Q3 2023 Taysha Gene Therapies Inc Earnings Call
Okay.
Good afternoon, and welcome to the Taser Gene therapy third quarter 2023 earnings call.
At this time, all participants are in listen only mode.
Christian and answer session will follow the formal presentation.
If anyone should require operator assistance during the conference Chief Press Star and then zero near term key pad.
Please note that this call is being recorded.
I'd like to turn the call event Haley Collins, the director head of corporate Communications and Investor Relations. Thank you and you May proceed Haley.
Thank you.
Good afternoon, and welcome to <unk> third quarter 2023 financial results and corporate update conference call earlier today <unk> issued a press release announcing financial results for the third quarter 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.
<unk> CEO.
You can learn a gantry president and head of R&D, and Cameron alone Chief Financial Officer.
The 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 therapeutic and commercial potential of patient 102, including the reproducibility and durability of any favorable results initially seen in our first and second patients dosed in the reveal trial and including our preclinical product candidates.
Positively impact quality of life and also the course of disease and the patients we seek to treat in a research development and regulatory plans for our product candidates. These statements may 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 in future operating results.
Discovery and development of product candidates strategic alliances and intellectual property as well as matters that are not historical facts or information.
<unk> risks may cause <unk> actual results to differ materially from those stated or implied in such forward. Looking statements. These risks include uncertainties related to the timing and results of clinical trials up and regulatory interactions for our product candidates our dependence upon strategic alliances and other third party relationships our ability to obtain.
Patent protections 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 who you see the reports we have filed with Securities Exchange Commission, including our annual report on form 10.
For the year ended December 31st 2022, and our quarterly report on Form 10-Q for the quarter ended September 30th 2023 that we filed today.
The conference call contains time sensitive information that is accurate only as of the date of this live broadcast November 14th 2023.
<unk> 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 third quarter financial results and corporate update conference call.
Today I will begin with a brief update on our corporate and clinical activities then Dr. Sue Mcandrew, President and head of R&D up to Asia will provide an update on the clinical development of our tissue 102 program.
Kamran Alam, our Chief Financial Officer will follow up with a financial update.
And I will provide closing remarks and open the call up for questions.
This quarter, we continued to advance the clinical development of our lead gene therapy program in Ret syndrome.
Including generating new clinical data and our adult trial in Canada and further engaging in regulatory discussions on our planned pediatric trials in the United States and United Kingdom.
As a reminder, the reveal phase one two adult trial is a first in human study that was designed primarily to evaluate safety recall.
Recall, when we initiated the reveal trial in Canada, there was low expectation of efficacy for the stage for adult population among the kols in the Ret syndrome community due to the advanced and relentless progression of the disease.
The focus was placed primarily on safety.
Therefore, it was very exciting when we announced the encouraging initial impacts the tissue 102 appeared to have across multiple clinical domains and the first adult patient treated.
Today, we are pleased to share that as of the week 12 assessment patient one has demonstrated a sustained response and key efficacy measures and new improvements in several areas, including hand function, which is a hallmark manifestation of ret syndrome.
Additionally, the second adult patient treated also demonstrated a consistent early response across multiple clinical domains four weeks following treatment.
The two patients have quite different genetic mutations with the first patients M to M. A C. P. Two mutation manifesting in a more severe disease phenotype than the second patients mutation.
Interestingly, while baseline characteristics and related assessments are very different between the two patients for example, patient one was completely non ambulatory and patient who could work with prompting.
<unk> patients demonstrated an improvement across key clinical domains and presented similarly in a number of efficacy measures as early as work weeks for following treatment.
The principal investigator observed at both patients demonstrated improvements across clinical domains, including autonomic function socialization and gross and fine motor skills with sustained in new improvements and the first patient at 12 weeks and initial improvements in the second patient four we.
Following treatment.
We believe these early improvements in both patients coupled with a sustained response through week 12, and the first patient support the transformational potential tissue, one or two across multiple genotypes of ret syndrome, and further validate our construct.
<unk> will discuss the clinical observations and data in more detail.
In addition to the positive clinical outcomes data. We are encouraged by the initial safety profile tissue won't owe to the data from the first adult patient showed tissue 102 was well tolerated with no treatment emergent serious adverse events as of the 20 week assessment.
And initial data from the second patient showed the tissue 102 was well tolerated with no treatment emergent serious adverse events as of a six week assessment.
The independent data monitoring committee or I D. M. C. Recently convened to review the initial clinical data from the second patient dose with tissue 102, following the patients required 42 day evaluation period as.
As well as the 20 week clinical data from the first patient based on the encouraging clinical data. The <unk> recommended the continuation of the reveal phase <unk> adult trial and provided clearance to dose the third patient in the first cohort.
<unk> the low dose of tissue 102.
Looking ahead, we remain focused on further exploring the initial therapeutic potential of tissue 102 across different ages and geographies, we expect to dose the third adult patient and complete dosing in the low dose cohort and either the fourth quarter of 2023 or the first quarter of 2000.
24.
Expansion of the T shirt 102 into earlier stages of the disease remains on track with dosing of the first pediatric patient and our planned U S trial anticipated in the first quarter of 2024.
Additionally, we expect to receive a response from the U K M. H R. E on our clinical trial application submission for Tisha 102 in pediatric patients with Ret syndrome by the end of this year.
We recently entered into a loan and security agreement with Trinity capital that includes no financial covenants or warrants and terminated our existing loan and security agreement with Silicon Valley Bank.
This has extended our cash runway by one quarter into 2026, which will further support the clinical development of tissue 102.
Cameron will provide more details on the agreement.
With the extension of our runway and encouraging clinical data in tissue 102, we believe we are well positioned to execute across our key value, creating milestones moving forward. We plan to continue to advance tissue 102 program in an effort to bring a potentially transformational treatment to patients living with.
This devastating disease I will now turn the call over to <unk> to provide a more in depth discussion on our clinical program in <unk> syndrome.
