Q2 2021 Taysha Gene Therapies Inc Earnings Call

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Operator: Welcome to Taysha Gene Therapy's second quarter 2021 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 call is being recorded today, August 16th, 2021. I will now turn the call over to Dr. Kimberly Lee, Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

Welcome to the Acacia gene therapies second quarter, 2021 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.

This call is being recorded today August 16th 2021.

I will now turn the call over to Dr. Kimberly Lee Senior Vice President of corporate Communications and Investor Relations. Please go ahead.

Joon So Lee: Good morning, and welcome to Taysha's second quarter 2021 Financial Results and Corporate Update Conference Call. Joining me on today's call are Ari Session II, Taysha's President, CEO, and Founder, Dr. Suyash Prasad, Chief Medical Officer and Head of R&D, and Kamran Alam, Chief Financial Officer. After our formal remarks, we will conduct a question and answer session, and instructions will follow at that time.

Good morning, and welcome to Tetra second quarter, 2021 financial results and corporate update conference call. Joining me on today's call are or a second the second patient as president CEO and founder Dr. C. V. S Prasad Chief Medical Officer, and head of R&D, and Kamran Alam Chief Financial Officer after our formal remarks.

We will conduct a question and answer session and instructions will follow at that time.

Joon So Lee: Earlier today, Taysha issued a press release announcing financial results for the second quarter and June 30, 2021. A copy of this press release is available on the company's website and through our SEC filings. Please note that on today's call, we will be making forward-looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational drug candidate. These statements may include the expected timing and results of clinical trials for our drug candidates and the regulatory status and market opportunities for those programs, as well as patient manufacturing plans.

Although today patient issued a press release announcing financial results for the second quarter ended June 30th 2021 copy of this press release is available on the company's website and through our SEC filings.

Please note that on today's call, we will be making forward looking statements, including statements relating to the safety and efficacy and the therapeutic and commercial potential of our investigational drug Kennedy.

These statements May include the expected timing and results of clinical trials for our drug candidates and the regulatory status and market opportunity for those programs as well as patient manufacturing plan.

Joon So Lee: This call may also contain forward-looking statements relating to Taysha's growth and future operating results, discovery and development of drug candidates, strategic alliances, and intellectual property, as well as matters that are not historical facts or information. However, various risks may cause patients' 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 and preclinical studies of our drug 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.

This call May also contain forward looking statements relating to patient growth and future operating results discovery and development of drug candidates strategic alliances and intellectual property as well as matters that are not historical facts or information.

Various risks may cause patients actual results could 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 and preclinical studies of our drug candidates.

Pendants upon our 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.

Joon So Lee: 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. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, August 16th, 2021. Taysha 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 law. With that said, I'd now like to turn the call over to our President, CEO, and Founder, R.A. Seshan II.

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.

This conference call contains time sensitive information that is accurate only as of the date of this live broadcast August 16th 2021 tissue undertakes no obligations 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 law.

With that I'd now like to turn the call over to our president and CEO and founder or a session. The second.

Mahdi Goudarzi: Thank you, Kim. Good morning, and welcome everyone to our second quarter financial results and corporate update conference call. Taysha continues to make significant progress on several key clinical manufacturing and strategic corporate initiatives, which were highlighted in our recent R&D and manufacturing investor meetings, as well as in our recent press release announcing our non-dilutive financing with Silicon Valley. I will elaborate on some of our recent key achievements and review the expected milestones for the remainder of 2021.

Thank you Kim good morning, and welcome everyone to our second quarter financial result, and corporate update conference call.

Can you still continues to make significant progress on several key clinical manufacturing and strategic corporate initiatives, which were highlighted at our recent R&D and manufacturing and the extra day as well as our recent press release announcing our non dilutive financing with Silicon Valley Bank.

I will elaborate on some of our recent key achievements and reviewed the expected milestones for the remainder of 2021.

Mahdi Goudarzi: Following this, I will turn the call over to Suyash and Kamran for updates on our pipeline development and financial results respectively. At our R&D day held in June, we presented positive data on a number of our key development programs. These data included phase 1 slash 2 visual acuity data for Taysha 120 in patients with gynecoma neuropathy, or GAN, genotypic-specific NECP2 expression data for Taysha 102 in Rett syndrome, natural history data in GM2 gangliosidosis, preclinical data for Taysha 118 in CLN1, natural history data in CLN1 disease, along with clinical patient phenotype data and SIRF1-associated leases.

Following this I will turn the call over to Sue you shouldn't camry for updates on our pipeline development and financial results respectively.

At our R&D day held in June we presented positive data on a number of our key development programs.

These data included phase one slash two visual acuity data for <unk> 120 in patients with giant experimental Robert or Gan.

Genotypic specific NEC P. Two expression data for <unk> 102, and breath syndrome.

Natural history data <unk> Gangliosidosis preclinical data for <unk>.

In Seattle, and one natural history data and ceiling, one disease, along with clinical patient phenotype data and surf one associated with syndrome.

Mahdi Goudarzi: We also disclosed the positive effects of Taysha 105 on seizures and associated deaths in SLC 1385 knockout mice. The Effects of Taysha-103 on Abnormal EEG Activity in SLC-6A1, Knockout, and Heterozygous Mouse Models, and preclinical data for Taysha 112 in APBB and Taysha 111 Leporin and Taysha 111 Malin Lastly, we disclosed the effects of Taysha-113 on tau expression in MAP-T-Associated Tau Operations and our two novel approaches for the treatment of Angelman syndrome. See you shall review these pipeline developments shortly.

We also disclosed the positive effects of patient one O far on seizures and associated deaths and that's healthy 13 day by knock out months.

The effects of patient one O three an abnormal EEG activity and S. O C fixed day, one knockout and heterozygous mouse models.

And preclinical data for Tisha 112, and a P. B D N Pasha 111.

In case, you're 111 knowledge and look for disease last.

Lastly, we disclosed the effects that patient 113 on Tau expression and that T associated telepathy.

And our two novel approaches for the treatment of Angelman syndrome.

So you should review these pipeline developments shortly.

Mahdi Goudarzi: Part of our success relies on robust, sustainable, and high-quality manufacturing to support our portfolio, and we are pleased to announce that we have achieved several successful GMP runs that further support our five planned Phase 1-2 clinical trials and numerous INB-CTA enabling studies. In July, we held a Manufacturing Day to highlight how our flexible and scalable approach, which seamlessly integrates R&D and manufacturing, de-risks our overall portfolio and supports consistent delivery of high-quality clinical materials across our broad pipeline. Our three-pillar approach to manufacturing includes dedicated capacity at UT Southwest, a collaboration with Paragon, a subsidiary of Cadillac, and the development of our internal manufacturing facility.

Part of our success relies on robust sustainable and high quality manufacturing to support our portfolio and we are pleased to announce that we have achieved several successful GMP runs that further support our five planned phase one slash two clinical trials and numerous INV life Cta, enabling study.

Yes.

In July we held a manufacturing day to highlight how our flexible and scalable approach, which seamlessly integrates R&D and manufacturing derisked, our overall portfolio and supports consistent delivery of high quality clinical material across our broad pipeline.

Our three pillar approach to manufacturing includes dedicated capacity at Ut southwestern.

Collaboration with Paragon, a subsidiary of Cadillac and the development of our internal manufacturing facility.

Mahdi Goudarzi: We continue to make progress on the construction of our multi-product facility in Durham, North Carolina, which will have 2,000 liters of capacity. Additionally, the capacity at UT Southwestern is expected to increase from 500 liters to 700 liters by the end of the year, which will continue to support our IND enabling and early clinical trial efforts and ensure high quality, efficient, and accessible production for our population. In order to further our mission in the development of novel gene therapies for the treatment of monogenic diseases of the CNS, we recently became a founding member of the newly formed Rare Disease Company Coalition.

We continue to make progress on the construction of our multi product facility in Durham, North Carolina, which will have 2000 liters of capacity.

Additionally, the capacity at UT southwestern is expected to increase from 500 leader to 700 liter scale by the end of the year, which will continue to support our IMD, enabling and early clinical trial efforts and ensure high quality efficient.

And accessible production for our pipeline.

In order to further our mission and the development of novel Gene therapies for the treatment of monogenic diseases of the CNS.

We recently became a founding member of the newly formed rare disease Company coalition.

Mahdi Goudarzi: A first-of-its-kind alignment of life science companies committed to discovering, developing, and delivering rare disease treatments We look forward to working together to expedite the delivery of our transformative affairs to the millions of patients with rare diseases. In the second half of this year, we expect numerous value-creating preclinical, clinical, and regulatory milestones. Recently, we had a number of meetings with multiple regulatory agencies regarding our Rett syndrome, GM2 gangliosidosis, and CLN1 disease programs as we prepare for IND slash CTA. I am pleased to share that we have received positive feedback from these agencies that paved the way for multiple anticipated IND-CTA filings in the second half of this year.

A first of its kind alignment of life science companies committed to discovering developing and delivering rare disease treatments.

We look forward to working together to expedite the delivery of our transformative therapies to the millions of patients with rare diseases.

In the second half of this year, we expect numerous value, creating preclinical clinical and regulatory milestones recently, we have had a number of meetings with multiple regulatory agencies regarding our ret syndrome, <unk> gangliosidosis and feeling one disease programs as we prepare for.

<unk> slash PTA submission.

I am pleased to share that we have received positive feedback from these agencies that paved the way for multiple anticipated INV flash Cta filing in the second half of this year.

Mahdi Goudarzi: For Taysha 120, we are pivotal stage product candidates in GAN. We anticipate data from the high-dose cohort in the second half of this year and expect to provide a regulatory update by year end. For GM2 gangliosidosis, we remain on track to report first-in-human safety and hexa biomarker data in the second half of this year.

For tissue 120.

Our pivotal stage product candidate and Gan, we anticipate data from the high dose cohort in the second half of this year and expect to provide a regulatory update by year end.

For <unk> Gangliosidosis, we remain on track to report first in human safety and hexane biomarker data in the second half of this year.

Mahdi Goudarzi: For our CLN1 program, which currently has an open IMD, we anticipate dosing the first patient in our phase one slash two trial in the second half of this year. Collectively, by year end, we anticipate that we will have five programs in clinical development. The rapid advancement of our numerous candidates would not be possible without the support of our dedicated and talented team. We recently appointed Mary Newman as Chief Development Officer. She was a former Senior Vice President of Regulatory Affairs at Estella's Gene Therapies, formerly Audentes, and brings over 30 years of experience in translational development, program management, and regulatory affairs.

For our ceiling one program, which currently have an open eye and B, we anticipate dosing of the first patient.

Phase one slash two trial in the second half of this year.

Collectively by year end, we anticipate that we will have five programs in clinical development.

The rapid advancement of our numerous candidates will not be possible without the support of our dedicated and talented team. We recently appointed Mary Newman as Chief Development Officer.

She was a former senior vice President of regulatory affairs at Astellas gene therapies, formerly our dentists and brings over 30 years of experience in translational development program management and regulatory affairs at.

Mahdi Goudarzi: At Taysha, we now have 155 employees, in addition to 70 colleagues at UT Southwestern across multiple functional areas, including discovery, translational development, GMP manufacturing, and clinical care. The collective expertise and dedication across these teams, including our seasoned board of directors, an independent, internationally renowned scientific advisory board, uniquely positions the expedited development of our gene therapy candidates and our technology. We have ambitious corporate objectives planned over the next 12 to 18 months.

Ah patients. We now have 155 employees. In addition to 70 colleagues at Ut southwestern across multiple functional areas, including.

Discovery translational development, GMP manufacturing and clinical care.

<unk> expertise and dedication across these teams, including our seasoned board of directors and independent internationally renowned scientific advisory board uniquely positions. The expedited development of our gene therapy candidate and our technology platform.

We have ambitious corporate objectives planned over the next 12 to 18 months.

Mahdi Goudarzi: And we are very pleased to have recently entered into a non-dilutive term loan agreement with Silicon Valley Bank that provides Taysha with up to $100 million in non-dilutive financing at an attractive interest rate that lowers our overall cost of capital, bolsters our cash position, and provides additional financial and operational flexibility. We believe full drawdown of this funding will extend our cash runway to support key value-creating milestones, including the release of Phase I-II data from the highest-dose cohort in GAM and Phase 1-2 data in GM2 ganglioside dosing.

And we are very pleased to have recently entered into a non dilutive term loan agreement with Silicon Valley Bank that provides acacia with up to $100 million and non dilutive financing at an attractive interest rate.

That lowers our overall cost of capital bolsters, our cash position and provides additional financial and operational flexibility.

We believe full drawdown at this funding will extend our cash runway to support key value, creating milestones, including the release of phase one slash two data from the highest dose cohort in Gan and phase one slash two data and GMP gangliosidosis.

Mahdi Goudarzi: CLN1 disease, and importantly, a potential regulatory approval for CASA 120, NGAN, without the need for additional financing. We look forward to updating you on our continued progress throughout the remainder of the year, including at our upcoming virtual investor miniseries for our CLN1, Rett Syndrome, and Angel Syndrome programs, where we will feature presentations from key opinion leaders and highlight progress made today. I will now turn the call over to Suyash to provide a more detailed update on our R&D initiatives. Suyash, please go ahead.

Feeling one disease.

And ret syndrome, and importantly, a potential regulatory approval for <unk> 120 in game without the need for additional financing.

We look forward to updating you on our continued progress throughout the remainder of the year, including at our upcoming virtual Investor Mini series for our ceiling, one ret syndrome, and Angelman syndrome programs, where we will feature presentations from key opinion leaders and highlight progress made.

To date.

I will now turn the call over to <unk> to provide a more detailed update on our R&D initiatives Jewish. Please go ahead.

Mahdi Goudarzi: We have made significant progress in the second quarter and continue to achieve important clinical advancements that further support a potential regulatory approval of our most advanced program, Taysha 120, which holds significant promise for patients with giant ancellular neuropathy or GAM. At our R&D day, in addition to the compelling clinical data demonstrating halting of disease progression as assessed by the well-validated and established motor assessment tool, the MFM32, we presented new visual acuity data from the ongoing Phase 1-2 trial investigating Taysha 120 in patients with GAM.

