Taysha Gene Therapies Q2 2023 Earnings Call Transcript

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Provided by Quartr
August 14, 2023

There are 10 speakers on the call.

Operator

Good morning. Welcome to Tayshia Gene Therapy Second Quarter 2023 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen only mode. Following management's prepared remarks, we will hold a brief question and answer session. As a reminder, this webcast is being recorded today, August 14, 2023.

Operator

I will now turn the call over to Hayden Allen, Director, Head of Corporate Communications. Please go ahead.

Speaker 1

Thank you. Good morning, and welcome to Tayshia's Q2 2023 Financial Results and Corporate Update Conference Call. Earlier today, Tayshia issued a press release announcing financial results for the Q2 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, Tayshia's CEO Sukumar Nagandran, President and Head of R and D and Cameron Alom, Chief Financial Officer.

Speaker 1

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 TASIA-one hundred and twenty and TASIA-one hundred and two and the therapeutic and commercial potential of TASIA-one hundred and twenty and TASIA-one hundred and two. 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 Tayshia's 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 Tayshia's actual results to differ materially from those stated or implied in such forward looking statements.

Speaker 1

These risks include uncertainties related to the timing and results of clinical trials of and regulatory interactions for our product candidates, Our dependence upon strategic alliances and other third party relationships, 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 Securities and Exchange Commission, including our annual report on Form 10 ks for the year ended December 31, 2022, and our quarterly report Form 10Q for the quarter ended June 30, 2023, that we filed today. This conference call contains time sensitive information that is accurate only as of the date of this live broadcast, August 14, 2023. Tayshia 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?

Speaker 2

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. Then Sukuna Gandran, President and Head of R and D of Tayshia, We'll provide an update on our clinical development programs. Cameron Allam, our Chief Financial Officer, will then follow-up with a financial update. I will provide closing remarks and open the call up for questions.

Speaker 2

There are 2 main areas of focus for today's call. First, we are pleased with the recent progress we've made in our 2 lead investigational programs with particular emphasis this morning data from the first patient dosed in the adult Rett syndrome trial. 2nd, we are very pleased to have significantly strengthened our balance sheet The private placement financing is expected to result in gross proceeds of approximately 150,000,000 dollars 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. For TASION-one hundred and two and Rett syndrome, the Independent Data Monitoring Committee or IDMC recently convened to review the initial clinical data from the first patient dosed with TASIA-one hundred and two following the patients required 42 day evaluation period.

Speaker 2

Based on encouraging initial clinical data, The IDMC recommended that continuation of the REVEAL Phase III trial and provided clearance to dose the 2nd patient in the 1st cohort. We are pleased to share that early data from the first adult patient showed TASIA-one hundred and two was well tolerated With no treatment emergent TASIA-one hundred and two related serious adverse events as of the 6 week assessment. We also have seen early improvements in key efficacy measures evaluating the overall disease and signs and symptoms of Rett Syndrome, As well as clinical observations supporting improvements in multiple domains, including autonomic function, vocalization, as well as gross and fine motor skills. Suku 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 4 weeks post treatment And the 1st adult patient with severe disease reinforces the transformative potential of TASIA-one hundred and two to address the root cause of Rett syndrome.

Speaker 2

Importantly, these early data indicate That the miRNA responsive autoregulatory element or miRARE technology is mediating MECP2 expression in the central nervous system on a cell by cell basis, supporting the regulatory control of MI Rare. We are highly encouraged by the initial data of TASION-one hundred and two and are focused on continuing to explore its therapeutic 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 TAYSHA-one hundred and two in pediatric girls 5 to 8 years of age.

Speaker 2

And we have submitted a CTA to the MHRA for TASION-one hundred and two in pediatric with Rett syndrome, which will expand our clinical evaluation to patients with earlier stages of disease progression. For TASIA-one hundred and twenty in 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 TASIA-one hundred and twenty 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 $150,000,000 from a group of new and existing Top Tier Investors. The private placement financing was led by new investor, RA Capital Management, With participation from a large institutional investor, PBM Capital, RTW Investments LP, Venrock Healthcare Capital Partners and TCGX 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 TATIA-one hundred and two program and the early clinical readout of the first patient treated in our REVEAL trial.

Speaker 2

We expect that the net proceeds from the pipe Together with our existing cash and cash equivalents, we will extend our runway into the Q3 of 2025 to primarily support the clinical development of TATIA-one hundred and twenty in Rett syndrome and provide support for TATIA-one hundred and twenty program activities 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 6 months, we plan to continue to advance our 2 lead clinical programs, including generating additional clinical data in adults and expand our clinical footprint into pediatric patients for TASIA-one hundred and two in Rett syndrome, and reviewing the potential regulatory pathway for TASIA-one hundred and twenty with the FDA. I will now turn the call over to Suku to provide a more in-depth discussion of our clinical programs in Rett syndrome and GAM.