Thank you Sean and good afternoon, everyone I'm pleased to provide an update on that additional one or two of gene therapy program in clinical evaluation for the treatment of breast syndrome.
As a reminder, there so one or two utilizes our novel and my read technology designed to mediate and Mississippi due especially in the central nervous system on a cell by cell based system to get risk of over expression.
Ex chromosomal inactivation and silencing of Mississippi to expression that all cause randomly.
<unk> syndrome is often a mixed set ourselves that either deficient in <unk>.
Especially in Mississippi to normally the heterogeneity and let me see if Peter expression is walk mixed reps syndrome challenging with the traditional small molecule and simple gene therapy approaches, but we believe our novel <unk> technology can appropriately addressed this challenge and provide therapeutic benefit.
Yeah sure one or two is currently being investigated in the ongoing reveal phase one two adult trial, our first in human open label randomized dose escalation and dose expansion study evaluating the safety and preliminary efficacy of <unk> one.
Adult females with Ret syndrome, Mississippi to loss of function mutation.
The trial, which was designed primarily as a safety study is also measuring pre specified efficacy measures.
All efficacy data being collected in this phase one two trial is hypothesis generating as we continue to generate long term data across more patients in cohorts. These measures will further inform our thinking relative to op came out of primary endpoint selection for Registrational study purposes.
Today at two adult patients have been dosed with dish out one or two in the first cohort evaluating the logos. We are highly encouraged by the early safety and efficacy data seen in both adult patients importantly, we believe these data which have been reviewed by the IBM Z reinforced the transformational potential of stage one or two.
Vishal, one or two was generally well tolerated with no treatment.
Serious adverse events.
20 to 20 week post treatment assessment for the first patient in the six week assessment for a second patient.
In terms of efficacy data as Shawn referenced earlier it is important to understand that we did not expect to see meaningful efficacy data in adults with <unk> syndrome, particularly in patients with the most advanced stage of disease due to the severity and progressive nature of Ret syndrome.
However, based on the clinical data from two adult patients in the low dose cohort, we are seeing clear signs of improvement across multiple domains following treatment with one or two including autonomic function socialization as well as gross and fine motor skills to provide you with a clear and collective picture, let's begin with an overview.
So of the baseline status of the two patients prior to treatment with one or two.
Both patients had been diagnosed with stage four X syndrome.
Motor deterioration stage, which is the most advanced stage of the disease. However, the patients possess different genetic backgrounds and mutation types in the <unk> gene, which manifest in dramatically different phenotypes in clinical studies.
Studies have confirmed that in Mississippi to mutation type is a reliable predictor of ret syndrome disease severity with more severe mutations correlating to greater motor dysfunction loss of ambulation, and a higher prevalence of scoliosis.
Patient one a 20 year old female has a large deletion with Mississippi, two gene that manifests as a highly severe phenotype.
Seven it is have you done by our clinical presentation at baseline.
Prior to treatment. She was in a constant state of hypertonia, the complete loss of Ambulation and was wheelchair bound she had lost the ability to sit or stand by it is old. Additionally, the patient had limited body movement required constant back support.
Last final gross motor function early in childhood, she had very little hand function with essentially no function of a non dominant she.
She experienced frequent beyond hyperventilation episodes and had a history of seizures.
The patient level of severity is affected in our baseline scores across there because he michelle including clinical global impression of severity are CGI S, which is a seven point scale that way. It's a separate idea the participants illness. So let's say for the clinicians experience with participants will have the same diagnosis at.
At baseline the patient CGI school was six indicating severely ill.
In contrast, the second patient a 21 year old female had <unk> mutations in <unk> gene that manifest milder phenotype.
Patient presented with a milder forms of disease, which is reflected in our clinical presentation at baseline.
Router treatment she had only Pos partial loss of ambulation and couldn't work with something but she experienced progressive sky forces and bradykinesia impacting her gait and balance.
Hi, stereotypical appeared at two years old and she mostly held our hands together.
To reach any grass objects was weak and you suddenly the patient experience frequent hyperventilation episodes and had a history of frequent seizures.
Our level of severity as reflected in our baseline scores across the efficacy measures a baseline CGI S school bus or indicating moderately ill.
The key takeaway is that there are phenotypic differences between the two stage four patients which are correlated to their genetic status. Importantly, we are seeing a consistent pattern of improvement across key clinical domains and efficacy measures in both adult patients following treatment with one or two despite the deferred.
Suddenly identity status and 70.
Based on clinical observations by the principal investigator that bought patients demonstrated improvements across multiple clinical demand impacting activities of daily living including autonomic function socialization and gross and fine motor skills following treatment with one or two.
Specifically 12 weeks following treatment the first patient demonstrated sustained the new improvements while my initial six week assessment and multiple clinical domains, including fine motor and hand function with again ability to grasp objects with her non dominant hand and transfer them to a dominant brand for the first time.
Since infancy.
It was also able to open our hands and the associate of fingers with again, the ability to scratch your nose and touch screen.
Progressive loss of hand function is a hallmark characteristic of Red syndrome, and a key area of concern for caregivers that impact a patient's ability to communicate and impedes daily activities, which ultimately limits independence.
These new improvements in hand function 12 weeks following treatment, which are not not observed in the natural history of Red syndrome are very encouraging and support the potential up there. So why not go to bring meaningful therapeutic benefit to patients and caregivers.
Further the patients achieved additional gross motor improvement since our initial six week assessment. When she has gained the ability to sit unassisted for three minutes for the first time in over a decade, but at week 12, the patients improve their ability to sit unassisted with cat give us reporting our ability to ship up to 15.
Minutes and see them unsettled restored movement in her legs.
The second patient also demonstrated clinical improvement following treatment specifically she demonstrated gross motor improvements four weeks following treatment, a posture gait and stability improve.
Instead, our posture to smooth the moments when walking.
Fine motor skills also improved following treatment.