Thanks, Alright.

We have made significant progress in the second quarter and continues to achieve important clinical advancements that further support the potential regulatory approval of our most advanced program tissue in 'twenty.

Which holds significant promise for patients with giant ASO neuropathy whole GAAP.

Our R&D day in addition to the compelling clinical data demonstrating culture of disease progression as assessed by the well validated and established motor assessment tool.

<unk> 32, we presented new visual acuity data from the ongoing phase one two trial investigating tissue in 'twenty and patients with GAAP.

Mahdi Goudarzi: In children and adolescents with GAN, there is an ongoing and progressive deterioration in vision towards blindness, which is understandably one of the most challenging and upsetting symptoms from the perspective of the patient and family. With this new data, we were able to demonstrate a dose-dependent trend towards stabilization of visual acuity, i.e., the ability of AAV9 gene therapy to preserve visual function, which otherwise would be lost.

And children and adolescence with GAAP, there is an ongoing and progressive deterioration and vision towards blindness, which is understandably one of the most challenging and assessing symptoms from the perspective of the patient and family.

With this new data, we were able to demonstrate dose dependent trend towards stabilization.

Visual acuity.

The ability of AAV non gene therapy to preserve visual function, which otherwise would be lost.

Mahdi Goudarzi: We also discussed in depth the natural history data in GAN that was published in the highly regarded neurology journal Brain earlier this summer. As a reminder, all GAN natural history data was generated and supported by the National Institute of Neurological Disorders and Stroke, or NINDS, under the leadership of Principal Investigator Carsten Bonham. Included in the publication was the largest cohort of genetically confirmed patients with early and late onset forms of GAM.

We also discussed in depth the natural history data again, it was published in the highly regarded neurology journal rain earlier this summer.

As a reminder, all GAAP natural history data was generated and supported by the National Institute of neurological disorders, and stroke or <unk> under the leadership of the principle investigator coston a bonds.

Included in the publication was the largest cohort of genetically confirmed patients with early and late onset forms of GAAP.

Mahdi Goudarzi: This large cross-sectional analysis highlighted clinical differences between patients with early-onset versus late-onset GAM based on performance on the MFM32, a validated and well-known scale to measure strength and motor function, as well as other functional motor scales and disease markers. Additionally, a robust assessment of many clinically relevant outcome measures for GANLs was performed, including motor, sensory, respiratory, neurophysiologic, MRI, and biopsy assessments. Moreover, this was the first clinical study ever to formally and comprehensively evaluate autonomic nervous system dysfunction in a cohort of individuals with GAM.

This large cross sectional analysis highlighted clinical differences between patients with early onset versus late onset GAAP based on performance on the <unk> 32.

Dated unwellness scale to measure strengths and motor function as well as other functional motor scales and disease markers.

Additionally, a robust assessment of many clinically relevant outcome measures for downloads performed including multiple sensory respiratory neurophysiology.

Try and pharmacy assessments.

Moreover, this was the first clinical study of <unk>, formerly and comprehensively evaluate autonomic nervous system dysfunction, and a cohort of individuals with GAAP.

Mahdi Goudarzi: Overall, this natural history study has been instrumental in clinical trial design for the ongoing phase 1-2 trial, and the data included in the BRAIN publication will serve as baseline data for the natural history comparator arm to the interventional study. As already noted, we remain on track to report clinical data. ...from this ongoing Phase 1-2 trial in the second half of this year and to provide a regulatory update on the program by year end.

Overall this natural history study has been instrumental in clinical trial designs. The ongoing phase one two trial and the data included in the brain publication will serve as baseline data for the natural history comparator arm to the interventional study.

As already noted we remain on track to report clinical data from this ongoing phase one two trial in the second half of this year and to provide a regulatory update on the program by year end.

Mahdi Goudarzi: We've also made significant progress across our preclinical programs. Recently, positive preclinical data for Tayshia 102 in Rett syndrome was published in the journal Brain that provided quantitative evidence of MIRare's ability to exhibit genotype-dependent regulation of MeCP2 gene expression on a cell-by-cell basis across different regions of the brain in both wild type and knockout mouse models of Rett syndrome. We recently had productive and collaborative pre-IND CTA discussions with several key regulatory agencies and received positive feedback that supports our anticipated IND CTA submission in the second half of this year.

We've also made significant progress across our preclinical programs.

Positive preclinical data rotation will now to address syndrome was published wholesale and the journal brain that provided quantitative evidence of <unk> ability to exhibit genotype dependent regulation of Mec, Pete two gene expression on a cell by cell basis across different regions of the <unk>.

Rain and west wall type and knockout mouse models of Ret syndrome.

We recently have productive and collaborative pre IMD CCA discussions with several key regulatory agencies and received positive feedback the support our anticipated ANZ Cta submission in the second half of this year.

Mahdi Goudarzi: In GM2 gangliosidosis, we were able to discuss in detail at our R&D day how the existing and in-depth natural history data on this condition informs us about disease progression and, in particular, motor development delays. We believe these data help provide a comparator for ongoing and future interventional trials. We continue to expect preliminary safety and biomarker data from the Queen's University Phase 1-2 trial for Taysha 101 in the second half of this year. Specifically, we will be disclosing HexA enzyme activity in serum and CSS, and expect that 5% HexA enzyme activity will be considered a positive result.

And GM to Gangliosidosis, we were able to discuss in detail at our R&D day at the existing.

In depth natural history data on this condition informs us about disease progression and in particular most of the development delays.

We believe these data to help fund the comparator for ongoing and future International trials.

We continue to expect preliminary safety and biomarker data from the Queen's University Phase one two trial for <unk> 101 in the second half of this year.

Specifically, we will be disclosing <unk> enzyme activity and serum CSS and expect a 5% expat enzyme activity will be considered a positive results.

Mahdi Goudarzi: In the US, we had a productive and informative meeting with the FDA. We remain on track to initiate a Phase 1-2 trial in the second half of this year. Moving on to our CLN1 program, additional preclinical data for Taysha 118 were presented at R&D Day, which demonstrated sustained preservation of motor function and rescue with higher doses of Taysha 118 and earlier intervention in CLN1 knockout mice. There are two ongoing natural history studies assessing CLN disease, which will help further our understanding of the disease, inform our clinical trial design, and serve as comparative data in a future trial for Tayshia 1.1a.

In the U S. We had a productive and informative meeting with the FDA.

We remain on track to initiate a phase one two trial in the second half of this year.

Moving onto a sale in one program additional preclinical data flotation at 118 were presented at R&D day, which demonstrated sustained preservation of motor function and the rescue with higher doses of <unk>, one one night and earlier intervention and sale and one knockouts.

Mice.

There are two ongoing natural history studies, assessing CLR disease, which will help further our understanding of the disease and form on our clinical trial design and serve as comparative data in a future trial sortation 118.

Mahdi Goudarzi: These two studies include a prospective observational study assessing the natural history of CLN diseases and a retrospective and prospective study to characterize the age at onset of major symptoms and the relationship between age and severity. Taysha118 currently has an open IND.

These two studies includes a prospective observational study assessing the natural history of sale and diseases and the retrospective and prospective study to characterize the Asia onset of major symptoms on the relationship between age outs severity.

Thanks, you one when they currently has an open <unk>.

Mahdi Goudarzi: We recently had very productive and collaborative meetings with several key regulatory agencies and positive feedback on the support dosing of the first patient, which we anticipate should occur in the second half of this year. Taysha 118 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Drug Designation from the FDA, and Orphan Medicinal Product Designation from the EMA for the treatment of CLN1 disease. For Taysha-104 and SIRF1-associated Lee syndrome, we announced at R&D Day new data demonstrating that only a small increase in COX-1 activity can significantly improve the clinical phenotype in these patients, further supporting our SIRF1 gene replacement strategy with KASIA 104.

We recently had very productive and collaborative meetings with several key regulatory agencies and positive feedback to support dosing of the first patient, which we anticipate should occur in the second half of this year.

<unk> has been granted orphan drug designation.

Pediatric disease designation and fast track designation from the FDA.

Orphan medicinal product designation from the EMA for the treatment of <unk> lung disease.

Potential when I fall in surf one associated Leigh syndrome, we announced at R&D day, new data demonstrating that only a small increase and Cox one activity can significantly improve the clinical phenotype disease patients further supporting offset form gene replacement strategy.

With <unk> when they fall.

Mahdi Goudarzi: Reduced COX activity also correlated with disease worsening in patient fibroblasts, further supporting the impact of COX activity on disease outcomes. This phenomenon draws correlations to other diseases that we are targeting, including GM2 and CLN1, where small increases in activity can have a pronounced physiological impact. We plan to file an IND CTA for Taysha 104 in the second half of this year.

Reduced Cox activity also correlated with disease worsening and patient fibroblasts further supporting the impacts of Cox activity on disease outcomes.

This phenomenon draws correlations to other diseases that we are targeting including GM to CLO, one while small increases in activity can have a pronounced physiological impact.

We plan to file a <unk> cta for tissue when they fall in the second half of this year.

Mahdi Goudarzi: Additionally, a natural history study that is part of our clinical development program is expected to enrol its first patient. This study will follow patients for an initial period of time prior to enrolment into the interventional trial. At our R&D day, Dr. Rachel Bailey, Assistant Professor in the Department of Pediatrics at UT Southwestern, presented positive preclinical data for Tayshia 105 in SLC13A5 deficiency that demonstrated improvement of EEG activity and reduction in seizures and associated deaths in SLC13A5 knockout mice.

Additionally, in natural history studies as part of our clinical development program is expected to enroll its first patient.

This study will follow patients for initial period of time prior to enrollment into the interventional trial.

At our R&D day Doctor Rachel Bailey Assistant Professor in the Department of Pediatrics at UT southwestern presented positive preclinical data for <unk> 105, and SLC <unk> deficiency that demonstrated improvements of EEG activity and reduction in seizures.

And associated deaths and SLC 35 knockout mice.

Mahdi Goudarzi: We continue to advance Taysha 105 towards the clinic and expect that patients currently enrolled in an ongoing prospective natural history study would be available to enter our clinical trial. We are currently considering an open-label, randomized, dose-escalation phase 1-2 trial to examine the safety, tolerability, and preliminary efficacy of Taysha 105 in the treatment of SLC13A5 deficiency. Biomarkers include citrate levels in the plasma, urine, and CSG.

We continue to advance tissue when they have five towards the clinic and expect the patients currently enrolled in the ongoing prospective natural history study would be available to enter a clinical trial.

We are currently considering an open label randomized dose escalation phase one two trial to examine the safety tolerability and preliminary efficacy of <unk> 105 for the treatment of <unk> deficiency.

Biomarkers includes citrate levels in the plasma urine CSF.

Mahdi Goudarzi: Moving on to Taysha 103 in SLC-601 haploid insufficiency disorder, at our R&D day, Dr. Kim Goodspeed, Assistant Professor in the Department of Pediatrics, Neurology, and Psychiatry at UT Southwestern, and Dr. Stephen Gray, Associate Professor in the Department of Pediatrics at UT Southwestern and Chief Scientific Advisor at Taysha, highlighted the nature of the disease and the positive pre In SLC-601 knockout and heterozygous mouse models, CNS administration of Taysha-103 rescued abnormal seizure activity. Notably, recently obtained positive data demonstrating rescue of functional measures such as nesting, open field activity, hind limb clasping, and latency to fall from the rotor arm.

Moving onto <unk>, 103, and <unk> 6001, <unk> insufficiency disorder.

R&D day, Dr. Kim good speed assistant professor in its farm to pediatrics, neurology and psychiatry at Ut southwestern and Doctor Stephen Gray Associate Professor in the department of Pediatrics, and Ut southwestern and Chief scientific adviser Acacia highlighted the nature of the disease and the pulse.

Preclinical data to date.

NFC <unk> knockouts Petro.

Heterozygous mouse models CNS administration of <unk> 103 rescued abnormal seizure activity.

Notably recently obtained positive data demonstrates rescue of functional measures such as nesting open field activity hind limb clasping on latencies for from the Rich Ross.

Mahdi Goudarzi: We are now evaluating dose and age response and finalizing the dose from our preclinical pharmacology experiments. We are also developing an interventional trial protocol. In APBD and Leuphora, Dr. Birj Minassian, Division Chief of Pediatric Neurology at UT Southwestern and Chief Medical Advisor at Taysha, provided an in-depth discussion about the nature of both diseases at our R&D day and highlighted positive preclinical data that support the advancement of these programs. Specifically, Taysha 112 reduced GYS1 expression in the APBD knockout model, which resulted in decreased polyglucoside body formation in mice brain.

We are not evaluating dose NIH response, and finalizing the dose from our preclinical pharmacology experiments.

We are also developing an intervention trial protocol.

And IP BD in La Fora sort of bearish Menasion division chief of pediatric neurology and Ut southwestern.

Yes.

Chief Medical device agitation provided an in depth discussion about the nature of both diseases at our R&D day and highlighted positive preclinical data that supports advancement of these programs specifically.

Specifically <unk> 112 reduced goyf's, one expression and the AP BD knockout model, which resulted in decreased poly glitches on body formation in my brain.

Mahdi Goudarzi: Taysha 111 leuphorin and Taysha 111 malin reduced GYS1 expression in the leuphorin and malin knockout models, which resulted in decreased leuphora body formation in mice brains. We continue to make good progress on both programs and are currently developing an interventional trial protocol. Preclinical data for Tayshia 1.1.3 in tauopathies presented at R&D Day demonstrated significant reduction in tau mRNA and protein levels, validating the potential use of AAV-mediated gene silencing to achieve lifelong reduction of tau protein levels and supporting further preclinical development for the treatment of tauopathies.

Thank you <unk> and Taishan 111, Mylan reduced goyf's, one expression and the foreign Mellon knockout models, which resulted in decreased before body formation in mice Brian.

We continue to make good progress on both programs and are currently developing an interventional trial protocol.