Speaker 2

Suku?

Speaker 3

Thank you, Sean, and good morning, everyone. I will begin with updates on TASIA-one hundred and As Sean mentioned, We are pleased to share with you today the initial safety and efficacy data from the first adult Rett syndrome patient dosed in Cohort 1, low dose, with TESHA-one hundred and two in our REVEAL Phase III trial. Based on these initial data, we believe our product candidate has transformative potential. As a reminder, CECI-one hundred and two utilizes a novel miRIA platform designed to mediate MECP2 expression in the Chromosomal inactivation and silencing of MECP2 expression that occurs randomly with Rett syndrome results in a mixture of cells that are either deficient in or express MECP2 normally. This heterogeneity in MECP2 expression is what makes Rett Syndrome challenging with traditional gene therapy approaches, but we believe our novel MRI technology can appropriately address this challenge and potentially provide therapeutic benefits.

Speaker 3

TASHA-one hundred and two is currently being investigated in the ongoing REVEAL Phase III trial, A first in human open label randomized dose escalation and dose expansion study evaluating the safety and preliminary efficacy of TAYSHA-one hundred and two in adult females with Rett syndrome due to MECP2 loss of function mutation. Following the IDMC's Please specify the review of the initial clinical data from the 1st adult patient dosed with TASIA-one hundred and two, the IDMC recommended the continuation of the REVEAL Phase 2 trial and provided clearance to dose the 2nd patient in the first cohort. It is important to understand that the REVEAL trials are designed to primarily measure safety in adult patients. We have seen a well tolerated safety profile in the 1st adult patient With no treatment emergent, TESHA-one hundred and two related serious adverse events as of the 6 week assessment post treatment. Due to the severity and progressive nature of the disease, we did not expect to see efficacy in adults with Rett syndrome, Particularly in patients with Stage 4 of Rett syndrome, the late motor deterioration stage, which is the most advanced stage of the disease.

Speaker 3

It typically begins around 10 years of age and can last for years or decades. It's masked 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 OVIX post treatment in the 1st stage patient with severe stage 4 Rett syndrome dosed with TASIA-one hundred and two. Specifically, the principal investigator of the REVEAL trial observed clinical improvements in multiple domains, including autonomic function, vocalization and growth and fine motor skills. To provide you with clear and collective picture, Prior to treatment with TASIA-one hundred and two, the patient was in constant state of hypotonia.

Speaker 3

She had limited body movements, required constant back support and had lost fine and gross motor function early in childhood. She has not been able to sit unassisted for over a decade. 4 weeks following treatment, we have observed improvements in breathing patterns and sleep quality and duration, including the normalization of nighttime behavior. The patient's vocalization has also improved with an increased Social Interest. Moreover, video evidence demonstrated the patient's improvement in gross and fine motor skills, including the gained ability to sit unassisted for 3 minutes for the first time in over a decade.

Speaker 3

The patient also demonstrated the ability to uncast her hand and hold an object steadily for the first time since infancy as well as use her fingers to touch a screen. The clinical improvement demonstrated in key efficacy measures 4 weeks post treatment provides supportive evidence that reinforces these clinical observations. Specifically, we measure Clinical Global Impressions Improvement or CGI, which is a scale that has been adapted to Rett Syndrome. It is a clinician reported assessment of overall improvement following treatment, and it accounts for key aspects of the disease, including language, Communication, ambulation, hand use, attentiveness, eye contact, seizures and autonomic function. CGII uses a 7 point scale with 1 being very much improved and 7 being very much worse.

Speaker 3

With the 1st patient, 4 weeks post treatment, an overall score of 2 indicating much improved was reported. Additionally, the Clinical Global Impression Severity Scale or CGIS is a clinician reported assessment of the overall severity of a patient's illness that uses a 7 point scale with 1 being normal, not at all ill and 7 being extremely ill. At 4 weeks post treatment, a 1 point improvement from the baseline score of 6 indicating severely ill to a score of 5 indicating markedly ill was Notably, the Rett Syndrome Behavior Questionnaire or RSVQ, which is a 45 item questionnaire that The Suttler's syndrome characteristics demonstrated a total score improvement of 23 points from the baseline score of 52 to a score of 29 4 weeks Sports Treatment. Specifically, RSBQ subscale total scores demonstrated the normalization of nighttime behavior as well as improvements in breathing, general mood and hand behaviors post treatment. The seizure diary demonstrated no quantifiable seizure events through weeks post 5 weeks treatment.

Speaker 3

There was no market changes for weeks post treatment in the revised motor behavior assessment or RMBA, This is a 24 question clinical reported scale measuring disease behaviors of Rett syndrome. In addition to these measures, We are collecting a plethora of data and measuring various endpoints for the protocol. Data collected will further inform our thinking relative to OPTIMA 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 dosed with TASHA-one hundred and two, Coupled with the improvements observed in autonomic function vocalization and fine and gross motor skills are encouraging and we believe support the therapeutic potential of TASIA-one hundred and two. Moving forward, We intend to provide additional clinical updates from the REVEAL trial quarterly.