Typically a hand studio to peers, which are repetitive purposeless and movements in a diagnostic hallmark of Ret syndrome improved for the first time since regression at H III.
Based on the principal investigators observations.
<unk> displayed less forceful hand wringing. Our hands are also opening relax at week, four providing new opportunities for fine motor skills.
Following treatment both patients demonstrated improved socialization with.
Increased interest in social communication and activities and improved autonomic function with improved breathing patents and reduced breathing, the CIT, including less but holding spells and infrequent hyperventilation.
The first special also demonstrated a sustained improvement in sleep quality and duration at week 12.
Overall, both patients also demonstrated improvements across key efficacy measures following treatment with dish and one or two which reinforced this critical observations by the principal investigator.
Let's begin with an update on the efficacy measures from the first patient.
The first patient demonstrated sustained and new improvement across key efficacy measures through week 12, specifically she have sustained improvement from the initial four week assessment and clinical global impression of improvement of CGI clinical global impression separate <unk>.
S and ret syndrome behaviour questionnaire honest in the queue.
Yes.
CGI is a clinician reported some one point assessment of overall improvement following treatment adapter direct syndrome that accounts for key aspects of the disease.
Status quo to indicating much improved was reported at week 12, which is consistent with the score reported at the week four assessment.
Suddenly the patient demonstrated a sustained one point improvement from the baseline score of six indicating severely ill go a score of five indicating markedly you'll at CGI S. At week 12, which is consistent with the weak for school.
<unk>, which is our fortify item questionnaire that assesses ret syndrome.
Six patients demonstrated a sustained cuts to point total score improvement from the baseline score of 52 gross cost 30 at week 12.
The school was driven by improvements in hand behaviors nighttime behaviors breathing problems and facial expressions.
Importantly, the fast fashion also demonstrated new improvements from the initial four week assessment and the revised smarter behaviour assessment or RMB parental global impressions improvement a P. G III and ret syndrome hand function scales Rs.
Yes.
The RMB, which is a 24 question clinician reported scale measuring disease behaviors about syndrome demonstrated a total score improvement of six points from the basement cohort three let's call. It 37 at week 12.
<unk> was driven by improvements in motor dysfunction, and social skills Pgi I used at Cagny about reported assessment of overall improvement following treatment.
This is a seven point scale scope, two indicating much improved loss reported at week 12.
The Rs, it's as fast as a clinician reported outcome of hand function in patients with Ret syndrome, which is evaluated by an experienced independent physical therapist with coarser demonstrated and functioning each video at one four levels ranging from no active glass spin off.
Objects to independent grasping the highest score that can be achieved as of for the <unk>.
First patient demonstrated a significant improvement in our S. Hff's at 11 weeks following treatment at week 11, although there were no changes from the baseband all three indicating the ability to hold an object practice two seconds and a dominant and she was able to increase the number of objects held from one to two.
Additionally, she gain from basic grass spades ability in our non Dominion Pan.
At baseline she could talk Paul any objects within non dominant hand, and at week 11 scope three was demonstrated indicating the ability to hold an object for at least two seconds. So you'll also demonstrated the ability to hold two different objects in a non dominant hand at week 11 again. This is very important to note that hand function improvements.
<unk> observed in the natural history of <unk> syndrome.
Now, let's discuss the efficacy data from the second patient recalls a second patient had a baseline CGI S severity score of four indicating a moderately ill versus the baseline C. J score of six indicating severely ill patients want the second patient.
One Sidney improvement four weeks post treatment in CGI, I Pgi I honest BQ in RMB.
Our school Street, indicating minimally improve was reported at week, four and bought CGI I and P. G I refer patients to.
The patient demonstrated a four point improvement in the outer speak your total score from a baseline sculpted salmon.
Call. It 33 at week four as a comparison the first patients artist Btu total score was 30 at week 12.
The second patient school was driven by improvements in body, rocky facial expressions walking standing and breathing abnormalities.
Alisha demonstrate a seven point improvement in the RMB a total score from the baseline score of 38 to scoff 31 at week, four which was driven by improvements in social skills and respiratory behaviors, including less frequent hyperventilating in bed Tony.
There were no changes four weeks post treatment and CGI S and Rs hff's in the second patient.
However, the principal investigator noted improved and Steve you can piece, which are not measured in the Rs HFF for the first time since regression at HD and the patient is spread less forceful handling with more abundant relax hands.
We'll continue to monitor the patients progress over time.
More details on the available data can be found in our Form 10-Q for the quarter ended September 32023 filed with the SEC.
The first patient severity and genetic background suggests that she has less to do with that Mississippi to a baseline and therefore it is reasonable that the treatment effect would be a greater magnitude than the treatment effect observed in the second patient with mild disease. However, while the two patients presented with very different clinical features at baseline both.
Patients responded in a clinically meaningful manner and presented similarly in a number of key efficacy measures at the weeks four week for post treatment assessment.
Critical takeaways at the following treatment with <unk> or early.
Early improvements observed across consistent clinical domains and key efficacy measures and the two stage for adult patients with different genetic mutation severity and phenotypic expression, which is encouraging and may allow us to address an unmet medical need for patients with ret syndrome across multiple genotypes.
Collectively these improvements coupled with the new and sustained response through week 12, and the first patient support the transformative potential of dish on one or two across multiple genotypes of ret syndrome.
We continue to look for consistent pattern of improvement as we dose more patients and evaluate the clinical impact of dish in Monaco in adult trial.
Looking ahead, we expect to dose the third adult patients and complete dosing in the low dose cohort in either the fourth quarter of 2023, our first quarter of 2024.
Intend to provide further updates on available clinical data from the low dose cohort in the reveal phase one two adult trial in the first quarter of 2024.
The effort to expand the clinical evaluation to pediatric patients with early stages of disease progression remain underway. We are focused on clinical trial initiation activities for our U S. Pediatric ret syndrome trial and anticipate dosing the first pediatric patient in the first quarter of 2024.