Preclinical data for <unk>, III and <unk> presented at R&D day demonstrated significant reduction in Tau mrna and protein levels validating the potential use of AAV mediated gene silencing to achieve lifelong reduction of Tau protein levels.

And supporting further preclinical development for the treatment of talent policies.

Mahdi Goudarzi: Lastly, we were very excited to highlight at our R&D day our novel approaches to treat Angelman syndrome. We are targeting the entire Angelman Syndrome population via knockdown of UBE3A-ATS to unsilence the paternal allele and also using a gene replacement strategy on UBE3A to mimic the maternal UBE3A allele expression. We have shown compelling fluorescence images of the cerebellum that demonstrate UBE3 expression following administration of Tayshia 106, our short hairpin RNA candidate.

Lastly, we were very excited to highlight at our R&D day on novel approaches to treat Angelman syndrome.

We are targeting the entire Angelman syndrome population via knockdown of <unk> Ats to unsigned list the personal allele.

And also using a gene replacement strategy on <unk> to mimic the maternal <unk> allele expression.

We have shown compelling fluorescence images of the cerebellum that demonstrates <unk> expression. Following administration of tissue. One six are short hairpin RNA candidates.

Kamran Alam: As you can see, our robust portfolio of clinical and preclinical candidates continues to advance expeditiously, and, as already noted, we have a number of clinical and regulatory catalysts expected in the second half of the year. We will continue to provide updates on our programs throughout the year. With that, I'll turn the call over to Kamran to review our financial results.

As you can see a robust portfolio of clinical and preclinical Kansas continues to advanced expeditiously and as already noted we have a number of clinical and regulatory catalysts expected in the second half of the year.

We will continue to provide updates on our programs throughout the year.

With that I'll turn the call over to Cameron to review our financial results.

Kamran Alam: Thank you, Suyash. This morning, I will discuss our recent non-dilutive financing and key aspects of our second quarter 2021 financial results. More details can be found in our Form 10-Q, which will be filed with the SEC shortly. We recently secured a non-dilutive term loan financing for up to $100 million from Silicon Valley Bank, or SVB, with $40 million available at closing, of which Taysha has drawn $30 million. We have the option to draw down the remaining tranches subject to certain conditions. The interest rate is the greater of 7% or the Wall Street Journal prime rate plus 3.75%.

Thank you <unk>. This morning, I will discuss our recent non dilutive financing in key aspects of our second quarter 2021 financial results more.

More details can be found in our Form 10-Q, which will be filed with the SEC shortly.

We recently secured a non dilutive term loan financing for up to $100 million from Silicon Valley Bank or SBB with $40 million available at closing of which Tisha has drawn $30 million, we have the option to draw down the remaining tranches subject to certain conditions the.

The interest rate is the greater of 7% or the Wall Street Journal Prime rate, plus 375% and there are no financial covenants or warrants associated with this financing.

Kamran Alam: And there are no financial covenants or warrants associated with this financing. We believe that full drawdown of this funding will extend our cash runaway through multiple key value-creating milestones, including a potential regulatory approval of Taysha 120 in GAN without the need for additional financing. Moving on, as indicated in our press release today, R&D expenses were $30.6 million for the three-month ended June 30, 2021, compared to $3.1 million for the three-month ended June 30, 2020.

We believe that full drawdown of this funding will extend our cash runway through multiple key value, creating milestones, including a potential regulatory approval of <unk> hundred 20, and Gan without the need for additional financing.

Moving on as indicated in our press release today R&D expenses were $30.6 million for the three months ended June 32021, compared to $3.1 million for the three months ended June 32020, the $27.5 million increase was primarily attributable to an increase of $10.3 million.

Kamran Alam: The $27.5 million increase was primarily attributable to an increase of $10.3 million in expenses incurred in research and development, manufacturing, and other raw material purchases, which included CGMP batches produced by Catalant and UT Southwest. We incurred an increase in employee compensation expenses of $8.5 million, which included $2.2 million of non-cash stock-based compensation and $8.7 million in third-party research and development expenses, which include clinical trials, CRO activities, GLP toxicology studies, and consulting for regulatory and clinical studies.

Of expenses incurred in research and development manufacturing and other raw material purchases, which included see GMP batches produced by <unk> and Ut southwestern.

We incurred an increase in employee compensation expenses of $8.5 million, which included $2.2 million of noncash stock based compensation and $8.7 million in third party research and development expenses, which include clinical trials CRO activities, GOP toxicology studies and consulting for regulatory and <unk>.

Kamran Alam: G&A expenses were $10.1 million for the second quarter ended June 30, 2021, compared to $0.9 million for the second quarter ended June 30, 2020. The increase was primarily attributable to incremental compensation expense, which included non-cash stock-based compensation and additional consulting and professional fees. The net loss for the second quarter ended June 30, 2021, was $40.9 million, or $1.09 per share, as compared to a net loss of $21.2 million, or $1.95 per share, for the second quarter ended June 30, 2020. As of June 30, 2021, Taysha had $197.4 million in cash and cash equivalents. This does not include funds from the recently announced debt relief.

Clinical studies.

G&A expenses were $10.1 million for the second quarter ended June 32021, compared to <unk> $9 million for the second quarter ended June 32020 the.

The increase was primarily attributable to incremental compensation expense, which included noncash stock based compensation and additional consulting and professional fees.

Net loss for the second quarter ended June 32021 was $40.9 million or $1.90 per share as compared to a net loss of $21.2 million or $1.95 per share for the second quarter ended June 32020.

As of June 30 of 2021 tissue had $197.4 million in cash and cash equivalents. This does not include funds from the recently announced debt financing.

Mahdi Goudarzi: And with that, I will hand the call back to RA.

And with that I will hand, the call back to Ara.

Thanks, Cameron we are pleased to have shared with you our success over the second quarter looking ahead.

Mahdi Goudarzi: We are pleased to have shared with you our success over the second quarter. Looking ahead. We will continue our focus on advancing our pipeline expeditiously and executing on key anticipated milestones in the second half of 2021. We reiterate guidance for the expected clinical, regulatory and pre-clinical milestones in the second half of 2021, including reporting data from the highest dose cohort from the Phase 1-2 Taysha 120 study in GAN, providing a regulatory update for the GAN program, reporting preliminary Phase 1-2 safety and biomarker data for Taysha 101 in GM2 gangliosidosis, and initiating Phase 1-2 trials in CLN1 disease, Rett syndrome, and SIRK1-associated lesions.

We will continue our focus on advancing our pipeline expeditiously and executing on key anticipated milestones in the second half of 2021.

We reiterate guidance for the expected clinical regulatory and preclinical milestones in the second half of 2021, including reporting data from the highest dose cohort from the phase one flash to patient 120 study and Gan, providing a regulatory update for the Gan program reporting preliminary.

Phase one flash to safety and biomarker data for <unk> 101 in GMP, Gangliosidosis and initiating phase one class II trials and feeling one disease Ret syndrome, and third point associated Leigh syndrome.

Mahdi Goudarzi: I would like to give special thanks to the continued support and dedication of our Taysha employees, Board of Directors, Scientific Advisory Board, collaborators, UT Southwestern, and the patients and advocates who remain our motivation every day to continue our mission to develop curative gene therapy. I will now ask the operator to begin our Q&A session. Thank you.

I would like to give special thanks to the continued support and dedication of our patient employees Board of directors Scientific Advisory Board collaborator Ut southwestern and the patients and advocates who remain our motivation everyday to continue our mission to develop curative gene therapy.

I will now ask the operator to begin our Q&A session operator.

Thank you at this time, we'll be conducting a question and answer session. If you'd like to ask a question. Please press star one on your telephone keypad.

Operator: At this time, we'll be conducting a question-and-answer session. If you'd like to ask a question, please press Star 1 on your telephone key. Your confirmation tone will indicate your line is in the question. You may press start.

A confirmation tone will indicate your line is in the question Kim you.

You May press star two if you'd like to remove your question from the queue for participants using speaker equipment. It may be necessary to pick up your handset before pressing the star keys.

Operator: Thank you. At this time, we'll be conducting a question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. In the interest of time, we ask that you each keep to one question and one follow-up. Thank you. Our first question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question.

The interest of time, we ask that you each keep to one question and one follow up thank you.

Our first question comes from the line of solving Richter with Goldman Sachs. Please proceed with your question.

Hey, good morning, guys and thank you for taking our question. This is Elizabeth <unk> for <unk> I just wanted to ask if you could provide a little bit more color on the nature of the pre IMD and Cta positive feedback you've gotten from regulatory agencies and then just I guess more broadly what are some of the venues that tisha could present the data.

And two in the second half of 2021, and just patients approach to data releases on the forward.

Mahdi Goudarzi: Sure, thanks, Elizabeth, and good morning. What I'll do is I'll take the first question and then, I'm sorry, I'll take the second question, and then we'll throw the first question to Suyash to give some color on some of our recent discussions with regulators. Essentially, our approach to releasing data is either gonna be primarily through a press release or doing an investor call. As you recall, we've done a number of these mini investor days over the last few months.

Sure Thanks, Elizabeth and good.

Morning, what I'll do is I'll take the first question and then I'm sorry, I'll take the second question and then we'll throw the first question to Cvs to give some to give some color around some of our recent discussions with regulators essentially our approach to releasing data, it's either going to be primarily through press release or an or doing.

<unk> Investor call.

As you recall, we've done a number of kind of these mini investor days over the last few months.

Mahdi Goudarzi: The first was our R&D day. The second was a manufacturing day. We have the CLN1 investor day coming up here in the next few weeks, and that'll be followed by our Rett Syndrome investor day and then our Angelman investor day. And so, depending on the timing of when the data is gonna be available to release, we're either gonna do it through a press release, which we would obviously do it through a press release anyway, but to provide some additional color, we may do a call around that

First is our R&D day, the second was a manufacturing day, we have the scale and one investor day coming up here in the next few weeks and that'll be followed by a Red syndrome Investor Day, and then our Angelman Investor day and so.

<unk> on the timing of when the data.

It's going to be available to release that we're either going to do it through a press release, which we would obviously press release, but anyway, but but.

To provide some additional color we may do a call around that as well so more to come but but certainly exciting times for the second half of the year.

Mahdi Goudarzi: So, more to come, but certainly exciting times for the second half of the year. Suyash, maybe you wanna provide just some general color around some of our regulatory interactions over the last few months, primarily the number of interactions that we've had over the last few months. Yeah. All right. And thanks for the question, Elizabeth.

Maybe you want to provide just some general color.

Around some of our regulatory.

Interactions over the last few months.

Primarily the number.

Of interactions that we've had over the last few months yes.

Yeah. Thanks, Alright, thanks for the question Elizabeth.

Mahdi Goudarzi: Thanks for the question, Elizabeth. We've had a very, very hectic schedule of regulatory activity over the past few months, and that was purposeful. As you know, with our approach to regulatory engagement, we file in multiple jurisdictions for each of our programs. So we've probably had close to 10 regulatory interactions, which include the FDA and several other countries. And in general, they've been very, very good. The tone has been collegial. We've been able to answer all their questions, and there have been very few surprises along the way.

We've had a very very high.

Schedule of regulatory activity over the past few months and that was purposeful.

As you know with our approach to regulatory engagements.

Falling in multiple jurisdictions for each of our programs. So we probably have close to 10 regulatory interactions.

Included the FDA and several other countries and in general they have been very very good the tender has been collegial.

We've been able to answer all the questions.

<unk> been very few surprises along the way.

Mahdi Goudarzi: You know, I think it would be fair to say that the actual discussions themselves have been very successful. We focused on a few topics of note, and I'll bucket them into three categories. One is CMC, and the last part of that is potency assay testing.

I think we it would be fair to say that the actual discussions themselves.

We focus on a few topics.

Of note.

Okay into three categories one is CMC.

And the last otherwise potency assay testing once again, we have a very similar approach across all programs kind of desk very disciplined way.

Mahdi Goudarzi: And once again, we have a very similar approach across our programs. We have a very rigorous way of looking at potency. We start all the work early, so that discussion goes well, and there are no general surprises there. On the non-clinical side, we have a very robust package of toxicology across all our programs, which include a combination of mouse, chronic tox, RAP, six-month tox, and NHP tox, which could be three to six months.

Im looking at pregnancy, we stockholder with early so that discussion goes well and there's no general.

No general.

Surprises that are going.

On the clinical side.

Have a very robust package of toxicology across all our programs, which include a combination of mouse.

Correlate talks rat.

Rat six month talks and HP talks, which could be three to six months and in general most of the agents are very favorable there is a few slight differences in what the expectations are some agencies want a little more incentive species and the duration of time on some agencies want a little bit less and possibly although the FDA.

Mahdi Goudarzi: And in general, most of the agencies are very favorable to it. There are a few slight differences in what the expectations are, i.e., some agencies want a little more in terms of species and duration of time, and some agencies want a little bit less.

Mahdi Goudarzi: And as we all know, the FDA tends to be a little more conservative. But once again, our plans are very robust and comprehensive. So the multiple agencies are generally very favorable to those, and the third bucket of questions usually tends to be around clinical study design and endpoints. And once again, we give a lot of thought to our endpoints. We weave in feedback from patients and families, and feedback from key opinion leaders. And we write the protocols in a very disciplined way. We make sure that the majority of our developmental progression assessments are videos.

Spent a little more conservative, but once again, our plans are very robust and comprehensive so the.

The multiple agencies are generally very favorable for those and the third bucket of questions usually tends to be around clinical study design and endpoints and once again, we have we give a lot of thought to our endpoints.

We have been feedback from patients and families feedback from key opinion leaders and we wanted the price goes with a very disciplined way, we make sure that the majority of our developmental progression assesses all videos and.

Mahdi Goudarzi: And that adds a little bit of robustness to the studies. And so once again, those discussions went well also. So lots of interactions, lots of very good interactions, and we have a few more yet to come. But I would say that there have been really very few surprises, and the engagement has been collegial and very positive thus far. In fact, one of the agencies even said to us at the last meeting, you know, well, we're looking forward to seeing you next time. So, you know, I think that that really just indicates the tone of the conversation.