Speaker 3

We expect to dose the second patient later in the current quarter and anticipate 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 TASHA-one hundred and two in pediatric patients. We have also submitted the CTA to the MHRA for TAYSHA-one hundred and two in pediatric patients with Rett syndrome. With recent IND clearance, we plan to initiate the clinical evaluation of TASIA-one hundred and two in Part A of the dose finding study, which is focused on identifying the maximum administered dose and maximum tolerated dose in pediatric girls 5 to 8 years of age with Rett syndrome. The safety and efficacy data and the maximum administered dose and maximum tolerated dose selected from Part A will be reviewed by the regulatory agency and the IDMC prior to initiating Part B of the study in pediatric girls aged 3 to 8 years.

Speaker 3

Data from Part A will be assessed to determine final key elements of Part B, such as hierarchy of efficacy endpoints and study duration can be further assessed. Part B will evaluate TESHA-one hundred and two in 2 age cohorts and expand at 5 to 8 years of age with a 1 to 1 randomization of randomized to treat cohort or delayed treatment cohort and a cohort for 3 to 5 years of age. As a reminder, no approved disease modifying therapies that treat the genetic root cause of Rett syndrome are currently available and there is high unmet medical need. CECI-one hundred and two has already received orphan drug and rare pediatric disease designations from the U. S.

Speaker 3

FDA and has been granted orphan drug designation from the European Commission for the treatment of Rett Syndrome. The estimated addressable patient population with Rett syndrome caused by a pathogenic likely pathogenic MECP2 mutation is between 15,021,000 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 TESHA-one hundred and twenty for the treatment of GaN, an ultrarare neurodegenerative indication with no approved Treatments are established regulatory pathways.

Speaker 3

As Sean mentioned, we have submitted our comprehensive data analysis utilizing the newly developed disease progression model or DPM and plan to discuss the potentially regulatory pathway for TASIA-one hundred and twenty in GaN with the FDA in the current quarter. New analysis of multiple functional electrophysiological and biological and structural endpoints in patients treated with TASIA-one hundred and twenty Compared to the natural history cohort, using a disease progression model demonstrates the treatment effect in objective and clinically meaningful endpoints. Importantly, we believe these findings that we overviewed at our R and D Day in June address FDA feedback on both the heterogeneity of disease progression in GaN and the effort defend the nature of MFN32 as a primary endpoint in an unblinded study. The FDA indicated that it's open to regulatory SeBILITY is a controlled trial setting and is willing to consider study designs, alternatives to a randomized double blind placebo controlled trial If they utilize objective measurements to demonstrate a relatively large treatment effect that is self evident and clinically meaningful, We look forward to having a collaborative dialogue with the FDA regarding the potential registrational path. Lastly, with respect to manufacturing, FDA feedback on our CNC Module 3 amendment concluded that the analytical data is sufficient to support the comparability of a pivotal lot and released for use in clinical studies.

Speaker 3

I will now turn the call over to Cameron to discuss our financial results. Cameron?

Speaker 4

Thank you, Shu Koo. Research and development expenses were $19,800,000 for the 3 months ended June 30, 2023, compared to $23,500,000 for the 3 months ending June 30, 2022. The $3,700,000 decrease was due to lower compensation expense as a result of reduced headcount and fewer manufacturing batches and other raw material purchases. General and administrative expense were $6,000,000 for the 3 months ended June 30, 2023 compared to $9,900,000 for the 3 months ended June 30, 2022. The decrease of $3,900,000 was due to reduced general and administrative compensation as a result of lower headcount, Consulting and Professional Fees.

Speaker 4

Net loss for the 3 months ended June 30, 2023 was $24,600,000 or $0.38 per share as compared to a net loss of $34,100,000 or $0.85 per share for the 3 months ended June 30, 2022. As of June 30, 2023, Asia had $45,100,000 in cash and cash equivalents. Subsequent to the close of the Q2, as Sean highlighted, we announced a private placement that resulted in gross proceeds of $150,000,000 and is expected to close August 16 before deducting placement, agent commissions and operating expenses. Under the terms of the transaction, Tayshia is selling an aggregate of 122,412,376 shares of its common stock at a price of $0.90 per share And in lieu of common stock to certain investors, pre funded warrants to purchase up to an aggregate of 44,250, 978 shares of common stock at a purchase price of $0.89 per prefunded warrant. The prefunded warrants will have an exercise price of $0.001 per share of common stock, be immediately 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 we will first seek to obtain 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.

Speaker 4

As Sean noted, our cash runway, including the expected net proceeds from this private placement, now extends into the Q3 of 2025. I will now turn the call back over to Sean for his closing remarks. Sean?

