Q2 2022 Taysha Gene Therapies Inc Earnings Call
<unk> syndrome, we are highly encouraged by late breaking neonatal data in preclinical mouse models, demonstrating near normalization of survival and normalization of behavior. As you will hear from Syria. Shortly we believe the totality of preclinical data generated to date by patient one O. Two is a comp.
Prehensile dataset and Ret syndrome that further supports earlier treatment and clinical advancement of this promising product candidates.
We look forward to reporting preliminary phase one class II clinical data in adult females with ret syndrome by the end of this year.
Now I will turn the call over to Fred to discuss updates on our comparability data for Taishan 120th game Bret.
Thanks, Sarah and good morning, everyone. In the next few slides I'll review, our manufacturing progress for the <unk> program and our comparability package that supports the transition to our final commercial manufacturing process.
Next slide.
Our manufacturing development program for <unk> 120 was kicked off in mid 2021, when we initiated our partnership with our CMO partner to deliver our commercial ready manufacturing process.
We have rapidly executed several tech transfer around leading up to production.
Of our 500 liter pivotal batch in April of this year.
In parallel we progressed several key analytical development efforts internally to deliver a comprehensive data package to support product release and comparability in line with agency guidance for pivotal stage programs.
Next slide.
Our commercial grade manufacturing run was highly productive yielding over 200 miles of finished drug product build into two separate lots that are currently undergoing release testing.
After inspection and testing over 50 patient doses are available for clinical use.
In addition to supporting the ongoing clinical study. These lots were enrolled in a comprehensive stability study to provide clinical critical shelf life data in support of our BLA filing.
The 500 liter production also represents our final commercial scale, which aligns with our commercial projections.
We believe this high yielding process supports a favorable cost of goods and assures us that we will be able to meet commercial demand with a reasonable number of batches annually next slide.
And considering the analytical panel for product release and comparability. There are four key areas of importance for gene therapies strength purity potency and safety.
These important attributes have informed the panel of assays that we are in the process of validating at our CMO partner to support both product release and comparability.
The analytical method selected align with agency expectations in terms of accuracy precision and robustness for measuring each product attributes.
Slide.
In order to assess comparability of our clinical trial material and the newly manufactured material from our commercial manufacturing process. We've applied this panel of release assays for side by side testing with our comprehensive assay panel.
Shown here are eight of the most critical attributes that reflect on the purity potency and safety of our product.
First our results demonstrated that both clinical trial material and commercial grade material or a high purity and lacked significant levels of wholesale our process contaminants, such as protein and DNA or aggregated species.
Victor purity was in excess of 95% for all three lines and wholesale protein contamination was below detection.
Aggregation of all lots will also very low.
Oh cell and plasma DNA contamination are also important attributes to discuss with regulatory agencies since carryover represents a theoretical immunogenicity or oncogenicity risks.
Residual plasmid and host cell DNA were similar for all lot, indicating a consistent product profile for both of them.
Empty capsid are a key attribute for AAV vectors since SMT taxes can stimulate immune responses to the vector and reduced potency.
All three lots were highly enriched in full particles and meet recent FDA draft guidance in terms of analytical methodologies and percent full captains.
Finally potency of AAV vectors as a key measure that is intended to correlate with clinical efficacy. We developed several product specific potency assays to measure functional activity of our product, which is reported relative to a reference standard.
These assays recapitulate, the biological activity of tissue 120, where AAV transduction process of cell entry DNA and packaging gene transcription and translation occur and then amortize mammalian cell line.
Functional activity as measured by quantitative of tissue in 'twenty, transgene, RNA levels or gig accident protein expression as two independent and complementary readouts.
We observed good agreement with both methodologies and the activity of all three GMP lots against a reference which gives us confidence that the lots are up high and comparable activity.
Overall these results support our view that our early clinical trial material and commercial grade material are biochemically and biophysical similar and should perform identically in a clinical study.
We plan to present. These final study results with additional regulatory agencies and anticipate regulatory feedback by the end of this year and next slide.
Recently regulators have encourage sponsors to conduct deeper analysis of product contaminants not covered by standard release assays to better assess product safety and comparability.
To comply with this guidance, we have added Pac bio next generation sequencing to our product characterization panel to better understand the nucleic acid composition of our products.
This method not only allows us to identify the source of nucleic acid, but also the fragment signs sequence variability, which often needs to be considered when assessing safety and efficacy.
Our analysis of clinical trial material and Kurt commercial grade pivotal batches demonstrates that the source and composition of transgene and contaminating hosts and plasmid DNA is nearly identical and provides further support that the nature of our product is unchanged between our early clinical and commercial grade batches.
Slide.
In summary, we have successfully executed six batches of <unk> hundred 20.
Our pivotal 500 liter scale GMP batch was productive yielding over five.
Excuse me 50 doses for the high dose cohort, which positions us for future BLA, enabling activities and commercial production and importantly, our comprehensive comparability analysis demonstrated that the clinical grade material and commercial grade material are nearly identical by key critical quality attributes measures, including next.
Generation sequencing analysis.
We have also made rapid progress developing a product specific potency method, which is on track for validation and product release, which aligns with regulatory expectations.
We feel this progress supports a strong regulatory package that we will discuss with additional regulatory agencies this year, including the FDA.
Now I'll turn it over the call to see us to discuss additional program updates for Dan.
Yes.
Thank you Fred and good morning, everyone.
I've already noted earlier, we continued to make notable progress in advancing our clinical programs for Gan on Ret syndrome unexpected exciting milestones throughout the remainder of the year.
I'll begin with recent updates on <unk> 'twenty program.
Building on the positive clinical efficacy on safety data on long term durability data that we reported earlier. This year. We are pleased to report new nerve conduction studies data <unk> 20 and GAAP.
We are grateful to our partners of the <unk>, the leading again natural history study.
The dimensional trial under the leadership of docs at constant Fundament principle investigator at the NIH.
Next slide.
Nerve conduction studies are in Europe physiological measure on the specific measure of relevance to Gan is the century.
<unk> potential or snap, which is considered a definitive clinical endpoint.
The test is performed by applying an electrical stimulus to the sensory nerve fibers and recording the ashram potential that's a point further along with that.
There are three main parameters. The first is the amplitude of the action potential which is the peak to baseline measurements.
On the functional significance is that this is related to the number of excellence and us.
With that said, we want to generation neuropathy. The primary feature is a markedly reduced sensory nerve action potential will snap amplitude.