So a robustness to the studies once we have those discussions go well also so lots of lots of interaction. So lots of very good interactions that we have a few more yet to come but I would say that there has been really very little surprises and the engagements been collegial and very close to thus far and Thats one of the agencies and said to us.

At the last meeting.

But we're looking forward to seeing you next time.

But that's really just signifies the tone of the conversations.

Yeah.

Great. Thank you so much.

Thank you. Our next question comes from the line of Joon Lee with true Securities. Please proceed with your question.

Operator: Thank you. Our next question comes from the line of Joon Lee with Truist Securities. Please proceed with your question.

Hi, Thanks for taking our questions.

For the update.

For the Ret syndrome, which is a relatively larger indication and a really interesting one you guided to clinical data by year end 'twenty, two but no mention of any biomarker data.

Joon So Lee: Hi, thanks for taking our questions and for the update. [inaudible] Data released in the press release. Are you planning to skip the biomarker data disclosure altogether in favor of the initial clinical data? This one just came in. Are you planning to skip the biomarker data disclosure altogether in favor of the initial study?

Releasing the press release are you skipping are you planning to skip the biomarin data disclosure altogether in favor of the initial clinical data.

Joon So Lee: This one just stood out to us given the planned biomarker data disclosures for the other programs. And also, is your microRNA active response element something that is patented, or is this more of a, you know, protected by, you know, in-house know-how? And I have a quick follow-up after that.

Just stood out to us given the planned biomarker data disclosures for the other programs and also is Europe micro RNA at Covid response element is something that is patented.

Or is this more of a.

Protected by.

In house, Knowhow and I have a quick follow up after that thank you.

Mahdi Goudarzi: Sure, well, I can take the question on the biomarker data, and then R.A. can talk about the IP. With regard to the biomarker data, you know, it's a great question, Joon. I really wish we had a good biomarker for Rett syndrome. Many, many scientists and expert clinicians and physician scientists have been looking for a biomarker for this particular disease, but sadly, there isn't a good blood-based biomarker or a good CSF biomarker.

Joe will often take the I'll take the question on the biomarker data and then alright can talk about the IP.

Sure with regard to the with regards to the biomarker data.

It's a great question do I really wish we have a good biomarker for ret syndrome. Many many scientists.

Expert clinicians patients physician signs have been looking for a biomarker for this particular disease, but the fact that there isn't a good blood based biomarker or a good CSF biomarker.

Mahdi Goudarzi: You know, I think with regard to biomarkers, the best biomarker that we have, which is not very good, is probably EEG. You know, the EEGs of children with Rett are abnormal, and it's possible that we'll see a modification in the EEG as an early read on the biomarker of activity of the drug. But it's not really a very good, very established, very robust, well-accepted biomarker, which is why we don't specifically guide that biomarker data.

I think with regard to Biomarkers the best Biomarkers.

We have which is not.

I'm not very good is probably AEG the cheese of children with retro abnormal and it is possible that we'll see a modification in the EG as an early read.

On the biomarker.

<unk> activity of the drug.

But theres not not really a very good very established very robust well accepted biomarker, which is why without specific guidance that biomarker data that if something looks interesting early we'll plan to share it.

Mahdi Goudarzi: But if something looks interesting early, we will plan to share it. I mean, I think the best hope for RET is really to see what we see from a safety perspective and then from an efficacy perspective thereafter. We are, however, collecting blood and CSF and performing full metabolomics and proteomics analyses. So if something does crop up as an interesting and useful biomarker, then we will see it there. I don't hold much hope for that, frankly, because many, many experts have been looking for a biomarker for a long time. So ultimately, we are guided to start the study by the end of this year and collect clinical data by the end of the 20th, and I'll hand over to RA now for the IP questions.

I think I think the best type of racks is really to see what.

What we see from a safety perspective.

With respect to prospective buyer Axa, we are however, collecting blood and CSF and performing full method below mix of proteomics analysis. So if something does Copa is an interesting and useful biomarker that we will see it.

I don't hold much hope for that frankly, because many many experts who have been looking for biomarker.

For a long time, so ultimately we do we our guidance is.

Enrolling the study of stuff in the study by the end of this year and clinical data by the end of 2022.

And I'll hand over to Ara.

IP question.

Mahdi Goudarzi: Sure. Thanks, Suyash and Joon. Thanks for the question. Good morning.

Sure. Thanks variation in June Thanks for the question good morning.

So our <unk> platform is covered by strong intellectual property, we're pretty excited about that and the broad applicability of the platform to not only.

Mahdi Goudarzi: So, our miRARE platform is covered by strong intellectual property. We're pretty excited about that and the broad applicability of the platform to not only show genotypic MeCP2 expression on a cell-by-cell basis but also the ability to exploit this platform for other indications where there may be a dose-sensitive nature to the protein. And so, there's a really nice correlation to this in a lot of other disease areas, Fragile X being one of them, Angelman being another, Pitt Hopkins, and FOXG1.

Show Genotypic.

Net <unk> expression on a cell by cell basis, but also the ability to exploit this platform for other indications, where there may be a dose sensitive nature to the protein and so there is a really nice correlation to there isn't a lot of other disease areas <unk> being one of them Angel maybe in another pit Hopkins.

Fox G. One there's so there's a number of these where you have the potential to either use the vaccine.

Mahdi Goudarzi: So, there are a number of these where you have the potential to either use the exact same microRNA binding sites to build another transgene or to pick a new subset of microRNA binding sites depending on the disease itself.

Micro RNA binding sites to build into another transgene or to pick a new subset of micro RNA binding sites two depending on the disease itself. So we're actually pretty excited about it I think it is something that significantly differentiates our approach to others and if you recall our approach to.

Mahdi Goudarzi: So, we're actually pretty excited about it. I think it is something that significantly differentiates our approach from others. And if you recall, our approach to gene therapy is really to use validated gene therapy technology, coupled with very targeted payload design. So, the validated piece, AAV9, intersecal delivery, HEK293 suspension, but really innovate around payloads. And my rare disease being an important piece of that. And so, as we continue to build out the data set in other disease areas, obviously, we'll continue to expand our IPS data around

<unk> therapy is really to use a validated gene therapy technology.

Coupled with very targeted payload design for the validated piece AAV nine interruptible delivery had 293 suspension, but really innovate around payloads and I rare being accordant piece of that and so.

As we continue to build out the data set in other disease areas. Obviously, we will continue to expand our IP estate around that.

Mahdi Goudarzi: And just a quick follow-up. For all your programs, given they all use the AAV9 vector, are your starting doses for all the other programs comparable, and is your dose escalation strategy also comparable between programs?

Excellent. Thank you and just a quick follow up for all your program given they all use the AAV vector.

Youre starting dose for all the other programs comparable and Asia are in dose escalation strategy also comparable between programs. Thank you really really really really good question and I think it speaks to this platform approach and again our approach to.

Mahdi Goudarzi: [inaudible] Sure, I can. It's a very good question.

Our approach to using kind of validated technology and using that and exploring that in multiple indications. So just maybe you want to give some thoughts there.

Mahdi Goudarzi: Sure I can, it's a very good question, and in general, I would say yes. We are approaching the first dose for each patient in each program. We're ending up in a relatively similar ballpark of around 5E14 total VG, which as you know is a high dose being directed to the brain and spinal cord but a low dose in terms of systemic exposure in comparison to systemic drugs which are dosed to VG per kilo.

Sure I can it's a very good question and in general I would say, yes, we are.

Approaching the first dose for.

Each patient in each program.

We ended we ended up in a relatively similar ballpark of around <unk> 14, total VGA, which as you know is a high dose.

Alright, the brain and spinal cord with a low dose in terms of systemic exposure.

And congrats to systemic drug you should test Vg per kilo.

Mahdi Goudarzi: Where I would say the programs differ a little bit is how aggressively we can accelerate or escalate the doses thereafter, and that depends on a couple of things really. The most important thing it depends on is the therapeutic window that we have, and for several of our programs, we actually have a very broad therapeutic window, for example, CRM1 or GM2, where you have a secreted enzyme so where you actually can, a little bit of enzyme goes a long way, but on the converse side, actually overproducing enzyme in superphysiological quantities actually has no impact that's detrimental whatsoever.

What I would what I would say the program is just a little bit is how aggressively we can.

With accelerate to escalate the dose as director and it depends on a couple of things really the most important thing it depends on is the therapeutic window that we have and for several of our programs. We actually have a very cruel therapeutic window for example, sale and one with GM to where you have a secrete enzyme.

You actually can.

With the vendor side Theres, a long way, but on the converse side actually over producing enzyme it's super physiological quantities actually has no impact that's detrimental whatsoever. So for those programs, we can accelerate and escalate the dosing quite rapidly. But then there are programs such as rats, whereas you know because of relatively narrow therapeutic.

Mahdi Goudarzi: So for those programs, we can accelerate and escalate the dosing quite rapidly, but then there are programs such as RET where, as you know, there's a relatively narrow therapeutic window, and we have to be a little bit more cautious in accelerating or escalating the dose. Despite the fact that we have the MIR platform, which self-regulates the proportion of MeCP2 that's being produced for RET. So I would say that we generally start in the same ballpark, but then as we escalate the doses higher, we do that at a slightly different rate dependent on the therapeutic window we have for each program.

Window, and we have to be a little bit more cautious and accelerating or escalations dose.

Despite the fact that we have the <unk>.

The MRI platform, which self regulates the proportion of <unk>, that's being produced for right. So I will say that generally starts in the same ballpark as we escalate the dose is higher we do that in a slightly different.

Right.

On the therapeutic window, we have for each program.

Operator: Thank you. Our next question comes from the line of Laura. Good morning, guys.

Thank you.

Thanks Joan.

Thank you. Our next question comes from the line of Laura Chico with Wedbush Securities. Please proceed with your question.

Laura: Thanks very much for taking my question. For my first question, I was just wondering if you could spend a minute on the loan agreement and perhaps why you think this makes sense now. And just wanted to clarify, how does that change the cash runway estimates? And then my follow-up, just around expectations for the 3, 5 E14 dose in GAN, you'd already seem to have an effect at lower doses. So just trying to understand which doses or doses would be advanced commercially. Thanks very much.

Hi, Good morning, guys. Thank you very much for taking my question. My first one I was just wondering if you could spend a minute on the loan agreement and perhaps why you think it makes sense now and just wanted to clarify how does that change the cash runway estimate and then my follow up just around expectations for the three five and 14 dose.

Can you would already seem to have an effect at the lower doses. So just trying to understand which doses are dose would be advanced commercially thanks very much.

Mahdi Goudarzi: Hey Laura, good morning. And what I'll do is I'll take the first question around non-dilutive financing, and then Suyash, we'll turn it over to you for Dan about dosing. So the way that we think about this and kind of from a timing perspective, we felt really strongly that we had the opportunity, in an environment where the cost of capital is at historically low rates, the ability to add this finance. In particular, we're in a situation where the equity capital markets are somewhat volatile and not necessarily accurately valuing innovative gene therapy companies.

Hey, Laura good morning, and what I'll do is I'll take the first question around the non dilutive financing and then so yes, we will turn it over to you for Gan around dosing.

So the way that we think about this and kind of from a timing perspective, we felt really strongly.

That we have the opportunity in an environment where.

The cost of capital is at historically low rates the ability to add this financing, particularly when we're in a situation where the equity capital markets are somewhat volatile and not necessarily accurately.

<unk> innovative.

Mahdi Goudarzi: And because we have such a robust portfolio, a number of programs in the clinic, a number of data readouts here to come later this year and kind of for the foreseeable future, and even the opportunity to reach a GAN approval without the need for additional financing, we thought this was as good a time as any to bring in this non-dilutive capital. I think a couple of things that we talked about is that the terms of this deal were quite attractive.

Innovative gene therapy companies and because we have such a robust portfolio a number of programs in the clinic number of data Readouts here to come later, this year and kind of for the foreseeable future and even the opportunity to.

The opportunity to reach a gain approval without the need for additional financing. We thought this was as good a time as any to bring on.

This non dilutive capital I think a couple of things that we talked about is the the terms of this deal we are quite attractive.

Mahdi Goudarzi: We talked about a 7% interest rate, which is a historically low interest rate. We talked about no financial covenants, no warrant coverage. This is about as clean a deal as you can get in a single partner to be able to do this with and one that has the credibility, I think, of the name that goes along with it, Silicon Valley Bank.

Talked about a 7% interest rate.

<unk>, which is a historically low interest rate, we talked about no financial covenants no.

No warrant coverage and this is about the clean deal as you can get in a single partner to be able to do this with and one that has the credibility I think of the name that goes along with it and Silicon Valley Bank and so for US. It's all about Optionality, it's all about being able to move things in best in class forward.

Mahdi Goudarzi: And so for us, it's all about optionality. It's all about being able to move things best in class forward and not necessarily have to slow anything down or make any particular tradeoffs as we get into the next year. Because we can't predict what's going to happen in the equity capital markets, we thought this was just a wonderful opportunity to be able to add some additional dry powder to the tank. That's literally it.

And not necessarily have to slow anything down or make any particular trade offs as we get into the next year, because we can't predict.

Whats going to happen in the equity and the equity capital markets. We thought this was just.

A wonderful opportunity to be able to add some additional.

Additional dry powder for the tank that that's literally it and we were pretty excited about again being able to announce this deal partnering with SBB.

Mahdi Goudarzi: And we were pretty excited about, again, being able to announce this deal partnering with SBB and being able to get into the second half of this year with multiple data readouts. We're talking about GAN high dose data, regulatory feedback around the registration pathway for GAN, GM2 gangliosidosis, safety and biomarker data, CLN1 first patient dose, and Rett syndrome open clinical trial, right? Just more of these and more of these to come. So I'll pause there and turn it over to Suyash. And Suyash, maybe you want to talk about the 1.8E to the 14 total VG dose versus the 3.5 to the 14 total VG dose. Absolutely.

And being able to get into the second half of this year with multiple data Readouts, we talking about Gan high dose data regulatory feedback around registration pathway on Gan <unk>, Gangliosidosis safety and biomarker data dealing one.

