Q2 2023 Taysha Gene Therapies Inc Earnings Call
<unk> prepared remarks, we will hold a brief question answer session.
Minder. This webcast is being recorded to date August 14th 2023, I will now turn the call over to Haiti talent director head of corporate Communications. Please go ahead.
Thank you good morning, and welcome to patients second quarter 2023 financial results and corporate update conference call earlier today <unk> issued a press release announcing financial results for the second quarter of 2023.
A copy of this press release is available on the company's website and through our SEC filings.
Joining me on today's call are Sean Nolan patients CEO , Sukarna, Ganden, President and head of R&D and Kamran Alam Chief Financial Officer, We will hold a question and answer session. Following our prepared remarks.
Please note that on today's call, we will be making forward looking statements, including statements relating to the existing clinical data for <unk> hundred 20, and patient 102, and the therapeutic and commercial potential of <unk> hundred 20, and patient went up to <unk>.
These statements include the expected timing and results of clinical trials for our product candidates and other clinical and regulatory plans and the market opportunity for those programs.
This call May also contain forward looking statements relating to patient growth forecasted cash runway and future operating results discovery and development of product candidates strategic alliances and intellectual property as well as statements involving the timing size and completion of the private placement financing, we announced today and other matters.
That are not historical facts or information.
Various risks may cause <unk> actual results to differ material relief from those stated or implied in such forward looking statements. These risks include uncertainties related to the timing and results of clinical trials and regulatory interactions for our product candidates our dependence upon strategic alliances and other third party relationship.
Our ability to obtain patent protection for our discoveries limitations imposed by patents owned or controlled by third parties and the requirements of substantial funding to conduct our research and development activities for a list and description of the risks and uncertainties that we face. Please see the reports we have filed with the security and Exchange Commission, including.
Our annual report on Form 10-K for the year ended December 31, 2022, and our quarterly report Form 10-Q for the quarter ended June 32023 that we filed today. This conference call contains time sensitive information that is accurate only as of the date of this live broadcast August 14th.
2023, Tisha undertakes no obligation to revise or update any forward looking statements to reflect events or circumstances. After the date of this conference call, except as may be required by applicable securities laws with that I would now like to turn the call over to our CEO Sean Nolan.
Thank you Haley and welcome everyone to our 2023 second quarter financial results and corporate update conference call.
Today I will begin with a brief corporate update Vince you can again interim president and head of R&D, Acacia who will provide an update on our clinical development programs.
Armen, along our Chief Financial Officer will then follow up with the financial update I will provide closing remarks and open the call up for questions.
There are two main areas of focus for today's call.
First we are pleased with the recent progress we've made in our two lead investigational programs with particular emphasis this morning on the initial data from the first patient dosed in the adult Red syndrome trial.
We are very pleased to have significantly strengthened our balance sheet with a private placement financing that is expected to result in gross proceeds of approximately $150 million from a prestigious group of existing and new investors, which I will discuss in greater detail shortly.
Let's begin with an update on our lead clinical programs.
<unk> 102 in Ret syndrome, the independent data monitoring committee or DMC recently convened to review the initial clinical data from the first patient dosed with <unk> 102, following the patients required 42 day Belo.
The evaluation period.
Based on encouraging initial clinical data the <unk> recommended the continuation of the reveal phase <unk> trial and provided clearance to dose the second patient in the first cohort.
We are pleased to share that early data from the first adult patient showed tissue 102 was well tolerated with no treatment emergent tissue 102 related serious adverse events as of the six week assessment.
We also have seen early improvements in key efficacy measures evaluating the overall disease in signs and symptoms of <unk> syndrome, as well as clinical observation supporting improvements in multiple domains, including autonomic function localization as well as gross and fine motor skills.
<unk> will review these data in further detail shortly.
We believe the initial safety data and clinical improvements across key efficacy endpoints seen this early at four weeks post treatment in the first adult patients with severe disease reinforces the transformative potential of <unk> 102 to address the root cause of <unk>.
Importantly, these early data indicate that the RNA.
RNA responsive auto regulatory element or my rare technology is mediating <unk> expression in the central nervous system on a cell by cell basis supporting the regulatory control of my rare.
We are highly encouraged by the initial data of tissue and 102 and are focused on continuing to explore its therapeutic potential with the dosing of the second patient expected later in the current quarter.
We also recently received IND clearance from the U S. FDA to initiate clinical development of <unk> 102 in pediatric girls five to eight years of age.
And we have submitted our Cta to the MH.
<unk> 102 in pediatric patients with <unk> syndrome.
Which will expand our clinical evaluation to patients with earlier stages of disease progression.
For <unk> hundred 20, and Gan, our new comprehensive data analysis, utilizing a disease progression model or DPM was submitted to the FDA and we plan to review the potential regulatory pathways for <unk> with the agency later in the current quarter.
This morning, we also announced that we entered into a securities purchase agreement for a private placement financing or pipe that is expected to result in gross proceeds of approximately $150 million from a group of new and existing top tier investors.
The private placement financing was led by new Investor capital.
Capital management with participation from a large institutional investor.
<unk> capital.
RTW investments LP, Venrock healthcare capital partners, and <unk> as well as other key investors.
We are pleased by the support from this prestigious group of investors, which we believe highlights the enthusiasm for our tissue 102 program and the early clinical readout of the first patient treated in our reveal trial.