As a reminder, part of a dose finding study will focus on identifying the maximum administered dose and maximum tolerated dose in pediatric goes five to eight years of age with Ret syndrome.
Data from part a will be assessed by the regulatory agencies and the idea of <unk> to determine final key elements of part B phase III study such as hierarchy of efficacy endpoint study duration.
<unk> be really relevant shawano due to age cohorts and expanded five to eight H cohort with one to one randomization of randomized to treat cohort or delayed treatment cohort cohort for three to five years of age.
We expect to receive feedback from the U K <unk> submitted clinical trial application.
The proposed pediatric study by the end of this year, which will further inform program timelines in the UK.
As a reminder, there are no approved disease modifying therapies currently available that treat the genetic root cause of ret syndrome.
There is high unmet need with ret syndrome caused by a pathogenic likely pathogenic <unk> mutation afflicting between 15 and 20000 patients in the U S EU and U K and a high burden of cat associated with it does show mono. Two recently received fast track designation and has already received orphan drug and wrap pediatric disease.
The signature from the U S. FDA and has been granted orphan drug designation from the European Commission for the treatment of Ret syndrome.
Overall, the highly encouraged by the early efficacy and safety data. The first two adult patients and look forward to sharing additional progress I will now turn the call over to Ameren to comprehend to discuss our financial results Kamran.
Thank you.
Research and development expenses were $11 $8 million for the three months ended September 32023, compared to $16 8 million for the.
Three months ended September 32022.
The net change was due to a $9 $3 million decrease due to lower compensation expense as a result of reduced head count lower license and milestone fees, you're manufacturing batches and fewer raw material purchases.
Was partially offset by a $4 $3 million increase in activity surrounding ongoing clinical trial effort in our rest of Europe reveal adult and pediatric.
General and administrative expenses were $8 $6 million at three months.
32023, compared to $8 $7 million spread the three months ended September 32022.
The decrease of <unk> $1 million was due to reduced compensation expense due to lower head count at $2 million and reduced consulting and professional fees of <unk> seven.
$7 million, partially offset by $2 $6 million issuance costs allocate a liability classified pre funded warrants issued in connection with a private placement financing completed in August 2023.
Net loss for the three months ended September.
<unk> three was $117 1 million or <unk> 93 per share as compared to a net loss of $26 $5 million or 65 per share for the three months ended September 32022, due to a $105 million noncash expense reported in Q3 2023.
From a change in the fair value of warrant liability from pre funded warrants in connection with a private placement financing completed in August 2023.
As of September 32023, the company had cash and cash equivalents of $164 3 million.
The company expects that its existing cash and cash equivalents will fund operating expenses and capital requirements into 2020.
<unk> entered into a loan and security agreement with Trinity Capital on November 30, and terminated its existing loan and security agreement with Silicon Valley Bank as Sean noted our cash runway now extends into 2026 as a result of this agreement and there are no financial covenants or warrants associated with alone do you agree.
Right.
I will now turn the call back over to Sean for his closing remarks.
Thank you Cameron.
We were highly encouraged by the clinical data observed in our tissue of 102 program to date. The initial safety profile of tissue, one or two and the early and consistent pattern of improvement in <unk> observed across clinical domains and both adult patients with very different genetic mutation severity.
Coupled with a sustained response through week 12 for the first patient is encouraging.
We believe the data presented today further validates the therapeutic potential of tissue, one or two for patients and families living with ret syndrome.
We remain focused on our key upcoming milestones as we approach 2024, including dosing additional patients in the reveal adult trial, and both low and high dose cohorts and expanding our clinical footprint into pediatric patients in the U S and U K.
With that I will now ask the operator to begin our Q&A session operator.
Yeah.
Thank you at this time, we will be conducting a question and answer session.
To ask a question please.
And then one on your telephone keypad.
Confirmation tone will indicate your line is in the question queue you.
You May press Star and then two if you would like to remove your question from the queue.
Please limit your questions to one question and one follow up question.
For participants using speaker equipment. It maybe makes it safe for you to pick up your handset before.
Before pressing sakes one moment, please while we poll for questions.
Yeah.
The first question comes from Whitney Jim from Canaccord Genuity. Please proceed with your question Mickey.
Hi, guys. Congrats on another good update first question for me.
Yeah.
Right data just curious, though in terms of the.
RSV Q it looked like in the first patient in increased slightly from week to week 12.
I'm, sorry, if I missed it but can you provide.
Provide any more color I guess on which domains in particular changed over that timeframe.
With me I can turn it over to <unk> to <unk>, but I think the main domains, where there were change where in breathing socialization and gross and fine motor skills.
Would you is there anything that you would add to that Sue group.
Sean I mean.
Pointed out those are the domains that actually improved and I think what is interesting to note is that it also correlates with some of the clinical observations that are obvious that have been evaluated by the pie as well as the evaluated when it comes to the broad application of C. G. I N C J S.
So it's pretty interesting correlation given that patient one was much sicker.
And patients do you also see the significant change there and be honest that is maintained from four weeks ago exposed treatment.
Got it okay.
That does yes, and then just kind of a broader question. How are you guys thinking about these two patients from a proof of concept perspective for the M. Eyewear attack I guess kind of what what else or what else in terms of data our patients patient number follow up would you be looking for to kind of consider this technology Derisked and can you remind us how you're thinking about it.
All indications, where it might make sense. Thanks.
Sure well I'll go first and certainly open up the suite group. He has additional comments, but I would say you know what's encouraging to US about you know proof of concept with PMI rare technology is that the first patient had significantly severe disease at baseline right I mean, the CGI S was at six <unk>.
So you would infer from that that she's got a relatively low level.
Endogenous <unk>, two and yet you know preliminarily with through week 12 were seeing encouraging response across clinical domains, and then you juxtapose that with patient too. So keep in mind that that phenotype from patient one is based on a significant deletion genetically.
Patient two had a miss sense mutation, resulting in a in a much less severe manifestations of the disease. So you would think she probably is generating more endogenous M UCP to the patient one.
