Taysha Gene Therapies, Inc. (TSHA) Earnings Call Transcript & Summary

Welcome to the Taysha Gene Therapeutics -- Therapies GAN Program Update and 2023 Corporate Outlook Conference Call. [Operator Instructions]. As a reminder, this webcast is being recorded today, January 31, 2023. I will now turn the call over to Dr. Kimberly Lee, Chief Corporate Affairs Officer. Please go ahead.

Thank you, Sherry. Good afternoon, and welcome to Taysha's GAN Program Update and 2023 Corporate Outlook Conference Call. Earlier today, Taysha issued a press release providing an update on the TSHA-120 program in giant axonal neuropathy or GAN, and corporate outlook for 2023. A copy of this press release is available on the company's website and through our SEC filings. On this call, we will review the regulatory feedback from FDA on our giant axonal's neuropathy program, discuss next steps for it and provide a corporate overview for 2023. Joining me on today's call are Sean Nolan, Taysha's CEO; and Sukumar Nagendran, President and Head of R&D. We will hold a question-and-answer session following our prepared remarks. Please note that on today's call, we will be making forward-looking statements, including statements relating to the existing clinical data and the therapeutic and commercial potential of GAN and our investigational product candidates. These statements may include the expected timing and results of clinical trials for our product candidates and the regulatory status and market opportunity for these programs. This call may also contain forward-looking statements relating to Taysha's growth and future operating results, discovery and development of product candidates, strategic alliances and intellectual property as well as matters that are not of 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 product candidates or dependent upon strategic alliances and other third-party relationships, our ability to obtain patent protection for 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, January 31, 2023. Taysha takes -- 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, I would now like to turn the call over to our CEO, Sean Nolan. Sean?

Thank you, Kim, and welcome, everyone, to our first conference call of the year. My apologies for the delay, and thank you very much for your patience. I am Sean Nolan, Taysha's Board Chairman and recently appointed Chief Executive Officer. I bring over 30 years of biopharmaceutical operating experience that most recently includes serving as CEO of gene therapy company, AveXis. Subsequent to that experience, I have focused on starting new biotech companies, several of which are in the gene therapy arena, including Taysha, where I've been involved since its inception. I'm excited to join Taysha in an executive and operational role at such a dynamic time in our journey. I'm energized to work with the team to expedite progress on our two lead clinical programs in GAN and Rett syndrome as well as further advance our strategic partnership with Astellas. Today, I will begin by providing a brief corporate outlook for 2023. Then Dr. Sukumar or Sukumar Nagendran, President and Head of R&D of Taysha, will provide an update on our clinical development programs. Following this, I will provide closing remarks before opening the call up for questions. 2023 will be a critical year of execution for Taysha, as we expect to deliver on several key milestones including the generation of first-in-human adult clinical data in Rett syndrome, the submission of a clinical trial application, or CTA, to the United Kingdom MHRA to enable initiation of a pediatric Rett syndrome study and an IND application to the U.S. FDA for Rett to further expand our clinical footprint for that program. Since Suku and I joined the company in mid-December, we have conducted a thorough review of our organization and business. And recently implemented operational, structural and personnel changes to enhance information flow, coordination, decision-making and execution to ultimately help us achieve the significant opportunities ahead of us and deliver on our commitments to key stakeholders, especially patients. Operational actions taken include cross-functional team formation, meeting cadence changes and modifications to governance structure intended to improve coordination, collaboration and facilitate information flow. Steps were also taken to further rationalize headcount and expense. Organizational structure was consolidated, flattened and further modified the streamline decision-making and bolster accountability. Personnel changes included both reductions in some areas and expansions of responsibility in other areas to facilitate company execution. I believe that the operational, structural and personnel actions recently implemented position us well as we endeavor to execute across our near-term milestones. For our GAN program, we received the written formal meeting minutes from the FDA following completion of our Type B end of Phase II meeting. We recently submitted follow-up questions to the agency to clarify some of the recommendations, including the feasibility of a proposed study design and the totality of evidence required for BLA submission. We are awaiting further feedback, which should help inform next steps for the program in this ultra-rare indication with no approved treatments. We look forward to working with the FDA on next steps for this program. I should note that our colleagues at Astellas did attend the Type B meeting and are fully aware of our planned next steps. For our Rett syndrome program, we have implemented changes following our business review to improve operational efficiency, and we are confident that we have the appropriate clinical development plan in place to advance TSHA-102 in a more expeditious manner. We look forward to executing across the updated timelines that Suku will review shortly. I will now turn the call over to Suku to provide a more in-depth discussion of our GAN and Rett syndrome programs. Suku, a Director on Taysha's Board and an accomplished physician, drug developer and biotech executive, was recently appointed President and Head of R&D. Suku?

