PTC Therapeutics - Q3 2023

Transcript

Operator (participant)

Thank you for standing by, and welcome to the PTC Therapeutics third quarter 2023 financial results conference call. At this time, all participants are on a listen-only mode. After the speaker's presentations, there'll be a question-and-answer session. To ask a question at that time, please press star one one on your telephone. Please be advised today's call is being recorded. I will now turn the call to your host, Jane Hanlon, Associate Director of Investor Relations. Please go ahead.

Jane Hanlon (Associate Director of Investor Relations)

Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' third quarter 2023 corporate update and financial results. I'm joined today by our Chief Executive Officer, Dr. Matthew Klein, our Chief Business Officer, Eric Pauwels, our Chief Commercial Officer, Kylie O'Keefe, and our Chief Financial Officer, Pierre Gravier. Today's call will include forward-looking statements based on our current expectations. Please take a moment to review the slide posted on our investor relations website in conjunction with the call, which contains our forward-looking statements. Our actual results could materially differ from these forward-looking statements, as such statements are subject to risks that can materially and adversely affect our business and the results of operations.

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q and annual report on Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP are available in today's earnings release. With that, let me pass the call over to our CEO, Matthew Klein. Matt?

Matthew Klein (CEO)

Thank you, Jane. Good afternoon, and thank you all for joining the call. I'm pleased to share our third quarter results and outlook for the remainder of the year, including an update on our development programs. I will begin with the recent announcement of our agreement with Royalty Pharma to monetize up to $1.5 billion of the Evrysdi royalty stream. This non-dilutive financing provides PTC the capital to support planned operations and allowed us to retire the Blackstone debt obligations. In addition, the deal structure includes flexibility for accessing additional capital over the next two years. Notably, PTC maintains its rights to the remaining $250 million of milestones related to the Evrysdi global net sales.

The royalty financing deal, along with the operating expense reductions announced in September, put PTC on very strong financial footing as we continue to focus our resources on our differentiated, high-potential R&D programs and robust global commercial infrastructure. Now I'll turn to our third quarter results. We had another solid quarter, with total revenue of $197 million, which keeps us on target for meeting our 2023 total revenue guidance of $940 million-$1 billion. Our DMD franchise revenue in the quarter totaled $136 million. This strong performance allows us to update our 2023 DMD revenue guidance to between $565 million and $595 million, from between $545 million and $575 million.

Eric and Kylie will provide additional details on our commercial performance shortly. I'd like to now provide an update on recent regulatory activities for several of our programs. Let me begin with an update on Translarna. Following the negative opinion from the CHMP on the conversion of the conditional marketing authorization to full marketing authorization and on the renewal of the conditional authorization, CHMP gave us the option to request reexamination of both opinions or only one opinion.

\We decided to pursue reexamination of the negative opinion on renewal of the conditional authorization only. As such, the reexamination process will focus solely on the allowance of continued conditional authorization of Translarna in Europe. We remain optimistic that we can address key concerns raised by the CHMP on the evidence of benefit in the Translarna clinical trials, as well as concerns raised on the methodological robustness of the STRIDE data analysis.

As previously discussed, in accordance with EMA guidelines, we expect the opinion from the reexamination procedure in late January, with adoption of that opinion by the European Commission 67 days later. The US, a Type C meeting with FDA to discuss a potential path to NDA resubmission, is scheduled for this quarter. Turning to sepiapterin, we held a pre-NDA meeting in the third quarter with FDA to discuss the NDA submission. At the meeting, FDA stated that the sepiapterin clinical safety and efficacy data supported NDA submission for the treatment of pediatric and adult PKU patients. However, they requested that we complete a 26-week non-clinical mouse study to assess potential carcinogenicity risk of sepiapterin prior to submission. This non-clinical study was initially not required when sepiapterin was acquired from Censa, as the NDA submission was planned under the 505(b)(2) pathway.

With our decision to file under the 505(b)(1) pathway, the 26-week study is considered a required NDA component if needed to inform labeling. We will continue to discuss with FDA the potential to submit the mouse study results during the NDA review process. We now expect NDA submission to occur no later than the third quarter of 2024. The submission could occur in the second quarter if FDA allows submission of the non-clinical study report during the review process. For the EU, we expect to submit a marketing authorization application to EMA in the first half of 2024. The delay in NDA submission in no way mitigates the strength of the APHINITY data.

Given the highly meaningful clinical effects observed in the trial, as well as the continued evidence of providing phenylalanine tolerance benefits to the full spectrum of PKU patients in the long-term open label extension study, we remain incredibly enthusiastic about the potential billion-dollar-plus global commercial opportunity for sepiapterin. Moving to the PTC518 Huntington's disease program, enrollment is ongoing in the PIVOT-HD study for both the stage two and early stage three cohorts. We expect the next data update to occur in the first half of 2024. This update will include 12-month data on the initial group of subjects on whom we reported data in June of this year. Regarding the status of the trial in the United States, we had a Type A meeting with FDA to discuss the clinical safety data needed to enable resumption of enrollment of the PIVOT-HD trial at U.S. study sites.

At the meeting, FDA stated that the existing three months of safety data could support 12-week dosing at 5 mg and 10 mg dose levels, and that six months of clinical safety data demonstrating a similar favorable safety profile could support 12-month dosing in the PIVOT-HD trial. This is very good news, as it suggests that the safety data being generated from PIVOT-HD should be sufficient to lift the partial hold in the United States. Turning to vatiquinone, the data in the MOVE-FA study demonstrated vatiquinone's treatment benefit across several disease endpoints, including favorable effects on the upright stability subscale of the mFARS assessment, which is predictive of time to loss of ambulation. We had a type C written response-only meeting with FDA in the third quarter to determine whether the data from MOVE-FA would be sufficient to support an NDA for accelerated approval.