And yet you know we through week.
Let's see week six havent seen any safety concerns with that particular patient so.
In a way Whitney I think with the first two patients seen youre youre seeing very very different.
[noise] genotypes corresponding phenotypes and levels of endogenous <unk> and Youre seeing consistent response across clinical domains and there appears to be a promising safety profile. So I would say these first two patients are good indicators of the potential safety of BMI rare technology.
And what I would add to what you just said Sean in very simple terms is given that there were two different types of different phenotypic presentation that fit into the classification of plastic correct syndrome. It is reassuring to see that our gene therapy actually worked quite effectively in both patients and as we continue to accumulate more data and accumulate different gene.
Types of present as classic Tourette syndrome, it'll also give us the confidence that this gene therapy will be applicable for the broader X syndrome patient population as a whole and the second piece of the puzzle is as you pointed out our U S.
And my wrap technology is critical to maintain a very tight control of M. A C. P. Tau protein levels in the nucleus and I think based on the clinical and for me are improvements that are good to happen very quickly post gene therapy, given that our product has self complementary technology as well that changes have been noted are not positive.
By the P. I just didn't want to do two weeks post dosing and this is also reassuring because it enables us to seek clinical improvements, which also precede the need for Biomarkers is such to measure response, which is sometimes what you need in other products because they take much longer to act.
Okay.
But thiago for your questions.
Yeah that does thank you so much.
Thank you very much. The next question comes from Christian. Please go from Cantor Fitzgerald. Please proceed with your questions Christine.
Hi, everyone. Let me also add my congratulations that a second patient and exited the year.
Sure.
This particular readout you commented a lot about the core.
Cardiac and respiratory item.
And I wanted to see if you can kind of give us a context about the importance of some of these.
From our understanding.
About a quarter.
Got it.
The complication from these matters.
Yeah, Let me, let me address that because that's a very important question. So ret syndrome patients typically do how autonomic dysfunction and when you think of autonomic dysfunction, it's usually a respiratory abnormalities I E. They have episodes of vaccines.
The tolling spells followed by significant hyperventilation, that's one second I have a history of seizures, depending on which part of the brain the foresight exist.
Exist. They also have significant sleep abnormalities that times, where they cannot fall asleep cannot stay asleep may have also sleep therapy and they also have Gi dysfunction, usually I think it's more constipation and diarrhea. So these are pretty standard when it comes to <unk> syndrome patients and what we highlighted in patient one and patient two is that our gene therapy.
Once dose within a week or two have significant positive impact on this respiratory abnormalities. So they have a significant reduction in these expenses were less hyperventilation episodes, we did not really talk about cardiac abnormalities. Because these patients did not have any cardiac abdominal isn't rhythm or any concerns on that.
<unk> done so those are not clinically appropriate at this point in time for an efficacy measure of a clinical evaluation with our gene therapy.
Okay. Thanks.
Looking at the two different.
Yes.
Yes.
Perfect anecdote.
Today way differently.
Hi, I'm, sorry is it more important.
Okay.
So I guess well all of these.
Sure they are important.
Ask the question.
Did any of them are particularly.
Weighed more for each of the different Pinot timeshare. Thanks again.
Yeah, Let me take that question. That's another very important question because when you look at reps syndrome patients you'd have to break them down into what is their clinical abnormalities that they present with what are the autonomic dysfunction abnormalities that present with and then the scale that we referred to CGI CGI S. RSV.
M B, a and the hand function scales.
I would really focus on the clinical impact of our gene therapy. Because for example, if you looked at patient one and patient pool, even though their phenotypes are different they bought our developmental milestone I've done I think it is.
Meaning patient one you know it was unable to sit I think after the age of some of our eight patient too.
<unk> and walking.
Appropriate maintenance of gait and posture, probably after the age of 10 of these patients also have difficulty with sometimes tracking objects with dies most of them do have significant hand function abnormalities stereotypic movements and they also have difficulties with social interaction and many of them have cognitive challenges. So clinically those are.
Bonus that we have to focus on and we did highlight that our gene therapy in both patient one and two did have impact on some of these aspects of the disease. We've also highlighted the impact on the autonomic dysfunction and then the scales that you referred to.
The numbers on the scale and the degree of change on these scales actually depend on how severe the phenotype is the more severe the phenotype of the higher the artist <unk> and the <unk> MBA schools can be and then post treatment of therapeutic efficacious, then youll see a relative change in the number and you will see that even in our RSV Q4 second the second patient.
The numbers are much lower because the patient overall it has a much milder phenotype. So you have to keep that relative aspect in mind and look at the broader clinical impact of the product because clinical transformation impact I think is far more important from a clinical management and regulatory review standpoint, sometimes than certain scales and I'll leave it at that for now.
Sure.
Thank you very much. The next question comes from Sal <unk> from Goldman Sachs. Please proceed with your question Calvin.
Hi, Thank you for taking our question. This is Elizabeth Arden for Salmine. Congratulations on the data I was hoping you could provide additional color on the seizure activity in the seizure diary, specifically what was the baseline seizure rate for each patient prior steroid treatment and what's being observed now.
And then also for the second patient if you could provide some color on.
How quickly improvements were observed I know for the first patient dose were observed.
Quite soon after treatment.
Any color there would be helpful. Thank you.
Yes, so that's a very important question that you asked because that's all.
I'm going to try and walk you through first special and second patient because there are lots of clinical aspects to the seizure history in both patients. So patient one stage for 20 year old female that I could see where that syndrome had four to five seizures fourth quarter before the gene therapy was given the first six.
<unk> post gene therapy, there were no reported seizures in the seizure diary, knowing the EEG that was reviewed by the <unk>.
After week six.
What most notice as you know, especially as on premise alone and Sirolimus and Sirolimus actually works on the Leland inhibits the cytochrome <unk> hundred 50 system, which result in our dilantin levels dropping significantly so what happened after week six up to now is that this dilantin levels dropped to below.
