trials and I have a follow up.
Yeah. Thanks, So we know that based on the mechanism of action and we're seeing it now that as we get to higher dose levels, we're expecting to see more of a response, especially in terms of seizure reduction and of course, we are seeing in terms of some of the non seizure effects now.
With longer dosing, so we do think that.
Having sufficient dose levels as well as time on drug.
At the proper dose frequency is going to be what's needed to show the full effect of this medicine in terms of the older patients we are continuing to.
Enroll those patients in our trials and following them in the open label extension studies. So we've had a very high rate of.
Rollover into our open label extension study is 96% of the patients from the monarch study rolled over so those will include the <unk> the older patients as well as the younger patients.
And so we'll be able to continue to monitor them and see whether there as we go as we.
Okay.
Theorized that the patients will benefit from longer time on drug.
Daniel This is Ed.
I think you know again, it's really important to remember that our approach is completely different from every other anticonvulsant therapy. That's been tried we're trying to again kind of reorganized the brain and it is what we've seen the older patients have been.
Basically had the disease for longer period of time is a lot of compensatory mechanisms that occur in.
And it takes time for that to Reaccelerate I think the really important thing, though is that the older patients.
Very severe need for new therapies, and so we want to make sure that we're not only addressing the younger patients, but also also making sure we're addressing the needs of the older patients.
Yes.
Got it.
One question on the CSF elevation as you have mentioned in the prior question to Lora and also what are the what we have observed in the literature, showing and I'll ask Mike 60% of elevation in epileptic patients maybe can you compare that to the amount you saw at baseline and at different time points in the study.
Well, yes.
At baseline prior to dosing.
Almost 10% of the patients that debt.
Evaluated.
CSF protein that was above normal.
And then as we mentioned that that did that presented did increase to 33% of the patients.
At some point during the dosing period that includes the open label extension study. So it's something that we continue to monitor we have not seen any clinical effects of that at this point.
And we are.
Im not sure exactly of the etiology, but again as we think we may space out the.
The number of procedures of lumbar punctures that patients have that may be able to address some of the increases.
Got it. Thank you very much congrats on the progress.
Thanks, Dave.
We will go next to Yaron werber at Cowen.
Great. Thanks for taking my question I got a couple maybe just the first one.
Like you said between 20 and 30 in terms of our exposure in the brain.
Slight increase but its in your slides, but in your slides.
You don't mention between 30 and 45 I think you spoke to that and you said you saw more.
Or you Didnt see a difference between <unk> 45, excluding TPG stones.
Elaborate on that and then secondly, what did you see in the nonhuman primates.
With respect to Japan.
Now capping.
The chronic dosing at 30 and 45 and at this point are you, saying, you're not going to go and do chronic dosing its revenue mix.
Until you have more data.
Got you Ron Thanks for the questions. This is Barry.
So.
<unk>.
The first issue was with the exposure levels. So what we showed.
The slides where the plasma levels.
In blood in the first 24 hours, which are indicative of the levels that are achieved in CSF in the brain.
We're.
Not substantially differentiated between the 20 and 30 milligram dosing group, but at the 45 level, where we're seeing a big step up there.
And in the CSF levels, we were seeing the 20th 30, again, which do reflect the brain levels that 20 and 30 milligrams.
Not substantially different from each other there was a slight increase in the 30.
But the data we don't we didn't show the data, but we have data that the 45 milligram CSF levels are substantially higher so there is a big step up which could potentially explain.
The difference in the 55% reduction that we're seeing at that 45 milligram level in those patients.
And just curious why didn't you include that in the slides and is that going to be at Aes.
Those data will be at a yes, yes that will be in the presentation that aes.
So as far as the nonhuman primate data.
So again those that study the chronic toxicology study that we did in the nonhuman primates was a dose regimen in terms of level and frequency that is not reflective of what we're doing currently right now so.
The results that we saw in those monkeys were not reflective and we don't think are relevant.
The current dosing paradigm.
And again, otherwise the safety profile that we've had so far in the clinic has been very favorable.
And we're not seeing any effects. There. So we did have discussions and determined that we would.