In the written response, the FDA stated that they, while they see the value of upright stability as a clinically meaningful endpoint, they believe the confirmatory study would likely be needed to support NDA submission. As this was a written response only, and we believe we can address the concerns raised by the FDA, we have requested a follow-up live meeting. In parallel, we are participating in a scientific advice procedure with the EMA to determine if the MOVE-FA data could support a conditional marketing authorization application in the EU. We expect to have the outcome of this procedure in the first quarter of 2024. Turning to Upstaza, we had an informal meeting with the FDA in the third quarter, at which time they said that the data we have provided to support comparability between the clinical drug product and the intended commercial drug product were still not sufficient.

However, in that meeting, the FDA said that the available data from the clinical study in the United States assessing the safety of the drug delivery cannula could be used to support a BLA for accelerated approval based on biomarker data demonstrating a treatment-related increase in de novo dopamine production. FDA suggested that we conduct a pre-BLA meeting to review the contents of the planned BLA. This meeting has been scheduled for December, and pending the outcome, we expect to submit the BLA shortly thereafter. Let me conclude by saying I'm incredibly proud of our team's continued ability to execute on all fronts. The recent Royalty Pharma financing deal, along with our operating expense reductions, position PTC as strongly as possible for future growth as we realize the potential of our many promising programs.

I will now turn the call over to Eric and Kylie to discuss our strong commercial performance in the quarter. Eric?

Eric Pauwels (Chief Business Officer)

Thanks, Matt. We are proud of the accomplishments of our global customer-facing team, which continues to deliver revenue growth and build on our success as we focus on a strong close to the year for our commercial portfolio of products. Once again, our global DMD franchise delivered a strong quarter with continued growth from new patient starts, high compliance, low discontinuation, dose adjustments, and geographic expansion. Let me focus on our two key products in the DMD franchise. Translarna and Emflaza continue to be important growth drivers, delivering $136 million in net revenue for the third quarter, which is 4% growth compared to the third quarter of 2022. With strong year-to-date performance, we are raising our DMD revenue guidance from $545 million-$575 million to $565 million-$595 million.

For Translarna, we achieved $69 million in quarterly revenue. Year-to-date sales were $281 million. The team has worked tirelessly to continue to bring this important treatment to existing as well as new patients in our markets around the world. The recently concluded World Muscle Society meeting was an opportunity to present and discuss with healthcare providers the totality of data and real-world evidence supporting the efficacy of Translarna, and reemphasizing the significant life-changing impact this treatment has on young boys suffering from this devastating disease, for whom Translarna is their only therapy that specifically targets nonsense mutation DMD. Our customer-facing teams have increased communications with healthcare providers in Europe, providing medical information on Translarna and its continued availability for all new and existing patients. Now, turning to Emflaza. The Emflaza business continues to be solid.

Quarterly net revenues was $67 million, which is 23% growth over the prior year quarter. We have had $188 million in year-to-date sales. We continue to see strong trends in the new patient start forms and high compliance. The continued Emflaza growth is impressive and highlights the brand loyalty in the DMD community in the United States, as our team is actively implementing plans to defend and protect the Emflaza brand ahead of loss of exclusivity next year. Now, I will ask Kylie to update the progress of our current and future new product launches. Kylie?

Kylie O'Keefe (Chief Commercial Officer)

Thanks, Eric. Let me begin with Upstaza, the first and only approved gene therapy infused directly into the brain. We continue to see transformative results for the patients we have treated thus far. Our rollout across Europe is progressing well, with our first patient treated in the UK this quarter, following the positive NICE recommendation earlier in the year. Patient identification, treatment center readiness, and access and reimbursement discussions continue to advance. We also continue to leverage early access programs and cross-border treatment opportunities, with a patient from the Middle East also receiving treatment in France this quarter. Moving to Tegsedi and Waylivra in Latin America, we continue to grow our franchise in the region with recent MAA approvals for Tegsedi in Argentina and Waylivra in Mexico. Patient identification is robust and patients on treatment continue to grow across the region.

In Brazil, we anticipate receiving new group purchase orders for both Tegsedi and Waylivra before the end of this year, which is in recognition of the increased number of patients who rely on these life-changing treatments. Lastly, as Matt mentioned, we are extremely excited about the sepiapterin opportunity. The APHINITY phase III data and the long-term extension study preliminary data were presented at the recent SSIEM Congress and were very well received by physicians and the PKU community. They are excited about the opportunity to bring a differentiated therapy to PKU patients in need. With strong differentiation from the mechanism of action and the affinity results, coupled with our global commercial infrastructure and proven track record in commercializing rare diseases, the team is actively working on launch activities to ensure a fast uptake upon approval.

The potential market opportunity for sepiapterin is composed of a number of key PKU patient segments, all of which our APHINITY data suggests we can address. First, patients who have not been trialed on Kuvan or are considered therapy naive. This includes many of the classical PKU patients, where we have demonstrated benefit in both the phase II study and the APHINITY study. Second, patients who have not responded to Kuvan. Third, patients who have achieved some level of blood Phe reduction from Kuvan, but are not well controlled, and for whom sepiapterin may deliver a better reduction in blood Phe levels. To these patients, a reduction in blood Phe to target Phe levels is clinically meaningful, potentially allowing them to substantially increase their protein intake and significantly enhance their quality of life.

