Welcome to the Taysha Gene Therapies First 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, May 11, 2021. I will now turn the call over to Dr. Kimberly Lee, Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

Good morning, and welcome to Taysha’s first quarter 2021 financial results and corporate update conference call. Joining me on today’s call are RA 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 the question-and-answer session and instructions will follow at that time. Earlier today, Taysha issued a press release announcing financial results for the first quarter ended March 31, 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 candidates. 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 Taysha’s manufacturing plans. 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 fact or information. Various risks may cause Taysha’s 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. 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, May 11, 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 laws. With that, I’d now like to turn the call over to our President, CEO and Founder, RA Session II.

Thanks, RA. As RA mentioned, Taysha has a robust portfolio of 26 gene therapy product candidates for monogenic diseases of the CNS. Our candidates target broad therapeutic categories of immense unmet medical need, including neurodegenerative diseases, neurodevelopmental disorders and genetic epilepsies. We have recently added TSHA-120 for the treatment of giant axonal neuropathy or GAN to our pipeline, making it our most advanced program. We believe the preclinical and clinical data generated to date hold significant promise for GAN patients. Preclinical studies have demonstrated strong proof-of-concept data for both the construct and the delivery modality. TSHA-120 performed well in preclinical studies demonstrating improved motor function and nerve pathology and long-term safety across several animal models. Preclinical data also demonstrated that TSHA-120 showed a significant improvement in the pathological appearance of the dorsal root ganglia, a key component of disease progression. DRG inflammation is a topic that has been the focus of much discussion within gene therapy circles in recent months. This is because it has been observed as a histopathological finding in some non-human primate gene therapy studies, although the NHPs exhibited no functional compromise. Interestingly, in down and in the majority of diseases in our neurodegenerative franchise, the DRG have a significantly abnormal histological appearance and function as a consequence of underlying disease pathophysiology. Thus, it was not surprising that when treated with TSHA-120, we saw considerable improvements in the pathological appearance of the DRG in the GAN knockout mice. We are fortunate that in addition to robust preclinical results, those considerable natural history that provides us with patient data to identify optimal marcus and endpoints for a clinical trial. To date, there are data in 45 GAN patients that demonstrate an average 8-point decline per year in the MFM32 scores that are consistent across patients of all ages.…

Thank you, Suyash. This morning, I will discuss key aspects of our first quarter 2021 financial results. More details could be found in our Form 10-Q, which will be filed with the SEC shortly. As indicated in our press release today, R&D expenses were $23.9 million for the first quarter ended March 31, 2021, compared to $5.5 million for first quarter ended March 31, 2020. The increase was primarily related to the company’s development program as a result of increased manufacturing related spend, clinical and preclinical activity and headcount. G&A expenses were $8.2 million for the first quarter ended March 31, 2021 compared to $0.07 million for the first quarter ended March 31, 2020. The increase was primarily due to an increase in personnel costs, resulting from increased headcount, professional services fees, and other corporate related expenses. Net loss for the first quarter ended March 31, 2021 was $32 million or $0.87 per share as compared to a net loss of $5.4 million or $0.50 per share for the first quarter ended March 31, 2020. As of March 31, 2021, Taysha had $228.7 million in cash and cash and equivalents. We continue to expect that our working capital will be sufficient to fund our operation into 2023 inclusive of the development, regulatory and operational milestones RA and Suyash have outlined today. And with that, I will hand the call back to RA.

We’ll now begin the question-and-answer session. [Operator Instructions] The first question comes from Salveen Richter from Goldman Sachs. Please go ahead.

Good morning. Thanks for taking my questions. So one question here about – good morning. One question here about capital and resource allocation as you’re running multiple trials building out a GMP facility and hiring employees. So how should we think about that over time? And secondly, with regard to the Rett program, maybe if you could touch on the registration path here and what you’d like to see from that first clinical data set to inform the pivotal program.