Limit the the dosing in the U S to 30 milligrams and in the.
UK at 45 milligrams for the open label extension studies.
The Admiral study continues in the UK at 70 milligrams. So we will be able to we will continue to get data at 70 milligrams in that study.
And we anticipate that we will move forward with the open label extension studies to collect additional data.
That we will use to determine the dose level for phase III.
As far as what dose level, we ultimately will have in the open label extension studies that is going to be a matter of negotiation in the future with with FDA and again.
With other regulatory agencies.
Are running a second study in the NH piece that is more reflective of what the current dosing regimen is and those data will be very informative for us in terms of going forward. So yes, Iran. I think one of the things of course that we saw is that the half life was as we find out more about the drug the half life is longer so.
30% and 45 milligrams I think you sort of gave us some really important information because we're going to want to know what what the dose level for maintenance therapy is going to be obviously, we have the potential.
If we need to go to higher levels based on the human safety data, but I think we're in a range where.
We're ranging chronically from 30% to 45% number going up to 70 milligrams. We have a lot of information that will tell us what the doses that we're going to need to go to in the phase III. So I think I think these are going to be very informative studies.
Okay.
Great.
If you don't mind, just a quick follow up so why not dose than 70 chronically.
In the in demand in the.
UK in long tail white cap it at $45. If everything is safe and 70, you're thinking 70 is okay and you've only seen that issue at much higher doses. Thank you.
Yes, you are on where we're just collecting now the data at 70 milligrams in the Admiral study. So we have to complete that in fact right now we have enrolled the initial four patients where you are.
Intending to enroll up to additional 10 patients in that 70 milligram dosing group based after a safety review so we'll be collecting those data and then.
At this point those patients are.
Not even eligible to roll over into the open label extension study. So once we get to that point, but we will see what what the outcome is but.
Right now we're still collecting just the data on the three doses in the Admiral study.
Okay very useful thank you.
We will take our next question from Tom Shrader with <unk>.
Good morning, and congratulations so I apologize if I missed some stuff the lines going silent for me a lot, but the big reduction in the 45 Mig group can you tell us is that being driven by a handful of patients or is it across the board I think you said your highest reduction was 70% and your average was.
55 is that correct.
Yeah, Hi, Tom This is Barry thanks for calling in so what we did see was that at the 45 milligram group as a cohort there was a 55% reduction in median seizure frequency in the younger patients and it was just two patients at the younger group, but they did show a <unk>.
74% reduction.
So that that to us it was quite meaningful.
Yes.
The reductions were.
Quite broad across the entire population. So we are seeing for <unk> 74 per station presented patients overall, we're having reductions in even in that 45 milligram dosing group, we saw that again that that.
Of the patients there they were fitting that same pattern, where at least three quarters of the patients were having reductions. So this is these meaningful results are not based on just one or two patients driving. These this is a phenomenon thats occurring across the board generally in the patients and <unk>.
These are still patients who are on top of.
<unk> and other anti seizure medications.
And then Ken maybe a little clarity on your PK comment, so youre, saying youre measuring all will go in in the plasma.
Why do you not assume that Youre saturating your target at something like 30, and then stuff is starting to build up and plasma is not that's not the way to think about it the fit leak before exceeds the target.
Okay.
Well said.
The <unk>.
Goal for US is to get the Ali go to as many parts of the brain as possible at <unk>.
Highest level as well as to have it a sustained effect over time and we know that.
It requires time on drug in order to really see these benefits and Thats what were seeing in that open label extension study with the non seizure.
Okay.
The assessment so.
What we think is that the.
CSF when we inject in the CSF the Oligos do go to the blood relatively quickly and that's what we're seeing in the first 24 hours is when we see the peak of Oligos in the blood Thats, not really a receptor or a substrate related phenomenon. That's just based on CSF flow. So the oligos.
It gets into the.
Into the blood, but it also gets into the brain readily and.
So what we're seeing is in the CSF as well, which is a better reflection of.
<unk> a brain levels that we are seeing a dose dependent now increase from the 30 milligram up to the 45 milligram level and Thats. What we think is explaining some of the big bump in effect that we saw in terms of seizure reduction.