Many experts who have treated patients with PKU across the world have indicated that based on the data they have seen from our APHINITY study, and from their understanding of the mechanistic benefits of sepiapterin, all interested patients should be trialed in sepiapterin. With an expected addressable population of approximately 15%-30% of the overall global PKU population, this would put us above a billion-dollar market opportunity. In conclusion, our third quarter builds on an excellent first half of 2023, with significant progress across all of our commercial products and across all geographies. Our customer-facing team is set to have a very strong closeout to the year, and set ourselves up for continued success in the future by continuing to build on our commercial capabilities and to execute pre-launch strategies for our future product pipeline.

Now, let me turn the call over to Pierre for a financial update. Pierre?

Pierre Gravier (CFO)

Thank you, Kylie. I would like to begin by discussing the financing with Royalty Pharma that we announced last week. That deal, together with the pipeline reprioritizations and OpEx reductions that we announced in May and September, puts PTC in a very strong financial position. We are pleased to work again with Royalty Pharma on this win-win transaction. The non-dilutive financing provides PTC with the capital to support operations and allows for increased operational and financial flexibility by removing the Blackstone debt obligation from our balance sheet. In addition, the deal structure provides the potential for additional non-dilutive capital over the next two years. To recap the details of the deal, PTC monetized up to $1.5 billion of the Evrysdi royalty stream. Royalty Pharma acquired additional royalties on Evrysdi for $1 billion upfront.

The agreements included options for PTC to sell up to an additional $7 million, or for Royalty Pharma to acquire half of such retained royalties for up to $25 million at a later date, less royalties received by PTC. PTC maintains all economics associated with up to $250 million in the remaining commercial sales milestone associated with Evrysdi global net sales. The agreement builds on a previous strategic partnership established with Royalty Pharma in 2020. The initial agreement was for the monetization of approximately 43% of the Evrysdi royalty stream. As a result of the current agreement, PTC will maintain ownership of approximately 19% of the total Evrysdi royalty stream, pending any exercise of future options by PTC or Royalty Pharma or the achievements of the cap from the 2020 royalty agreement.

I'll now share the financial highlights of our third quarter 2023. Please refer to the third quarter earnings press release issued this afternoon for additional details. Beginning with top line results. Total revenue for the third quarter was $197 million. This consisted of DMD franchise revenue of $136 million, and other revenue of $61 million. Starting with the DMD franchise. Translarna net product revenue in the quarter was $69 million, while Emflaza net product revenue of $67 million. Moving to Evrysdi. Third quarter global revenue of CHF 360 million, which equates to over $400 million, was achieved by Roche, earning royalty revenue of $50 million for PTC.

As Matt mentioned, the third quarter performance puts us in a strong position to achieve 2023 total revenue guidance of $940 million-$1 billion, including an expected $100 million milestones when Evrysdi surpasses $1.5 billion in annual net sales. Non-GAAP R&D expenses were $150 million for the third quarter of 2023, excluding $14 million in non-cash stock-based compensation expense, compared to $150 million for the third quarter of 2022, excluding $15 million in non-cash stock-based compensation expense. Non-GAAP SG&A expenses were $16 million for the third quarter of 2023, excluding $13 million in non-cash stock-based comp expense, compared to $67 million for the third quarter of 2022, excluding $14 million in non-cash stock-based compensation expense.

Cash, cash equivalents and marketable securities total approximately $295 million as of September 30, 2023, compared to $411 million as of December 31, 2022. I will now turn the call over to the operator for Q&A. Operator?

Operator (participant)

Thank you. Again, ladies and gentlemen, if you'd like to ask a question, please press star one one on your touchtone telephone. Again, to ask a question, please press star one one. One moment for our first question. Our first question comes from the line of Eric Joseph of J.P. Morgan. Your line is open.

Eric Joseph (VP and Equity Research Analyst)

Hi, good afternoon. Thanks for taking the question. Just a couple on PKU, from us. Really just around this regulatory path here, I guess, can you just clarify when the decision was made to pursue a 505(b)(1) path for sepiapterin over 505(b)(2), and maybe what prompted that decision? And, and then I guess, in electing to go with the 505(b)(1), was it not clear that a carcinogenicity study would be needed, would likely be a requirement? And really, ultimately, I guess, just looking forward, what should give investors confidence that, you know, assuming that a carcinogenicity study turns up nothing, that the NDA submission and review cycle should otherwise be straightforward? Thank you.

Matthew Klein (CEO)

Thanks for the questions, Eric. So let me just first start with a little bit about 505(b)(1) versus 505(b)(2). The 505(b)(2) pathway is typically used for me-too compounds, where it has already been, and then there's an existing approval for the active ingredient in the compound for which one seeks approval. Alternatively, the 505(b)(1) pathway is for innovative therapies, which is much more appropriate for something like sepiapterin, which while its active ingredient is BH4, which is, which is basically the active component of Kuvan, it has many factors that make it differentiated, which underlies the superior efficacy, we've observed to date, and why this is such a promising therapy.