We expect that the net proceeds from the pipe together with our existing cash and cash equivalents, we will extend our runway into the third quarter of 2025 to primarily support the clinical development of <unk> 120 in <unk> syndrome and provides support for <unk> hundred 20 program activities in Gan.
Working capital and other general corporate purposes, Cameron will review this transaction in greater detail.
This capital infusion significantly bolsters, our balance sheet and enables us to focus on execution as we endeavor to deliver on key value creating milestones.
Over the next six months, we plan to continue to advance our two lead clinical programs, including generating additional clinical data in adults and expand our clinical footprint in the pediatric patients for tissue a 102 in <unk> syndrome and.
In reviewing the potential regulatory pathway for Tisha, one <unk> with the FDA.
I will now turn the call over to <unk> to provide a more in depth discussion of our clinical programs in <unk> syndrome and Gan.
<unk>.
Thank you, Sean and good morning, everyone.
I will begin with updates on <unk> 102, our investigational gene therapy program in clinical evaluation for the treatment of <unk> syndrome.
As Sean mentioned, we are pleased to share with you today, the initial safety and efficacy data from the adult Tourette syndrome patient dose in cohort one low dose potential one or two in our reveal phase one two trial.
Based on these initial data we believe our product candidate has transformative potential.
As a reminder, <unk> utilizes our novel <unk> platform designed to mediate and Mississippi two expression in the central nervous system on a cell by cell basis without risk of overexpression.
<unk> in activation and silencing of <unk> expression.
Randomly with Tourette syndrome result in a mixture of cells that are either deficient in express <unk> normally.
This heterogeneity in Mississippi to expressions.
<unk> syndrome challenging.
With traditional gene therapy approaches, but we believe our novel <unk> technology can appropriately addressed this challenge and potentially provide therapeutic benefit.
<unk> is currently being investigated in the ongoing reveals phase one two trial a first in human open label randomized dose escalation and dose expansion study.
Elevating the safety and preliminary efficacy of <unk>, one or two.
Adult females with <unk> syndrome, due to <unk> loss of function mutation.
Following the Ibm's pre specified review of the initial clinical data from the first adult patient dosed with <unk>.
<unk> recommended the continuation of the reveal phase one two trial and provided clearance to dose the second patient in the first cohort.
It is important to understand that the reveal trial designed to primarily measure safety in adult patients we.
We have seen a well tolerated safety profile in the first adult patient with no treatment emergent peso Vanuatu related serious adverse events as up to six week assessment post treatment.
Due to the severity and progressive nature of the disease, we did not expect to see efficacy in adults with ret syndrome, particularly in patients with stage four of Ret syndrome, the lit motor deterioration stage, which is the most advanced stage of the disease.
It typically begins around 10 years of age and can last for years or decades.
By reduced mobility muscle weakness joint contractures, and scoliosis and can lead to the inability to walk.
However, it is evident that we have seen improvements in efficacy as early as four weeks post treatment.
First stage patient with Cvs stage for Ret syndrome, dosed with <unk>, one or two.
So typically the principal investigator of the reveal trial observe critical improvements in multiple domains, including autonomic function localization and growth in fine motor skills to <unk>.
Provide you with clear and collective picture.
Treatment with <unk>, the patient was in constant state of hypertonia.
She had limited body movements required constant back support and had lost final gross motor function early in childhood.
She has not being able to sit unassisted for over a decade.
Four weeks following treatment, we have observed improvements in breathing presence and sleep quality and duration, including the normalization.
Our pipeline behavior. The patients vocalization has also improved with an increased social interest.
Moreover, we do evidence demonstrated the patient's improvement in growth and fine motor skills, including the gain the ability to sit unassisted for three minutes for the first time in over a decade.
The patient also demonstrated the ability to unclasp, a hand and hold an object steadily for the first time since infancy as well as user finger touch screen.
But clinical improvement demonstrated in key efficacy measure four weeks post treatment provide supportive evidence that reinforces the clinical observation.
Typically we measured clinical global impressions improvement at CGI.
So scale that has been adapted to ret syndrome. It is a clinician reported assessment of overall improvement following treatment and it accounts for key aspects of the disease, including language communication.
Relation hand use attentiveness, I contact seizures and autonomic function.
CGI I used as a seven point scale with one being very much improved and seven being very much work.
With the first patient four weeks post treatment and overall score of two indicating much improved was reported.
Additionally, the clinical global impression of severity scale CGI.
Is a clinician reported assessment of the overall stability of our patients illness that uses a seven point scale with one being normal and someone being extremely ill at.
At four weeks post treatment, a one point improvement from the baseline score of six indicating CBOE to a score of five indicating markedly was demonstrated.
Notably the <unk> syndrome behaviour questionnaire, RSV, Q, which is a 45 item questionnaire that assessment that syndrome characteristics amongst created a total score improvement of 23 points from the baseline score of 52 to a score of 29 four weeks post treatment.
Specifically the <unk> sub scale total score demonstrated the normalization of nighttime behavior as well as improvements in breathing General board and hand behaviors post treatment.
The seizure diary demonstrated no quantifiable CJ event, two weeks post five weeks treatment.
There was no market changes four weeks post treatment in the revised motor behavior assessment RMB eight which is up 24 question clinical reported scale measuring disease behaviors of Ret syndrome.