Thank you, Sean, and good afternoon, everyone. I'm excited to join Taysha's management team as we strive to advance the development of potentially life-saving or life-changing treatments for monetary disorders of the central nervous system. Notably, our two lead clinical programs in GAN and Rett syndrome. I bring over 30 years of medical experience, most recently, including serving as President of R&D and Chief Medical Officer, at Jaguar Gene Therapy and previously Chief Medical Officer of AveXis, both gene therapy-focused companies. Today, I will begin with an update on TSHA-120 for the treatment of GAN. As Sean mentioned, we recently received the former written meeting minutes from the FDA following completion of our Type B end of Phase II meeting on our GAN program. The FDA agrees that the available data and the overall approach for the -- approach to the manufacturing of pivotal or to the marketed product was deemed appropriate, pending review of a planned submission of the chemistry manufacturing and controls, or CMC package for TSHA-120. We believe the extensive long-term clinical data generated to date for TSHA-120 are encouraging and support the disease-modifying potential of the therapy. The agency acknowledged moderate efficacy of TSHA-120 and that the MFM32 is an acceptable endpoint with the recommendation that additional patients be dosed in a double-blind placebo-controlled trial. The FDA indicated that the effort driven motor function measure MFM32 endpoint may have subjective bias unless evaluated in a blinded trial. As a reminder, GAN is an ultrarare novel neurodegenerative indication with no approved treatments or established regulatory pathway. The MFM32 endpoint was proposed, based on its use as a validated scale for motor function measurement and other regulatory approvals for indications in neuromuscular disease. It uses a 32-item scale to clinically assess the severity and progression of motor function across the broad spectrum and in three functional domains, including standing, transfers and ambulation, proximal and axial function and distal function. In addition to using the MFM32 endpoint, we are evaluating the effect of TSHA-120 on the functional and structural aspects of the retina and the optic nerve, given that patients with GAN experience deterioration of visual acuity, along with optic nerve degeneration over time. We are appreciative of the thoughtful feedback from the FDA and the collaborative dialogue regarding the potential registrational path to bring TSHA-120 patients with GAN, who to reiterate have no approved treatment. After fully reviewing the formal meeting minutes, we recently submitted follow-up questions on the recommended study design and the totality of evidence required for BLA submission. We are waiting their response and expect to provide an additional update when agency feedback is provided. We look forward to working closely with the FDA to assemble the most robust data package possible for registration. Now let's turn to TSHA-102, our gene therapy program for the treatment of Rett syndrome. TSHA-102 utilizes an innovative miRNA responsive auto-regulatory element or miRARE platform to regulate transgene expression genotypically on a cell-by-cell basis. The totality of preclinical data presented to date, TSHA-102 represents a robust data package supporting the clinical advancement of a gene therapy program in Rett syndrome. As Sean noted, we have implemented changes to our TSHA-102 physical development program following our business review to improve execution efficiency. We are on track to dose the first adult patient with Rett syndrome in the first half of 2023 and expect to share initial available first-in-human clinical data in the first half of this year and on a quarterly basis thereafter, primarily safety-related update. We also intend to submit a CTA to the U.K. MHRA to enable initiation of a pediatric trial in mid-2023. In the second half of 2023, we plan to submit an IND application for TSHA-102 in Rett syndrome to the FDA. I will now turn the call back over to Sean for his closing remarks. Sean?