Since we initially was in thinking about the 505(b)(2) pathway, that's where things were lined up when we acquired it, and after we did our own analysis and understanding of the relative benefits of each pathway, it became clear to us that 505(b)(1) was much more appropriate. Now, with the 505(b)(2) pathway, since here there is an active ingredient already approved, you can utilize the studies, not safety and efficacy studies, but other supportive studies, like non-clinical studies, that were used to support that approval. With the 505(b)(1) pathway, you don't have the ability to rely on those existing studies. Now, the decision to switch was based on a couple of things. One, sepiapterin is, is quite differentiated in terms of its efficacy profile from Kuvan.

Second, if you go a 505(b)(2) pathway, the company's product, the company whose product you refer to, to utilize their studies, can actually block you from launching the therapy for up to 30 months if they still have an Orange Book-listed patent. So obviously, we did not want to be in a situation where we would risk the launch of the compound. And then again, this really is a novel, innovative compound, much more suited to the 505(b)(1) pathway. Then obviously had interactions with the agency to understand what would be required under the 505(b)(1) pathway, and that included things like juvenile toxicity and repro tox, all of which, studies will be conducted, including the NDA, no issues there.

For carcinogenicity, what's typically required is that you submit to the agency a weight of evidence request to request a waiver for carcinogenicity. Now, obviously, we were quite confident in getting that waiver. One, there's no evidence of genotoxicity of sepiapterin, and the sepiapterin non-clinical studies, the six-month and nine-month studies, there was no evidence of sepiapterin-related carcinogenicity, pre-neoplastic lesions, and neoplastic lesions. Furthermore, while we weren't referring to the Kuvan NDA, the clinical experience with Kuvan over many years clearly demonstrates that there's no carcinogenicity risk associated with BH4. So we submitted all of that to the agency. Now, the agency obviously came back and said that there are two different carcinogenicity studies. One is a two-year rat study.

They said, "Fine, do that post-approval, no problem, but since you're in the 505(b)(1) pathway, they would want the 26-week mouse study to inform the label, because in the label, they have to say whether or not there's a potential carcinogenicity risk." And while we were under 505(b)(2) pathway, we could use the labeling in the Kuvan label, which referred to a risk of adrenal tumors, which has never been seen clinically. But they said, "Look, we have nothing to refer to. We have nothing to inform the label, so we need you to do this study." And since it's a standard part, would be considered a standard part of the 505(b)(1) pathway, it'd be something you would need to submit with the NDA.

Now, I'll also say, and just the other part of your question, in our discussions, it was clearly stated that the safety and efficacy data we have with sepiapterin could support the full spectrum of patients, which would be our desired label. So we fully expect that once we get the study results, if it's required to have the study report for the mouse study for submission, once we have that, we expect a very smooth path from there. Again, given the incredible strength of the efficacy data we have, the safety data we have, and obviously, while far from ideal, the additional time we're gonna have now is only gonna build that dossier further with greater length of exposure, greater ability to show more durability effect, the kinds of things we're seeing in the long term open label study.

And obviously, we're gonna have even more data showing Phe tolerance. We recently reported the latest update in the Phe tolerance data at the SSIEM meeting in September, again, showing that patients are able to tolerate beyond the recommended daily allowance of protein and still have control of phenylketonuria. So the strength of this data is, remains. It is in no way impacted by the need to do this non-clinical study. It is an unfortunate delay. We're gonna continue discussions with the agency if we could submit the application sooner. But the bottom line is this is a strong differentiator, compound. The data we have to date, the studies we've done, show there's no evidence of carcinogenicity risk, according to the study reports we have, genotoxicity and the like. And again, this continues to be a very, this will be a very strong package.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Kristen Kluska of Cantor Fitzgerald. Kristen Kluska, your line is open.

Kristen Kluska (Managing Director and Biotechnology Equity Research Analyst)

Hi, everyone. First, just wanted to congratulate you on the Royalty Pharma deal, and I had a question about Translarna. Can you talk about why you're only pursuing reexamination of the conditional authorization? I guess, what advantages do you see going this way versus both? And assuming that you do get the green light, how are things gonna be moving forward? Will it be kind of similar, like what we've seen over the last eight years when they've given you the green light, or will you be required to conduct any type of work in the background? Thank you.

Matthew Klein (CEO)

Kristen, thank you very much for the question. So as we mentioned in the, in our prepared comments, we the previous procedure, there were two opinions. There was actually two procedures in one. One was the conversion of the conditional marketing authorization to full marketing authorization, and the other was continuation of the conditional authorization. Through nuances of the procedural elements in Europe, they had brought them together and said, "We're gonna issue two opinions, but really get together." So when they went negative on the conversion to full authorization, they elected to go negative as well for the renewal of the conditional.

Then they gave us the option to say: Do you want to pursue one or both? Look, our priority here is to make sure this drug stays on the market, stays available for the boys in Europe, when there's no other targeted therapies for nonsense mutation available. And we believe that best chance of doing that is to focus solely on maintenance of the conditional authorization for now.

We also believe in a way that by not asking for a conversion to a full approval, that the issues, some of the issues they raised with having a negative primary analysis population analysis in Study 41, may become less of an issue, really, and focus on the other important and strong data in Study 41, including in the ITT population, where we have clear evidence of benefit over a number of different endpoints, as well as obviously the long-term STRIDE data. So we really feel that by focusing this question on just renewal of the conditional authorization, that we can provide evidence that can get this opinion from negative to positive. Now, as you mentioned, what happens from there? As you asked, what happens from there?