Speaker 2

Thank you, Cameron. As you heard today, we have made significant progress in our 2 lead clinical programs, including the generation of the initial clinical data in the REVEAL Phase III trial in Rett syndrome that we believe reinforces the therapeutic potential of TASIA-one hundred and two. We are excited to potentially bring a transformative treatment option to the Rett syndrome community. Collectively, We believe that the data from our 2 lead clinical programs continues to support our gene therapy approach and the therapeutic potential of our programs to address Severe unmet needs in monogenic central nervous system disease. In the second half of the year, We expect to continue dosing additional adult patients with TASIA-one hundred and two in our REVEAL Phase III trial in Rett syndrome and provide quarterly updates on available clinical data.

Speaker 2

Additionally, we have begun clinical site trial initiation activities for the U. S. Pediatric Rett syndrome trial and anticipate dosing the 1st pediatric patient in the Q1 of 2024. We expect to receive feedback from the MHRA in the second half of twenty twenty three for the proposed pediatric study, which will further inform program timelines in the UK. For TASIA-one hundred and twenty and GaN, we look forward to having a regulatory discussion with the FDA regarding a potential path forward for TASIA-one hundred and twenty and GaN later this quarter.

Speaker 2

With our balance sheet Substantially strengthened, we believe we are well positioned to execute across key upcoming value creating milestones for our Rett syndrome and GaN programs. With that, I will now ask the operator to begin our Q and A session. Operator?

Operator

Thank you. One moment while we poll for our first question. Our first question comes from Yan Xu with Wells Fargo. Please proceed.

Speaker 5

Hi. Thanks for taking our questions and congrats on all the progress and the initial data, which sounds extremely exciting for patients. So could you remind me that Maybe I missed this, the age of this patient, who is obviously an adult patient. And can you speak to how does this data compare with the approved therapy debut? And whether you have additional observations at later time points beyond the 6 week that was noted in the press release and on the call?

Speaker 5

Thank you.

Speaker 2

Thanks, June. Appreciate it. Let me take a high level perspective on that and then I'll turn it over to Suku for a little bit more Detail, but this patient was 20 years of age. She has stage 4 disease, which is the most severe form Of the disease. And I think what I'd ask Suku to do is kind of just really describe the patient For the audience here, so we can try to characterize just where she was physically and what she was and wasn't able to do.

Speaker 2

SUKU can also do a bit of a comparison to the trofinetide, although again, There's a lot of caveats there with one patient versus they had significantly more patients, it's 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 IDMC. 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.

Speaker 2

So with that, I'll turn it back over to Suku. And Suku, if you could characterize that patient High level and put into context what we're seeing here, that'd be great. Thank you.

Speaker 3

Yes. Thanks, Sean, and thanks for the question, Joon. So So this patient is a 20 year old female with severe Stage 4 Rett Syndrome, okay, as I think Sean described. And the data is the data as is because given for the protocol, we have only access to the 4 week assessment and the 6 week assessment at this point in time. This patient, as I said, is a female, who was hypertonic, had contractures, was literally either in a wheelchair with Inability to really use her Apollo extremities was unable to sit with over the last decade and had decreased tone of her neck and was unable to vocalize or really socially interact as well.

Speaker 3

Furthermore, this patient also had multiple episodes of respiratory insufficiency where she would have spells or acne spells where couldn't breathe, coupled with hyperventilation. She also had significant sleep abnormalities, where she would wake up at night and essentially not have a quiet night where her parents were also constantly disturbed from, 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 severe stage 4 Rett syndrome. Now as far as the response goes, we've already described that the patient, once given our intrathecal gene therapy, Started showing clinical responses within 1 week post gene therapy and then at 4 weeks we've already shared And at 6 weeks, video evidence shows that this patient was able to sit up almost 3 minutes without assistance.

Speaker 3

The back Support was not necessary at that point in time. She was quite socially interactive and was attempting to vocalize, including saying the word mama multiple times during the day. Furthermore, she was also moving her upper and lower extremities and moving her fingers of both upper extremities and was also able to grasp a toy or a ball, which was observed by the PI and the parent. Furthermore, she was also able to use her lower extremities against gravity, which she has been unable to do for a very long Thanks. And what is incredibly important is the impact that the gene therapy also had on the autonomic features, which is her ability suddenly post Gene Therapy to now sleep throughout the night without waking up and screaming, which also enables her parents to sleep through the night.

Speaker 3

Furthermore, her respiratory abnormalities, which are due to autonomic irregularities, which include acne spells or inability to breathe or holding her breath, coupled with hyperventilation episodes, are also decreased significantly. And furthermore, at the time of assessments done for the protocol, A seizure activity was absent for the seizure diary and EEGs reviewed by the PI at that point in time. Now finally, as Sean said, this is one patient dosed with the lower dose of our gene therapy where we saw these clinical results, which we think are quite relevant and one could consider quite impactful. To compare that to trofinetide, one patient versus a fairly large Randomized clinical trial of almost 200 patients, I will attempt to do that, but with the caveat. The trofinetide or DEBU Phase 3 trial Use as their primary endpoints for approval, CGI and the Rett syndrome behavior questionnaire, and they use the combined endpoint.