So Tom.
It is helpful to look at this we saw that Mark reduction in seizures at 45 and that really corresponds very nicely with the increase in the plasma and more importantly in the CSF. So it looks like we're at 45, we're getting into that therapeutic range.
Or are you seeing clinical efficacy and so I think it does seem the story seems to make sense to us now.
Got it thank you.
We will go next to Charles Duncan of Cantor Fitzgerald.
I don't know the income line for Charles Thank you for taking our questions.
I have one on the three key findings I was wondering if you thought there was any correlation between on responses.
Well as a reduction in seizure and.
Yes.
The younger patients performed better on <unk> as well just as they appear to do so.
Seizure frequency.
Yes.
Yes. Thanks for the question so on a brief again.
The natural history study the butterfly we saw.
At one year no reductions.
And that was a consistent phenomenon across age groups as well and then in the open label extension. These are small numbers of patients. So we had eight patients at the four month time point and five patients at the eight month time point.
We continue to see a consistent response there in terms of an improvement in the overall score, but those numbers are small relatively small and so breaking it down by age or by CTO response really makes it more difficult more difficult to interpret so we're looking forward to having additional patients as we go.
Forward.
There will be able to follow what we've done them over time and at that point, we'll have a better sense in terms of breaking down.
And looking at the subgroups.
Yes.
Okay. That's helpful. Thank you.
And I guess, one quick follow up is with respect to the theater freight.
Seizure frequency at three months as tissue I guess broadly talk about how that compares to what you saw lots, one and CTO and just generally.
What are you seeing with respect.
The reduction in seizure frequency over the course of time. Thanks.
Yes, so what we do see consistently is that in the first months after dosing.
There is relatively little effect.
Seizure level stay pretty much at baseline and then after that we start to see reductions that lead to that peak at three months after.
The last dose, where we saw that 55% reduction in the 45 milligram dosing group and that's about the rate consistent phenomenon, we're seeing across the dosing groups and across patients.
It does indicate to us that this mechanism of action based because we know that it takes.
From the Monkey studies several weeks.
It's not up to four weeks to see the increases in the net $1 one levels in the brain and the restoration of normal levels, we expect in the patients.
And so this is a phenomenon that we were expecting to see and as I said is consistent with the mechanism of action and consistent with what we've been seeing across all the dosing groups now.
In terms of going forward, we did see in the swallowtail study.
That the reductions that were seen in the monarch study were.
Were maintained in the swallowtail study.
So it appears that that every four month dosing regimen may be sufficient to provide adequate seizure control in senior management and then of course, we're also very eager to see the additional data where we're looking at syndrome management, we're going to.
Be able to.
SaaS whether over time the other non seizure parts of this disease, which are quite devastating for these patients can be addressed as we've already started to see with debris <unk> measurement.
Okay wonderful. Thank you for taking my questions and congratulations on the progress.
Thank you.
We'll go next to Greg Harrison at Bank of America.
Hey, good morning, Thanks for taking the question.
<unk>.
I know, it's a little early but curious what characteristics you would target for a pivotal study.
Things like number of patients.
Placebo control or would it be.
Patients have.
Comparison to baseline seizure frequency.
Hi, Greg This is Barry Thanks for the question, it's good to hear from you.
So in terms of phase III.
The first thing is that we are we need to identify the.
Dose level and the dose frequency that we would bring into phase III and we think we're very well on our way towards that right now the data that we reveal to date.
Vacate that we are now reaching the therapeutic range for our drug dosing and it's going to give us a good idea of what the.
With the potential for the correct.
Dose level and dosing interval will be <unk>.
Once we get there.
Then we do have the precedent of other.
Medications that had been approved for Dravet syndrome.
Which showed which used a placebo controlled trial with a primary endpoint of seizure frequency at a three or four months time point so.
That certainly will be the guide for us and likely would be the path that we follow but we still have to have.
Discussions with our clinical advisors with regulatory agencies.
Before we can finalize those plans, but we have as I said.
<unk> tried in Paas already that we can follow the part that.