Thank you, Suku. With the operational and infrastructure changes recently implemented, we believe we are well positioned to execute across our near-term catalysts throughout the year. Looking ahead, our cash runway continues to support currently planned operating expenses and capital requirements into the first quarter of 2024. In summary, we remain highly enthusiastic about the potential portacious innovative pipeline to offer transformative treatments for patients. Our focus throughout this year will be on executing on our two lead clinical programs in GAN and Rett syndrome. With that, I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] Our first question is from Gil Blum with Needham & Company.

Just a couple from us. Assuming you will require a randomized study for GAN, how do you plan to drive enrollment?

So Gil, this is Sean. Let me go first and then certainly ask Suku to just step in and provide his perspective as well. I would say that part of the response that we're looking for the FDA is further stepping through their recommendation on the trial design because we have significant questions about the feasibility of executing a randomized placebo-controlled trial for a couple of reasons. One of them is that you're dealing with very low numbers of patients to begin with. And then when you talk about patients that would meet potential criteria to enter the trial, you're going to further reduce that number. And when you do the statistics on what it would take, mathematically, it looks challenging. So we've shared that information in terms of trying to get clarification from the agency, and we're awaiting their feedback. And I would also say that in parallel with that, what we're doing is we're further undertaking additional analysis around certain aspects of the data collection. So as an example, we're doing different cuts of the MFM32 to see if there's additional supportive information in there. We're looking also at visual data both in terms of things such as OCT, retina layer thickness, visual acuity, et cetera, to see if there could be more objective endpoints to support the MFM, but the FDA did acknowledge -- had moderate efficacy display. So we're stepping through it in parallel. We hope to get more clarity. And as Suku said in his comments, work in concert with the agency to find a path forward for this specific ultra-rare disease state. And in parallel, we're also working to further explore the data that we have that can potentially further augment what's been put in front of the FDA and that totality of data may be able to further our case with the agency. So let me ask Suku if there's anything that he'd like to add.

Sean, I think overall, you captured it quite well. And the only additional detail I would add to that question and response is that, as you pointed out, the number of patients available for a randomized placebo-controlled trial are very few. So it would not be practical trial to operationalize. And also when you run the stack, which you've been doing, the number of patients needed to show certain differences may be too large at the present time. And beyond what Sean identified as data evaluations that we're doing with MFM32 for neuromuscular function and visual evaluations of structure and function in the retina, there is also some very interesting observations around nerve conduction potential. So sensory nerve action potentials have improved in a fair number of patients, which I think is highly unusual in a neurodegenerative disorder. So collectively, I would emphasize, as we await the FDA response to our clarifications and questions, we are evaluating the database that we have from the NIH based on the intervention study and the natural history work we have done to put together a comprehensive clinical package that we hope will -- have promised in making this gene therapy available to patients and their families sooner rather than later.

Thank you for a very comprehensive update on that. And our second question, and this is just to clarify, is it fair to assume that there is a bit of a slowdown here in Rett compared to kind of the earlier timelines disclosed?