The next parameter as latency, which is the time from stimulus from the initial electrical deflection.
This can be compromised and the tmall in 19 neuropathy.
Lastly, conduction velocity is the speed with which the electrical signal travels down enough. This.
This can be affected by axonal loss, but most side with demyelination.
The NIH natural history study suggest rapid an irreversible decline in sensory function early in life and patients with Gan.
Snaps are within the normal range early in life, and then undergo a rapid reduction in snap amplitude around the Asia symptom presentation.
This graph depicts the metis amplitude age the natural history population and the NIH study.
The horizontal black line represents the level of limited normal.
As you can see the youngest shown this graph is approximately two years of age and as a snack well within the normal range.
As children reach the ages of three or four years, which is the actual age of symptom presentation.
Deteriorates markedly.
You may recall that the initial symptomatology in the three to four year old includes an steadiness and a wide based gate, reflecting the fact that they lose the ability to fill the ground beneath our feet.
It is therefore unsurprising the nerve conduction studies reflect this symptomatology.
The first Green line depicts the fact that every patient with Gan has an abnormally like snap amplitude by the age of four years reflective of compromised sensory function.
The second Green line indicates that 100% of patients.
Fully absence snap by the age of nine years, which will be considered to be irreversible.
Next slide.
This image as the same data as the previous slide but with a line of best fit added to demonstrate the rapid decline in snap amplitude from normal.
Absent hasnt totally page.
Next slide.
Of the patients treated in the efficacy dose arms of the study, 42% or five of 12 patients had the positive snap partially age of nine years.
Patient visits which is remarkable considering that none of the natural history patients had a positive snap past the age of nine years.
The specific values for the five patients in question are shown in the graph on the right well one of the patients demonstrated near complete recovery and continued upward trajectory from a baseline of zero at the time of treatment.
Next slide.
Many of the patients who were dosed in the interventional trial have an absence snap response would not be expected to recover.
From this graph you can see the 100% of patients treated with <unk> hundred 22 had a positive sensor response initially maintained a positive response after treatment rather than continuing to decline to zero as would normally be expected.
Once snapped reaches say right sensory function is considered non recoverable.
Notably 100% of these patients which is three three at par.
Value at baseline and.
<unk> maintained that posed to snap at the last study visit.
The longest Spanish three is to date and the patients continue to maintain an upward trajectory.
Next slide please.
These five crops demonstrate individually plotted patient snap changes from baseline and importantly includes the patient running data from the natural history study.
There is continuing improvement in snap amplitude from either a declining snap on absence snap.
Importantly, and remarkably two patients had a snap amplitude that had been absent for over a year and the natural history study and after dosing demonstrated consistent and sustained improvement.
This recovery of function and then Europe histological measure such as definitive and consistent overtime is contrary to natural history and exciting to see.
Next slide.
Earlier this year, we shed posed to pathology data from nerve biopsies, which confirmed that treatment with <unk>, one 'twenty can stimulate activity with generation of axons.
The entire data set demonstrating 100% of <unk> 120 treated patients had to regenerative nerve clusters present, one year treatment and the biopsies.
Peripheral nerve biopsies were obtained at baseline and a one year post gene therapy transfer.
Official of radial sensory nerve.
Analysis of 11 of 11 Evaluable samples completed to date consistently demonstrates an increase in the number of regenerate clusters.
One compared to baseline.
The remaining two samples were unable to be assessed due to biopsy limitations.
Collectively these data confirm the presence of regenerating the clusters, suggesting active regeneration of nerve fibers and improvement in disease pathology.
This coupled with no collection study data provides evidence that the peripheral nervous system can also had to respond to treatment, but actually improve as opposed to just stabilize.
Yeah.
Here, we have included a representative patient case studies, showing the superficial radio sensory nerve at baseline on the <unk>.
One year post treatment with <unk> hundred 20.
At baseline on the left the Ara identifies a giant degenerating Exxon on the star identifies a regenerating cluster.
On the right is it looks like one year after treatment.
The yellow arrows, indicating regenerative clusters, which as you can see on notable in number.
This pathology data on the neurophysiology are suggestive of recovery of neuronal tissue. After administration of <unk> hundred 20, and such endpoints given the unbiased a definitive nature are often viewed favorably by regulatory agencies.
Next slide.
We believe our gallon program includes a comprehensive set of evidence generated across diverse disease manifestations supporting a robust clinical package.
These include MFN 32 motor function assessments of <unk> hundred 20 treatment, demonstrating clinically meaningful slowing of disease progression across all therapeutic dose cohort compared to natural history decline with a durability of effect.
Electric Fisher logic nerve conduction studies provided definitive clinical end point and support the comparability stabilization and in some cases improvement and sensory response in patients treated with <unk> hundred 20.
Non of biopsy histopathology confirm that treatment with <unk> hundred 20 detect the presence of regenerative clusters suggestive of activity regeneration of nerve fibers.
Pathological biomarker measurements of retro.
But last thickness as assessed by optical coherence tomography demonstrated stabilization.
<unk> on the visual loss following <unk> treatment.
Visual acuity as assessed by lock mall also stabilized after treatments.
And lastly, we heard from Fred earlier.
About how an extensive panel of release assays demonstrated its clinical and commercial grade material the comparable across key quality attributes and confirmed by next generation sequencing.
Next slide please.
Now, let's review the NHRA regulatory feedback we have received to date for our <unk> program and discuss how this feedback supports our continued regulatory discussions.
We believe this initial feedback coupled with the CMC comparability data that Fred discussed.
<unk> as well to further advance tissue from 'twenty through regulatory approval.
Next slide.
A number of recent product approvals and positive regulatory opinions with therapies targeting Iraq, CNS indications and indeed, non CNS gene therapies, especially in the context of unmet clinical need points to flexibility in the current environment from a regulatory filing perspective.
This includes a number of agreements from regulatory agencies for the use of accelerated or conditional pathways to approval.
Some examples include <unk> for the treatment of cerebral Luca dystrophy.
<unk> for the treatment of.
<unk> deficiency.
Page 9001 for Duchenne muscular dystrophy.
Jefferson assault one payless.
Yes.
Next slide.
Our discussions with the <unk> have been collegial and collaborative and helpful.
The MH already agreed with our commercial manufacturing and release testing strategy, including potency assays.
The recommended dosing a few patients with commercial grade material, which will be released in September 2022.
And lastly, there was supportive of our proposal to perform validation work, including patient and family feedback, which is ongoing on the MSM 32, as a key clinical endpoint.