Well, if you have a conditional marketing authorization in Europe, you are required to conduct or collect additional evidence to continue to support the benefit. Now, we believe there's many potential sources of this, including continuing to collect data in STRIDE. While we've obviously been able to show clear benefit in delaying time to loss of ambulation by 3.5 years in the most recent analysis, and continue to show meaningful multi-year delay, loss of pulmonary function. As we continue to collect more data over time, there'll be even more patients informing the loss of ambulation analysis, even more patients informing the pulmonary function analysis and hopefully, ultimately cardiac function and mortality. So there's still a lot more meaningful data that can truly inform the long-term benefit of Translarna from STRIDE.

There's also the possibility to talk about bolstering STRIDE, either with additional analyses or a second registry. That's a possibility. I think in the universe of possibilities, could they ask us to do another clinical trial? I think that's possible. Probably not likely, given a lot of the feedback that the scientific experts gave in the scientific advice portion of the procedure. Last time was that clinical studies for genetic-directed therapies in DMD are really hard and really difficult to produce meaningful data. And the experts have told CHMP they believe that these longer-term data collection mechanisms that are really most useful for understanding the true benefit. So that's a long answer. The short answer is: Look, we'll have to collect additional data. It will be well positioned and, quite honestly, pleased to do so.

The priority now is to keep this therapy on the market in Europe, and we believe by pursuing just the renewal of the conditional puts us in the strongest position to do that.

Kristen Kluska (Managing Director and Biotechnology Equity Research Analyst)

Okay, thanks. And just second part of that, I would imagine since you had the announcement that the community was probably pretty upset, especially the ones that have been on the therapy long term. So wondering if there's anything you can collect from them, anecdote, stories, et cetera, and, and if they can be of any help ahead of this, this upcoming meeting and, and decision. Thanks again.

Matthew Klein (CEO)

Yeah, Kristen, good question. I think needless to say that physicians and the patient community was surprised, disappointed, and quite honestly, scared. For the patients, obviously, this is the only therapy they have that is directed for nonsense mutation patients. Many of them have been on the therapy for years and observed the benefits that we've been reporting. For physicians, they understand the context of the disease, they understand the strength of the data that we've produced, and they can't, as many have said, imagine having to take patients off a drug that's safe and effective. They'll... The patients on their own, you know, have the ability on their own to reach out and let their voice be heard. I'm sure in many parts of Europe that'll happen, given the fear and concern they have.

And I think similarly for the physician community, they'll want to speak up. You know, our sense here is that most people, as we were, never thought this day would come, or this would be a reality. So I think this is a little bit for them, a call to speak up and let their voice be heard, and importantly, as you say, share their story, share their experience, particularly the physicians who are experts and can truly articulate the benefits they've observed and the importance of this therapy for patients with nonsense mutation DMD.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Sami Corwin of William Blair. Sami Corwin of William Blair, your line is open.

Sami Corwin (Healthcare Research Analyst)

Great. Thanks so much. On the topic of Translarna, I guess since the negative opinion, have you seen any change in how physicians are writing scripts, or if patients are accumulating medication ahead of the potential that the opinion is not reversed? And then can you speak a little bit as to if you've increased your sales efforts in non-EU areas since the negative opinion as well? Thank you.

Matthew Klein (CEO)

Yes, Sami, thank you for the question. Again, I think the in the physicians we've spoken with, the first response was, you know, clarifying, and we confirmed that in no way did things change. Patients can stay on the drug, they can write new prescriptions, and obviously everyone's going to do everything they can to make sure patients stay on therapies. But let me just kick it over to Eric. I don't know if you want to give some more detail on, on prescriptions.

Eric Pauwels (Chief Business Officer)

Yeah, thanks for the question, Sammy. First of all, we haven't actually seen an impact since CHMP has issued their opinion. In fact, you know, we've seen physicians who have actually been very, very, they've been very, very supportive. In fact, our customer-facing team has actually stepped up their interactions with healthcare providers, advocacy groups, and others to emphasize that the drug is actually available. And I think that's one of the most important things. We've made specific calls to every prescribing physician, and we've worked with them because we've had relationships now for many, many years with many of these physicians. They know about the treatment. They've been treating patients for many years, and we've been reaffirming that the, the, that Translarna is not only just available, it's available for existing patients, but it's also we've seen new prescriptions as well.

The fundamentals that we see, Sami, is basically there's been limited to no discontinuations because of the CHMP information. New patients continue to get scripts. Compliance has actually remained very high, and we've been able to maintain dose adjustments. We've had even patients that have gone from ambulatory to non-ambulatory and been maintained as well. And then to your question about... geographic expansion and outside. While that some of the information has gone out to other countries, we've actually been able to continue to work with healthcare providers in other parts of the world and still continue to generate and see growth from Translarna in the quarter.

So, the simple answer, of course, is that we have not seen any discontinuations, and the fundamentals remain strong. And we're as I mentioned earlier in my talk, we're not only very confident in what we did this quarter, but we're very confident in how we'll finish 2023. And we've actually raised guidance, and our DMD guidance is now $565 million-$595 million, which includes Translarna growth in the fourth quarter. Combined, that would equal about 11%-17% year-over-year growth for the DMD franchise compared to last year.

Sami Corwin (Healthcare Research Analyst)

Great. Thank you.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of David Lebowitz of Citi. Your line is open. David Lebowitz?

David Lebowitz (Biotechnology Senior Research Analyst)

Thank you for taking my question. When looking at the Translarna European sales or overseas sales, can you please give us a breakdown of what those sales are in Europe versus rest of the world? Also, could you give us insight as to what other geographies might have their opinion affected by the EU opinion?