And one first patient dosed Ret syndrome open clinical trial, right just more more and more of these to come.

I'll pause, there and turn it over to <unk> and see if maybe you want to talk about the one eight to.

To the <unk> thousand 14, total BG dose.

<unk> moved from three five to the 2014 total BG dose.

Mahdi Goudarzi: Absolutely. Thanks for the question, Laura. Yes, you're right, actually.

Absolutely. Thanks for the question Laura.

Yes, you're right to assume that the $1 eight a 14 guidance looks very very very very good.

Mahdi Goudarzi: The 1.8E14 dose looks very, very, very, very good. You know, we see clear stabilization of disease progression at that dose. We have patients out for quite some considerable time at that dose, so showing sustainability of effect. And that improvement is clinically relevant and clinically meaningful, i.e. it halts the 8-point decline in the MFM32 scale, which translates to an 8-point improvement every year, 16.72 years of effect

We see clear stabilization of disease progression at that dose.

We have patients out his question considerable time without dose showed a sustainability of effect.

Prove it is clinically relevant clinical clinically meaningful.

He holds the eight point decline in the MSM 32 scale.

Which translates to an eight point improvement every year $16 over two years et cetera.

Mahdi Goudarzi: And also, when you run the Bayesian analyses, and we have these slides in our corporate deck, we know that that 1.8014 dose patient who is dosed will have a 98.1% chance of a clinically meaningful improvement. So it's a really solid dose, and the drug would be approvable at that dose. What I will say is that when Carsten Bonneman was at the NIH, and this is a study that's been run at the NIH for several years, it's been run very, very nicely.

Also when you run the Bayesian analysis, when we have these slides in.

In our corporate deck, we know that.

<unk> 14 dose patients.

Who is dosed will have a 98, 1% chance of a clinically meaningful improvement. So it's a really solid dose of the drug would frankly be.

Provable on that on that dose what I will say is that when cost environment at the NIH and this is a study that's been run at the NIH.

And for several years has been run very very nicely constant initially setup to run the dose response study going all the way up to $3.5 billion 14 total BJ now.

Mahdi Goudarzi: Carsten initially set out to run a dose response study going all the way up to 3.5E14 total VG. Now, three patients have actually been dosed at that higher dose, and we will have data to share at the one-year time point on those three patients in the second half of this year. And my guess is that those patients will either show at least the same as the medium-high dose of the 1.8014 or will be slightly better.

Three patients have actually been dose to the highest dose and we will have data to share on the one year time quotes on those three patients.

The second half of this year.

And my guess is is it.

Those patients a lot of the show.

At least the same as the medium high test with the <unk> 2014, all will be slightly better.

Mahdi Goudarzi: And for these children, with this relentlessly progressive neurological deterioration towards death, you have to give them every chance of having the most significant clinical benefits. What I will say is that as we approach our regulatory meetings towards the end of this year, we have this really wonderful data package. We will have the 3E14 dose as part of the package. And as you know, we have this great natural history study, we have dose responsiveness, and we have clear stabilization of the disease at the medium-high dose.

And for these children with this relentlessly progressive.

Neurological deterioration towards death do you have to get in every best chance of having the most.

The most significant clinical benefits what I will say is that as we approach our regulatory maintenance towards the end of this year.

We have this really wonderful data package, we will have the $3.40.

As part of the package and us.

You know we have this great natural history study, we have dose responsiveness, we have cliff stabilization of disease of the medium high dose I expect there'll be at least the same in the in the high dose.

Mahdi Goudarzi: I expect there will be at least the same in the high dose. We have long-term safety, long-term efficacy, and long-term durability. So I'm looking forward to having those discussions with the regulators. But in terms of commercializing, I think it'll likely be the 3.5 E14 dose. But as I say, the 1.8014 would probably be more than enough as well. Let me stop there. Thank you.

Long term safety long term efficacy links into Europe, where let's say so I'm looking forward to having those discussions with the regulators, but incentive commercializing I think likely it would be the $3.

$2 five equal seen dose.

But.

As I say, the 114 would probably be moving up as well.

Let me stop there thank you.

Operator: Thank you. Our next question comes from the line of Gil Blum with Needleman Company. Please proceed with your question.

Thanks.

Thank you. Our next question comes from the line of Gil Blum with Needham and company. Please proceed with your question.

Gil Blum: Good morning everyone, and thanks for taking our question. So do you guys have any thoughts on the recent lifting of legal gender equality my clinical hold on on the IT administration, and do you think this is just a fad?

Good morning, everyone and thanks for taking our question. So do you guys have any thoughts on the recent lifting of vehicles to them from a clinical hold on the Ikea administration.

And do you think the suggest.

Mahdi Goudarzi: I have a follow-up. Hey Gil, good morning.

Change in the way the FDA abused the risk benefit for for IP, AAV gene therapy, and I have a follow up.

Mahdi Goudarzi: Maybe I'll start and Suyash, please provide some additional comments. I think for us, we were really excited to actually see the news come out about a week or so ago that not only did the FDA lift the clinical hold on the IT formulation for Zolgensma but also the fact that Novartis was going to be conducting a phase three study in the type two and three patient population. And again, I think we've seen the data from the original study, where Zolgensma demonstrated a significant improvement in Hammersmith, essentially twofold over what would be considered clinically meaningful, that was sustained, safe, and effective in the patients that were treated with the intersequal dose.

Hey, Joe Good morning, maybe I'll start and see is pleased to provide some additional comments I think for US we were really excited to actually see that news come out about a week or so ago than.

Not only did the FDA lift the clinical hold.

On the it formulation of <unk>, but also the fact that novartis, we're going to be conducting a phase III study.

In the type two and three patient population and again I think we've seen the data from the original study where they were.

As old Gen <unk> demonstrated a significant improvement in the hammer the Hammersmith essentially twofold over what would be considered clinically meaningful that was sustained safe and effective.

The patients that were treated with the <unk> dose and so we were quite excited by that that we felt like the clinical data both from an efficacy perspective, but also from a safety perspective support that and again when you think about the totality of data, particularly around the combination of AAV nine NRC equally we think again this is.

Mahdi Goudarzi: And so we were quite excited by that, and we felt like the clinical data, both from an efficacy perspective but also from a safety perspective, supports it. And again, when you think about the totality of data, particularly around the combination of AB9 intersequally, we think, again, this is an extremely effective way of administration to be able to deliver directly to the CSF. This has been demonstrated in our very own Gynosomal Neuropathy Study but also in the Amicus CLN6 trial, which has had phenomenal data, their recent CLN3 studies, and then again, we talk about Zolgensma.

<unk>.

An extremely effective way and route of administration to be able to deliver directly to the CSF. This has been demonstrated in our very own Jonathan on the <unk> study, but also in the amicus feel in fixed trial, which has had phenomenal data their recent field in three studies.

And then again, we talk about Xeljanz mode and so.

Mahdi Goudarzi: And so from a regulatory perspective, I believe the clinical hold was listed based on some NHP toxicology data that the agency asked Novartis to submit. And so I think, again, the fact of the matter that they conducted those additional toxicology results, and the fact that Zolgensma has now been in well over 100, sorry, 1,400 patients globally, really speaks to the safety and efficacy of using AB9 as a gene therapy approach for the treatment of monogenic CNS diseases.

From a regulatory perspective, I believe the clinical hold was lifted based on some and HP.

Toxicology data that the agency at Novartis to conduct and so I think again, the fact of the matter that they conducted those additional toxicology results. The fact that xeljanz and have now been in well over 100, sorry 1400 patient.

Globally, I think really speaks to.

The safety and efficacy of using AAV nine as a gene therapy approach for the treatment of monogenic CNS diseases, and so again I think this kind of mirror some of the recent feedback we've gotten from the agency, where they've taken a very pragmatic approach.

Mahdi Goudarzi: And so, again, I think this kind of mirrors some of the recent feedback we've gotten from the agency, where they've taken a very pragmatic approach to your toxicology package, and then the fact that we go in with three species of toxin, in most cases, this dovetails nicely with what they're looking for. I'll stop there. Suyash, I know you probably have some additional questions.

To your toxicology package it and the fact that we go in with three species of Pax in most cases.

This dovetails nicely with what Theyre looking for I'll stop there. So I know you probably have some additional comments.

Mahdi Goudarzi: Sure, thanks Sarai and thanks Gil for the question. You know, I think that we've had a year and a half where the FDA seems to have been clamping down with clinical holds, both for safety matters and for CMC-related issues in the AAV gene therapy space. I do wonder if that's changing now. Actually, we had the Soljesma clinical hold lifted recently, and this morning, it was also announced that the hold was lifted once again for AAV9 gene therapy for Danone, the Rocket Pharmaceuticals program.

Sure. Thanks, Alright, Thanks Gil for the question.

I think that.

We've had a year year and a half like the FDA has seeming to have been clamping down with clinical holds.

Both the safety masses and for CMC related issues in the AAV gene therapy space I do wonder if thats changing now actually we have suggested the clinical hold lifting recently and this morning, we also announced the lifting of the holes, what's kind of AAV non gene therapy for sit down on the rocket pharmaceuticals.

Program so.

Mahdi Goudarzi: So I wonder if there's a bit of a shift in the perspective of the FDA, and they're just getting a little more comfortable spending less time on COVID and more time on gene therapy now. I think specifically that Soljesma product is definitely transferable to the wider AAV9 space.

Wonder if there's a bit of a shift in the perspective of the FDA and then just a little more comfortable.

Spending less time on Covid and more time on gene therapy now.

I think specifically with our <unk> products, it's definitely translate trust variable to the to the wider.

Why dry benign space is good news for a benign as already mentioned the clinical data from that from the extra week will study. The strong trial was actually very very positive we saw clinically meaningful effects.

Mahdi Goudarzi: It's good news for AAV9. As I already mentioned, the clinical data from that intrathecal study, the STRONG trial, were actually very, very positive. You saw clinically meaningful effects on the Hammersmith scale, which is a scale that's used for slightly older children than the CHOP intends to treat, because you're going into SMA type 2 and type 3, and the doses are in the E14 ranges. So once again, you can learn quite a lot, and it's quite translatable to our programs as well.

On the Hammersmith scale, which is a scale thats used for slightly older children. The chop intend because she's going into SMA type two type three.

The doses are in the 14 ranges so I once again.

<unk> talked about quite translatable.

All programs as well.

Mahdi Goudarzi: The issues have been for safety, but that's now been lifted with the NHP study. Our approach to toxicology, as I've already mentioned, is very robust, and thus far, in our discussions with the FDA, it's been very effective for us and acceptable for us. So I'm hoping this is shifting the FDA's paradigm a little bit. But the fact that Zolgesma came off clinical hold was good news for AAV, as was the lifting of the hold for Danone disease this morning as well.

The issues have been for safety, that's not listed with NH Pea study Ah.

Approach to toxicology is before you mentioned is very robust and thus far in our discussions with the FDA have been very.

Except to fourth acceptable.

For it so.

I'm, hoping this is <unk>.

Shifting the FDA is paradigm a little bit.

But the fact, the Sanchez with came off clinical hold was good news.

As was the lifting of the hold for Donlin disease.

Gil Blum: Thank you for all the color. And could you maybe give us an idea of the number of patients that you can treat?

This morning as well.

Alright, Thank you for all the color and could.

Could you maybe give us an idea of the <unk>.

<unk> of patients that you can currently treat with the GMP runs that you've conducted.

Gil Blum: Currently, treating with the GMP runs that you've conducted, would these be sufficient for, you know, your initial clinical studies?

With the SEC sufficient for your initial clinical studies in the programs that you mentioned.

Mahdi Goudarzi: of Clinical Studies and the programs that you mentioned.

Mahdi Goudarzi: No, it's a really good question, Gil, and we appreciate it. And that's absolutely correct. When we go in and we do a GMP run, not only are we doing GMP runs for our IND-enabling TOCS package, but we're also doing GMP runs for the entire cohort of a clinical trial, because what we want to do is make sure that there's consistency between material given to the same patient in a particular indication and not necessarily adding any unnecessary veritability into a clinical trial by having, you know, a certain set of patients treated with one GMP run and then having another set of patients treated with another GMP run.

No. It's a really good question go when we appreciate it and that's absolutely correct. When we go in and.

And we do a GMP run not only are we doing GMP runs for our IND, enabling tox package, but we're also doing GMP.

GMP runs for.

The entire cohort of a clinical trial, because what we want to do is make sure that there is consistency consistency.

Between.

Between material, giving to the same patient in a particular indication and not necessarily adding any unnecessary variability.

And to a clinical trial by having.

A certain set of patients treated with one GMP run and then have another set of patients treated with another GMP run and so what we can do is because of our capacity, we do have the ability to be able to manufacturer.

Mahdi Goudarzi: And so, you know, what we can do is, because of our capacity, we do have the ability to manufacture GMP materials for an entire dosing cohort within a clinical trial. So we're pretty excited about that. Not only do we have that material, but we also have material left over for retains to make sure that we could do any type of needed analytical comparability between any type of preclinical material that we also keep and kind of put in the freezer to make sure there's always the ability to go back and do analytical comparability or any recharacterization that would be potentially needed to support a regulatory file. Alright, thank you for taking our questions and congrats on the progress.

<unk> material for an entire dosing cohort.

Within our clinical trials. So we're pretty we're pretty excited about that not only do we have that material, but we also have material leftover for routines to make sure that we could do any type of needed analytical comparability between any type of preclinical material that we also keep in and kind of put in the freezer to make sure Theres always.

The ability to go back and do analytical comparability or any re characterization that would be potentially needed to support a regulatory filing.

Alright, Thank you for taking our questions and congrats on the progress.

Operator: Thank you. Our next question comes from Line of Union.

Awesome. Thanks Bill.

Thank you. Our next question comes from the line of Union with Jefferies. Please proceed with your question.