We believe this positive feedback from the MH array in conjunction with the totality of preclinical data generated to date. The <unk> 'twenty represents a robust packages supporting additional discussions with regulatory agencies, we expect additional regulatory feedback.
Including from the FDA by year end.
Next slide.
We continue to work with regulatory agencies with the goal of achieving conditional approval in Europe and accelerated approval in the United States based on EMA and FDA industry guidance for gene therapies and Euro degenerative diseases.
Based on key registrational requirements from regulatory agencies, including the FDA and EMA, we have outlined some possible scenario for approval.
With the EMA, we believe there is potential to file for conditional approval based on current data set for EMA guidance documents.
So the FDA. The first scenario is immediate filing for approval based on the current data set on comparability.
Alternatively, we may need to dose a few more patients to demonstrate comparability of clinical effect between clinical and commercial grade material, which was a similar approval pathway fizzle, Jasmine and spinal muscular atrophy.
The loss scenarios to perform a new pivotal trial, which we think is unlikely given the recently published FDA guidance documents on gene therapies for neuro degenerative diseases, and extensive long term safety and efficacy data set available.
Let me share a feedback further aligns us with scenario, two which is our base case.
We expect to have additional regulatory guidance, including the FDA by year end.
Yeah.
As a reminder, tasha <unk> previously received orphan drug and wrap pediatric disease designation from the FDA.
Next slide.
Now, let's turn to the late breaking preclinical data, we reported <unk> and Ret syndrome.
Next slide.
As a reminder syndrome is an X linked neurodevelopmental disorder, which is characterized by mutations in the <unk> a protein essential for neuronal synaptic function in the brain.
Female heterozygous patients with ret syndrome on Mosaiq carriers of normal mutated <unk>.
The challenge in junior replacement therapy might be to is finding the appropriate balance with sufficient is geologically expression to correct. The deficiency, whilst also avoiding over expression on the associated toxicity.
The estimated prevalence of rest syndrome is 350000 patients worldwide with an incidence of one in 10000 female births worldwide.
Next slide.
Because of this spectrum and risk of toxicity developments of a gene therapy for Ret syndrome requires regulates the expression of <unk> <unk>.
<unk> two gene therapy approaches of course, the dose dependent side effects after intra CSF administration and wall type.
Syndrome knockout mice.
We have developed a novel.
RNA responsive target sequence called MRI rack to regulate the expression of the <unk> transgene and prevent the risk of over expression toxicity.
We believe our approach provides a superior therapeutic profile to that of other regulated <unk> gene replacement.
Next slide.
<unk> wanted to regulate expression of <unk> and our novel Micro RNA responsive auto regulatory element platform known as <unk> that is exclusively licensed to <unk>.
Developed by doctors Cyrus Senate on Steven Great of Ut Southwestern Medical Center.
<unk> provides a sophisticated regulation of transgene expression gene are typically on a cell by cell basis, ensuring controlled expression that avoids excessive levels.
Mris targeted panel for endogenous micro Rnas, which regulate might be two expression.
And the presence of high levels of intracellular make pizza and <unk> Downregulates <unk> micro Rnas are secreted as part of the cells normal feedback inhibitory process, which then bond <unk> platform on the construct and reduced output and the expression of <unk> <unk> from the construct.
This ensures the intracellular levels of <unk>, whether in a wild type style or mutated cell and mosaic patient stay within appropriate physiological levels.
Next slide.
Today, we are excited to shine near normalization of survival and neonatal mouse models of Ret syndrome. Following <unk> went into administration.
Survival was significantly extended and met Pete two knockouts male mice. Following a single CSF injection at day two of <unk> 102 at 888, 10, Vg per mouse, which is the human equivalent dose of 286, a 14 total V.
And a little lower than planned for the human clinical trial.
Preliminary data demonstrated approximately 70% of the treated knock on males survived study conclusion at 34 weeks of age versus nine weeks.
Vehicle treated mice.
All cohorts, including vehicle with sacrifice to 34 weeks.
Next slide.
We then look to the bad score, which is a composite measure of six different phenotypic abilities that relates to ret syndrome. These include breathing.
<unk> general condition hind limb clasping mobility on the tremor.
The course of the study takes you wanted to appear to normalize behavior as assessed by the Bird school.
Next slide.
The totality of preclinical data generated to date <unk> represents the most robust package supporting ret syndrome clinical advancement for gene therapy.
I've just reviewed the recent preclinical study in May and April rents knockouts mice, demonstrating near normalization of survival.
Normalization of body weight on normalization of behavior as assessed by Bird School.
We have previously discussed the pharmacology data demonstrating significant improvement and survival, while the white motor function on risk grocery health across treatment ages and knockout mouse models.
And while we were able to ascertain a minimally effective dose.
We have also previously discussed toxicology data supporting a favorable safety profile of Taisha wanted to Sprague Dawley Wild type wraps up to a six month time point and up to human equivalent doses fourfold over the clinical starting dose.
The nerve conduction studies performed remains the normal range for all groups at all time points signifying no evidence of dorsal root ganglia inflammatory change.
And lastly, toxicology data supporting takes you wanted two was well tolerated at human equivalent doses of up to two <unk> at total BG.
And demonstrates the broad by distribution to brain spinal cord and systemically in non human primates.
Perhaps most importantly, the toxicology studies demonstrated that the Downregulates <unk> MRI wrap platform is working well and that there was minimal expression of <unk> in a wild type cell with normal pre existing levels might be too.
These full preclinical studies together represents a comprehensive and robust package supporting the clinical advancement of Taisha, one I'd say for Ret syndrome.
Next slide.
Our first in human Phase one two study of <unk> 102 for Ret syndrome also known as the reveal study is ongoing.
<unk> mother, and Child University Hospital Center in Montreal, Quebec, Canada is the initial clinical signs of the study which is under the direction of principal investigator Dr. Elsa Wassa Neal.
Target recruitment is up to 18 adult females. It is a three plus three study design with three randomly selected delayed treatment control participants in each dose cohort.
And each cohort may be expanded with up to three additional participants.
Next slide.
We look forward to preliminary phase one two clinical safety and efficacy data in adult females by year end 2022.
We have completed GMP manufacturing for Rex using our commercial process.
Lastly, a study in the pediatric PMO Rep population on the rescue study and males are planned the 2023.
As a reminder, Taisha 102 has been granted rare pediatric disease designation and orphan drug designation from the FDA and more recently orphan drug designation from the European Commission.