In addition to these measure we are collecting a plethora of data and measuring various endpoints for the protocol.
Data collected will further inform our thinking relative to optimal primary endpoint selection for Registrational study purposes.
The critical takeaway here, though is that the positive efficacy response seen in validated measures in the first adult patient dose with Tesla, one or two coupled with the improvement observed in autonomic function localization and fine and gross motor skills.
Currently and we believe support the therapeutic potential of one or two.
Moving forward, we intend to provide additional clinical updates on the reveal trial quarterly.
We expect to dose the second patient later in the current quarter.
Despite continued dosing of adult patients throughout the second half of the year.
We have also initiated efforts to expand our clinical evaluation to children with earlier stages of disease progression and recently received IND clearance from the FDA to initiate clinical development of <unk> in pediatric patients.
We have also submitted the Cta to the MSR potential one or two in pediatric patients with direct syndrome.
With recent IMD clearance, we plan to initiate the clinical evaluation of <unk>, one or two in part a of the dose finding study, which is focused on identifying the maximum administered dose and maximum tolerated dose in pediatric goes five to eight years of age with Ret syndrome.
Safety and efficacy data and the maximum administered dose and maximum tolerated dose selected from Pate will be reviewed by the regulatory agency and the identity prior to initiating part B of the study in pediatric growth is 3% to eight yield.
Data from part a will be assessed to determine final key elements of part b such as hierarchy of efficacy endpoints in study duration can be further asset.
Part B will evaluate potential one or two in two age cohorts and expanded five to eight years of age with a one to one randomization of randomized to treat cohort are delayed treatment cohort and a cohort for three to five years of age.
As a reminder, no approved disease modifying therapies that treat the genetic root cause of <unk> syndrome are currently available and there is high unmet medical need.
<unk> has already received orphan drug and rare pediatric disease designations from the U S. FDA and has been granted orphan drug designation from the European Commission for the treatment of <unk> syndrome.
The estimated addressable patient population with typical ret syndrome caused by a pathogenic or likely pathogenic in Mississippi to mutation is between 15020 thousand patients in the U S EU and UK.
We are encouraged by the initial efficacy and safety data and look forward to sharing additional updates throughout the year.
Now, let's turn to Tasha <unk> 20 for the treatment of Gan and ultra rare neuro degenerative indication with no approved treatments are established regulatory pathway.
As Sean mentioned, we have submitted a comprehensive data analysis utilizing the newly develop disease progression model of DPM and plan to discuss potentially the regulatory pathway for <unk> hundred 20, and again with the FDA in the current quarter.
New analysis of multiple functional electrophysiology, <unk> and biological and structural endpoints in patients treated with <unk> hundred 20.
Compared to the natural history cohort using a disease progression model demonstrate a treatment effect and objective and clinically meaningful endpoint.
Importantly, we believe these findings that we overbuilt at our R&D day in June .
Feedback on both the heterogeneity of disease progression in Gan and the effort defender nature of <unk> 32, as a primary endpoint in an unblinded study.
The FDA indicated that it's open to regulatory flexibility.
Control trial, setting and is willing to consider study design alternatives to a randomized double blind placebo controlled trial, if the utilized objective measurements to demonstrate a relatively large treatment effect.
But it's self evident and clinically meaningful.
We look forward to having a collaborative dialogue with the FDA, regardless regarding the potential registrational path.
Lastly, with respect to manufacturing FDA feedback on our CMC module to the amendment concluded that the analytical data is sufficient to support the comparability of our pivotal locked and released for use in clinical studies.
I will now turn the call over to Cameron to discuss our financial results Kamran.
Thank you Sue.
Research and development expenses were $19 8 million for the three months ended June 32023, compared to $23 5 million for the three months ending June 32022 to.
The $3 $7 million decrease was due to lower compensation expense as a result of reduced head count and fewer manufacturing batches and other raw material purchases.
General and administrative expense.
Were $6 million for the three months ended June 32023, compared to $9 9 million for three months ended June 32020 to the.
The decrease of $3 $9 million was due to reduced general and administrative compensation as a result of lower head count consulting and professional fees.
Net loss for the three months ended June 32023 was $24 6 million or <unk> 38 per share as compared to a net loss of $34 1 million or <unk> 85 per share for the three months ended June 32022.
As of June 32023, <unk> had $45 $1 million in cash and cash equivalents.
I went to the close of the second quarter as Sean highlighted we announced a private placement that resulted in gross proceeds of $150 million and expected is expected to close August 16, before deducting placement agent commissions and offering expenses under the terms of the transaction <unk> selling an aggregate of 122.
412, 376 shares of its common stock at a price of <unk> 90 per share and in lieu of common stock to certain investors pre funded warrants to purchase up to an aggregate of $44 million 250978 shares of common stock at a purchase price of 80.
Nine nine per pre funded warrant.
The pre funded warrants will have an exercise price of <unk>.
<unk> per share of common stock.
Ideally exercisable subject to certain beneficial ownership blockers and our receipt of stockholder approval of an increase in the number of authorized shares of our common stock, which will we will first ETF team at a special meeting of stockholders to be held no later than December 31, 2023, and the pre.
Funded warrants will remain exercisable until.
Exercised in full.
As Sean noted our cash runway, including the expected net proceeds from this private placement now standing for the third quarter of 2025.