Unknown Caller: Thank you. I have a couple of questions regarding 1.20 on the clinical and regulatory update that we are expecting by the end of this year. So will the highest core, highest dose core data come out before the regulatory update? So that's the first question. And the second question is, so you're going to be requesting an end-of-phase meeting with the FDA and engaging you with the EMA by year-end. So do you think that you would have an update on the regulatory agency discussions, or is it possible that you could request a meeting and wait for the meeting to happen potentially early next year? Thank you.

Thank you I have a couple questions any harding one 'twenty on the clinical and regulatory update and then we are expecting by end of this year. So will the highest core hoist or does the core data.

Come out before the regulatory update so that's the first question. The second question is.

So you're gonna be requesting.

Ananda phase and meeting with the FDA and engaging with the EMA by year end so do.

Do you think that you would have.

An update from the regulatory agency discussions or is it possible that you could sustain request the meeting and waiting for the meeting to happen.

Actually already next year. Thank you.

Mahdi Goudarzi: Good morning, and it's great to hear from you, and thank you for your questions. So, from a disclosure perspective, I think it's likely that we would share the high-dose data cohort before we would disclose any particular feedback from any regulatory agency discussions that we plan to have here in the second half of the year. So, you know, that is the cadence from a timing perspective.

Good morning, and it's great. It's great to hear from you and thank you for your question.

I'll take both of these so from a from a disk.

A disclosure perspective.

It's likely that we would.

Sure the high dose data cohort before we would disclose any particular feedback from any regulatory agency discussions that we plan to have here in the second half.

The year so so.

That is the cadence from a timing perspective, the goal is to have feedback.

Mahdi Goudarzi: The goal is to have feedback by the end of the year and not request a meeting by the end of the year. So, we'll be putting in those submissions, those meeting submissions here in the next month or so in order to ensure that we will have feedback, depending on the workload of the agency. Obviously, it's up to them when they grant you a meeting, and with COVID, what we've tried to do is to request those meetings early because we know that, in some cases, those meetings can be a little bit delayed.

By the end of the year and not request the meeting by the end of the year. So.

So we will be putting in those submission those meeting submission here in the next month or so in order to ensure that we will have feedback depending on the workload that the agency obviously, it's up to them when they have granted a meeting in and with Covid, what we've tried to do it.

To request those meetings early.

Cause we know that in some cases those meetings can be a little bit delayed and so we're going to take a similar approach here from a GAAP perspective, particularly in the U S, where we're going to put in the meeting request.

Mahdi Goudarzi: And so, you know, we're going to take a similar approach here from a GAN perspective, particularly in the U.S., where we're going to submit the meeting request in time to receive feedback here by the end of the year. In Europe, particularly in MHRA, from a scientific advice perspective, and EMA, from a scientific advice perspective, those meetings are a little bit more straightforward, to be quite honest, and those agencies have been granting meetings in somewhat of a normal time period.

And tying to receive feedback here by the end of the year in Europe, particularly with the NHRA from a scientific advice perspective, EMA from a scientific advice perspective.

Those meetings are a little bit more straightforward can be quite honest then.

And.

Those agencies.

Yes.

Have been granting meetings in somewhat of a normal.

Mahdi Goudarzi: Particularly MHRA, you're able to get a face-to-face meeting with them relatively, you know, relatively efficiently. So, you know, that's the way that we're going to approach regulatory interactions here in the second half of the year, and hopefully, we'll have that feedback in time in order to provide an update to the street by the end of this year. But certainly, that's our approach.

Time period, particularly NHRA youre able to get a face to face meeting with them.

Relatively relatively efficiently so.

So that's the way that we're going to approach regulatory interactions.

And here in the second half of the year.

And hopefully we will have that feedback in time in order to provide an update to the street by the end of this year, but certainly that.

Unknown Caller: Okay, thank you for the clarification. And I have one quick question on the financials. So, in second quarter R&D, you have this around $10 million in R&D manufacturing and other raw material purchases. So, going forward, the third quarter, I mean, the second half of this year, should we assume that R&D increases quarter over quarter would be more normalized from the first quarter run rate? Or with, you know, all the clinical programs advancing, would you expect R&D to increase from the second quarter run rate?

That's our going in approach.

Thank you for the clarity and I have one quick question on the financials.

In second quarter RMB, you'll have this out $10 million in R&D manufacturing and other.

Raw material purchases.

No.

Going forward the third quarter I mean, the second half of this year should we assume that R&D increases.

<unk> of our quarter over to the more normalized from the second quarter, the first quarter run rate.

Sure.

You know all the clinical programs advancing.

And what do you expect R&D to increase from the second quarter run rate. Thank you.

Unknown Caller: Thank you.

Mahdi Goudarzi: Really, really good question. I'll start, and Kamran, maybe you want to provide some additional color. You know, as we discussed, we've had a number of GMP manufacturing campaigns to support multiple clinical trial starts here in the first half of this year, particularly in the second quarter, and those that were being conducted in collaboration with our partners over at Catalent. And again, the goal was to have, you know, high quality, robust material that we had a high degree of confidence in that would be able to treat our patients effectively.

Really really good question I'll start and Cameron, maybe you want to provide some additional color.

I think as we discussed we've had a number of.

Of GMP manufacturing campaigns to support multiple clinical trial starts here.

In the first half of this year and particularly in the second quarter and those are were being conducted in collaboration with our partners over at Cadillac and again. The goal was to have high quality robust material that we had a high degree of confidence then that would be able to treat our patients effectively.

With a portfolio as large as ours and kind of the way that.

Mahdi Goudarzi: With a portfolio as large as ours, and kind of the way that the programs are kind of running from a cadence perspective, you know, we expect to have a number of new programs move into clinical development next year, as well as a number of programs that are currently in IND, CTA enabling studies that will be moving into that will be moving into clinical development as we get into 2022. And so, you know, I think you'll see some level of consistency and normalization, but with the breadth of the portfolio that we have, there'll certainly be some growth. I'll stop there. Kamran, maybe you want to provide some additional color.

The programs are kind of running from a cadence perspective, we expect to have a number of new programs move into <unk>.

Moving to the clinical development next year as well as the number of programs that are currently in IND, enabling.

Enabling studies that will be moving into.

That'll be moving into clinical development as we get into 2022, and so I think youll see some level of consistency and normalization, but with the breadth of the portfolio that we have there will certainly be some growth I'll stop there Cameron maybe you want to provide some additional color.

Kamran Alam: Yeah, thanks, Ra. And thanks for the question, Eun. So ultimately, as we continue to initiate clinical trials on numerous programs in our portfolio, you can expect to see some additional clinical trial expenses getting incurred in the second half of this year and into 2022 as well. Thank you very much.

Yes, Thanks, alright, thanks for the question Europe. So ultimately as we continue down the clinical trial initiation numerous programs in our portfolio you can expect to see some additional clinical trial expenses getting incurred in second half of this year and into 2022 as well.

Okay. Thank you very much.

Operator: Thank you. Thank you. Our next question comes from the line of Raju Prasad with William Blair. Please proceed with your question.

Thank you.

Thank you. Our next question comes from the line of Rajiv Prasad with William Blair. Please proceed with your question.

Mahdi Goudarzi: Thanks for taking the question. You know, I kind of just want to understand how the kind of commercial scale up and identification

Thanks for taking the question.

Can I just want to understand how the kind of commercial scale up and identification of patients who is going particularly in the 120 a lot of questions that we get a kind of related to how big that market opportunity is and maybe if you could just talk about the number of kind of prevalent patients that you've identified and how youre kind of looking at building up the commercial scale up.

Mahdi Goudarzi: how the kind of commercial scale-up and identification of patients is going, maybe particularly in 120. A lot of questions that we get are kind of related to how big that market opportunity is. So maybe if you could just talk about the number of kind of prevalent patients that you've identified and how you're kind of looking at building up the commercial scale, and then I got another question. It's a really good question and good morning, Raj.

And then I've got another follow up.

It's a really good question and good morning, Raj and so the way that we're thinking about patient identification where actually.

Mahdi Goudarzi: And so the way that we're thinking about patient identification, we're actually being quite pragmatic, particularly today. So not only have we brought in our head, our chief commercial officer, who led the commercialization of Zolgensma, but when he joined Taysha, he was actually the U.S. general manager for Zolgensma. We've also brought on the leadership team below him, our VP of marketing, who was the VP of marketing on the Zolgensma program, our head of payer engagement, who also led that effort on the Zolgensma program, as well as our head of product distribution, who also led that program on Zolgensma.

Being quite pragmatic, particularly today, so not only have we brought on.

Our head of our Chief commercial officer, who who led the commercialization of <unk> and when he joined Asia. He was actually the U S.

The General manager, Virginia Adult gentlemen, we've also brought on the leadership team below him.

Our VP of marketing, who was the VP of marketing.

The <unk> program are ahead of pace payer engagement, who also led that effort.

Program as well as our head of product distribution, who also led that program, although Jasmine, So first and foremost it was about bringing on people.

Mahdi Goudarzi: So first and foremost, it was about bringing in people that knew exactly what they were talking about. That was kind of the first and foremost thing that was important to us. From a patient identification perspective, what we've done is we've partnered not only with MDT on a previously announced partnership, which we're continually expanding on, but we've also recently partnered with GeneDx, particularly around patient identification XUS. And what we know about this population is that this is really a prevalent population split into two segments, early-onset GAN and late-onset GAN.

That knew exactly.

What what they were talking about that that was kind of the first and foremost.

Thing that was important.

To us from a pro forma.

From a.

<unk>.

Patient identification perspective, what we've done is we've partner not only with <unk> with two of our previously announced partnership which we're continuing continually expanding on we've also recently partnered with <unk>, particularly around.

Particularly around patient identification.

Ex U S and what we know about this population is that this is really a prevalent population split into two segments early onset Gan and late onset Gan early onset Gan.

Mahdi Goudarzi: Early-onset GAN being kind of the more progressive form of the disease that typically progresses to death around, you know, late teens and early 20s. And then late-onset GAN that typically presents in kind of the teenage years and has a significant quality of life impact but typically doesn't progress to death. And, you know, these patients tend to live into their fifth decade of life, albeit with a pretty compromised quality of life.

Being kind of the more progressive.

<unk> of the disease that typically.

[noise] progresses to death around.

Late teens early 'twenty and then late onset again that typically.

<unk>.

And kind of the teenage years and has a significant quality of life impact, but typically doesn't progress to death.

These patients tend to live.

And to their fifth decade of life, albeit it's a it's a it's a pretty compromised.

It's a pretty compromised.

Mahdi Goudarzi: And so the majority, the split between those two populations is about 25%, 75%, 25% being the early-onset GAN, 75% being the late-onset GAN. And because that's the larger population and those patients tend not to progress as quickly, we're really able to build up a fairly large prevalent population. So when you think about this, this is a real widespread opportunity.

Quality of life, and so and so the majority the split between those two populations is about 25%, 75% and 25% be too the early onset Gan, 75% being in the late onset Gan and because that's the larger population and those patients 10 <unk>.

Not progressed as quickly.

We were really able to build up a fairly large prevalent population, but when you think about this this is a real prevalent opportunity the incident.

Of these the incidence here.

Mahdi Goudarzi: The incidence of these, the incidence here would be relatively small. We're talking in the U.S. about 30 or so patients, or U.S. and Europe somewhere around 30 or so patients. But the prevalent population is actually quite big. And the late-onset patients are all identified, but they haven't been genotyped. And I think that's an important piece.

It would be relatively small we're talking in the U S somewhere around 30, or so our U S and Europe somewhere around 30 or so patients.

But the prevalent population is actually quite big.

And the late onset patients are all identified.

But they haven't been genotype and I think that's the important piece and this is what we're going to be doing with with Jean <unk>, It's really going out partnering with the CMT Foundation. So we're working through our partnership discussions right now with the PMT Foundation really around Genotyping all the CMT two patients that are currently.

Mahdi Goudarzi: And this is what we're going to be doing with GeneDx, really going out, partnering with the CMT Foundation. So we're working through our partnership discussions right now with the CMT Foundation, really around genotyping all the CMT2 patients that are currently in their network of clinics. And they've done a fantastic job with a number of validated clinical sites throughout the U.S. and Europe.

<unk> in there.

Network of clinics and they've done a fantastic job with a number of.

With a number of validated.

Ah clinical sites throughout the U S and Europe in the way you think of that CMT.

Mahdi Goudarzi: And the way you think of that CMT, the way you would think about the GAN population or the late-onset GAN population that is in that CMT group is, There are about four million births in the U.S. per year. The CMT incidence is about one in 2,200 or 2,200 patients, of which type two is about 17% of that. And then around 6%, it could even be higher, we've seen in some literature, but the number that we actually use for our 2,400 patients is around 3%.

The way you would think about the Gan population or the late onset gam population that had been that CMT.

That's in that CMT grew.

Group is.

So there was about 4 million births in the U S per year with DMT incidence is about one in 2200 or 2200 patients.

Of which tie to is about 17% of that.

And then around 6%.

It could even be higher we've seen in some literature, but but the number that we actually used for our 2004 hundred patients with around 3%, but the literature goes.

Mahdi Goudarzi: But the literature goes and is fully disclosed at 6%. We wanted to be a little bit more conservative, but up to 6% of the CMT type two population has a confirmed GAN mutation. We've actually seen literature, like I said, that gets into the double digits. But this is ultimately how we back-calculate our epidemiology and get to the numbers, the 2,400. Likely, the number is a lot higher in the U.S. and Europe. It's probably closer to about 3,000 to 3,500, but we wanted to be conservative with our estimates.

Our fully disclose that 6%, we wanted to be a little bit more conservative, but up to 6% of the TMT type. Two population has a confirmed <unk> mutation, we've actually seen literature like I said that gets into the double digits, but this is ultimately how we back calculate.

Our epidemiology and get to the numbers.

2004 hundred likely the number a lot higher in Europe.

The U S and Europe, it's probably closer to about 3000 to 3500, but we wanted to be conservative with our estimate.

Mahdi Goudarzi: Great, thanks. And then, and then, you know, with the FDA panel coming up next month, you'll obviously see some clinical holds come off.

That helps.

Great. Thanks, and then and then.

The FDA panel coming up next month.