Thanks for the question. What I would say is that during our business review, we did find that there were several operational issues that were impacting Rett enrollment. So I would say that there's patients that are very interested, like that's not the issue. The issue is -- and I'll kind of lay it out for you. First of all, there's a legal aspect, it's called a Legally authorized representative or LAR process in Canada. And its specific legal consent required to conduct clinical research studies in patients that are older than 18 years of age, but they cannot make decisions for themselves. So it's somewhat analogous to U.S. power of attorney, but it's specific to research studies in Canada. And there are several steps to the process, and it can take several months. So that's one aspect in terms of impact to enrollment. Another one has been the COVID vaccine requirements. And that obviously, these patients are going to be taking immunosuppressants. And generally, when you have a protocol written, you make sure people are up to date on their vaccines. And when you think about the COVID situation we've all been dealing with, that was included. And what we're finding is that most of the patients aren't vaccinated and they don't want to get vaccinated. And the third thing is that this specific site in Montreal is unable to accept ex-Canada patients. So there's also patients that have been identified in other countries, including the U.S. that want to participate, but the site is not open to accepting them. So what I'll say at a very high level, is that we've taken steps to mitigate these issues. And our goal right now, we're working actively to open up at least one other site that can help us with more of the latter issue. So Suku can give you a little bit more perspective on that, but I just want to be clear, these are operational issues rather than patient number issues. Suku, anything you would add?

Well, no, Sean, I think you've captured the -- I guess the operational inefficiencies that we observed last year quite accurately. And as you pointed out, the teams are working very closely and cross-functionally to really move this trial forward such that we can start gathering safety data and eventually efficacy data in the adult Rett population with our gene therapy product. Back to you, Sean.

[Operator Instructions] Our next question is from Joon Lee with Truist Securities.

I'm sure that when you met with the FDA in December, you must have asked the challenges associated with doing a randomized trial for GAN, what did they say? What were their response to your questions back in December?

The best way for me to answer that would be that they acknowledge the challenges but feel that with MFM32 being effort driven, scientifically the best way to control for that is with the placebo and the randomization. So that's why we wanted to have further discussion to see if there may be ways to step this forward given some of the considerations we've outlined for this ultra-rare patient population. And again, we're also working in parallel to see if there's things we may be able to do to bolster the overall comprehensiveness of the efficacy package to help them as they weigh the evidence that's in front of them. Again, I'll ask Suku if there's more that you would add to that, but that's what happened.

Yes, Sean. So the only thing I would add and with the disclosure that I wasn't at that meeting because I wasn't with Taysha at that point in time. I mean the FDA interaction took place. I think overall, in theory, the quest by the FDA absolutely make sense because of what they've observed with MFM32. But in the bigger picture, when you look at the disease state being ultra-rare, if we have the totality of clinical evidence to make our case, where we find the disease state can be -- the progression of the disease can be slowed down given it's a neurodegenerative disease. But if you treat earlier, potentially the impact could be even greater. So I think as the FDA, and hopefully, we will get a response from them to our queries and questions, we plan on doing all the analysis necessary in close collaboration with members of the NIH and other experts in the field to hopefully have a future interest -- robust discussion on the disease state and the totality of the data. So we have to still wait as we accumulate our data and do the analysis so we can make our case. Back to you, Sean.

Yes. The only other thing I would say is, obviously, we are very respectful and -- to the agency, and they've been very professional and collaborative in the discussions. It's been very transparent and direct. And we're doing everything we can to see if there are other things that we may be able to do to help mitigate some of their concerns about the fact that MFM can be considered upper base. So if there's other things that we can do that are more objective in nature to further augment that when you look at that totality of data in our view and talking with KOLs, there's a definite positive impact on this disease with the product. So we'll do everything we can to make that case.

Our next question is from Whitney Ijem with Canaccord Genuity.

I guess maybe I'll ask a CMC one. It sounded like there was some discussion on the CMC side, though additional data was submitted. So I guess, can you help us understand what the discussion was there? And in particular, I think you mentioned, or it had been mentioned previously that the clinical batch was ready to dose additional patients if that was needed. Is that batch still viable, I guess, based on this discussion you've had with regulators at this point?