With that I will turn the call over to Cameron to review our financial results.
Cameron.
Thank you Sue.
I will discuss key aspects of our financial results for the second quarter ended June 32022 more.
More details can be found in our Form 10-Q, which will be filed with the SEC. Shortly next slide.
As indicated in our press release today research and development expenses were $23 $1 million for the three months ended June 32022, compared to $36 million for the three months ended June 32021, $7 $5 million decrease was primarily attributable to a decrease of $3 8 million in third party R&D primarily related to GOP toxicology.
<unk> studies, a decrease of $3 $2 million in R&D manufacturing costs, and lower employee compensation expenses of <unk> $5 million.
<unk> and administrative expenses were $9 9 million for the three months ended June 32022, compared to $10 1 million for the three months ended June 30 of 2021. The decrease of approximately <unk> $2 million was primarily attributable to a decrease of $1 1 million in professional fees related to market research recruiting.
Accounting and patient advocacy activities. This.
This was partially offset by <unk> $9 million in incremental employee compensation expenses.
Net loss for the three months ended June 30 of 2022 were $33 $9 million or <unk> 84 per share as compared to a net loss of $40 9 million or $1 90 per share for the three months ended June 32021.
As of June 32022, the company had cash and cash equivalents of $66 2 million compared to $149 1 million on December 31, 2021 peso continues to expect that its current cash and cash equivalents. In addition to a full access to our existing term loan facility is sufficient to fund operating expense.
Into the fourth quarter of 2023, and with that I will hand, the call back to Ari.
Thanks Cameron.
We remain focused on achieving our anticipated near term milestones in 2022 and building long term value.
Our programs in Gan and Brett syndrome continues to advance and demonstrate exciting disease modifying potential. That's further supported by the new clinical nerve conduction data in Gan and neonatal preclinical data and Brett syndrome presented today.
As we look ahead, we expect a regulatory update for organic program and preliminary phase <unk> data for <unk> 102 in adult females with Ret syndrome.
By year end.
I'll now ask the operator to begin our Q&A session operator.
Thank you and at this time, we will be conducting a question and answer session. If you'd like to ask a question. Please press star one on your telephone keypad.
Information tone will indicate your line is in the question queue.
You May press Star two if you would like to remove your question from the queue for participants using speaker equipment. It may be necessary to pick up your handset before pressing the star keys.
One moment, please while we poll for questions.
And our first question comes from the line of Joon Lee with <unk> Securities.
Please proceed with your question.
Good morning, Thanks for taking the question just ask you Osman for June .
Just wondering has there been any discussions with the FDA on regulatory allow me for 120, just thinking most in terms of the three scenarios that you've previously laid out on whether or not the FDA might ask to re dose patients with GMP material.
Also said discussions have occurred with safety database of fishing or has the FDA indicated additional need for efficacy biomarker or a clinical data. Thank you.
Okay.
Good morning, maybe I'll start and then I'll turn it over to <unk> to provide some additional insight.
What we've guided to this morning was that we will have additional feedback.
From regulatory agencies, including the FDA by the end of the year I think the regulatory feedback that we've been noted problem NHRA kind of aligned ourselves with what we considered scenario two which is the need to dose additional patients using the commercial.
Cereal.
We kind of see that as our base case, and that's what we've been planning for.
The good thing about that is the patients are already identified they are currently at our natural history study and what we would do with the jets rollover patients from the natural history study aimed to the current ongoing trial, we would do that once our GMP material is actually fully release, which should happen here. The next few weeks.
Which we're quite excited about and the fact that as we've been noted on the call that the original clinical trial material and the new commercial grade material are virtually identical.
All key quality metrics. So I think when you look at all of those things in consideration I think that lines up nicely for how we're planning to move forward, which we consider a scenario two is probably the most likely case that would be the need to dose a few more patients using the commercial material I think ultimately.
Our discussion with the agencies will really be about how to.
Accelerate whatever the potential filing would be and I think the use of <unk>.
Our rolling submission would be something that I think we would be more encouraged to ask Scott the agencies about I think this environment, what we're seeing from a regulatory perspective is a good environment, particularly for gene therapy and CNS therapy.
The agency has shown significant flexibility and I think we've lifted off a number of those examples both the FDA and EMA. So we feel pretty good about our approach keep in mind. We've now shown you data across multiple functional endpoint. We've now show new data across pathological endpoints. We've now shown you data across definitive endpoint that include.
Yes.
Again, our hard endpoints right.
Don't include any type of perceived bias, but with all of that totality of data coupled with the.
The.
Comparability data that we now have in hand, we feel pretty good about.
Our discussions moving forward with the agency the whole plot there yes.
Yes, do you have anything to add or we can move on.
I think you said all right.
Perfect.
Alright. Thank you and then if I can just ask the yield of the <unk> dose at that you've already manufactured.
Well thats quite the highest dose that was tested in clinical trials for all 50 of the doses that are ready to go.
Thank you.
The answer to that is yes that 50 doses at the high dose, which is three five to the 14th.
Okay. It sounds great. Thank you.
Thank you.
And our next question comes from the line of.
Joe Bloom with Needham <unk> Company. Please proceed with your question.
Good morning, everyone and thanks for taking our question. So just the question of clarifying that.
Sure.
We understand that.
The additional regulatory feedback.
We will be getting by year end 2022 changed from previous estimates.
So thanks Bill for the question and good morning, So our previous guidance was that we would have regulatory feedback by year end we.
We didn't disclose from what agency, we would have that feedback from so essentially the feedback that we provided on the call today is in line with our previous guidance, what we've decided to do because of the success of our commercial grade manufacturing line and the comparability data that we've generated from back including potency assay.
<unk>.
Including relief that base as well as the additional clinical trial data that we showed you guys to date, what we decided to do was essentially hold.
The submission to the FDA until we had a fully robust baked CMC package. We now have that I think you would probably can figure that package extremely comprehensive again across all the clinical endpoint that we've shown you, but more importantly, I think the CMC data, which is really where I think the crux of the conversation that was going to be.
The fact that we're seeing.
Virtually identical material across a number of key attribute <unk>.
Including next generation sequencing I think is going to be extremely compelling to the agency. So we wanted to make sure we actually had that data in hand.
<unk>.
Manufacturer run got underway and we saw the progress that it was making and the good progress that it was making we decided to hold that and so now we'll be submitting that full data package.