I will now turn the call back over to Sean for his closing remarks, Sean.
Thank you Cameron.
As you heard today, we have made significant progress in our two lead clinical programs, including the generation of the initial clinical data in the reveal phase one two trial in <unk> syndrome that we believe reinforces the therapeutic potential of <unk> 102.
We are excited to potentially bring a transformative treatment option to the ret syndrome community.
Collectively we believe that the data from our two lead clinical programs continues to support our gene therapy approach and the therapeutic potential of our programs to address severe unmet needs and monogenic central nervous system disease.
In the second half of the year, we expect to continue dosing additional adult patients with tissue 102, and our reveal phase II trial in <unk> syndrome, and provide quarterly updates on available clinical data.
Additionally, we have begun clinical site trial initiation activities for the U S. Pediatric Ret syndrome trial and anticipate dosing the first pediatric patient in the first quarter of 2024.
We expect to receive feedback from the NHRA in the second half of 2023 for the proposed pediatric study, which will further inform program timelines in the U K.
<unk> hundred 20, and Gan, we look forward to having a regulatory discussion with the FDA regarding a potential path forward for <unk> 120, and Jan later this quarter.
With our balance sheet substantially strengthened we believe we are well positioned to execute across key upcoming value, creating milestones for our ret syndrome and Gan programs.
With that I will now ask the operator to begin our Q&A session operator.
Thank you we will now conduct a question and answer session.
To ask a question please press star.
On your telephone keypad.
A confirmation tone will indicate your line is in the question queue. You May Press Star two if you would like to read.
Move your question from the queue for participants using speaker equipment, it may be necessary to pick up your handset before pressing.
Our key.
Once again Thats Star one one moment, while we poll for our first question.
Our first question comes from Danielle <unk> with Wells Fargo. Please proceed.
Hi.
Thanks for taking our questions and congrats.
The progress and the initial data, which sounds extremely exciting for patients. So.
Could you remind me.
Maybe I missed this to age of the patient.
Sure.
Who is obviously an adult patient.
And.
Can you.
Peak two how does this data compare with the approved therapy debut.
And whether you have additional.
Observations at later time points beyond the six week that was noted in our press release and on the call. Thank you.
Thanks, John appreciate it let me, let me take a high level perspective on that and then I'll turn it over to sue for a little bit more detail, but this patient was 20 years of age.
Stage four disease, which is the most severe form of the disease.
I think what I would ask <unk> to do is kind of just really describe the patient.
For the audience here. So we can try to characterize just just where she was physically and what she wasn't wasn't able to do.
<unk> can also do a bit of a comparison to the <unk>, although again.
There is a lot of caveats, there with one patient versus they had significantly more patients Thats Cross study comparisons what have you. So we can only give a high level perspective on that and I will answer the third question June which was basically.
The data that we're reporting is the data that has been quality controlled and presented to the <unk>. So we don't have line of sight to additional data subsequent to that we plan to provide updates on a quarterly basis with quality control data.
That is ready for presentation, so with that I'll turn it back over to <unk> and <unk>. If you could characterize that patient high level and put into context, what we're seeing here that'd be great. Thank you, yes, thanks, Sean and thanks for the question on June . So this patient is a 20 year old female.
With Cvs stage for Ret syndrome, I think Sean described and the data is the data because given per the protocol, we have only access to the full week assessment in the six week assessment at this point in time.
This patient as I said as a female was hypotonic had contractors was literally either in a wheelchair with.
Any ability to really use a far lower extremities.
Was unable to slip.
With over.
Over the last decade, and have decreased tone of a neck and most unable to walk Eliza really socially interact as well. Furthermore, this patient also had.
Multiple episodes of respiratory insufficiency, we actually would have spells our ethnic spells where she couldnt breed coupled with the hyperventilation.
She also had significant sleep abnormalities, we actually would wake up at night and essentially not have a quiet night, where her parents. While also constantly disturbed from a I guess, a social standpoint, and frankly also had a history of seizures, usually especially when the dilantin levels dropped to sub therapeutic levels. So again.
To emphasize this was a 20 year old female with Cvs stage for Ret syndrome.
Now as far as the response goes.
We've already described that the patient one given are in traditional gene therapy started showing clinical responses within one week post gene therapy, and then at four weeks, we've already shared the assessments with you and then six weeks video evidence shows that this patient was able to sit up almost three minutes without a fifth.
The back support was not necessary at that point in time, he was quite socially interactive and was attempting to walk of life, including saying the word maman multiple times during the day.
Furthermore, she was also moving to the upper and lower extremities and moving her fingers.
Both of our extremities and was also able to grasp a toy or a ball.
As observed by the <unk> and the parent.
Furthermore, she was also able to use her lower extremities against gravity, which has been unable to do for a very long time.
And what is incredibly important is the impact that the gene therapy also had on the autonomic feature which is her ability suddenly post gene therapy to now slipped throughout the night without waking up and screaming, which also enables our parents to sleep through the night.
Furthermore, her respiratory abnormalities, which are due to autonomic irregularities, which include ethnic spells our inability to breathe of holding our breath.
A couple of the type of ventilation episodes are also decreased significantly and Furthermore, at the time of assessment done per the protocol.
Activity was absent further seizure diary and eeg's reviewed by the <unk> at that point in time.