So thanks for the question, Whitney. Yes, let me start with the last question first. Yes, the clinical or the new version of the product is available for clinical study. It's been released. So that's ready to go. Overall, the way I would describe it is pretty much what we put in the press release and the script is that the data that was provided to the FDA, along with the plans that we have that would be part of a BLA submission, the FDA was supportive of all that. And essentially, just the language was what you would expect, which is essentially that we want to see the full package, and they'll make their determination at that particular time. So there were no real surprises on the CMC side. Most of the -- I can say, most of the discussion, again, I wasn't there either, but most of the discussion was focused on these clinical matters.

Our next question is from Salveen Richter with Goldman Sachs.

This is Elizabeth on for Salveen. Two from us. So when do you anticipate it's possible to receive feedback from the FDA on your questions? And then hoping that you can help us better understand the cash runway and kind of what exactly is included in that 1Q '24 cash runway number, does that include running the placebo-controlled trial and just helping us kind of quantify some of these changes on your cash position?

Sure. So on the budget question, everything that we've outlined in the press release and the script relative to the Rett studies, for example, filing the CTA, getting that up and running, a U.S. IND in the second half of the year, getting that up and running. The Canadian program that's ongoing and looking at additional sites and getting those going as well as budget for Rett relative to both what would be needed CMC-wise, as well as potentially dosing other patients. We do not have a randomized placebo-controlled trial in the budget, but we have other call it, clinical trial type expenses in there. So we're comfortable with the guidance. And again, I would just state from a feasibility perspective, we don't think that particular design is feasible. To answer your second -- your first question, in terms of timing, with the FDA feedback. I can't put an exact clock on it because it's not a formal meeting. I would anticipate that later in the quarter, we would be able to provide an update on that based on what I understand to be the case now.

Our next question is from Eun Yang with Jefferies.

So GAN program, so you obviously waiting for the FDA's response. But what's your best guess when you may be able to file for approval?

Well, Eun, it's hard to speculate on that simply because I think we have to step through a few more things. So the first would be getting their feedback, we have to digest that feedback and see, is it crystal clear or -- and/or as we've done some additional work, and we continue to do so on the data side, it could be that there may be another step in the discussion before you really have the clarity that you're essentially looking for. So I think the best I can say right now is the next step we should -- we anticipate getting some feedback this quarter, which we would share. And I think that's going to inform next steps. So if you can bear with me, we'll provide that information and more clarity as we have it. But I'd hate to speculate at this particular point in time, given the issues that we're stepping through.

So how does this impact your regulatory plan outside the U.S.?

For GAN? So I think the question was how does this impact our regulatory plans outside the U.S. I would say, right now, our focus is on the U.S. And until that is remedied or the path is very, very clear, we would not step into additional discussions relative to ex U.S. regulatory filings for GAN.

Our next question is from Geulah Livshits with Chardan.

Can you hear me okay?

Yes.

Yes. This is [indiscernible] for Geulah. Just two for us. So trying to understand the response to the FDA that you're waiting on feedback from. So are there any alternate scenarios that you highlighted that would allow you to prepare or file for BLA with the proposed -- with the design that's similar to the Phase II? So for example, did you propose dosing more patients, adding patients, the existing Phase II trial or any other strategies like that to try to I guess, convince them for not having to do an entirely pivotal placebo-controlled trial?

Yes. Listen, I would prefer not to get into the specifics of the FDA meeting in great detail. But I would say that we had fulsome discussions around alternatives. And for right now, the FDA was very focused on MFM32, rightly so. I mean that was where the bulk of the data was focused. And so all the discussion kept going back to if MFM32 is the end point then given the fact that there's effort-based aspects of it, the only thing you can do is a placebo-controlled trial. So hopefully, that gives a little context to some of the discussion and why we'd like to respectfully talk to the FDA about this in a little bit more detail and again, potentially be able to bring additional information to further augment what they've seen as well.

Our next question is from Kristen Kluska with Cantor Fitzgerald.

The one that I had is, assuming you do need to have a placebo-controlled design, how would you expect the placebo arm to perform in light of the work that's been done around natural history?