Two additional regulatory agencies, including the FDA and so we expect that to provide the FDA the information to be able to provide clear guidance around what the registration pathway would look like and for US we think that aligns with probably most likely scenario too.
Use of the accelerated pathway, but the need to dose a few basins using that material, which is actually released in September . So this all lines up nicely and it's pretty consistent with what we said when we when we talk about what a potential launch date could be.
Okay.
And maybe a question on snap.
Yes.
Snap as a surrogate endpoint for function and again I mean.
Barry This is.
Remarkable to see something going from zero to something but.
Just to make that help us understand the functional benefits.
Absolutely. So yes, do you want to answer and I can provide some comment after.
Sure Yeah, Hi, Gail.
I think that.
This is really the first time.
Snap amplitude data Scott. Thank you in general has been.
Presented or published.
For large quality of patients with Gan.
Quite remarkable is quite.
What is notable here is the consistency.
All.
What you see in the natural history of how it mirrors clinical progress of these patients you saw on the image.
So Brian the Asia to the snaps are all within our normal range and they rapidly decline from the age of about two and a half to right to the point of Wap.
By the end of for every child has an abnormal snap by the age of nine after one has an absence snap ads.
And what I would say is that this kind of pattern is quite consistent with other OXXO neuropathy is another similar how registry century, mostly in Europe , Please where you do see.
<unk> nerve conduction studies being affected quite dramatically.
What I think is important with Gan is the fact, it really mirrors whats happening clinically and correlates very nicely, we've talked before about how patients with this disease generally a symptom free in the first few months of life.
The math slightly delayed most of milestones around the age of two two and a half. These children present without steadiness on the wide based gate at a high staffing gate, because I feel the ground beneath our feet and this is exactly what is in their production of studies are all demonstrating.
I think one point I will make is that.
And what you are looking I tried to get into this in the presentation. There are three primary because you cut within the connections of the amplitude which is the height of the electrical deflection.
Latency and we should have quickly.
Electrical stimulation types to start and velocity, which is used for speed down the.
The actual.
And.
Nevertheless this.
Really.
Thomas we used in the model of items sold is in multiple sclerosis.
Tended to see more effects on licensee and more effects on philosophy.
For these.
Selling your equities, while you're losing excellence amplitude is the key parameter and you can see how it correlates very nicely in their natural history, but more importantly actually.
Clearly stabilizes or even improves.
All right.
A handful of patients that grew from zero and is still continuing on an upward trajectory.
<unk> is very impressive and is also reflected in what we what I've shared in the biopsy data, where you saw an increasing presence of regenerate the clusters let.
Let me stop there I could go on even longer but let me stop there.
The only thing that I would add.
The only thing that I would add to what you mentioned is I think it's important to note that map is a definitive clinical endpoint essentially it's a hard endpoint and its functional and I think when you look at that and correlates into what's the as you mentioned around how it correlates to MSM 32, how it correlates to biopsy data our correlate to.
The log Mar data that we've shown before I really start to see all of these things are moving the exact same way.
You really start to put together a really nice clinical package.
And it really you have to look at the totality of the data set that's all moving the exact same way. So we feel really good about this and again, having the data in hand.
<unk> allows us to get half EBIT more robust engagement with regulatory agencies around the most accelerated pathway.
Thank you that's very helpful.
One on <unk>.
But would you need to dose mail rescue study, that's the timing there seems pretty anymore, but if you can talk to.
Hello.
It's a really good question. So just maybe you just want to comment on kind.
The phenotype of the Mayo and how they correlate to the knockout animal and and and then maybe go deeper into <unk> question.
Sure Yes.
Yes.
Patent thing here is that the miles on knockouts and for an excellent disease. This means that they have no <unk> whatsoever.
Contrast, the females while the females.
So half the cellphone novo levels are likely to if you are a hall pass.
<unk> tied to their option that P J.
So in the clinical setting and miles.
Yeah, Mark severely affected and the vast majority and then he was situations. She Dion you too right.
A handful survive.
And.
While survive through the infancy in May.
Die in the first few amongst lifeful, sometimes local to Asia till three.
And then so come usually to choose a respiratory infection.
Some respiratory compromise.
It's a very very severe form of breath and there are many of these patients the mail.
Males.
Survive and perhaps 200 in the world.
So.
They have also been a fairly.
Yes, I've forgotten group on the Rex.
Patient came in as you are actually very pleased that as part of our clinical development program, which as we alluded to earlier in the call was starting in adults initially.
During the course of 2023, we'll start with pediatric <unk> study and that will also go a pediatric study of rescue study.
Passion Canadian very happy that we're actually addressing this kind of on the SaaS population.
Specifically on your question around the dose scale is a really interesting question on the.
<unk> had an argument to go.
With a higher dose because these boys.
Hi, guys. So starting crore a pediatric study, which is starting at $5 814 total Vijay.
Our previous pharmacology match Pharmacology study, we have obtained the minimally effective dose was around 314 total BG. So we're actually getting in a bulk lots of five vehicles in total paycheck.
Nothing is slightly higher than that in the mouse with actually all partners just off the same dose thus far the 14 total Vijay is the pediatric fully study.
It will be.
Quite significantly improving their phenotype.
Likely we will go to a second dose of a $1 15 as well.
Alright, Thank you for taking all of our questions and good luck.
Thank you Joe.
Thank you Ian in the interest of time, we do ask that each person limit themselves to only one question again in the interest of time. Please limit yourself to only one question. Our next question comes from the line of.
<unk> Richter with Goldman Sachs. Please proceed with your question.
Hi, Thanks for taking our question congrats on the progress. This is Tommy on first olivine, we have a follow up on the snap question could you help us gauge the expected consistency in snap across treated patients for example, if theres characteristics that baseline that might impact. The response after treatment and on the NHRA feedback how many patients.
Do you think will need to be dosed with the commercial grade material and how does this affect the timelines. Thank you.
Thanks for the question I'll turn it over to see issue, maybe I'll provide some additional comment once you've done so yes.
Yes, Scott, it's an interesting question.
We.
It's hard to know exactly what characteristics of the patients would predict some good response.
And it's also hard to know.
Simply because there are not that many patient numbers.
Okay and dose trail to ascertain that.
To that degree of accuracy, what I would say is that the suggestion that makes full sense.
The earlier you treat the more luck you asked Rob response, the younger patient you treat the more likely you also had a response and also I think importantly, and this makes perfect sense is that if you.
If you didn't treat before the snap.
Lost $12 absent.
More likely to.
I see an improvement in the in this hard endpoints.