Now finally, as Sean said this is one patient dose with the lower dose of gene therapy, where we saw these clinical results, which we think are quite relevant and one could consider quite impactful to compare that to pro forma tied one patient versus a fairly light.
A randomized clinical trial of almost 200 patients I will attempt to do that but with the caveat.
The <unk> phase III trial.
<unk> says they are primary endpoints for approval CGI, I and direct syndrome behaviour questionnaire and they used a combined endpoint. So to give you. Some comparison here with our one patient <unk>.
CGI I assessed at <unk> gave us a score of tool, which when talking to experts who actually designed CGI told us that was quite clinically relevant.
Indeed, <unk> type trial 12 weeks post treatment in the phase III when the treatment arm was compared to the placebo arm. The actual change between the two arms of if I recall around 0.3 summit, which was significant from a P value standpoint.
Then if you look at RSP acute the behaviour questionnaire for our one patient the changed four weeks post treatment was the number 23, which was quite big for that one patient with our gene therapy.
The average change between the treatment arm to the placebo arm in the <unk> trial from what I recall was around $4 seven and Sean you May want to correct me I think that's the number I remember, which reached a significant P value and the broader or the largest decrease in that trial in patients. If you look at the <unk>.
<unk> was a change of 10.
For Us we had one patient who had an improvement of 23 points, which is far larger than the average range seen within the prototype trials. So my hope is if we continue to see this kind of.
Impactful clinical changes both from a purely clinical observation standpoint, which.
One would consider quite impactful and from these measures of CGI in RSV Q, the differences could be quite different compared to the <unk> dataset, so I'm going to sub debt and hand this back over to Sean to add anything additional color. Thank you Sean.
Thanks, Sue group, we'll take the next question please.
Our next question comes from Jack Allen with Baird. Please proceed.
Great. Thank you thanks for taking the questions and congratulations on all the progress.
Yes, maybe one for <unk>.
If you could talk a little bit more about the progression of responses in those patients. It seems like you have data from one $4 six weeks I'd love to hear a little bit about the changes you're seeing over time I know, it's really early.
That regard and then.
Just as a secondary question any color as you can that you can share as it relates to the sharing of this data with astellas that would be great as well.
Thanks, so much.
Thanks, a lot Joel appreciate it.
<unk> I'll take the Astellas question, and then turn it over to you.
So.
I think everybody is aware that Astellas has an observer seat on our board so.
The data that has been shared publicly here in the press release.
It has been presented to the board Astellas is very aware of that data and all the data that is currently available in the trial. So they've seen everything that the company has seen to date.
With that SKU you want you want to take the question about the.
Progression on what we're seeing over time and maybe just one more comment from me just so everyone has the timeline here the efficacy end points that we're talking about were measured at week four per the protocol.
And there is safety data out to six weeks per the protocol.
And then there was video evidence that was generated at six weeks that looked at gross and fine motor skills in particular.
That's what we have right now.
And so with that <unk> do you want to talk a little bit about the progression.
The effect over time that the.
Investigator has seen.
Yes, Thank you, Sean and thanks for kind of clarifying that timeline I think that's very helpful for everybody on the call.
So as Sean highlighted.
I am going to talk about right now is up to six weeks post gene therapy.
Given that the patient was dosed on may 31st I cannot comment beyond that because as Sean pointed out per protocol. There are visits ongoing data is being accumulated and that has to be further analyzed and cleaned up from a database standpoint. Okay. So so what is important here to note is that.
Gene therapy has self complementary technology. So once it is given to the patients. It turns on very quickly within 48 to 70 to us and what was absolutely fascinating is that when we first went into this adult study where the patients are dosed 18 years and older. We were told that.
This is really a safety study, we would not see really any clinical efficacy given that these patients when their latest all worst stage of disease.
What we observed was one week post gene therapy. The investigators noted that the patient started improving significantly from a clinical evaluation standpoint, an observation standpoint, both from her aspect as well as from our pet parents aspect, but Furthermore, Dallas significant impact on the autonomic dysfunction that I already commented on previously.
<unk>, which includes breathing abnormalities.
<unk> activity and sleep overnight.
This improvement continued as Sean pointed out four weeks in we're not only the clinical improvements.
Ill continue to improve at that point in time, but also other measures, which included CGI IAC Gis and also the <unk> syndrome behaviour questionnaire, which all further validated that our gene therapy was having real clinical impact and at six weeks time point, we have video evidence that actually shows that the patient is able to sit up without assistance did not.
Need the back support of a wheelchair or the hospital bed didn't need the significant use of our breath that supported it back. It was also able to move ahead.
And track quite effectively and was very socially interactive and must also attempting to walk of life. This was quite a change compared to our baseline and baseline assessments and videos that short her quite inactive hypotonic flaccid and at the same time unable to really move our legs Opex limited in an appropriate manner and was not very socially interact.
And most of that Vocalizing much. So I hope that gives you a perspective of the dramatic impact of the gene therapy on the first adult patients that we have dose with Cvs stage for Ret syndrome.
Thank you.
That's great color. Thank you so much and congratulations again on the progress.
Thanks, Jeff.
The next question comes from Christian cluster with Cantor Fitzgerald. Please proceed.
Hi, good morning, everybody congrats on the progress as well as your private placement.