Well, I'll let Suku answer the specific question. I just would go back to the fact that we are questioning the feasibility of even doing this type of a study given the patient population and given the statistical plan that you would have to do. So if you don't have the right number of patients and the right stats, doing the study really wouldn't be a worthwhile endeavor. So I'll pause there and turn things over to Suku for his comments.

Yes. Thanks, Sean. So when we look at natural history for GAN, what has been observed is that there is a significant decline in multiple components of the MFM32, which evaluate both fine and gross motor function. So I would anticipate the placebo arm if a randomized trial was ever done in this ultra-rare disease would follow the same patent. So if you look at MFM32, over a course of time, I think there's almost a 9-point drop over the first year and second year and third year and so forth. And something similar has been observed when it comes to the visual evaluations that have been done as well. So again, I don't see placebo performing any differently than the natural history that the NIH has accumulated up to this point in time.

Our next question is from Yanan Zhu with Wells Fargo Securities.

I was wondering, have you had any discussion with regard to these other endpoints like retina, optimal nerve and nerve conduction parameters? Have you raised any of that in your discussion with the FDA? And what's your feeling of their ability to accommodate those kind of readouts? And also just curious, wouldn't having a randomized design, have this issue of compatibility with the immunosuppression regimens for the liver enzyme, wouldn't that kind of partially unblind the study and defeat the purpose of having a blinded study?

Thanks for the question. I'll answer the second one and ask Suku to take the first one. But in terms of the aspect that you're bringing up, which is if you're going to basically have a placebo control, right, there'll be some sham procedure, and you certainly would not give immunosuppression through the placebo group. And so I think it's a very real aspect that you're bringing up, and we agree that functionally, you would be unblinded because you would be able to look at the study participants and determine whether or not they were on immunosuppression. So that is another aspect of this recommended approach, and it is something that we're in dialogue with the agency about. Suku, would you mind taking that first question?

No, absolutely, Sean. My response to that question would be with the caveat that I wasn't at that meeting in December, I know that the team had briefly discussed the visual changes and potentially other structural changes that might take place in the retina. So that is an area that we are obviously evaluating further. Also when it comes to the nerve conduction abnormalities seen in GAN, especially the median nerve and ulnar nerve that they usually do these measurements, there was a brief discussion around the changes in the sensory nerve action potential. So -- but when you talk to experts in the field, the lots of the sensory nerve action potential is consistent and being able to reverse it or restore it, I don't think has ever been really observed before. So these are things that we, as a team and as a company are evaluating further to see if that can be put together as a comprehensive data package for the future for this specific program. Back to you, Sean.

Our next question is from David Hoang with SMBC.

I just wanted to ask, I think it sounded like the -- your Astellas colleagues were present at the meeting. Is there anything -- did they have any input that you can disclose from there? And then given the update that's being shared today, does this impact the -- anything with the option that Astellas has on the GAN program and timing of that option?

What I would say is, again, Astellas was involved in some of the planning going into that meeting. They attended the meeting. They're aware of everything that we're doing. We have a very collaborative relationship with them. I would say we're aligned with them. But that's about all I should say because they should speak for themselves. Specific to the option in the agreement, there is a time bound element to it. And I would say we've never really outlined specifically what that timeline looks like. But what I will say is that we certainly don't want to let the tail wag the dog on something. So if it was that for Astellas to have more clarity based for what the FDA is providing, and it takes a little bit longer than they have been contemplated in the in the original contract, that's something that we would absolutely consider and certainly work to collaborate with them on. We certainly feel it's fair and right that they have to have information to make their decision, and it shouldn't be constrained by what was initially thought of in the agreement. Hopefully, that helps.

Our next question is from Sami Corwin with William Blair.

Based on the GAN meeting, are you reconsidering running the Rett trials as placebo-controlled trials? And then also with regard to the IND plan to file for Rett, would that trial be in adult or pediatric patients? And are you still looking at -- analyzing that TSHA-102 in pediatric male as a possible route to accelerated approval?