So not as well worked out of course is are these non seizure effects because the currently available therapies are symptomatic treatments that are used for senior management, but since we're bringing a completely different paradigm with a new approach for treating dravet syndrome, and the only approach that's going to be addressing that.
The root cause of the disease.
Management of the syndrome in general and the non seizure assessments is something that we're going to also talk to the regulators about and how we assess those in our pivotal studies, but again the likely primary endpoint would still be.
Seizure endpoints.
And Greg I think one of the things that helps us a lot as we've learned a lot from the butterfly study on what are the appropriate.
Tests that we can be used in this various age groups. So it's very likely we will use a lot of the tests that we learned about and butterfly and again as Barry said, we're really going to be emphasizing which is different from most anti seizure medications is really trying to focus on what's their cotton and quality of life, but some of the non seizure comorbidities and so that will be an import.
And part of some of the discussions we have with regulatory authorities.
Great. Thanks, that's helpful. And then just one quick follow up on that.
Do you have a time point in mind, when you would expect to see significant non seizure benefits that can be measurable or stat Sig.
And how would you expect that to vary according to patient age.
Some of the Kols, we've talked to.
As suggested.
If you treat patients beyond.
You don't start until there are certain age maybe there is permanent.
Damage that spend on that that's not flexible.
Yes, so Greg.
A question that we're trying to answer with our clinical trials. So it's difficult to give you an answer right now.
We know that these are patients who are highly refractory to treatment thereon three four medications. Some of them are up to seven medications and are still not having adequate seizure control even on fenfluramine. They continued to have seizures.
So here in this case any.
As our clinical advisors have told us in these patients where they have no treatment options to offer to these children and their families.
Any reduction in seizure is going to have a benefit from a clinical perspective in these patients.
And that holds for the older patients as well as the younger patients. So we think that as we are seeing the older patients are having a response they are having consistent and dose dependent reductions in seizure frequency. We saw that again with the 45 milligram, we're seeing more of a response and we are seeing substantial.
<unk> and even the older patients. So at this point, we think that older patients.
Could benefit from our medicine, we don't see a reason to exclude them from treatment and.
So as we move forward, we will continue to enroll both older and younger patients in our studies.
Got it yeah, I mean, I guess that my question was more towards the non seizure benefits.
Benefit that.
Alright, thank caution everyone can benefit on the seizure frequency.
Marvel titles.
Sort of aspects.
Yes, that's an even more uncertain question.
We're doing something for the first time here and for all of seizure management. This is this something new for the epilepsy field, where.
Where we are bringing a medicine, that's actually addressing the root cause of the disease here, we're going to.
Restore sodium channels back up to normal in these patients that's never been done before so it's not clear exactly what to expect but certainly.
Our hypothesis is that if we see benefits on the seizure front, which means that the nerve cells are now functioning normally and are reducing the number of seizures that that in this disease should go along with the change in the non seizure effects as well so we would expect that.
As patients around the medicine for long enough period of time.
And the.
<unk>.
Restoration of normal connections in the brain happens.
The non seizure effects should also improve but thats something that we obviously have to see over time.
And Greg one thing to the differentiation between <unk> and some of the neuro degenerative diseases, you've taken Parkinson's or Alzheimer's disease, where youre, losing ourselves all the time <unk> syndrome is really a disorder of connectivity of the axons in synapse in Denver is and I think what we are.
What we're hoping is that we can have an effect on the children because the neurons are still there and the hope is that we can make those connections and get some of those children and some especially some of the older children to have some improvements.
Great. That's really helpful. Thanks for taking the question.
Hi, Andrew we'll take two more callers.
Thank you and the next one will come from Judah Frommer at credit Suisse.
Okay.
Yes, hi, thanks for taking the questions and congrats on the data just a question kind of on background for the patients do you have a sense for where the patients were in kind of seizure reduction achieved by the background meds before they got into this study so effectively seizure adoption versus when they initially presented at clinic before.
You guys got a hold of them.
Sure.
Hi, Judah thanks for the question.
So these patients have.
When treated with pretty much the standard course of their medicines and this this fact that half the patients were on.