Obviously, you're seeing some clinical hold come off.

As well as.

Mahdi Goudarzi: [inaudible] Moving forward. Awesome. Suyash, maybe you want to take this?

Rocket.

Dana disease program. This morning, I, just wanted to kind of get your thoughts on how to look at.

How are you guys looking at that.

That panel.

Mahdi Goudarzi: Suyash, maybe you want to take that question?

Moving forward. Thanks.

Awesome.

Maybe do you want to take that question.

Sure.

Mahdi Goudarzi: Yeah, thanks for the question, Raju. I think it's going to be interesting. I'm looking forward to seeing the panel, actually, just seeing how the discussion goes. You know, the way the FDA has structured the panel, they're looking at five specific areas. They're looking at vector integration and oncogenicity risks, hepatotoxicity, thrombotic microangiopathy issues, and then non-clinical findings of toxicity, especially related to PRG, and then clinical findings of neurotoxicity that are based on brain MRI findings. So I think we're actually just looking forward to listening and learning.

Yeah.

The question Rajeev I think.

Yeah, it's going to be interesting I'm looking forward to seeing the panel actually interesting how the discussion guys. The way we have structured the parallel look there are five specific areas.

Back to integration and Oncogenicity risks.

The toxicity thrombotic microangiopathy issues.

And then non critical fronts of toxicity, especially related to <unk> and <unk>.

The critical points of neurotoxicity that based on Brian MRI findings, so I think.

We're actually just looking forward to listening and learning all of those five areas that if they're talking about gives us some considerable thought too and have mitigated against them. Both by looking at them looking for some of these issues specifically in our preclinical work for example, we look at <unk>.

Mahdi Goudarzi: All those five areas that the FDA is talking about, we've given some considerable thought to and have mitigated against them, both by looking at them and looking for some of these issues specifically in our preclinical work. For example, we look at DRGs in all of our preclinical NHP studies now, and thus far, we haven't seen any signs of DRG inflammation. And not just looking at things from the non-clinical perspective, but we also build in appropriate mitigations into the clinical trial design as well, i.e.

And all of our <unk>.

Preclinical NH piece for this now and thus far we haven't seen any signs of DRG inflammation.

And not just looking at things from the clinical perspective, but it also build an appropriate mitigation and the clinical trial design as well I E. We built in monitoring local toxicity issues with built in clinical monitoring platelet counts, which gives a clue to early issues with thrombotic microangiopathy.

Mahdi Goudarzi: We build in monitoring to look for hepatiotoxicity issues, we build in clinical monitoring to look at platelet counts, which gives a clue to early issues with thrombotic microangiopathy. We look at, we actually have, it's been an interesting discussion with the regulators just in general about how to monitor for DRG inflammation in the clinical trial. And essentially, we came up with a good plan that the regulators seem very accepting of, which is looking at reflex testing periodically at each visit, so specifically the six reflexes in the body, ankle, knee, etc., and also nerve conduction studies at baseline and the three-monthly periods for the first year thereafter. So we've been giving this a lot of thought. I'm not expecting to hear anything at this meeting that's a big surprise to us.

We look at.

We actually have.

It is an interesting discussion with the regulators just in general about how some Melissa for DRG inflammation.

Because the clinical trial and essentially we come.

Come up with good plan, the regulators very exceptional off which is looking at reflex testing.

Periodically.

Each visit so specifically the six.

Six reflects is in the <unk> ankle.

Ne et cetera.

And also nerve conduction studies at baseline and the three months compared to the first year. Thereafter, so we've been given a lot of thoughts I'm not expecting to hit right at the end of this meeting.

That's a big surprise to us I am hoping to learn more about im hoping it will go into more detail around the mechanism of whats happening and I'm also hoping that they take the safety issues that I'm thinking about <unk>.

Mahdi Goudarzi: I am hoping to learn more, but I'm hoping that they go into more detail around the mechanisms of what's happening. And I'm also hoping that they take the safety issues that they're thinking about and considering and look at them from the context of the balance of risks and benefits for patients. Because once again, for the patient communities that we're trying to serve, these are children who have devastating illnesses, often with a rapid progression toward death. In that context, some minor safety issues should not preclude a child from being included in a clinical trial or being dosed.

And they look at it from the context of the balance of risks and benefits and the patients because once again for the patient community is that we're trying to serve.

These are children, who have devastating illnesses were off for the rapid progression towards that.

And.

In that context, some on the safety issue should not be should not preclude a charter being treated in a clinical trial or being dosed.

Mahdi Goudarzi: Yes, maybe you want to just comment on some of the recent NHP data that we've obtained in our GAN program because I think this kind of plays into just the, you know, kind of what's going on in the field. Sure. And, um, yeah, so it is.

Yes, maybe you want to just comment on some of the recent NH B data that we've obtained in our Gan program, because I think that kind of plays into just the kind of what's going on in the field.

Sure.

Yes, it's a good reminder.

Mahdi Goudarzi: Sure. And yes, it's a good reminder. All right, thank you.

Alright. Thank you, yes, we recently.

<unk> is another step.

Mahdi Goudarzi: Yeah, we recently conducted another study for our GAN program, specifically an NHP study that looked at our redosing approach. But as part of that assessment, we actually gave a clinically meaningful dose of the GAN vector and redosed these NHPs, redosed some of these NHPs, eight weeks subsequent to dosing. And we took down all the NHPs, those that received both one dose and those that received two doses, and we looked very carefully for any signs of toxicity or inflammation in the necropsy.

Study.

In the.

The <unk> program, specifically in NIH Peace study.

Looked at.

Re dosing approach for this part of our assessment, we actually gave a clinically meaningful dose of.

The GAAP effector and re dose these at Hps readers some of these NIH pace.

Eight weeks subsequent to dosing and we took down all the NIH piece does that you received one dose.

We received two doses and we looked very carefully for any signs of <unk>.

Toxicity or inflammation in the knee cropsey and with a specific focus of course, there's lots of interest in the <unk>.

Mahdi Goudarzi: And with a specific focus, of course, there's lots of interest in the DRG and spinal cord and neuronal tissue. We saw no evidence whatsoever of any kind of inflammation in any of the samples we took. So from our perspective, that's very reassuring. And it's specifically a vector that's already in the clinic for us.

Sponge quota neuro tissue.

So no evidence whatsoever of any kind of.

Or any kind of information.

In any of the softness we tilt so from our perspective it was very reassuring specifically effects of this already in the clinic of alignment across.

Operator: Awesome.

Great. Thanks.

Awesome. Thanks Ross.

Eun Kyung Yang: Thank you. Our next question comes from the line of Yoon Song with BTIG. Please proceed with your question.

Thank you. Our next question comes from the line of Utah with BTG. Please proceed with your question.

Eun Kyung Yang: Hi. Excuse me.

Alright, excuse me thanks, very much for taking my questions. So first question on GM to program.

Eun Kyung Yang: Thanks very much for taking the question. So, first question on the GM2 program: do you expect the biomarker data to include substrate reduction? And how long do you think the patient will need to be followed for you to see any signals suggesting clinical efficacy?

Do you expect the biomarker data to include the substrate reduction.

How long do you think the patient will need to be followed for you just see any signals, suggesting clinical efficacy. Please.

Mahdi Goudarzi: Thank you, and good morning. And maybe I'll just take the first question, and Suyash can take the second.

Thank you and good morning, and maybe I'll just I'll take the first question and so you can take the second.

Mahdi Goudarzi: From a data disclosure perspective, what we're expecting to disclose will be safety data from the Queens Phase 1-2 study, as well as HexA enzyme activity data from the CSF. Those will be the two measurements that we'll be disclosing, and then in subsequent disclosures as we move into the first half of 2022 and then later in 2022, we'll be providing some additional disclosures around other key aspects of the disease. But for the second half of this year, those will be the two markers that we'll be providing feedback on. Suyash, maybe you want to take Eun's second question around the, your second question around the kind of timing of when you would see any kind of clinical impact.

From a data disclosure perspective, what we're expecting to disclose there'll be.

Safety data from the Queens Phase one class II study as well as hefei enzyme activity data from.

From the CSF those will be the two measurements that.

That will be disclosing and then in subsequent disclosures that we've moved into.

The first half of 2022, and then later in 2022 will be will be providing some additional disclosures around other key aspects of the disease, but it but for the second half of this year those will be the two markers that we'll be providing feedback feedback on <unk>, maybe you want to take.

Your second question around.

The second.

Second question around kind of timing of when you would see kind of clinical impact.

Mahdi Goudarzi: Sure. Thanks, Ian, for the question. And I think it's an important question, just the cadence of events. You know, what will happen after we dose a patient with GM2? You know, what's the normal course of it? What's the expected course of events? So, RA is quite correct, and the biomarker data we will be showing will be Hex A levels in the CSF and in the blood. You asked specifically about GM2 ganglicide reduction. We are, of course, measuring that.

Sure.

Thanks for the question and I think it's an important question just the cadence of events and what's going to happen after we dose a patient.

With <unk>, what's the normal course, what's the expected close of events, so alright quite correct. So far.

Im architecture, we will be sharing will be <unk> levels in the CSF and in the blood.

You asked specifically about G into Canada.

<unk> decided reduction we are of course measuring that my guess is that will take a little bit longer than the <unk> to change and so that will be theres also relates to disclosure and in terms of clinical improvements.

Mahdi Goudarzi: My guess is that it will take a little bit longer than the Hex A to change, and so that will be the result of a later disclosure. And in terms of clinical improvement, my hope is that... You know, I anticipate that if you think about the cadence of events, you dose a patient, you should get a maximal transgene expression maybe three weeks after dosing. So I guess by the first month, you should be seeing a nice increase in hexa activity.

My hope is that.

I anticipate if you think about the cadence of events you dose a patient you should get Maxwell transgene expression, maybe three weeks after dosing. So I guess the first month, you should be say, a nice increase in that activity and then by three months after initial doses should be maximo.

Mahdi Goudarzi: And then by three months after the initial dose, it should be maximal. My guess is that clinical stabilization won't start to see until about three months. I would hope to see the beginnings of some change in clinical progress by about three months. It may take even longer; it may be six months, but my guess is that 3MIS will start to see the signs.

My guess is that the clinical stabilization you wouldn't start to see to about three months I would hope to see the beginnings of some change in clinical progress by about three months. It may take even longer maybe six months, but my guess is that three months will start to see the funds or something.

Eun Kyung Yang: Okay, and then on the Rett syndrome program, do you have a target range that you hope to see that the gene transferring expression will fall into that range, or would you just rely on the self-regulatory mechanism of the technology to look more at the clinical kind of end point?

Okay.

Then on the Brent syndrome program do you have a target range that you.

Hope to see that.

Transferring suppression will fall into that range or would you just rely on the self regulatory mechanism of the technology to them.

Mahdi Goudarzi: Yeah, so this is another good question. Oh, go ahead. Yes. Yeah, that was it.

Look more on the clinical kind of endpoint.

Mahdi Goudarzi: We both were saying the same thing, but go ahead. Well, I'll start our own. You jump in if I miss anything out. It's a really good question, Eun, and it's been, we've had...

Yeah. So that's another good question go ahead.

Yeah that was just presented people go ahead.

Mahdi Goudarzi: Well, I'll start our own, and you jump in if I miss anything out. It's a really good question, Eun, and it's been, we've had... Okay, 100%. Is it between 80% and 120%? What's the upper limit?

Well I'll start alright, you jumped ahead of 55%.

It's a really good question.

And it's been we've had.

Actually 100% is it between 80 to 120.

Percent, what's the upper limit, we know that 200% this too much because you get an <unk> obligation, but this 150% levels, okay and none of the clinicians can answer that.

Mahdi Goudarzi: We know that 200% is too much because you get MeCP2 duplication, but there's 150% levels that are okay. And none of the clinicians can answer that. What I will say is that in the animal studies, when you hit about 150% of MeCP2, you are starting to see some kind of deterioration. But our intent is to try and keep the level of MeCP2 generally physiological, i.e. About normal, being a little bit more conservative.

What I will say is that in the animal studies when you hit about 150% levels of magnitude you are starting to see some covenant deterioration, but our intent is to try and keep the level of met P to generally physiological IAA about normal.

A little bit more conservative in the way Steve Gray has designed the micro RNA binding sites that they just they run a little bit lower than 100% to between 19, 90% levels of expression.

Mahdi Goudarzi: You know, the way Steve Gray designed the microRNA binding sites, they run a little bit lower than 100%, so between 90% and 100% levels of expression. Now, of course, we can't measure MeCP2 expression in a child because, in order to do that, you'd have to biopsy the brain and look at levels of MeCP2 expression. It's technically possible, but ethically, you wouldn't be able to obviously take that biopsy. Except, of course, in the unfortunate event if a child was to die, we'd perform an autopsy and get the data that way.

Now of course, we can't measure it might be two expression and HR because notes to do that you touch a box of the brain and looked at.

Levels of magnitude expression. So it is technically possible for ethically you wouldn't be able to obviously take a biopsy.

Except of course near portion of extended the charters of di would perform an autopsy and get the data that way, but we wouldn't be able to measure <unk> expression in the clinical setting and the vast majority of cases, and so we're going to be relying in particular on the clinical improvements, but the target is going to be physiological levels, which the.

Mahdi Goudarzi: But we won't be able to measure MeCP2 expression in the clinical setting in the vast majority of cases, and so we're going to be relying in particular on clinical improvement. But the target is going to be physiological levels, which the self-regulatory feedback loop is able to attain very, very nicely.

Self regulatory feedback loop is able to obtain very very nicely.

Mahdi Goudarzi: Great, thank you. Thank you. Thank you. Our next question comes from the line of Michael. Morgan Stanley, please.

Great. Thank you.

Thank you.

Thank you. Our next question comes from the line of Mike <unk> with Morgan Stanley. Please proceed with your question.

Hey, guys. Thanks for taking the question just just for the gym to program.

You're on track to give an update sort of later this year, but.

Operator: Thank you. Our next question comes from the line of Michael's with Morgan Stanley. Please proceed with your question.