Matthew Klein (CEO)

David, thank you for the question. Let me start with your second part first. You know, as we've talked about in the past, many of our largest markets outside of Europe have independent regulatory agencies that do their independent assessments, and will continue to make their independent regulatory decisions, independent of the CHMP and the European authorization. In terms of revenue, we have said in the past that while many years ago, Europe would have been the primary source of our Translarna revenue, we've done a lot of work over the past year, past years to diversify our business. I know, Kylie, do you want to go into a little bit more detail about the breakdown of revenue?

Kylie O'Keefe (Chief Commercial Officer)

Yeah, absolutely. As, as Matt was just saying, we've spent substantial effort and time over the last couple of years to geographically diversify the business. And this was the intent of evening out and sort of ensuring that we have contribution from a number of regions to total Translarna revenue. So where we stand today, we have a number of growth markets that have continued to grow over the last couple of quarters and last year, and this has allowed us to have a little less than half of EU revenue contribution to total revenue, and then the remainder being ex-US.

David Lebowitz (Biotechnology Senior Research Analyst)

Sure. I mean, is there, is there any way you can let us, I guess, zero in on what the particular number might be in the range of? Just, just in case, things don't work out in Europe, we're trying to understand, what the implications might be going forward, with respect to our projections.

Kylie O'Keefe (Chief Commercial Officer)

Yeah. So, David, I think from that perspective, I think it sits roughly around 45%-48%. But the one thing I would say, and what's important to note, is those European markets are some of our more mature markets. And so as you look over time, you would expect that the contribution to total revenue for more mature markets doesn't have the growth trajectory as some of our newer and growth markets. And so while it currently sits around the 45%-48% currently, you wouldn't expect that number to remain flat over the coming years.

David Lebowitz (Biotechnology Senior Research Analyst)

Got it. And with respect to expenses going forward, is there any way you can give us, I guess, some level of bandwidth on what to expect for 2024 and beyond, when the restructuring is in full place?

Matthew Klein (CEO)

Yes, so David, we've announced the revised our OpEx guidance, previously to $810 million-$860 million. Also, obviously, we then announced the subsequent cuts, and how that would have an impact of additionally another approximately 20% that when in run rate 2024. Obviously, we'll give the updated OpEx guidance at J.P. Morgan in January.

David Lebowitz (Biotechnology Senior Research Analyst)

Thank you for taking my questions.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Kelly Shi of Jefferies. Your line is open.

Yun Zhong (VP of Biotechnology Equity Research)

Hi, this is Yun for Kelly. Thanks very much for taking the question. So, the first question on Translarna. Assume that you are able to get the negative opinion reversed. Is there a deadline for you to eventually have to convert that conditional approval to full approval? And then on the pre-BLA meeting for AADC deficiency, on the comparability, in terms of manufacturing, are there any specific assays that you have to develop before the meeting?

Matthew Klein (CEO)

Yeah, thank you very much for the question. So on your first question regarding the positive opinion, if we're able to convert that to a positive opinion, the continued conditional marketing authorization, there's typically not a fixed timeline to that. Typically, what goes along with the conditional marketing authorization in Europe is something called a specific obligation, and that specific obligation is typically some requirement to collect additional data to support the benefit and risk profile of the therapy. So there's no timeline per se, but there'll be a, there would be a specific obligation that would require us to collect data, and obviously, the shape or form of that and design of that data collection study would have some timeline likely tied to it. Also, as part of a conditional marketing authorization, as we've done for years, requires an annual renewal.

For the past several years, we've done that, and that's a lot of that has relied on the continued evidence of safety we're seeing in STRIDE as well as benefit that we have seen in STRIDE. And there are therapies that have had conditional marketing authorization status for, you know, decade, two decades. So this would not be the first time that a therapy continued in a conditional framework for a bit more time. On your second question regarding the BLA meeting and the issue of comparability. So comparability analyses are done to show that the material that we used in the clinical studies is as similar as possible to the material that we intend to use commercially, and usually that includes, as you referred to, a number of different analytical assays.

One of the challenges that we had is that the clinical trial material, that we, for which we had to establish comparability with the commercial process is, over a decade old. Those are clinical studies that were started in the early 2010s, and there simply is not enough of that residual clinical supply available to provide the additional replicates and additional data that the agency wanted us to have, to finalize the comparability analysis. We obviously had data across all the assays that we believe show that the process is comparable. We asked for some additional analyses, and it's a bit challenging to get that material given the age of the material.

Now, importantly, we're able to discuss with them the potential to leverage the accelerated approval pathway using our ongoing study in the U.S., which is using material made with the commercial process. So it is the commercial-like material for which there was no comparability assay. And what we're able to show in AADC, which is a genetic disease of dopamine deficiency, is that when we give the drug, we're able to measure increases in dopamine. Obviously, that's a reliable, quantifiable biomarker that's not only incredibly important to the disease pathology, but also logically will precede the subsequent development of dopamine-related motor function, which is exactly what we observed in the clinical study. So that fits squarely in the framework of accelerated approval, and I think everyone has seen lately in CBER, there has been increasing interest.

Peter Marks has talked about this, the head of CBER, of using the accelerated pathway for rare disease gene therapies as a way to quickly get these therapies to patients. So we're looking forward to a pre-BLA meeting in December. They asked us to do that to make sure we're aligned on the contents of that accelerated approval BLA package, and then pending the outcome of that meeting, we'd expect to submit the BLA shortly thereafter.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Brian Abrahams of RBC Capital Markets. Brian Abrahams, your line is open.