Our understanding is that stage for typically begins after around 10 years old. So this patient this particular patient potentially heartburn and stage for some time as our understanding is kras does progress quite a bit. So can you talk about how much variability in terms of baseline factors you would expect.
See in adults in general and again I think our expectations here.
Check the box on safety, but how are you also thinking about maybe.
How this one patient changes the way you are thinking about expectations across other adults as well as pediatric thank you.
Thanks, a lot.
Just to take on that second question first Sukru mentioned this early on is that as we talk to the experts in the field about the adult study. There was there was a very strong consensus and I would say there was a union eliminated frankly that we really shouldn't expect to see.
<unk> from an efficacy perspective, which is why we kind of share that view with all of you and that this would really be a safety focused study.
<unk> will comment on this in a little bit, but given that this is a neurodevelopmental diseases.
<unk>.
<unk>.
Theoretically there has always been our view that perhaps you really can have a greater impact on.
On the disease since full damage may not have occurred cellular depth may not have occurred.
Within our neuro degenerative disease I think what this is showing is that theres a lot for us to learn about this this particular disease state.
It's certainly very encouraging to see I think across the clinical domains. When you look at the autonomic nervous system and the breathing and.
In the sleep and when you look at the gross motor function and you look at the.
The vocalization and how she wants to socialize and be part of things. It's very very striking so what I would say is that we want to get through.
Let's see the first cohort of patients and I think it's going to help us really be more informed about endpoint selection as an example, and keep in mind too. We also are at the low dose I mean, so we also can step up the dosing.
<unk> has a greater effect there so the way we've designed the trial is that we are.
Using a number of endpoints Sukru mentioned, a plethora of endpoints, we're going to evaluate that and determined as we go forward what would be the best for us from an endpoint perspective that really captures the impact of the disease.
So with that let me do this let me turn it over to <unk> <unk>.
<unk> feel free to expand on what I just said there and then maybe you could also just talk a little bit about patient variability.
Symptom variability with people at stage four of the disease.
Yes, so thanks for that Sean So what I'd like to do first is to answer your question by taking you back to preclinical models in my experience with drug development I have only one scene a preclinical model translate one to one into the human and that was in the work we did on the <unk> with spinal muscular atrophy type one rather.
Seven mouse model translated one to one into the humans now with Ret syndrome, given the disease state itself and given how severe these patients was I didn't expect to see this kind of one to one translation.
That is what we are seeing here as well as you probably are aware.
We have done a fair amount of work using direct syndrome broadened models at zero to <unk> 14, and <unk> 28, with a gene therapy that show significant improvement in survival motor function and autonomic dysfunction. We have also spoken to many clinical as well as preclinical experts who've done decades worth of work on different <unk>.
Broadened model, including at <unk> 35, and.
46.
An increase in the MCP to levels of their 5% to 10% above baseline with appropriate therapies can actually restore function and improve survival and lo and behold I think thats, what you saw with the suspension at.
At Cvs stage for Ret syndrome. So so I guess, what I'm, saying is I didn't expect to see this type of clinical impact in such a short time, but now working backwards I think the preclinical dataset and the understanding of the disease pathophysiology now is extraordinarily to see why we are having this kind of impact with our gene therapy and again.
To answer your question about disease variability as you said stage for technically begins around age 10, but as the disease progresses and the children get other female patients with ret syndrome gets older. The disease does tend to get much severe and I think if you see this kind of response with a cvs stage for patient.
Cautiously optimistic that in patients with different types of presentations of stage for ret syndrome, especially if they are much younger than age 20, we should have clinical impact that is hopefully.
Meaningful and will change patients' lives and their caregivers a parent lines as well and then from an endpoint standpoint, as Sean pointed out we have many endpoints that our hypothesis generating not testing and as we gather more and more data than we hope to use these.
End points for the confirmatory trials with the caveat, though if we see this type of clinically meaningful of transformative results consistently across patients as we dose them both in the adult and eventually in the pediatric trials then I think the clinical data will speak for itself beyond even this functional measures that we have built in there.
Similar to what we may see or have seen with diesel against my trials. When we went to the FDA and other regulatory agencies. So I sincerely hope that <unk> will continue to have meaningful clinical impact for these patients and change the airlines. Thanks for the question by the way.
John back to you.
Thank you <unk> next question please.
Our next question comes from Silvan <unk> with JMP Securities. Please proceed.
Hey, good morning, Congrats on the data and replacement and thanks very much for taking my question.
Just going back to the safety side for the.
<unk> syndrome, which is one of our safety risks here.
How far are we out of the woods with this one patient when could we should put on test if there would have been a complications or uneven keene or what is the timeline until we can estimate fairly confident about it is not a problem and <unk> is working well and then I have a question about the <unk>.
The sleep.
This improvement obviously in our discussions with Kols, that's been one of the main problems with adult patients.
Doctors really saw that burden.
Hello.
Sleep that when you measure of improvement is that every night.
Just give us some more color around the improvement of steep. Thank you so much and congrats again.
Thanks, a lot silver Yasuko would you mind, taking both of those questions.
Regarding sleep and the other regarding the timing of maybe even describing what the <unk> duplication, how would that manifest itself what would it look like.
And is that something that the <unk> would have picked up on in.
The review of the safety data, so I'll turn it back to you.