And more likely to see a functional improvements as well having said that very surprisingly we were very pleased to see that in.
Number of patients, who actually had an absence of that and access that prepared a time.
We actually saw improvements and conduction snack constitute the continues on an upward trajectory.
With regards to the MH alright, yes. We this is although this isn't one of the questions that were.
We talked about in detail.
It was clear that they wanted us to dose.
More patients.
And.
This is in line with our thesis of option to buy a handful more patients with clinical trial material.
We tried in our discussion and it was a very collegial fruitful long in depth discussion across all aspects of the program I mean, I wish that was over to Iot tools.
Clinical data the clinical data index and Theres a lot of in depth discussion on the CMC.
Pace as well.
But I would not really be helped to a specific number.
Essentially said a handful of patients for a period of time for us to come back with a proposal. So what we decided to do.
All previous thoughts have always been it's probably going to be about.
Three to five patients for about six months.
Our thinking was well less also continue with other agencies are also got the feedback from all agencies would come up with a proposal on the specific number of patients.
But my guess as I say is it is going to be around about three to five patients for about six months.
Thank you.
Thank you for the question.
Our next question comes from the line of Mike <unk> with Morgan Stanley . Please proceed with your question.
Hey, guys. Thanks for taking the question just on Gan you mentioned doing some additional validation work on the MSM 32 endpoint could.
Could you just give us a sense of your plans, there and maybe how long that valve.
Validation work might take.
Thanks, Mike Good morning.
One comment I'll make before I turn it over to C issue.
That validation work has actually been ongoing for quite some time, so we feel pretty good about the timeline there.
And the fact that MSM 32 has been used as a <unk>.
Regulatory accepted endpoint in a number of neuromuscular diseases. So we also feel good about that there. The particular work on Gan I'll turn it over to Cvs.
To discuss further.
Yes.
Sure Thanks, and thanks for the question Mike.
So.
The always quite correct.
32 is actually validated the pediatric neuromuscular disease in general.
Been used.
Several times previously.
S and supporting evidence.
And regulatory discussions before having said that it's always best to fall or validation as far as you can for the specific disease. A question. So the plan has always been for us to formally filed last night.
<unk>.
MSM 32, Jonathan solely neuropathy, and we actually talked about this with the NHL Ryan.
<unk>.
I hope it soon and accepting and I'm pleased that with actually started this work now there's three pieces to this was the first is.
So any kind of validation work. The first this is general.
<unk>.
Feedback solicited from <unk>.
Patients and families and clinicians, Pts ots and a structured into the sector.
And that work has been completed and actually we're just in the process of broadening out that work.
We'll be submitting that for publication.
I'm guessing in about six to eight weeks time, so you'll be able to see that work.
And in detail in the future. The second phase is to take all the information and run it through a specific.
There is a way of analyzing this qualitative semi structured interview data on this process or content that validation. So that felt in the next step and then once we've done the constant presentation. There's another whole.
Whole additional process.
Metro validation and while we take all the natural history study data.
Take all the data from Interventional study looked at how the MSM tends to correlate with other aspects of.
Other endpoints other aspects of the disease and also with the qualitative information that we've picked up and the qualitative interviews.
Under the consent of validation takes.
And then we'll do a formal psychometric validation that will get written up as a package will usually published this work and it'll end up being quite a significant report that goes in with the.
With the with the actual.
BLA filing on that.
Regulatory interactions in terms of timing the process.
A can take and can usually take quite a long time, you know 12 to 18 months to do it properly having said that because we have this large natural history study with 60 patients worth of data all of whom have done the MSM.
This trump paced timeline somewhat so it's probably going to be.
Our guests nine to $12 nine to 12 month process from now.
Got it thank you.
Thanks, Mike.
Our next question comes from the line of <unk> Yang with Jefferies. Please proceed with your question.
Thank you very much for squeezing me in so.
One question and one the other one other very quick questions. So first the question is for the Ret syndrome data that we are expecting.
You started.
The study in Canada.
Probably.
R&D second quarter, so how many patients do.
Data also RV Shang.
That's question number one and second question.
Kind of a quick question so in the past.
You consistently set the scenario number two is the most likely a regulatory outcome with that.
<unk> anticipated a potential launch by end of 2023 in the U S. So is this still on track. Thank you.
Good morning, and thanks for the question, maybe I'll take the question that Sirius had anything to add I'll turn it over to him but on the on your first on your first question. We typically haven't commented on how many patients worth of data that we provide.
And any of our other indications or data update.
So I think we're going to remain consistent with.
That operating procedure, what we will guide to is that you will have data in ret syndrome.
By the end of the year patient data and Red syndrome by the end of the year that will disclose to the street.
So we're staying consistent with that guidance your second question.
Around.
What we've guided to in the past from a timing perspective again, I think again I think we're staying relatively consistent.
I think the <unk>.
Initial regulatory feedback that we've received.
Aligns itself with scenario too I think.
Some of the recent discussions that have happened in other indications and other companies with both the FDA and the EMA has shown a nice flexibility around the use of the accelerated approval pathway I think the way that our comparability protocol has has that played itself out as well as the.
The commercial yields are the yield that we've gotten from our commercial Brian all support.
This notion of being ready to file a BLA as soon as possible.
So ultimately I think we're still on that same time period.
What I've guided to the pack as always by the end of 2023 or early 2024.
From a commercial launch perspective, and I think we're still.
On that time period.
Ultimately this is going to be a discussion point for the regulators, but certainly the preclinical data is all completed the majority of the preclinical data has been published for quite some time, we now have a strong team.
Z comparability package that basically shows that.
Our material from the clinical trial and our commercial ready material are virtually identical by a number of key attribute and we now have significant clinical data.
Across multiple functional pathological hard endpoint.
Coupled with biopsy right I think when you look at that it's probably one of the most robust packages.
From a rare disease perspective, and so we feel pretty good about it and the fact that all the data will be the exact same way. So what I'll say is I think we're consistent with that timing.
Previously I think I've always guided by the end of the year. The end of 2023 or early 2024, and so I think we're still within that time.
Thank you.
Yeah.
Our next question comes from the line of Jack Allen with Baird. Please proceed with your question.
Hi, Thank you so much for taking my questions and congratulations on all progress.
Just two quick ones one is really on.
It's quite straightforward I guess I'll start with that.
Do you have a meeting with the FDA on the books for the second half of this year as you work the game that guidance again, and then I was just.