Absolutely. Thanks, RA and thanks for the question, Salveen. Yes. So for Rett syndrome, I think we’ve been spending a lot of time thinking about the clinical development program and the pathway to approval. And we’re going to take a slightly more cautious approach for some of our other conditions such as GM2, CLN1 GAN where the diseases are a little less common and where there is an ongoing relatively high-risk of mortality quite early on. So the way we think about Rett is that the first study of a group of two will be more of a Phase 1/2 primarily safety study with some exploration of preliminary efficacy. Following on from that, you will then perform a Phase 2/3 study, which focuses – it takes learnings from the initial Phase 1/2 study, take the learnings from that and applies it into a more expensive Phase 2/3 pivotal efficacy study. Now with regard to the first study, the Phase 1/2 study likely we’ll be do hit all older patients. As you know, FDA tends to push you away from children towards adults first and in this particular situation, we actually tend to agree with that approach. There are these risks of toxicity with over-expression of MECP2. So we just have to be quite mindful when we design this initial study. So the first study will be Phase 1/2 clinical pivotal safety, primary efficacy in the adult population in terms of endpoints will be looked at the safety aspects of safety initially. And then we’ll be looking at efficacy really in three different buckets. The efficacy will be looked at, firstly with a number of the different Rett-specific clinically rated scales, for example, the Rett syndrome motor behavior assessment, the Rett syndrome behavior question are. So they are the Rett scales, we’ll also be looking at seizures in some detail because children with Rett syndrome have significant seizure activity. So we’ll be looking at how frequent the seizures are, how many medications on, what triggers the seizures, how durable the seizures are and over time, hopefully will be able to see a reduction in seizure activity and bring them off medications and also see an improvement in the EEG. And then the third bucket kind of assessments will include a general multi systemic, multi-organ type aspects of Rett syndrome disease characteristics, such as the respiratory assessments, which, as you know, you have respiratory rhythm in Rett syndrome, sleep apnea issues, cardiac issues such as QT prolongation. So I think that the first, once again, will look at safety initially and some of these areas of preliminary efficacy, we will build on that and design the Phase 2/3 study subsequent to that. As we’ve already talked about, we’ll be engaging with regulatory agencies during the course of this year to pressure test our thinking around these particular plans, and we’ll be starting the clinical study towards the end of the year.

Thank you.

The next question comes from Matthew Harrison from Morgan Stanley. Please go ahead.

Good morning, this is Thomas on for Matthew. Can you give an update on where you are with manufacturing for the GAN program, in particular, what sort of assay work do you still need to complete? Thank you.

Yes, thanks, RA. Thanks for the question, Matthew. Yes, obviously we’re in the process of onboarding the GAN program. And so where we’re really beginning is with the assays, reviewing the assays that were conducted by the NIH for the Phase 1, Phase 2 two clinical material, and what our intention is just try to update those methods to qualify and then validate them to prepare for a late-stage pivotal work. So, we’re actively engaging on all the critical quality attributes assays with our partners to move that forward with our CDMO. In addition, we’re looking very deeply into the potency assay development work, and this is something that’s happening, jointly between Suyash’s group and my own to move forward a potency assay very quickly to kind of synchronize a fully developed and qualified potency assay with pivotal lot manufacturing. I’m happy to answer any questions about that?

[Operator Instructions] Then one, the next question comes from Raju Prasad from William Blair. Please go ahead.

Hey guys, thanks for taking a question. Congrats on the progress. I’m kind of looking down your pipeline and I see a lot of the technologies that you’re de-risking from a payload perspective, the miRARE platform, the bicistronic vector, I could see follow-on indications once those technologies are derisked. But my question was more on the regulatory side. As you’re kind of dealing regulators on these different indications, what types of aspects of the programs do you think will be derisked by clinical data there? Is it on endpoints and deal with endpoints with the FDA? Is it on the IT administration? Maybe some color there would be great. Thanks.

Thanks, RA and thanks Raju for the question. Yes, there’s lots and lots of commonalities, I think, between our programs, over and above the simple – the trifecta of comments we about AAV9, HEK239 and IT administration. There’s many, many other commonalities, I think we shared and we – as a platform more than anything. Let me touch on a couple of things – I think we’re going to learn a huge amount from just one program to inform the next. There’s a lot of debate in the field about IT versus ICM versus ICV and several contribution between them all. I keep coming back to the perspective that IT administration works has worked for decades. I’ve given it myself in the world of oncology and anaesthesiology and it’s worked for decades there. When you look at the clinical data from GAN from CLN3, CLN6, and another in Zolgensma, you see it works, and it works beautifully. And I think as we continue to build our portfolio of programs, we can really I think the FDA and other regulators will just become increasingly comfortable with intrathecal administration. And there’s many nuances around that, but many details. For example, we spent some time yesterday talking about a different type of think kits you might use to give intrathecal drug and the comparability – compatibility test you might need to do for some of these different methods of administration. So I think there’s lots and lots of learning, in particular from GAN that will inform the rest of our portfolio. Another piece of learning, I think that’s important from GAN and as our programs progress, just on the immunosuppression regime we like to use. So the whole world of the immunology of gene therapy has evolved and evolved rapidly over the past…

Yes, that’s extremely helpful. Maybe just a quick follow-up on that last point. As it relates to the upcoming FDA discussions on the GAN program, how should we be looking at the results of those discussions as it relates to the potential request from the FDA. I’m thinking particularly about natural history comparator versus having to run a placebo arm or control treated arm. I mean is that something that you’re looking to see kind of as to extrapolate to the rest of the pipeline? Like if they do give you a natural history comparator for pivotal, that’s something that you might try for GM2 and some of the rare diseases? Or do you think that the discussions on GAN are only going to be related GAN and each individual indication will probably be a different – kind of a different kind of discussions with the agency. Thanks.