<unk> 50, which is very low and therefore, there was some breakthrough seizures in this patient from what I recall I think this patient had about seven seizures. During the period. Following the six weeks post treatment, which is also of interest to note before the gene therapy was given whenever this patient one hep seizures, usually it was when the dialectic.
Levels were below 100, but I think usually about 50, so I would say that even though this patient had breakthrough seizures six weeks post gene therapy. This happened when the dilantin levels below 50, and therefore, I think the gene therapy still had a protective effect, but the dilantin levels got way too low too which allows for breakthrough.
Seizures, so that his patients one patient is doing well patient understand.
So just to try to hit a punch line on that question Elizabeth.
Would say pre and post treatment through week 20.
Seizure rates are comparable yes.
As pre treatment the patient generally experienced seizures of sheet had dilantin levels below 100.
And now what it's looking like post treatment is that the seizures occur when she is less than 50, so at a much lower amount of Thailand.
Thank you Sean for clarifying that and then patient who had roughly four seizures per month, which is oh seizures I guess every quarter.
Following gene therapy treatment with our product. This patient had one breakthrough seizure up to week six I tried to call on data <unk>, but that was it just one sees.
That is a good signal that gene therapy is most likely to have an impact on seizure incidents in this patient as well so.
On the <unk> a question for you. Thank you.
Super Helpful. And then just on the second question of the rapidity of response observed in the in the second patient.
Yeah. So that's another important question. So just again to go back to the technology product.
Product has a self complementary DNA. So once it's given into the central CSF and gets into the central nervous system.
We saw this form within 48 hours and we think starts producing the <unk> protein and.
The principal investigator has noted that clinical impact appears to be noted within seven to 10 days in Italy post the gene therapy, being given where lumbar puncture and this includes the impact on some water function as well as reducing some of the autonomic abnormalities. So we're pleased to see that and we hope that will continue because that.
Hopefully keep some of these patients rapid relief of the serious symptomology.
Thank you so much and congrats again.
Thank you. Thank you.
Thank you. The next question comes from Gil Blum from Needham <unk> Co. Please proceed with your question.
Hey, good afternoon, and allow me to add my congratulations itself, it's actually rather impressive.
So one thing I do want to understand about some of these metrics.
Could there be a ceiling effect I mean, specifically talking about RSV Q.
We're kind of seeing a leveling around 30, I'm not super familiar with them, but the scale, but is that a possibility.
A ceiling effect.
So the question of well, what I would say to that deal.
Our non clinician would be.
Yes, I think we have to take into account the stage of the disease. The age of the patients and the dose that we're in at this particular point in time that the study all have to be considered into whether or not there is a ceiling being demonstrated we are right now are landing in some similar spots to your point and it's still a little early in the assessment, but with that.
Ill defer to sue on the clinical question.
That's an important question that I think we are still struggling to assess because keep in mind that both these patients adult sites. So they were 2020 one year old females, where we frankly did not expect to see much effect and the more severe the patient the higher I assume the <unk> score should be given that there.
There are 45 items in that scale and 38 of them are used to maximize the school to up to a 90 and also keep in mind.
It is very important to understand who actually does the assessment, it's usually done by the parents or the caregivers over a period of time. So they have to reflect on how the patient or their child is doing over a course of a week or so so there can be some variability in the skull being assessed as well and then finally as far as there being a ceiling effect.
What we are observing with the gene therapy is the more the sicker patients the highest score in the greater the drop.
So if the patient is not as sick the drop may not be as significant because they are starting at a much lower baseline I think I can probably answer your question, who wants to dose a few more patients and we have a little more data and then the other thing to keep in mind with.
<unk> is that the question do you have to actually look at the questions being asked because some of the questions have been designed to evaluate the disease process that wilsons overtime RSV Q frankly was not developed to evaluate the therapeutic intervention now the caveat is profanity deduce Rs <unk>.
Combined with CGI I for a combined endpoint to get their approval and if you look at the 17% to 20 year old group that <unk> studied that drop in the RSP was only two points. So I guess in relative terms I Wonder I don't like doing cross study comparisons our first patient showed a 223 point drop in the second patient who.
As much milder disease at a full point of growth and the severity of the severity that's right.
That's right so.
This is very very helpful.
Great. This is very small.
Smart for educational purposes.
My second question, so kind of a segue in a hypothetical adult study.
Would it be beneficial to look at patients with more severe disease just to increase the signal to noise.
Yeah, you're saying basically enrich the study with more severe patients to show a bigger effect.
You know what's interesting Joe when you look at the <unk> data there.
They generally are there third P value difference essentially off the severe patients, but there really wasn't much effect in CGI I or <unk> in mild to moderate so your point your point's a good one I think what what's exciting us.
We have to see more patients I think to get to a more definitive answer but what we liked about this was the fact that the genotype were so different and the corresponding phenotypes were so different yet we're still seeing response.
It's very encouraging that again to the population that could be treatable here continues to remain significant so I would say.
Reaffirmed <unk> point, let's see some more patience.
Let's get to the high dose as well.
That will certainly inform how we think about.
B endpoints and trial design.
Yes. Thank you very much for the comprehensive answer.
Thanks, Joe.
Thank you. The next question comes from <unk> from Wells Fargo Securities. Please proceed with your question.
Great. Thanks for taking our questions.
I have a question on <unk>.
R and D a.
And I think.
If I heard this correctly I think the patient number two is our MBA improvement is.
It's roughly seven point and that sounds like that.
That said the date as patient number was 12 week improvement and much bigger.
Bigger than patient number one four week improvement.
If you comment on.
Why despite of the.
Milder disease.
This patient.
Our NDA improvement appears to be quite striking and if you can provide the baseline R&D a score for these patients that would be great.
Maybe one or two products. Thanks.
So the baseline scores to your point, we're patient one was <unk> 43.
For patient two was 38.
And then at week four for patient two is 31.