Thanks, Sean and by the way. So those are very good important question that we will also grappling with menu initially working on our protocols in the past, but also evaluating these patients so I'm going to try and walk you through and linking kind of the science behind the <unk> two expression levels and clinical.
Manifestations, but also the <unk> technology and link it to I would say the clinical findings so well keep in mind, though that.
Our construct has my red which is a regulatory element that is part of the construct that is sensitive to endogenous <unk> production that worked through the endogenous micro RNA that then modulate.
Extra salt construct and regulate the amount of <unk> produced by our gene therapy. So essentially in the animal models in nonhuman Primate work, we had reassurance that this <unk> technology actually works very well, especially in <unk>.
Either the rodent models are now in the human that have normal in Mississippi to levels now the reason I have confidence based on this one question set of data and obviously I'd love to see this repurchase as we dose more patients.
Is that the construct a concept started having clinical result within one week post treatment. So it turned around very quickly and therefore, the patient continued to improve assessments.
Especially with the impact as you pointed out on fleet, which is a difficult aspect of the disease to treat and frankly, if the Mississippi to production by a construct actually went beyond the therapeutic range.
You would've seen abnormal manifestations, both clinically and I assume on some of the question is that we use to assess the pace in which included the RFP queue. So those measurements have reassured us up to now that the patient is doing quite well clinically but the.
Expression levels of MCP to within each cell. This at an appropriate level to control the neural network that <unk> to <unk>.
Protein level actually controls within the fall that has still continued to result in positive clinical manifestations and working backwards, though again keep in mind.
One is that $4 six weeks at this point in time as we have shared and given the rapidity of the positive clinical impact my assumption again at this point in time is it.
We are going to be features of duplication syndrome, which thankfully clinically very similar correct syndrome with some differences, especially when it comes to patient activity there might be other psychiatric features of mania in HDD, but can also manifest as part of the application syndrome that has not been observed and the IBM Z when they reviewed the data.
In mid <unk>.
Operator.
Your line disconnected I will try to make that that cycle brings to the next speaker through.
Sure This is Sean.
Well wait for <unk> to dial back in I think the other part of the question. The Sylvan asked was around sleep and.
And all I can say to that without sugar being on the call.
Is that from.
A caregiver reported and clinician reported perspective, there was dramatic impact on the sleep noticed almost immediately by the family that she was sleeping through the night and when you look at some of the subscales of the RSP queue, which is caregiver generated.
Score went to I want to say it was it was almost normal.
It was it was a normal indications so.
Very distinctive improvement.
From the parents perspective in terms of her quality of sleep.
So with that why don't we ask for the next question.
The next question comes from Joe <unk> with choice Securities. Please proceed.
Hey, congrats on the progress and thanks for taking our questions.
Results from the reveal study are studying Anthony styling, but is there any CSF biomarker or EMG and coupled with.
To complement the findings confirm target engagement.
Can you put the findings of a single patient, which again sounds impressive in the context of natural history study can you give what gives you confidence that the findings are real and that noise.
<unk> really for Citigroup and Haynesville sure Shawn I appreciate it thank you.
Okay.
Let me ask <unk> on the call.
Alright, well, then I'm going to do my I'm going to do my best where we deal with us so.
To answer your first question about the Biomarkers.
I know that there is no direct way to measure as an example, what's happening with the levels of <unk> <unk> to <unk>.
Because it's not freely able to be captured so you would ultimately you'd be in a very negative situation like looking at autopsy in doing biopsies and things like that to really determine that so at this point in time. There are no real biomarkers that we're aware of that would allow you to capture the activity that you have.
Seeing in <unk>, so it really would be the manifestations clinically and what types of improvements are you seeing there.
As it relates to is this is this real.
You know I understand the perspective of the one patient and look we caveat to that as well I think.
What's so dramatic about this is that.
When you talk to the Kols and the people that treat rare patients on a daily basis stage four is exceptionally severe.
<unk> did a good job painting, the picture of the patient, but essentially envisions somebody.
But for a decade at least.
Has been unable to sit unassisted has been in a wheelchair.
Has to wear a back brace to have some severance semblance of the ability to hold themselves.
Right they have to be supported when they're sitting to look around the room very very.
Poor muscle tone very hard to hold the head up.
Very hard to to track unable to hold hold objects in their hand.
And I would just say based on the video.
I've seen is that very very quiet.
Very much within herself I would say.
In terms of vocalization and communications is very very quiet very placid.
And then after treatment.
Again, the physician reported and we've seen the video where chicken chicken chicken you put them into a sitting position and she can sit there.
For three to five minutes, so thats <unk>.
<unk> was here he'd say thats demonstration of axial strength versus getting muscle tone back into her.
Like her limb girdle region, if you will and it has the strength to do that much more movement and coordination of the upper extremities and beginning to see some things some activity in the legs <unk>. Good to have you back on board I've been doing my best.
Paint the picture of the page.
<unk>.
So <unk>.
<unk>, maybe you should take it from here, but the question was really around.
Is this affect real is there a lot of heterogeneity in these patients and maybe they have.
Periods, where they are very very difficult.
They are very severe in their symptoms of them they get better.
I tried to paint the picture of what she looked like before and after but I think the folks who would appreciate hearing it from a from an MD more than myself.
Yes, thanks, Sean and by the way.
I apologize I, just got disconnected, so adding him back on.
When it comes to stage four reps I know somebody asked this question previously as well.