Suku, would you mind taking that question?

I will try, Sean. There were, I think, multiple components to the question. So based on my response, if the analyst wants to clarify further, I'm open to that as well. So think of our current plans and as disclosed in the press release, we have an ongoing trial in Canada for adult patients where we are trying to also open a second site. So that is, I think, our efforts to gather data, safety and eventually efficacy in an adult patient population. We are also evaluating going to the U.K. and hoping to file a CTA with MHRA mid-2023. And our plan there is obviously get into the pediatric population because I think even in a neuro developmental disorder like Rett, the current thinking is the greatest impact of an intervention, especially gene therapy, may come in the younger age groups of the patients with the disease process. We've also disclosed that we are evaluating filing an IND in the U.S. in 2023 as well, hopefully, the second half, which will allow us to explore different age groups as appropriate based on our data package that can be given to the FDA. So collectively speaking, we do have a regulatory strategy laid out and now we must execute on that such that the technology that we have, the science that we have in this construct can be fully realized in the first in-human studies and beyond. And hopefully, will have significant clinical impact. But obviously, time will tell as we get to the clinic and gather more clinical data. I hope that kind of answered your question, but if it didn't, please clarify.

Suku, I think part of it was around the need for a placebo control in the Rett trials. And maybe you can talk a little bit about -- that depends on natural history, it depends on endpoints that are being measured.

Yes, absolutely, Sean. I think I missed that question. So the -- so I will -- what I would point out is that if there is robust natural history for a disease state like Rett, then the natural history could serve as a comparator arm in an open-label study design. And ideally, that's where we would like to take this program as we assess the availability of different types of natural history basis that we are aware of. At the same time, with Rett as a disease process, one other design could be that you have a delayed treatment cohort where you have, hopefully, you can follow, you can do the randomization at 3:1, 2:1, whatever the expenses are appropriate based on the statistical poof the study. And then with the delayed treatment arm, then you intervene, and then you see if you can show a difference in the catch-up over time, but then use the delayed treatment arm as your control arm to the treated arm with the product. So that is something that could also be applied depending on or not whether the natural history is strong enough. So stay tuned as we do the evaluations and complete our protocols for submission this year and in the future. Anything else you would add?

The only thing I would add is that the delayed treatment is -- protocol is what we're using up in Canada. And so we're stepping through, as Suku said, protocol design for the U.K. and the U.S., and we'll take all the most recent information into our consideration as we step it through. But every disease states different. I don't think you can take a look at what the FDA may be asking for in this particular circumstance with GAN and what's driving them there is the MFM as an end point. So if you have more objective other endpoints and/or have very strong natural history, as Suku said, you may not need to do something like that or you can consider a delayed control. The last part there was around studying males. And right now, our focus and given the fact that we have to prioritize our capital and our resources, the broadest population in need is the females, and that's where we would conduct our trials initially. Next question?

Our final question is from Silvan Tuerkcan with JMP Securities.

So maybe could you just get some more color on how I -- if I were to paraphrase your approach to GAN. So to me, it sounds as if -- and considering also your cash guidance that if the FDA keeps on insisting on a placebo-controlled trial here, would that be the end of the GAN program for you? Or would you leave it over to Astellas to pick it up if they wanted to? Is that correct? Or would you go ahead and try to run that placebo-controlled trial?

Well, I would -- that's a good question. And what I would say is that if that were the case, we -- what we would do is reassess strategic options for the program. and determine the best path forward for patients and for the company. Hopefully, that answers your question.

We are out of time. So I would like to hand the conference back over to you, Mr. Nolan for closing comments.

Thank you again for joining us on the call. I wish you all a happy and healthy new year. Enjoy the rest of the day. Thank you.

Thank you. This does conclude today's conference. You may disconnect your lines at this time, and thank you for your participation.