Three of our four or more medications when they enrolled in the trial is not unusual for Dravet syndrome, we know that Theres a high.
Essentially failure rate of the anti seizure medications.
Symptomatic treatment and that patients continue to have seizures, despite escalations and additions of new therapies.
Standard way that <unk> treated is that a medicine has tried it as patients continued to have seizures in another medicine is added on and it continues to add on in this way and Thats why we are seeing patients who have up to seven treatments that theyre getting.
We know from even the trials that were done with fenfluramine that there is a very low rate of complete seizure freedom in these patients so seizures continue to happen despite.
Some relatively effective medicines and Thats basically where we were seeing in this trial.
We know that the rate of seizures that were seeing that enrolled in monarch and add more trials with similar to what was seen in the other phase III trials. So these are patients who in terms of severity are equally if not more severe than were enrolled in other phase II trials and.
We're still continuing to C C.
Seizure reductions on top of all of that so that for us.
<unk> was a very encouraging sign.
Okay. That's helpful. And then just if you could kind of further connect the dots on the 20 and 30, Meg CSF exposures versus <unk>.
Seizure adoption.
The seizure reduction and in the 20, Meg looks compelling obviously, it's a small number of patients is your contention that that that 20, Meg wine on slide 17 might move toward the 30 Meg line if more patients were dosed.
Yes.
So the data that we have right now did show both in the plasma and CSF that the 20 and 30 milligram levels, where we're not substantially different our expectation would be that if we had more patients in the 20 milligram group more than those for patients.
That we would probably continue to see that there was that the levels were slightly below the 30 milligram, but not substantially differentiated and so that's why we were very encouraged to see with the 45 milligram group that as.
As we were seeing in the <unk>.
<unk> reduction that we think that we're now getting into a therapeutic range with the medicine and with the levels that we're achieving in the brain to have a substantial clinical effect.
Okay. Thank you.
We will take our final question from Rudy Li at FCB Securities.
Okay.
Thanks, My taking my question congrats on the data.
It seems like we have seven patients within our response that you did not have seasonal reduction where some space.
How many patients from each cohort, including the medium CDN reduction data.
Any additional color here would be helpful.
Sure so what.
What we did see was that three quarters of the patients were having seizure reductions and that was pretty consistent across all the different dose cohorts.
So.
Again this is not something that's being driven by one or two patients. It's relatively consistent that we're seeing in all the dose cohorts. Some degree of reduction is just at that 45 milligram dose group, we were seeing even more reductions that we were seeing at 20 or 30 and Thats, how we got to that 55% reduction and again, even with <unk>.
The younger patients.
We are also seeing that there is a.
Consistent response in the younger patient groups and in fact, it at 7%.
Amounted of 74% reduction.
As seen at the level.
In the patients.
Very younger glue.
Okay.
Got it.
Quick follow up so what data should we expect at the upcoming Aes conference.
Yes, we're very excited to be able to present data next month in Nashville.
What we will be presenting we have multiple presentations that we will be presenting some additional.
The data on the.
<unk> nation from the Admiral and swallowed sorry, Admiral and monarch studies in terms of the seizure reduction it won't be more patients. So we aren't going to be adding additional patient data from the total number but we'll be adding additional data, especially in terms of the safety and PK and we will have a separate presentation on peak.
That will show again more data that we showed from the plasma and CSF levels.
We will have data from the monarch, sorry from the butterfly study our natural history study, where we now have data out to one year.
And then the exciting part or the Swallowtailed data, where we're starting to see some of these non seizure comorbidities affect it and so we will have data on that brief Pete again not not.
Increased number of patients, but we will be able to show those data for the brief <unk> against.
Got it that's very helpful. Thanks.
The other the other thing that we will be showing us some EEG data. So we do follow EEG in these patients and we have some data that will be worth looking at four.
<unk> changes that we see in these patients.
Yes.
Okay. Thanks, everyone for joining today the IR team is available for any follow up questions. The rest of the day.
And this concludes today's conference call. Thank you for your participation you may now disconnect.
[music].
Yes.
Yes.
[music].
Sure.
[music].
Okay.
Okay.