Speaker 3

So to give you some comparison here with our one patient, CGI I assessed at 4 weeks gave us a score of 2, which when talking to experts who actually designed CGI, told us that was quite clinically relevant. In the trofinetide trial, 12 weeks post treatment in the Phase 3, when the treatment arm was compared to the placebo arm, the actual change between the two arms was, as I recall, around 0.37, which was significant from a p value standpoint. Then if you look at RSBQ, the behavior questionnaire, For our one patient, the change 4 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 profanotide trial from what I recall was around 4 point 7, and Sean, you may want to correct me, I think that's the number I remember, which reached a significant p value and the broadest or the largest decrease In that trial in patients, if you look at the range, was a change of 10. So for us, we had one patient who had an improvement of 23 So my hope is if we continue to see these kind of Impactful clinical changes, both from a purely clinical observation standpoint, which one would consider quite impactful and from these Measures of CGI and RSVQ, the differences could be quite different compared to the trofinetide dataset.

Speaker 3

So I'm going to stop there and hand this back over to Sean to add anything of additional color. Thank you, Sean.

Speaker 2

Thanks, Suku. We'll take the next question, please.

Operator

Our next question comes from Jack Allen with Baird. Please proceed.

Speaker 6

Great. Thank you so much for taking the questions and congratulations on the progress. I guess, maybe one for Suku. If you could talk a little bit more about the progression of response in this patient? It It seems like you have data from 1, 4 6 weeks.

Speaker 6

I'd love to hear a little bit about the changes you're seeing over time. I know it's really early from that regard. And then Just as a secondary question, any color that you can share as it relates to the sharing of this data with Astellas would be great as well? Thanks so much.

Speaker 2

Thanks a lot, Chad. Appreciate it. Suku, 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 has been presented to the Board.

Speaker 2

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, Suku, you want to take the question about Yes, the progression and what we're seeing over time. And maybe just one more comment from me just so everyone has the timeline here. The efficacy endpoints that we're talking about were measured at week 4 for the protocol And there is safety data out to 6 weeks for the protocol.

Speaker 2

And then there was video evidence that was generated at 6 weeks that looked at gross and fine motor skills in particular. So that's what we have right now. And so with that, Suku, you want to talk a little bit about the progression and the effect over time that the Investigator Huttseen?

Speaker 3

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, what I'm going to talk about right now is up to 6 weeks post gene therapy, Given that the patient was dosed on May 31, I cannot comment beyond that because as Sean pointed out, per protocol, there are visits ongoing, data is being accumulated That has to be further analyzed and cleaned up from a database standpoint, okay? So what is important here to note is that our Gene therapy has self complementary technology.

Speaker 3

So once it is given to the patient, it turns on very quickly within 48 to 72 hours. And what was absolutely fascinating is that when we first went into this adult study where the patients were 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 were in their latest or worst stage of disease. What we observed though was 1 week post gene therapy, the investigator noted that the patient started improving significantly from a clinical evaluation standpoint, both from her aspect as well as from the parents' aspect, but furthermore, there was significant impact on the autonomic This function that I already commented on previously, which includes breathing abnormalities, seizure activity and sleep overnight. Furthermore, this improvement continued, as Sean pointed out, 4 weeks in, where not only did the clinical improvements Continue to improve at that point in time, but also other measures, which included CGI I, CGIS and also the Rett Syndrome behavior question, which all further validated that our gene therapy was having real clinical impact.

Speaker 3

And at 6 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 a brace that Reported her back, she was also able to move ahead and track quite effectively and was very socially interactive and was also attempting to vocalize. This was quite a change compared to a baseline and baseline assessments and videos that showed her quite inactive hypertonic flaxid And at the same time, unable to really move her legs off her extremities in an appropriate manner and was not very socially interactive and was not vocalizing much. So I hope that gives you a perspective of the dramatic impact of the gene therapy on this first adult patient that we have dosed with severe stage 4 Rett syndrome. Thank you.

Speaker 6

That's great color. Thank you so much and congratulations again on the progress.

Speaker 3

Thanks, Jeff.

Speaker 2

You bet.

Operator

The next question comes from Kristen Clusta with Cantor Fitzgerald. Please proceed.

Speaker 7

Hi, good morning everybody. Congrats on the progress as well as your Private placement. So for Brett, our understanding is that Stage 4 typically begins after around 10 years old. So this patient pop This particular patient potentially had been in the stage for some time, if our understanding is correct, does progress quite a bit. So can you talk about how much variability in terms of baseline factors you would expect to see in adults in general?