Wanted to ask on the snap results and Dan any comments you can make with regard to the doses those patients received in a dose dependent you saw the snap results would be great. Thank you so much.
Hey, Jack Good morning, and thank you for your question. So to your first question I don't think we would guide to.
The weather, we had a meeting or have a meeting on the books I think what we what we are confirming is that we will have feedback from the FDA around the regulatory pathway.
By the end of the year, we feel we feel pretty good about that guidance.
And I think that is not only the FDA, but that will be also other regulatory agencies, we would be able to provide a pretty robust.
Date on that by the end of the year. So we're seeing kind of with that guidance, but I do think the data that we've shown you guys. This morning, more particularly the comparability data that Fred and his team have done a great job being able to generate.
It's really what the key outstanding question, I think probably more so from.
From the analyst community, but also the fact that are you able to produce at commercial scale identical product in order to get the order to get those same clinical results right and.
Again, I think the approach to that.
Credit taken.
It's just been phenomenal and the team has done a great job in generating these results not only across a bunch of key attributes, but also being able to confirm it by next generation sequencing and I think that's a very important point as well that we're basically seeing identical product.
Look back at the old old Gen.
Pathway back in the day, when we were having similar discussions around the clinical trial material generated at nationwide and then eventually what became the commercial material.
That waste generated at the Libertyville facility is.
Literally was night and day it was 90 days with what we're actually seeing and.
At what Brad's team has been able to do so we feel pretty good about going into those meeting having solved the big question. That's always been the big question also around potency assay and bread and her team along with <unk> and his team.
Now generated a matrix.
Potency assays across again, a number of key quality attributes that we feel extremely good about that are functional in nature.
And reproducible and we've now finished that work in house and had tech transfer that work out.
Two zero. So again everything is moving exactly the way that we'd like it in order to hit the timeline that I just laid out so we feel pretty good about that so hopefully that answers. Your first question Jack could you could you repeat your second question.
Yep Yep. Thank you so much for the color on the first question that was a great job of.
The second question was just really briefly any comments you can make around dose dependence of the snap <unk> alright, I realize theres eliminate cohort here, but love to hear about what doses with patients received.
No. It's actually a really good question. So yes, do you want to comment there.
Sure Yes.
It's essentially in keeping with what we saw across the other end points.
Recall, there's four different dose cohorts in the study.
The initial dose three five years <unk> seen as more of a safety dose generally didn't show much efficacy Atlas detectable, even though some timely setup.
There are some cost improvements.
Two was a one two week 14 pillar III.
14.
And cohort four was a $3 5 billion 14 total Vijay and those three of the doses are clustered quite close together I think as we designed the study now you would actually not have full dose cohorts and you would have probably in two dose cohorts would have a bigger.
Range between the two.
What I would say is that across all the end points.
The data from <unk>, two three and four were generally pretty comparable.
Truth of the snap you saw nothing.
Nothing for the very low dose cohort, but you saw improvements in the higher dose cohorts.
Our suggestion that youre choosing a bit more of a dose response some of the snap theres a suggestion that the highest dose is getting a little bit more in the way of improvements on the amplitude than cohort two or three but in general to cohorts two three or four all results can cause improvements both in snacks and in the presentation.
Richard No clusters.
Great. Thanks, so much.
Thanks, Dan.
Our next question comes from the line of Yun Zhong with BTG. Please proceed with your question.
Hi, Thank you very much for taking my question so.
Wanted to confirm that.
The feedback that you received from <unk>.
Does not change your confidence that you will be able to file based on available data when you talk to the media and also wanted to confirm that.
By year end, when you provide feedback with us feedback in crude.
EMA feedback as well and because.
Sometimes can be less flexible in terms of clinical endpoint versus surrogate endpoint that you've talked on the call. Thank you very much.
Yeah.
Thank you and maybe I'll start and then I can turn it over to you.
So that that can provide.
Date I think.
Your second question.
I think the EMEA actually it's a little bit.
I think it maybe opposite of your assessment, they've actually shown quite a quite a bit of flexibility, particularly around the use of air conditional approval.
Pathway as well.
Around the totality of data what I would also say is the fact that there is no surrogate endpoints here I think what's interesting is we have multiple functional endpoint. We have now shown you guide a definitive hard endpoint.
Now I've shown you. We've now shown you guys' data around visual acuity and the stabilization of visual acuity the stabilization and the loss of retinal nerve fiber thickness. We've now shown you guys biopsy data that correlates to all the functional outcome.
And couple that with again, the comparability data that will be laid out so we feel pretty good.
About.
We feel pretty good about going into those discussions.
Going into those discussions with it with a very robust package.
And just on top of that I think most important the safety across.
Call. It seven years. This was the first <unk> gene therapy trial in history. So we now have seven years worth of safety data and the safety is as has been consistent.
And this drug seems to be extremely well tolerated and the clinical study and so for US we feel again really really good about it.
I think to your first question around will that update.
By the end of the year include.
Feedback specifically from the EMA.
We'll say is.
We will have feedback from multiple regulatory agencies.
Including the FDA.
By the end of the year, we do plan to engage the EMA.
Within that time period as well.
Did that answer your question.
Oh, yes. Thank you very much okay perfect. Thank you.
Our next question comes from the line of Sami Corwin with William Blair. Please proceed with your question.
Hi, guys congrats on the progress and thanks for taking my question.
Do you think your additional patients.
We're going to see additional <unk> patients are going to get us.
Well also satisfy the FDA if they wanted additional patient Joseph clinical material and then can you just broadly kind of.
Speak about how dosing in the ret trials going.
So to answer you.
To answer your second question.
First we typically don't guide around first patient dosed or kind of ongoing dosing of patients we get them kind of remain consistent with that and does reiterate the guidance that you will have.
Preliminary clinical data base.
Pacing data by the end of the year and we're pretty confident about that I think most important.
With the late breaking predict preclinical data that we showed you guys today, which Jeff in my opinion was with extremely remarkable in a disease like rather than extremely severe mouse model.
Which is the male knockout model.
Where we saw near normalization of survival and absolutely never got to a median survival throughout the life of throughout the conduct of the study was just extremely encouraging for me, Jeff reinforces the need to keep moving this program for quickly, but also the ability to be able to get down into that period.
Pediatric <unk> population.
Which are the most effective patients, but also those pediatric Boyd that the fact that we're able to see the result.
Not only consistent from a survival perspective, but also from a behavior being able to normalized behavior.
By the bird score being able to normalize the body weight.