Beyond the age of 10 as the patients working and getting to the Cvs stage I think the heterogeneity based on my discussions with many of the experts get less and less.
And what is important to note, though is that in this patient and again, we've described the patient profiles. The many experts who have seen the videos under CDA.
They do all except the fact that the restaurant, yes, what clinically dramatic but it is pretty obvious because the patient continues to consistently demonstrate the improvement compared to baseline and I've already described some of these improvements that go way beyond just the autonomic dysfunction, which by itself by possible dramatic but also the fact that the patient could not see.
It up without the port for over a decade is able to do that.
Rest of axial muscle tone and neck. Don there is now recognized a function of the upper extremities, which is the ability to hold the ball on an object and also the ability that she appears to now attempt to interact socially and also attempt to walk of life, which I hope over time will turn into more words, and maybe even shrink sentences together.
So collectively speaking this is a dramatic response and I assume the youngest of patients in that stage four period, we will have to assess each patient based on their baseline to see what type of improvement you will see clinically, but remember therefore, we'll get that approved on CGI.
And the RFP queue, and hopefully we will see these kinds of dramatic changes in CCI on RF Btu as well in the patients we treat with the pediatric population in the adult population that will further cement the impact of our gene therapy.
I hope that helps address any kind of turnaround variability, but in this specific patient 20 year old female with Cvs stage for again I emphasize we did not expect to see any kind of efficacy impact about gene therapy. This quickly so again.
Cautiously optimistic that we can reproduce this result, and hopefully make a big difference indirect syndrome patient lives and their caregivers. Thanks, Sean back to you.
Susan can you also just confirm that there is no to our knowledge. There is no biomarker available to measure <unk> levels.
That's correct at the present time, we do not have the ability to measure in Mississippi to levels in the sell off in the serum bile in the CSF and the Biomarkers that are out there and we are collecting in CSF and serum samples to look at different biomarkers. These.
These biomarkers such as neuro filament level, bdnf et cetera, do not have enough data yet to core related to activity levels from a clinical standpoint. So we will continue to collect the samples and hopefully when there is more data maybe we might be able to link some of these biomarkers to clinical impact of our product and other caveat.
Though is given how quickly a gene therapy work from a clinical impact standpoint, biomarkers may not be necessary. If we continue to have this kind of clinical impact so I'll leave it at that financial arm.
Thanks, Luke next question please.
Once again to ask a question. Please press star one on your telephone keypad. Our next question comes from Gil Blum with Needham. Please proceed.
Good morning, everyone and thanks for squeezing us in.
Very impressive data set, especially given how early it is.
Maybe I would love your thoughts here and how you think this data could evolve over time.
We used the same functional measure it take.
Quite a while to really ramp up thank you.
Thanks Gil.
I'll take a stab at that and then turn it over to <unk>, but in terms of how the data can evolve over time I think that from my perspective based on talking to the Kols and understanding.
The disease States.
I think it's a bit speculative to say what might happen.
My view is basically that what we've seen thus far in a stage four patients.
Is very dramatic very unprecedented.
So I think the question you're getting at goes is there going to be incremental improvement over the course of time as youre going to continue to get better.
There are unknowns I think this is a major first step and I think what we can do to potentially help and I know <unk> team is working on this but.
As our physical therapy that can be done to help her get stronger and utilize the muscle tone that she is beginning to regain.
Can she worked with speech pathologists and what have you to gain further utilization and ability to communicate.
These types of things I think are unprecedented.
<unk> patients and so I think we're blazing new ground and I think it also highlights the fact that the <unk>.
Sooner that you get into the treatment probably the best outcome, you can possibly get but so too.
Basically have this level of impact on a stage for 20 year old adult I think really is encouraging.
For the broader patient population out there, but <unk>. Please feel free to augment anything that I that I have said.
So Sean I mean, I think you explained it quite well and.
One piece of information I would add Gail again.
The disclosure and disclaimer.
It's speculative is that my team the experts who've seen the pgi CPI data <unk> data well.
Quite surprised and impressed with how rapid the impact and how big the impact was on this one patient when it comes to the scale and the changes versus baseline and obviously, it's a 1% comparison to the prototype data set so what I would say it again speculatively at this type of consistent results in the adult space.
With that we're dosing methane the next I don't know pipe expansion.
The the dramatic nature of the change if that continues.
And then I think that should correlate hopefully with the clinical impact as well, which could lead to hopefully very useful discussions with regulatory agencies for the future, but my caveat is it's one person I would like to see that we produce and then let it develop for the program and hopefully also influence the regulatory pathway in the most appropriate way.
Okay.
So that question Gil.
Now the other thing that I would add to that too Joe is that oftentimes when you look at a population of Av.
People affected by the disease. The real question is who are the treatable patients who can derive a benefit and I think if we see the next couple of patients have a similar type of effect I think what's so encouraging and exciting for the REIT community is that.
There could be a much broader population that 15 to 20000 patients that could drive a very significant and meaningful benefit from gene therapy. Thank you very much next question.
There are no further questions. This concludes our question and answer session I will turn it back to Mr. Nolan for his final remarks.
I really appreciate everyone joining the call. This morning, we wish everyone a very happy day take care and we'll talk soon thank you.
Yeah.
Thank you again for joining today's teleconference. You may disconnect. Your lines at this time and thank you for your participation.