For for patient one was 48 and now at week 12 patient wants a 37, so theres been a six point drop in patient one over 12 weeks and a seven point drop in patient to over four weeks and then I'll turn it over to sue to try to get at the rest of your question sort of on what.
It's driving the right. So that's an important question because the RMB as a clinician.
Assessment of the patient as well and it has five components I think goes up gross cost as you can see on the scale.
The first patient who was much sicker.
These RMB, yes call was influenced by anxiety right and fear and also increased bruxism, right, which shifted the score in a manner that didn't show improvement, but actually when we talk to some of the experts the understanding was that increased more muscle function in the fed's included.
Muscles <unk> boxes them is actually positive but in the assessment of these questions that was set up as I said that they will raise and designed to actually show disease worsening not necessarily the therapeutic restaurants and to my knowledge RMB has never been validated evaluated therapeutic intervention in patients.
Poodle.
Given that this patient had much milder disease.
The change I think is positive because especially the already did not have some of the previous abnormalities of severe patients anticipation on one hand, and therefore the question is often the RMB it didn't.
Cloud <unk>.
Assessment. So I guess my point again is that you need to really understand what the questions are within some of these measures to make sense of the eventual numbers and come in do you want to comment on that though yeah. Yeah sure. So the in terms of our provides motor behavior assessment some of the improvement <unk> social skills and respiratory behavior.
Right.
So I guess, if I can add to punctuate that point, though what I would also say is that the clinical assessments of each of these patients, especially hopefully for a transformative therapy will significantly overcome sometimes the need for the skills that mostly have not been validated for therapeutic intervention in assessment.
Right.
Thank you and then.
No.
[noise] I'm sorry.
My follow up is.
That for the four point improvement in <unk>.
S B, Q, which sounded like similar to a phenotype.
And if I can.
<unk>.
But but it's also on the other hand, it sounds like the patient had many improvement clinically.
Could you comment on what.
They improve the nature of the improvement differ in what you saw in this patient compared with if this patient had been treated which can phenotype for example.
And maybe lastly.
How about patient number three I was just wondering have you identified that patient.
So how severe that patient is thank you.
Yeah, I don't know.
C.
With the <unk> piece of the question.
When you look at patients that had moderate or mild disease. The impact on RSP Q was was one.
So in this particular circumstance you would definitely grade dispersed one order is a mild or moderate and the impact that we demonstrated was was for on that particular scale.
And as we said it was driven primarily by.
The breathing the socialization and the gross and fine motor skills.
So you know it's it's very.
Very consistent with the feedback that's being put forward by the.
The physician and her assessments and observations by the parents and their assessments and observations.
And where she's landing is 33.
As in the same ballpark at week 12 was where the first patient is landing which is at 30.
So you know it looks like we're getting a very very nice response from from her and.
Again, I think to <unk> point, the scales I think to me are becoming.
It's good to see correlation that the scales are moving in the right direction, along with what's being observed clinically and we're seeing a lot of congruence across clinical domains, which I think is a testament to the product getting to where it needs to be.
<unk> being put.
Forward into a more therapeutic area and which is why we're seeing some comprehensive behavior across the table.
As it relates to patient number three.
I would say that we have identified the next adult patient.
She has not yet gone through screening and Theres a couple of things that play which is why we modified the guidance to Q4. This year Q1 next year dosing is that.
Its final stages of an L. A R process, which we've talked about it in the past, which we don't have absolute line of sight to so we know what's in it should be in that window and within the institution.
Windows of time.
Given the holidays and what have you where the patient can slot in so it's still possible this year.
Could be Q1 next year, we will keep you apprised on that but but we do not know any baseline characteristics at this particular juncture.
We just do know that it would be a stage for patient.
Got it very helpful. Thank you.
Thanks, John.
Thank you. The next question comes from Jack Atkins from Baird. Please proceed with your question Sir.
Great. Thanks, so much for taking the question.
Hoping you can provide some more context around the.
Third regimen, that's given proposed dose here and how the results from patient one are shaping up in the context of the steroid taper.
What degree of confidence do you have that these results are different from them.
Potential and any potential impact that could be due to steroids in the short term posts.
Gene therapy.
Yes, so so for this protocol.
All patients over the age of 18.
Will it be started on prednisolone, one milligram per kilogram from day minus seven.
And that will be continued out to 16 weeks and then it'll be tapered off over a certain number of weeks down to five milligrams per kilogram and then to fight. These patients also get.
Sirolimus.
Much lower dose than was used for transplant based on the body surface area also.
Starting around the minus seven and runs if I call. It three to six weeks and then it tapered off the deck. We've looked extensively to the literature, we've talked to all the experts who treat ret syndrome, and they've all said that both prednisolone and sirolimus in Norway or form impacts the clinical progression of the disease. Some people have actually done some X.
Paramount's two and they say, there's no impact and therefore, an improvement seen with the disease is actually due to the gene therapy that has been given.
Got it great and then just as it relates to the thrombus dosing and potential implications that had on the seizures. The patient to have you given any consideration to.
Modifying that that dosing moving forward.
Yeah, we've actually started looking into it but.
The issue is the Sirolimus.
Sirolimus with Prednisolone and you have some experience always began program where we showed that.
Patients could be dosed, regardless of the zero positivity to AAV nine antibodies, which is actually very helpful, especially given that.
Our gene therapy is working in adult patients as well, where there is the highest year of positivity, but do you have to balance that as you said with the type of anti seizure medicine being used especially if levels due dropped significantly like what happened with Dilantin. So I guess the bigger question is if you.
Are there other medicines that we can try which are not processed through the liver and impacted negatively by sirolimus. So I think thats something that we have to continue to assess for now yeah. I would just add to that Jack that the it was patient one that was on the the Dilantin zone and the other thing at least based on her history.
She's tried multiple products to control the seizures and Dilantin was the only one that appeared to work. So it may be a bit of a unique circumstance. We will just have to see and monitor carefully as we proceed in the study.