Brian Abrahams (Managing Director and Co-Head of Biotechnology Research)

Hey, good afternoon. Thanks for taking my questions. As you prepare for the MAA filing for sepiapterin next year, what are your expectations for what the carc study requirements will be, for Europe approval? And then secondarily, I guess on Translarna in the U.S., where do you stand in terms of key discussion items, and potential areas of focus that you're expecting, for the Type C meeting? And when might we see an update from that? Will it be shortly after the meeting, or should we expect a little bit of a time gap to allow for the minutes to be collected? Thanks.

Matthew Klein (CEO)

Thanks for the questions, Brian. So, on the question regarding the MAA in Europe, I think this is another example of how regulatory authorities tend to look at things differently. The feedback we have gotten from Europe regarding carcinogenicity is they understand very well that the active metabolite for sepiapterin is BH4. And they understand that BH4 and sepiapterin are both naturally occurring cofactors. They understand the data we've collected to date in terms of carcinogenicity risk, and they have said, they would like us to not only have our own data, but that we can rely on the data and the experience of Kuvan. How, for many years, there's a knowledge base that exists, that there's been no carcinogenicity risk associated with BH4 use clinically for many years.

So, we don't believe that the issue we have at FDA will be an issue with Europe for that reason. So again, just different authorities looking at things differently, and again, that's why we're able to move forward with that submission, as we said, in the first half of 2024. On your question regarding the Type C meeting for Translarna, that, the purpose of that meeting is really to focus on the evidence that we have, the many sources of evidence we have, showing that not only there's clear evidence of benefit in studies such as study 41, but that can be confirmed a number of ways, including meta-analysis, the long-term real-world STRIDE registry.

and so really working constructively with the division to say: What are the components we need and how do we formulate them in order to support the NDA resubmission? As we typically do, once we have clarity in the outcome of the meeting, sometimes that can come from the meeting itself, sometimes that requires minutes, sometimes that requires some back and forth. Afterwards, as soon as we have clarity, we'll certainly share it.

Obviously, we know a lot of people are quite interested in the outcome of this meeting, not the least of which are the, you know, boys with nonsense mutation DMD in the U.S. who have waited years for therapy, and then also the large number of boys in the U.S. who've been on Translarna for a number of years, and their participation... In clinical studies and beyond, all of whom are quite interested in ensuring that this drug can be available in the U.S. for them.

Brian Abrahams (Managing Director and Co-Head of Biotechnology Research)

That's really helpful. Thanks, Matt.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Colin Bristow of UBS. Your line is open.

Colin Bristow (Managing Director and Biotechnology Analyst)

Hey, good afternoon. Thanks for taking the questions. On the sepiapterin NDA filing timeline, I'm just curious, why is the latter end of your guidance 3Q 2024? I'm curious, can you confirm whether the study has started? And it just seems like a sort of extreme upper bound of this timeline, if, if this study is all that's needed. And then on the AADC, could you just give a little more detail on, why FDA thinks the comparability data is still not sufficient? And then what are you sort of hoping, or what will be discussed at the, the pre-BLA meeting in December? Thank you.

Matthew Klein (CEO)

Yeah. Thanks for the questions, Colin. So if you just, you know, when you find out you have to do a study, it takes a little bit of time to actually organize the study, get the slot at the CRO, get the animals in order, get the doses confirmed, get the protocol set, get the protocol agreed upon, and start the study. We expect to begin dosing in the study, have all those things ready and dosing that study to start in December. That's a six-month study, so by the clock, all the animals get dosed in December, the in-life portion should be done in June. Once the in-life portion is done in June, they have to sacrifice the animals, go through the histological studies, all the histological analysis, and write their reports.

We're obviously going to work as quickly as we can to accelerate those timelines. Obviously, we can't shorten the 26 weeks, but we're doing everything we can to shorten the time for data analysis as well as re-getting the audited draft report, which is necessary for submission. So that's where you get the 3Q time bound from. It's merely the realities of to do a 26-week study takes more than 26 weeks, and that's and we wanted to give an accurate depiction of what we think could be the longest possible date or the latest possible time for that submission.

Obviously, as we mentioned, the management team received, we're able to work out something with the agency where perhaps we could submit those, data at, during the day 120 safety review or end late stage review, and that's going to be the basis of our ongoing conversations. Because otherwise, we believe we have a package that has every other component there. And again, as the agency indicated in our discussions with them, they see our safety and efficacy data as being, supportive of the NDA. And so we look forward to, being able to submit that as soon as possible. In terms of comparability, this is simply a matter of not we had very limited supply of the clinical material.

So we're able to. There's only a certain number of assay runs we were able to do to provide data to compare to the assays that were conducted with commercial material. They wanted additional data points, greater, a greater number of samples that we simply couldn't provide due to limited supply. In terms of the pre-BLA meeting, it was suggested that we hold the pre-BLA meeting because they wanted to make sure that we're aligned on the contents of the package, how we're going to present their integrated safety summary from all the studies that are being done. How are we going to present the efficacy data? How are we going to include other components of the regulatory studies in the package?

They thought it would be very important to make sure, as we were told in the meeting, it's not required, but we tell all companies it's important to have this, so we're sure that the file meets the format and specifications we want to avoid any file issues. So we believe the most prudent thing to do is to have that pre-BLA meeting and then pending the results, be in a position to submit as quickly thereafter as possible.