Speaker 7

And again, I think our expectations here was just to check the box on safety, but how are you also thinking about maybe How this one patient changes the way you're thinking about expectations across other adults as well as pediatrics? Thank you.

Speaker 2

Thanks a lot. Just to take down that second question first, Suku mentioned this early on Is that as we talk to the experts in the field about the adult study, there was a very strong consensus. And I would say there was a unanimity frankly that we really shouldn't expect to see anything from an efficacy perspective, Which is why we kind of shared that view with all of you and that this would really be a safety focused study. And Suku will comment on this in a little bit, but given that this is a neurodevelopmental disease and Theoretically, there's always been a view that perhaps you really can have a greater impact On the disease, since full damage may not have occurred, cellular death may not have occurred like it would in a neurodegenerative disease. I think what this is showing is that there's a lot for us to learn about this particular disease state.

Speaker 2

And 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 the sleeping and you look at the gross motor function and you look at 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 say the 1st cohort of patients and I think it's going to help us really be more informed about Endpoint selection is an example. And keep in mind too, we also are at the low dose. I mean, so we also can step up the dosing And see if there's a greater effect there.

Speaker 2

So the way we've designed the trial is that we are using A number of endpoints, Suku mentioned a plethora of endpoints. We're going to evaluate that and determine as we go forward what would be the best For us from an endpoint perspective, it really captures the impact of the disease. So With that, let me do this. Let me turn it over to Suku. Suku, feel free to expand on what I just said there.

Speaker 2

And then maybe you could also just talk a little bit about Patient variability and symptom variability with people at Stage 4 of the disease.

Speaker 3

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 once seen a preclinical model translate 1 to 1 into the human And that was in the work we did on Zolgensma with spinal muscular atrophy Type 1, where the delta-seven mouse model translated 1 to 1 into the human. Now with Rett Syndrome, given the disease state itself and given how severe this patient was, I didn't expect to see this kind of one to one translation, That is what we are seeing here as well.

Speaker 3

As you probably are aware, we have done a fair amount of work using the Rett syndrome rodent models At p02, p7, p14 and p28 with our gene therapy that shows significant improvement in survival, motor function and autonomic function. We've also spoken to many clinical as well as preclinical experts who've done decades worth of work on different rodent models, including at P35 and P46, where an increase in the MECP2 levels of, say, 5% to 10% above base And with appropriate therapies can actually restore function and improve survival. And lo and behold, I think that's what we saw with this first patient You have severe Stage 4 Rett Syndrome. 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 data set and the understanding of the disease pathophysiology now is Explanatory to see why we're having this kind of impact with our gene therapy and again to answer your question about disease variability, As you said, Stage 4 technically begins around age 10, but as the disease progresses and the children get other female patients with Rett syndrome get older, Yes, disease does tend to get much severe.

Speaker 3

And I think if you see this kind of response with a severe stage 4 patient, I'm quite cautiously optimistic That in patients with different types of presentations of Stage 4 Rett 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 or parents' lives as well. And then from an endpoint standpoint, as

Operator

Sean pointed out, we have many endpoints that

Speaker 3

are hypothesis We have many endpoints that are hypothesis generating, not testing. And as we gather more and more data, then we hope to use these As our endpoints for the CONFIRMATION trial, with the caveat though, if you see this type of clinically meaningful or 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 these functional measures that we have built in, very similar to what we may see or have seen with the Zolgensma trials when we went to the FDA and other regulatory agencies. So I sincerely hope that TASIA-one hundred and two will continue to have meaningful clinical impact for these patients and change their lives. Thanks for the question, by the way. Sean, back to you.

Speaker 2

Thank you, Zukun. Next question, please.

Operator

Our next question comes from Silvan Turcan with JMP Securities. Please proceed.

Speaker 8

Yes, good morning. Congrats on the data and the placement, and thanks very much for taking my questions. Just going back to the safety side for the MECP2 duplication syndrome, which is one of the safety risks here, how far are we out of the woods with this one patient? When could we Should this onset if there would have been complications already been seen? Or what is the timeline until we can estimate fairly confidently that That is not a problem and MiWaya is working well.

Speaker 8

And then I have a question about the sleep. And the SIP improvement, obviously, in our discussions with KOLs, that's been one of the main problems with adult patients that Doctors really saw the burden. How the sleep that we measure the improvement, is that every night? Is it Could you please give us some more color around the improvement of sleep? Thank you so much and congrats again.

Speaker 2

Thanks a lot, Sohrab. Yes. Suku, would you mind taking both of those questions, one regarding sleep and the other regarding the timing of And maybe even describing what the MECP2 duplication, how would that manifest itself? What would it look like? And is that something that the IDMC would have picked up on in their review of the safety data?

Speaker 2

So I'll turn it back to you.