So it’s a really important point. The – how much data are already existing for a particular disease. And it’s – there are certainly commonalities there from proven the program, but there are also some subtle differences, and we’re doing things a little bit differently from program to program. What I will say is a higher level is some very nice guidance that was published by the FDA on gene therapy development for neurodegenetive disease and have a specific section on natural history study in historical controls. They said very clearly, this may be appropriate for gene therapy product to treat a rare and serious neurodegenerative disease. If there’s a clear unmet medical need, which is absolutely the case for most of our programs, where the inclusion of current control is not practical or ethical, which is also true, certainly for programs like GM2 or CLN1, where there is ongoing higher risk of mortality. They also talk about the disease course is well documented. And the expected treatment effect is large, it may be very, very suitable to use a natural history comparator as a control. Now for GAN, specifically, we have 45 patients, in fact, more than that, we’ve presented data of 45 patients in the natural history study with data, that patients were enrollments in 2013. So it’s rates of [indiscernible] (0:47:23) data on some of these patients. And we’ve got very, very clear indication that there’s a consistent drop in the primary efficacy endpoint, the MFM32 8 points per year. I think because of that, it’s also predictable. The disease course is predictable. And so for GAN, very rare disease. With – and we’re seeing a very nice treatment effect in our international study. So all those things really contribute to the fact that for GAN, in…

No, that’s extremely helpful. Thank you for the question.

The next question comes from Eun Yang from Jefferies. Please go ahead.

Thank you. Thank you. So today, when we talk about address the patient population for your gene therapy programs, it’s been kind of a focus on the U.S. and Europe. But now you look to potential approval of TSHA-120 in 2023, what are you thinking about the market opportunity outside the U.S. and Europe?

Thank you. And I have one more question on Rett syndrome program. So I’m sure that you’re familiar with the Novartis program. And I don’t know how much you can speak about it, but aside from your program, potentially have a better regulation of the transgene expression. Can you talk about kind of a differentiation compared to Novartis, and Novartis actively pursuing their Rett program? Thank you.

Yes. Thanks, RA, and thanks for the question. I think it’s an important question. As RA mentioned, the only – the major difference really is the fact that we include – we have the mini MECP2 gene, which was developed by Professor Sir Adrian Bird and very esteemed and ineligible Rett experts from Edinburgh who was actually first person to demonstrate unequivocally that Rett syndrome is a highly reversible disease. So we use his design for the mini MECP2 gene. And then we attach this strip of micro RNA binding sites, the miRARE platform, which stands for micro RNA a responsive of auto regulatory element. So when MECP2 levels go up within the sale as a consequence of the gene therapy, the down regulatory micro RNA binding sites are triggered, they bind to this miRARE platform, which is in the untranslated region of the construct and bring down levels of MECP2, as RA suggested, acting as a safety valve. Now we’re very excited to be able to say to you that the first quantitative data demonstrating this reduction in MECP2 expression to the point where you have enough so it’s efficacious, but not too much that is toxic, was published in brain, which is a very prestigious [indiscernible] (0:55:16). It went online on Friday, and we issued a press release yesterday. And I would encourage you to look at the paper, the lead author is Sara Sonet and senior authors are good friend and colleague, and our Chief Scientific Adviser, Steven Gray, there’s a particular diagram in that paper, which I’d suggest you look at, which looks specifically at different levels of expression of MECP2 in different parts of the brain in different parts of the spinal cord. And you can see very nicely that the non-miRARE construct over expresses whereas the miRARE construct expresses enough so that it is efficacious, but not toxic. So we’re very excited about that fixer paper. So I think that’s the main difference. The fact that we can demonstrate this – the ability to express MECP2 within these normal physiological parameters now we’ve shown in different parts of the brain, and we’ve shown it quantitatively as well. My understanding is that Novartis is still moving forward with that program. Last I heard was the planning to move forward as an IND, but I don’t know exactly where they are with that. But I think that’s the main difference really between our products unless.

Thank you for the details.

There are no further questions. I will now turn the call over to Mr. Session for his closing remarks.

Ladies and gentlemen, this concludes today’s presentation. Thank you once again for your participation. You may now disconnect.