Assuming you get positive results. There are you planning to advance a single dose into the phase one two U S study or might you decide to advance multiple doses there and then secondly.

Mahdi Goudarzi: Hey Mike, thanks for the question. I'll take the second question, and Siyash, maybe you want to talk about dosing. But to your second question, the material that we produce for the Canadian study is made in the exact same facility with the exact same process that the U.S. clinical trial material is being manufactured with. So, that'll be the exact same like-for-like material with the same analytics, same product characterization, and same release testing. So, we're pretty fortunate for that.

Do you need to make any process modifications to the material you plan to use in the U S study versus the material that you're currently using in the Queen's study. Thanks.

Hey, Mike Thanks for the question I'll take the second question in May.

Maybe you want to talk about dosing.

But to your second question the material debt.

We produce for the Canadian study is made in the exact same facility with the exact same process that the U S. Clinical trial material is being manufactured with so that'll be the exact same like for like.

Material with the same analytic themed product characterization, saying the leaf testing. So we're pretty fortunate for that and the reason why we do that is to make sure that if we do see a remarkable results that we're able to take that to regulators.

Mahdi Goudarzi: And the reason why we do that is to make sure that if we do see a remarkable result, that we're able to take that to regulators and then start to have discussions around regulatory pathways relatively quickly versus having to go back and do some type of process development change. So, to your original question, that's the exact identical material from the same facility, same process. Siyash, maybe you want to just talk about dosing. Sure. Um, yeah, thanks for asking.

And then start to have discussions around regulatory pathway relatively quickly versus having to go back and do some type of <unk>.

<unk> development change so that vote. So to your original question that.

Thats the exact identical material from it from the same facility same process. So yes, maybe you wanted to talk about dosing.

Mahdi Goudarzi: Sure. Yeah, thanks for the question, Mike.

Sure.

Yes, thanks for the question, Mike and <unk>.

Mahdi Goudarzi: And, you know, the good thing about GM2 is that it's one of the programs that has this very wide therapeutic window that I've already touched on, i.e., you don't need much to get a significant improvement. We assume 5% levels of enzyme will be more than enough to result in a dramatic improvement. And I say this based on the current data that exists that show that infants with the disease have less than 0.1% activity of HEXA. When you go up to about 2% to 3%, i.e., the adult forms of the disease, they actually have a normal lifespan by then.

The.

<unk>.

Good thing about GM too is it's one of the programs that has this very wide therapeutic window that I've already touched on I E. You don't need much together quite quick to get significant improvements, we are seeing 5% levels of enzyme.

We'll be more than enough to result in a dramatic improvements and I say this based on the <unk>.

Currently exists that show the infants for the disease have less than 41% activity of <unk>. When we go up to about 2% to 3%.

Apple phones, the disease, they actually happened normal lifespan by that.

Mahdi Goudarzi: So if you're hitting 5%, then more likely that will be enough to give you quite a dramatic clinical improvement. So you don't need much to get to a level that results in a considerable clinical improvement. On the other hand, you can actually express the enzyme supraphysiologically, and we've seen this in our toxin pharmacology preclinical work, and it's a very safe enzyme, so you can actually express it supraphysiologically on the other hand, and there are no adverse consequences there.

If you're hitting 5% than more likely that will be enough to give you quite a dramatic clinical improvements so you've done in March.

To get to.

A level that resulted in considerable clinical improvement on the other and you can actually expressed the enzyme superefficient logically it will extend the small talks and pharmacology preclinical work and it's a very safe Amazon. So you can actually express sacrificial logically on the other end.

And there are no adverse consequences. So we have a very broad therapeutic window now to give you. Some context five years 14 total BG is a high dose being given interests equally but it's a relatively low dose and comparison to sistema to administer gene therapies. So we actually think that we're likely to have quite a significant benefit.

Mahdi Goudarzi: So we have a very broad therapeutic window. Now, to give you some context, 5E14 total VG is a high dose being given intrathecally, but it's a relatively low dose in comparison to systemically administered gene therapies. So we actually think that we're likely to have quite a significant benefit with that 5E14 dose. Now, if we're seeing a good benefit from that 5E14 dose from a biomarker perspective, and more importantly, from a clinical perspective, we will probably just go ahead with the 5E14 dose in the US study and file on that data.

For the 14 days.

Now if we're seeing a good benefit and that Pfizer 14 dose from a biomarker perspective and more product from a clinical perspective, we will probably just go ahead with the <unk> 14 dose in the.

In the in the U S study and file on that data. If it does we think theres room for improvement we have absolutely the opportunity to go higher if we need to all my guess is we'd probably go for 2014.2015 total BG.

Mahdi Goudarzi: If, indeed, we think there's room for improvement, we absolutely have the opportunity to go higher if we need to. And my guess is we'd probably go from 5E14 to 1E15. We have that possibility of doing that. The study design for the US is not fully finalized yet, and I think it's fair that we're going to learn a little bit from the Canadian study before we actually finalize the design of the US study. But 5E14, I think, is likely to be good enough. But if there's any potential room for improvement, we absolutely have a scope to go up to 1E15. Great, thank you.

So we have the possibility of doing that the study lines to the U S is not fully finalized yet and I think it's fair that we're going to learn a little bit from the Canadian study before we actually finalize the design of the U S study, but $5.14.

Think is likely to be good enough, but if there is any potential room for improvement and we absolutely have the scope to cut to the $115.

Great. Thank you.

Thanks, Mike.

Operator: Thank you. Our last question comes from the line of Kristen Kluska with Cantor Fitzgerald. Hi, good morning. Thanks so much for taking my question. For the GAN program, could you please discuss what you hope to see in some of the assessments beyond MFM32, including muscle strength and brain imaging, especially in light of the understandings and the correlation that were reported with MFM32, including in the recent BRAIN publication, and I guess specifically what signals would help you further validate that the gene therapy is slowing down the disease progression? Thank you.

Thank you. Our last question comes from the line of Kristen <unk> with Cantor Fitzgerald. Please proceed with your question.

Hi, good morning. Thanks, so much for taking my question for the Gan program could you. Please discuss what you hope to see on some of the assessments beyond Amazon 32, including muscle strength in brain imaging, especially in light of the understandings and the correlation that were reported with.

Amazon 32, including in the recent brain publication, and I guess, specifically what signals would help you further validate that the gene therapy is slowing down the disease progression. Thank you.

Kristen Kluska: Hey, Kristen, good morning. So, yes, I'll turn it over to you. I think probably some of the best data that we have is something that we just recently shared, particularly around visual acuity. I think that particular endpoint is going to be extremely clinically meaningful to patients because it's such a quality of life endpoint. And so yeah, so maybe touch on that and then some of the other endpoints that Kristen discussed. Sure. Thanks for the question, Kristen.

Hey, Kristen good morning.

So, yes, I'll turn it over to you I think probably some of the best data that we have.

Is it something that we just recently shared particularly around visual acuity I think that particular endpoint is going to be extremely clinically meaningful to patients because it's such a quality of life endpoint and so yes, so maybe touch on that and then some of the other endpoints that.

That Kristen discussed.

Sure. Thanks for the question Kristen and.

Mahdi Goudarzi: Sure. Thanks for the question, Kristen. And, you know, I could probably spend a good 10 or 15 minutes talking about this. There's such a wealth of data being collected in this NIH study. It's really, it's really remarkable. So we've seen the MFM32, which is, I always describe it as the chopping 10, but for older children. You've got three domains, looking at central strength, proximal muscle strength, so our shoulders and hips, and distal strength, fingers and toes.

It's probably spend a good.

Hello, 50 minutes talking about list their assignment such a wealth of data being collected and this NIH studies is really.

It's really remarkable.

Yeah.

So we've seen the NFL 32, which is I always describe it as the chop intend with older children.

You've got three domains looking at central strengths proximal muscle strengths of our shoulders and hips.

Real strength fingers, and toes and we see clear stabilization of disease at the meeting.

Mahdi Goudarzi: And we see clear stabilization of disease at the medium-low and the medium-high doses in this progression. The MFM32 drops by eight points a year in kids with GAN. This is a clinically significant decline every year. Four points, don't forget, is deemed to be clinically meaningful. And we show clear stabilization of disease at that medium-low and the medium-high doses.

Low in the making high dose in this progression and necessity it drops by eight points a year and kids with Gan. This is a clinically significant decline every year for points for gas is deemed to be clinically meaningful I wish a clear stabilization of disease.

Not making low in the medium and high dose in conjunction with that as already mentioned, we have now presented data on vision and visual acuity and specifically will look us in the Covid a lot more scale LNG Ma.

Mahdi Goudarzi: In conjunction with that, as I already mentioned, we have now presented some data on vision and visual acuity. And specifically, we look at something called the LOGMAR scale, L-O-G-M-A-R. This is a bit like the Snellen chart. You know, when you go to the optician, you sit there, and you read the letters on the wall. LOGMAR does this, but in a more rigorous kind of research-focused manner.

This is a bit like the smell and shot you know when you guys got tissue and you sit there and you recollect this off the off the wall at the local mall does this but in the more rigorous.

Kind of research focused manner.

Mahdi Goudarzi: And what we've seen in patients that have been treated, we've seen a dose-response difference in stabilization of the LOGMAR. So, children who have... Ghan. Their vision deteriorates over time, and it's one of the most significant, most worrisome clinical effects. I think one of the things that parents and families worry about so much is the fact that the child loses their ability to see, because more than anything, it means they stop being able to communicate in the same way, as they're also losing their ability to articulate words and hear, for example.

What we've seen in patients that have been treated with a dose response difference instead or rest of the lockbox, so children, who have GAAP.

That vision deteriorates over time, and it's one of the most significant less worrisome clinical.

<unk>.

One of the things that the Paris of foreigners worry about so much that the child.

Loses their abilities to see because more than anything it means they stopping us communicating the same way as that also losing their ability to articulate words and here for example says very troubling for the patient and family perspective.

Mahdi Goudarzi: So it's very troubling from a patient and family perspective. And what we see, and there's a nice slide in our corporate deck now, you see that a LogMath score of about 0.3 is when you need glasses; a score of about 0.6 is when you have significant visual deterioration. When you're hitting about 1.3, that's when you're legally registered as being blind. And for the vast majority of patients, apart from one outlier in our data set, the LogMath scale deteriorates over time and progresses towards blindness. When you treat it, you actually halt the decline.

And what we say there is a nice slide in our corporate debt now you see that local score of about <unk> <unk> when you need glasses.

Score of about <unk> six is when you have significant visual deterioration when you're hitting.

About one three thats when youll legally registered just being blind after the vast majority of patients apart from one outlier in our dataset to love more scale to terrorists overtime are progressing towards blindness. When you treat holds.

Halt the decline so similar theme, except thirty-two official QTS declining you treat a sublease stabilizes apps.

Mahdi Goudarzi: So it's similar to the MFM32 where visual acuity is declining, you treat it, and then suddenly it stabilizes out at the level of function. So you are preserving vision for, you know, for the duration in these children. Certainly, we've seen a significant duration of visual preservation in this particular study. So vision is key.

Level assumption, so you're preserving vision.

For yeah.

For the duration in these children certainly we've seen a signal generation of visual preservation in this particular study submission is key.

Mahdi Goudarzi: In terms of other endpoints, we're looking at neuropathy type scores and looking at sensation. My guess is that sensation is going to improve or stabilize, but it's one of those. Parameters that are quite hard to measure. You also alluded to muscle strength. My guess is that muscle strength will also improve in already stabilizing the deterioration myometry will stabilize, and I think that's also true for some of the other motor assessments such as the timed 10-minute walk test, the 74-step plan, etc.

In terms of other endpoints, we're looking at.

Neuropathy type scores sensation. My guess is the sensation is going to improve or stabilize but it's one of those.

Parameters, that's quite hard to measure you also alluded to muscle strength. My guess is that muscle strength will also improve.

Already stabilized and to share our leg deterioration in myeloma will stabilize and I think that's also true with some of the.

Motorists estimate session at times.

Mahdi Goudarzi: Karsten and the team were also looking at respiratory muscle strength, and I anticipate once again that the force fiber capacity will stabilize out the way the MFM stabilizes out, and I say these things with confidence because all of these assessments are highly, highly correlated in the natural history study in the brain paper that you mentioned earlier. Now, in addition to the clinical measures, we're also doing a number of tests in the study as well.

Costa and the team were also looking at respiratory muscle strength and I anticipate once again that.

The full swap capacity it will stabilize out of the way then it stabilizes out.

These things with confidence because.

All of these assessments are highly highly correlated in.

The Nash Nash natural history study and the brain paper, but you mentioned earlier now in addition to the clinical message. We're also doing a number of tests in the in the study as well so we're fully nerve conduction studies.

Mahdi Goudarzi: So we're performing nerve conduction studies, i.e., looking at electrophysiology, looking at MRI scans, and also, importantly, we're performing biopsies in these patients too. I am looking forward to seeing how the data pan out, but my guess is the vast majority will reflect and mirror what we've seen with the MFM30.

Electrophysiology looking at MRI scans and also importantly, we're performing biopsies in these patients too.

I am looking forward to seeing how that based upon that but my guess is the vast majority of it will reflect in there what we're seeing is at the end of sensors.

Operator: Thank you. Ladies and gentlemen, that concludes our question and answer session. I'll turn the floor back to Mr. Session for any final comments.

Great. Thank you for taking my question.

Thanks Kristen.

Thank you, ladies and gentlemen that concludes our question and answer session I'll turn the floor back to Mr session for any final comments.

Mahdi Goudarzi: Thank you, operator. And thanks, everyone, for joining the call today. We look forward to building on the momentum ahead till the end of this year, and I'll continue to keep you updated on our progress throughout the remainder of this year. Operator, we'll turn it back over to you.

Thank you operator, and thanks, everyone for joining the call today, we look forward to building on the momentum ahead.

Till the end of this year and will continue to keep you updated on our progress throughout the remainder of this year.

Operator.

We will turn it back over to you.

Operator: Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.

Thank you. This concludes today's conference you may disconnect. Your lines at this time. Thank you for your participation.