Speaker 3

Yes. Thanks, Sean. And by the way, Silvan, those are very good important questions that we were also grappling with when we were initially working on the protocols in the past, But also evaluating this patient. So I'm going to try and walk you through and linking kind of the science behind the MECP-two expression levels and clinical manifestations, but also the miRIA technology and link it to, I would say, the clinical findings. So keep in mind though that our construct has miRARE, which is a regulatory element, right, that is part of the construct that is sensitive to endogenous MECP2 production that works through the endogenous microRNA that then modulates Our exosome construct and regulates the amount of MECP2 produced by our gene therapy.

Speaker 3

So essentially, In the animal models and non human primates work, we had reassurance that this MRI technology actually works very well, especially in cells within either the rodent models or now in the human that have normal MECP2 levels. Now the reason I have Confidence based on this one patient set of data and obviously, I'd love to see this reproduced as we go through more patients is that the construct our construct started having clinical results within 1 week post treatment. So it turned on very quickly and therefore the patient continued to improve per assessment, especially with impact, as you pointed out, on sleep, which is a difficult aspect of the disease to treat. And frankly, if The MECP-two production by our construct actually went beyond the therapeutic range. You would have seen abnormal both clinically and I assume on some of the questionnaires that we use to assess the patient, which included the RSBQ.

Speaker 3

So those measurements have reassured us up to now that the patient is doing quite well clinically, but the expression levels Of MECP2 within each cell, is that an appropriate level to control the neural network that the MECP2 Protein level actually controls within the cell that has still continued to result in positive clinical manifestations. And Working backwards though, again, keep in mind, our assessment is at 4 6 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 if there are going to be features of duplication syndrome, which Frankly, clinically, it's very similar to Rett syndrome with some differences, especially when it comes to patient activity. There might be other psychiatric features of mania and ADD But can also manifest as part of duplication syndrome that has not been observed and the IDMC when they reviewed the data in mid

Operator

The operator of Sumco line disconnected. I will try to reconnect back and bring the next

Speaker 2

This is Sean. While we wait for Suku to dial back And I think the other part of the question that Sylvain asked was around sleep. And all I can say to that without Suku 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 RSPQ, which is caregiver generated, The score went to, I want to say it was almost normal. In fact, it was a normal indication.

Speaker 2

So it was a Very distinctive improvement from the parent's perspective in terms of her quality of sleep. So with that, why don't we ask for the next question?

Operator

The next question comes from Joon Lee with Truist Securities. Please proceed. Hey, congrats on the progress and thanks for taking our questions. The results from the REVEAL study are stunning at face value, but Is there any CSF biomarker or ENG in couple with to complement the findings and confirm target engagement? And you put the findings of the single patient, which again sounds impressive in the context of natural history study.

Operator

Can you give what gives you confidence that the findings are real And not noise, this is really for Suku, but anything you can share, Sean, would be appreciated. Thank you.

Speaker 2

Okay. Let me ask, is Suku on the call? All right. Well, then I'm going to do my best while we deal with this. 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 MECP II because it's not freely able to be captured.

Speaker 2

So you would ultimately you'd be in a very negative situation like looking at autopsy and 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're seeing in MECP2. So it really would be the manifestations clinically and what types of improvements are you seeing there. As it relates to Is this real? I understand the perspective of the one patient and look we caveated that as well.

Speaker 2

I think what's so dramatic about this is that when you talk to the KOLs and the people that treat RET patients on a daily basis, Stage 4 is exceptionally severe. I mean Suku did a good job painting the picture of the patient, but essentially envisioned somebody that 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 semblance of the ability to hold themselves upright, 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 track, unable to hold objects in their And I would just say based on the video that I've seen is that very, very quiet, very Kind of much within herself, I would say, in terms of vocalization and communication, just very, very quiet, very placid. And then after treatment, again, the physician reported and we've seen the video where She can you put her into a sitting position and she can sit there for 3 to 5 minutes. So that's Suku was here, he'd say that Demonstration of Axial strength, she's getting muscle tone back into her like her limb girdle region, if you will, And has the strength to do that, much more movement and coordination of the upper extremities and beginning to see something, some activity In the legs.

Speaker 2

Suku, good to have you back on board. I've been doing my best to paint the picture of the patient. So, Sooku, maybe you should take it from here. But the question was really around, Is this effect real? Is there a lot of heterogeneity in these patients and maybe they have periods where they're very, very difficult They're very severe in their symptoms and then they get better.

Speaker 2

I tried to paint a picture of what she looked like before and after, but I think The folks would appreciate hearing it from an MD more than myself.

Speaker 3

Yes. Thanks, Sean. And by the way, I apologize. I just suddenly got disconnected. So anyway, I'm back on.