I think taking that data and the neonatal model also correlates to what we've shown you from the from that large pharmacology study that we presented we presented this data at ACC.
Where again, we saw improvement in survival motor function behavior, but also respiratory function, which was quite remarkable so for us we think that again, the totality of data both efficacy and safety with this program.
Kind of put this program in a rarefied air.
Be quite honest and just really encouraged us to move quickly in order to get to dose those pediatric girls.
As well as <unk>.
Well as that rescue boys study.
And to do it.
Urgently for patients so that that's the that's our question on Red and could you could you just repeat your question on Gan.
Yes.
Do you think these additional Gan patients you plan on dosing in September once the clinical trial material are starting to see a commercial materials relief do you think that quad.
Quantity of patients and duration of follow up will also satisfy the FDA if they wanted additional patient test.
Sure I'll start and I'll, let <unk> take over I think that's exactly what.
That's exactly what our plan calls for is alignment around patient numbers I think what we had always planned to do was to proactively dose patients right as soon as the commercial material is available which should be here in the next few weeks, we expect that material could be fully released.
With all the comparability were completed.
We plan on initiating patient dosing, where these basically are essentially already identified we had a protocol amendment that went through about about four to five months ago, if not longer that it allows us to dose down to 283 to actually start dosing younger patients. So it's always been our intent.
To continue dosing patients, but I would say to get alignment between all regulatory agencies, particularly around the number but also the duration I think is extremely important but I think consistent with what these agencies have shown recently.
Again gives us a high degree to a high degree of confidence I think the plan that <unk> laid out which is what we are.
Internally, our planning for three to five patients for about six months of follow up.
I think should be sufficient but again, we really do need to have that conversation with regulators I'll stop there. So yes, do you have anything to add.
No one has to ask but just to emphasize the fact that.
We'll look at all the regulatory agency feedback and such how let's say.
<unk>.
Conduct the study.
On an ongoing basis in order to meet all the needs and my guess is yes. It will be three to five patients six months worth of data and that should meet the needs of the NHRA. The Eni. The FCA and then you have the regency, we're in discussions with.
The only thing that I would add great. Thanks, guys.
Yes, basically I mean, the only thing that I would add to <unk> point.
Is that again this timing is consistent with what we've kind of laid out I think what the big piece and what the.
In Alaska for US will be is the fact that if we can initiate a rolling submission because again the CMC data the comparability that profitability data kind of all completed.
The potency assay is completed that work gets being tech transferred right now when you start to think about the.
The majority of the clinical data.
It's been ongoing for seven years, and both from a safety and efficacy perspective across multiple endpoints natural history data has been ongoing for two years before that right. So we're approaching almost 10 years of natural history data. So it's a big wealth of data.
The wealth of data.
<unk>, a relatively small population, which I think we are quite encouraged about but certainly the FDA needs. Some time and other agencies will need some time to go through it. So we feel really strongly about this approach around.
<unk>.
A rolling submission in the use of an accelerated pathway, so that ultimately going to be.
Yeah.
Yeah.
And our last operated on from the.
Sure.
<unk> comes from the line of Chris <unk> with Cantor Fitzgerald. Please proceed with your question.
Good morning. This is a break on for Christian. Thank you for taking our question just a question on the individual patient snap data it looks like patient <unk> appeared to show little change from baseline could you talk about how you're thinking about the specific case and what it might be telling us potentially about baseline characteristics or time at dosing. Thanks.
Thanks for the question I think was probably more important is how you relate this towards the natural history and the fact that this patient actually has a positive map three years after dosing, which is I think it's extremely important when you look at when you contrast, this with natural history virtually every patient in the NAV.
History cohort at this particular time point and this would be consistent with patient a wood had zero snap.
So the fact that we're actually seeing stability and a positive response.
Is extremely remarkable so.
What I would say it is a small dataset, but even with patient <unk>.
Showing stability and a positive in a positive way that's durable is extremely important particularly in the context of a.
Relentlessly progressive Neurodegenerative disease, essentially so this is consistent with what we're seeing in the biopsies.
But this is in total contrast to what you would see in the natural history I'll pause there do you have anything to add.
I would just echo what you're saying.
Patient <unk> on its own is actually what we were hoping to see.
Would have been very pleased if all patients stabilize because this is a chart. If you look at that based on what that dose.
That scores about six microvolts.
That is well below the normal limit on it.
From natural history data.
Very rapid downward trajectory, so that's that would've disappeared probably six months after.
That's a ton of dosing if they haven't been dosed and we saw stabilization and.
And that's what we're hoping to say the only reason that doesn't look so good is because the other patients are still so much better.
So, yes, we were happy with that.
Heck of a patient's performance.
And especially.
Compressed natural history, but simply because most of the other patients did significantly better and once again.
Just to emphasize the fact that to go from zero snap.
If you look at patient B.
Patient D. Those patients have been zero snap amplitude well over a year.
And then to <unk>.
Prove and patient pay in particular to be close to normal at the three and a half year conflict I'm still on an upward trajectory.
Really very significant and you would not expect to see this in our new <unk>, So it's pretty powerful.
Okay.
Thank you Cynthia.
Thank you thanks for the question.
And we have reached the end of the question and answer session now I'll turn the call back over to Mr. Ari session for closing remarks.
Thank you operator, and again I think we've been quite excited about the progress that the company has made across our core programs in <unk> syndrome.
I think we will remain focused on these two key programs moving these programs forward, particularly in the case of patient 120, <unk> towards a an accelerated regulatory pathway, we will provide guidance and feedback from regulatory agencies by the end of the year, including from the FDA, but we are quite excited with the data that.
We've shown you guys today I think again.
This allows us the opportunity to have the most robust package.
Gross robust the question with these agencies really around the totality of the data set that all it moving the exact same way I think the data that our CMC group.
Led by Fred Porter, our Chief Technical Officer presented today again shows the fact that we're getting almost virtually indistinguishable drug from our clinical trial material to our commercial scalable process again continued to support this notion around.
Like for like material and then turning to our Ret syndrome program, we feel extremely encouraged by the late breaking preclinical data that we've shown you guys today, which are showing near normalization of survival.
Very severe mouse model and again, we look forward to reporting.
Preliminary clinical data by the end of the year from our ongoing phase <unk> II studies. So I wish you guys a wonderful rest of the week, a wonderful day, and we look forward to connecting here in the near future.
And this concludes today's conference and you may disconnect your lines at this time.
Thank you for your participation.
[music].
Yeah.
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Right.