Got it great. Thanks, so much for taking the questions and congratulations on the progress.
Thanks Jack.
Thank you. The next question comes from young Li from Truth Securities. Please proceed with your question.
Hi, Congrats on the data and thanks for taking our question. This is maybe on for June.
You have a.
Direct competitor in gene therapy of Ret syndrome.
Nutrition and Jim for one could you please elaborate on.
Anything the specifics are in your program.
Could be viewed as a strong differentiator of your program I mean.
From construct designed routes of administration dose levels because.
Because the account fees it seems to be the same.
And I have a second question, which is related to patient.
<unk> 'twenty again, so are there what's the latest there is there any takers are are there any negotiations going on for this program. Thank you.
Thanks June.
Let's start with the the Gam question.
I would just say, there's not a lot to comment on specifically.
We are in the process that we've outlined of stepping through strategic alternatives and I wouldn't want to comment on.
You know anything until its actually been resolved so.
State stay tuned on that one.
But nothing to report specifically as it relates to two neuro gene I guess, a couple of things I can say high level would be.
You are correct that the both.
<unk> constructs use AAV nine as the capsid, but that's one that that's where the similarities.
And.
So number one we have a mini gene there before linked gene.
Promoters are slightly different I think I think the key aspect is really the regulatory element.
Am I right that we have versus the exact technology that they have.
So you know the way I would describe our construct is that it's a able to take into account and read the endogenous levels of M. A C. P. Two in each cell that it goes into.
And based on the level of endogenous M. A C. P. Two it will either create exogenous <unk> or not.
And so I think that's the distinguishing feature where our understanding of the exact technology is that essentially regulates itself.
It is not taking into account the endogenous levels of M. <unk>, so potentially there could be <unk>.
Additional risks for the overexpression with that construct and we'll find out in the clinical setting.
But that's that's a key area of differentiation I would also just note that we're going through an interim piece will delivery versus the ICB route.
The <unk> team is is embarking upon there. So there's a there's a lot of differences I don't I can't comment anymore on the <unk> program I'm not aware of anything specific.
But I would just say at this particular point in time, where we're quite pleased with what we're seeing in our construct and I would just go back to the first question that Whitney asked them.
Proof of concept with our.
Construct with these two very different phenotypes and genotypes is encouraging right. We saw very severe patient that would arguably have very low levels of <unk> and we're seeing a nice response.
And in a patient with a less severe mutation.
Where you would expect her to be producing.
Frequently more M UCP too.
We're seeing response, coupled with the fact that we're not seeing any.
Signs of overexpression.
So hopefully that gets at your question.
Thank you very much and congrats again on the data.
Yes.
Thank you and ladies and gentlemen, just another reminder, if you'd like to ask a question. Please press star.
And then.
The next question comes from sovereign Chicken from JMP Securities. Please proceed with your question.
Thank you very much for taking my questions and congratulations on the great update here.
Just considering this is one single trial site and one investigator can you just comment on the objectivity and variability of especially autonomic dysfunction measures I would assume.
Bye.
Some sort of scale of device.
How does the breathing pattern how's the measured how does it improve and also the sleep quality and duration I think that's a very important measure here. Thank you.
Yeah, I would just say that there is a lot of those both of those functions are measured via different scales and by different people. Some of them are going to be measured like the CGI is an example, the RBA that's going to be measured by the clinician. That's her clinical observations of what's happening during a clinical assessment.
Whereas with the RSP cure the Pgi, that's gonna be caregiver administered and theyre going to lock that in and demonstrate what they're what they're seeing there and then we do have examples like when we look at motor function like.
Like the hand function is a good example, alright, that's being videotaped incentive an independent party to review and score that so sukru I'll turn it over to you to add more color.
Also I think your question was with reference to autonomic abnormalities as I've seen in these patients. So so I'll break this down for you. So remember in these adult patients who have been referred into the single center in Montreal. They do have physicians, who will be taking care of them now for a very long time. So you have the medical history that allow as documents.
Abnormality seen with it and sleep seizure history respiratory abnormalities or Gi function also when it comes to sleep. Usually these patients also have sleep lab evaluations, where appropriate and possible that documents. The abnormalities that are observed when it comes to seizures that unusual seizure diaries parental diaries and also EEG.
The activities that have been measured that gives you some sense of how often decisions happen and then when it comes to GI dysfunction. It depends on clinical reports, but also sometimes you do mortality studies in this patient that may give you a good sense.
Normal Gi function could be so those are the general parameters that are used to make these assessments and then the pie obviously does the assessments based on past history, and then post treatment evaluation for the protocol and then finally some of these questionnaires.
Scale that Sean was referring to may have several questions obvious questions that gives you. Some hint of is are there continue to slip abnormalities are there continued the motor dysfunction are there continued respiratory abnormalities et cetera. So it's a collective assessment of each patient overtime.
Great. Thank you and.
Guarding the dosing of the Napa fair pricing, but that might be higher going to the higher dose. If another piece would be meeting required to switch to the higher dose post dosing of a purposeful. Thank you so much.
Yes.
Third patient is dosed.
You know you have six weeks and then you collect the data clean the database and then you have to meet with the IDM CRD SMB before you go to the higher dose cohort of 115.
Yeah. Thank you so much for the color and thanks for taking my question.
Okay. Thank you.
Thank you. The next question comes from Ian Yang from Jefferies. Please proceed with your question.
Yeah.
And it seems like we no longer have even connected on the line and at this time the art no further questions in the queue, ladies and gentlemen, we have reached the end of the question and answer session and I'd like to turn the call back to Sean Naughton for closing remarks. Thank you.
Yeah.
Just wanted to thank everyone for attending the call. We appreciate the questions and look forward to speaking again soon take care.
Thank you.
Ladies and gentlemen that does.
This concludes today's conference. Thank you very much for joining us.
Thanks Caroline.
Okay.
Yes.
Yeah.
Yes.
[music].