Speaker 3

So when it comes to Stage 4, Rett, I know somebody asked question previously as well. Beyond age of 10, as the patient's working and getting to the severe stage, I think the heterogeneity based on my discussion with many of the experts gets less and less. And what is important to note though is that in this patient, and again, we've described the patient's profile to many experts that have seen the videos on the CDA, And they do all accept the fact that the response, yes, was clinically dramatic, but it is pretty obvious because The patient continues to consistently demonstrate the improvement compared to baseline. I've already described some of these improvements that go way beyond just the autonomic by itself I thought was dramatic, but also the fact that the patient could not sit up without support for over a decade is able to do that. There's restoration of axial muscle tone and neck tone.

Speaker 3

There's now restoration of function of the upper extremities, which is the ability to hold a ball or an object, And also the ability that she appears to now attempt to interact socially and also attempt to vocalize, which I hope over time We'll turn into more words and maybe even string sentences together. So collectively speaking, this is a dramatic response. And I assume the younger the patients in that Stage IV period, we will have to assess each patient based on their baseline to see What type of improvement you will see clinically, but remember, their program got approved on CGI and the RSBQ. And hopefully, we will see these kinds of dramatic changes in CGI and RSBQ as well in the patients we treat, whether it's The pediatric population or the adult population that will further cement the impact of our gene therapy. So I hope that helps address any concern around variability, But in this specific patient, a 20 year old female with severe stage 4, again, I emphasize we did not expect to see any kind of efficacy impact of our gene therapy this quickly.

Speaker 3

So again, I'm cautiously optimistic that we can reproduce this result and hopefully make a big difference in the Rett Syndrome patients' lives and their caregivers. Thanks, Shawn. Back to you.

Speaker 2

Suku, can you also just confirm that there is no to our knowledge, there No biomarker available to measure MECP2 levels?

Speaker 3

That's correct. At the present time, we have Do not have the ability to measure MECP2 levels in the cell or in the serum or in the CSF and the biomarkers that Out there, and we are collecting CSF and CRM samples to look at different biomarkers. These biomarkers Such as neuro filament levels, BDNF, etcetera, do not have enough data yet to correlate 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. Now the caveat though is given how quickly our gene therapy works from a clinical impact standpoint, Biomarkers may not be necessary if we continue to have this kind of clinical impact.

Speaker 3

So I'll leave it at that for now, Sean.

Speaker 2

Thanks, Suku. Next question, please.

Operator

Our next question comes from Gail Blum with Needham. Please proceed.

Speaker 9

Good morning, everyone, and thanks for squeezing us in. Very impressive data set, especially given how early it is. Maybe I'd love your thoughts here on how you think this data could evolve over time. So we're used to seeing functional measure take Quite a while to really ramp up. Thank you.

Speaker 2

Thanks, Gil. I'll take a stab at that and then turn it over to Suku. 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. I mean, my view is basically that what we've seen thus FAR in a Stage 4 patient is very dramatic, very unprecedented. And so I think the question you're getting at Gil is, is there going to be an incremental improvement over the course of time?

Speaker 2

Is she going to continue to get better? Those are unknowns. I think this is a major first step. And I think what we can do to potentially help and I know Suku's team is working on this, but is there physical therapy that can be done to help her get Stronger and utilize the muscle tone that she's beginning to regain. Can she work with speech pathologists and what have you to gain Further utilization and ability to communicate, those types of things I think are unprecedented And Rett patients.

Speaker 2

And so I think we're blazing new ground. And I think it also highlights the fact that The sooner that you get into the treatment, probably the best outcome you can possibly get. But So basically have this level of impact on a Stage 4 20 year old adult, I think really is encouraging for the broader patient population out there. But Suku, please feel free to augment anything that I have said.

Speaker 3

Sean, I mean, I think you've explained it quite well. And one piece of information I would add, Gail, again, With the disclosure and disclaimer, this is absolutely speculative, is that my team, the experts who've Seeing the CGI I, CGI F data, RSVQ data were quite surprised and impressed with how rapid the impact 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 one patient comparison to the Profanatite data set. So what I would state again speculatively is if we see these type of consistent results in the adult patients that we are dosing, Let's say in the next, I don't know, 5 to 6 patients, the dramatic nature of the change, if that continues, 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 patient I would like to see this reproduced and then let it develop for the program and hopefully Also influence the regulatory pathway in the most appropriate way possible.

Speaker 3

So thanks for that question, Gil.

Speaker 2

The other thing that I would add to that too, Gil, Oftentimes when you look at a population of people affected by a 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 I think what's so encouraging and exciting for the Rett community is that there could be a much broader population That 15,000 to 20,000 patients that could drive a very significant and meaningful benefit from gene therapy. Thank you very much. Next question?

Operator

There are no further questions. This concludes our question and answer session. I'll turn back to Mr. Noller for his final remarks.

Speaker 2

I really appreciate everyone joining the call this morning. Wish everyone a very happy day. Take care and we'll talk soon. Thank you.

Operator

Thank you again for joining today's teleconference. You may disconnect your lines at this time and thank you for your participation.

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Earnings Conference Call
Taysha Gene Therapies Q2 2023
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