Colin Bristow (Managing Director and Biotechnology Analyst)

Great. Thank you for that.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Jeff Hung of Morgan Stanley. Your line is open.

Jeff Hung (Biotechnology Equity Research Analyst)

Question. In your discussions with the EMA on vatiquinone, what gives you confidence that it may accept MOVE-FA for conditional market authorization? And is there anything that you can update in terms of analyses or presentation that would increase your confidence for a positive outcome on the conditional marketing authorization, given the feedback you've received from FDA? Thanks.

Matthew Klein (CEO)

Yep. Thanks, Jeff, for the question. So, you know, the frameworks in FDA and EMA are slightly different, and the discussions we're having with FDA are around the potential for accelerated approval based on upright stability being an intermediate clinical endpoint. Obviously, upright stability, as we've talked about, is of all the four sections of the mFARS, which was the primary endpoint, the one that has been shown to be most important in pediatric and young adult patients, particularly ambulatory patients, because it's been shown to be able to predict time to loss of ambulation. Obviously, in Friedreich's ataxia for ambulatory patients, the key thing for a therapy to do is to delay that time to loss of ambulation, delay loss of ambulation. And so to have an endpoint that can do it, we believe meets that criteria for intermediate clinical endpoint.

We look forward to continuing the discussions with the agency, as is often necessary in rare diseases. There's a lot of back and forth to talk about the analyses we have, and as you indicated, could we provide some additional supportive analyses to move FA, in particular, the fact that we have a six-month open label extension study during which all subjects are blinded. So that gives us an opportunity to look at changes in trajectory, for example, for the placebo patients once we switched on to active. That's the U.S. In terms of Europe, the conditional marketing authorization, there's a number of criteria set out for a conditional marketing authorization. Do you have initial data that shows that there's a favorable benefit risk of a therapy? Are you meeting it on that medical need?

Getting this therapy to patients sooner, potential public health benefits. And I think when you consider the vatiquinone and the MOVE-FA study and the other data we have, we clearly meet all of those criteria. While we didn't hit the primary endpoint of the overall mFARS score, there's a number of important sources of benefit in the MOVE-FA study, not only on upright stability, on Bulbar subscale, also on fatigue, which is the number one symptom for patients. And then if you look at the well-established safety profile of vatiquinone, particularly in pediatric patients, we can clearly demonstrate that this initial study has a favorable benefit risk profile. Obviously, it's unmet medical need, not only for pediatric patients, but there's no approved therapies for FA in Europe for patients of any age.

and obviously, given when you have a therapy that can potentially slow, delay, and loss of ambulation, that's an irreversible morbidity, and those patients will therefore benefit from access to therapy sooner. The final point, obviously, we know very well from the Translarna experience, is to be able to demonstrate that you can collect more data on FA patients to support the condition, support the conditional approval and confirm that you have a favorable benefit-risk balance. We obviously believe there's many sources of additional data that we could generate to confirm the benefit-risk profile. So again, we believe we meet all of the necessary criteria for additional authorization, and we look forward to the discussions with the EMA to gain alignment with them on this point.

Jeff Hung (Biotechnology Equity Research Analyst)

Great. Thank you.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Alexander Xenakis of Truist Securities. Your line is open.

Alexander Xenakis (Equity Research Analyst)

Hi, thanks for taking my question. Congrats, first of all, on securing the royalty financing deal. That's great. Maybe two for me, one on sepiapterin. When might we see another cut of the OLE Phe tolerance data? And then one on Translarna, if you are able to overturn the conditional marketing, the ongoing conditional marketing authorization and have that ongoing study, but you don't have the official full marketing authorization, have you done any market research to see how that would affect referencing countries worldwide, and if they would be required to hold sales or not? Thanks.

Matthew Klein (CEO)

Yeah. Thanks for the questions, Alex. First, on the Phe tolerance, as we shared, we gave an update on the Phe tolerance data at the SSIEM meeting in Israel in September. Those were, again, really great data showing now with over 40 patients enrolled in that Phe tolerance protocol, that we're seeing patients move through and get to levels, get to levels of Phe tolerance beyond the recommended daily allowance. These are incredibly important data. As we said all along, the Phe tolerance component is really not for regulatory purposes, necessarily. We have the sufficient efficacy data for that, and are able to show in the long-term extension that we're having important durability of sepiapterin treatment effect as well as long-term safety. This is really the Phe tolerance data are really quite important, one, for differentiation.

This is something Kuvan was never able to demonstrate, and for physician adoption and for payer discussions, particularly outside of the U.S. On the Translarna front, Look, again, you know, we, we see the ability to keep the conditional authorization as a big win, not only obviously for us, but really most importantly for the patients. Why don't I turn it over to Kylie, if you want to comment, Kylie, on the, what you think the global payer impact could be with any, on a conditional authorization?

Kylie O'Keefe (Chief Commercial Officer)

Yeah, I think from a payer impact, I think it will be quite minimal, Alex. I think one of the things that the team has done an incredible job is with the conditional authorization that we've had over the last nine years, is being able to secure a favorable pricing corridor and reimbursement and being able to maintain that over the years. So I think at this stage where we stand, we don't see any sort of negative impact from continuing conditional authorization, and of course, we'll continue to focus on it.

Alexander Xenakis (Equity Research Analyst)

Definitely. Thanks for taking the question.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Joseph Schwartz of Leerink Partners. Your line is open.

Joseph Schwartz (Managing Director and Senior Biotechnology Analyst)

Great. Thanks very much. I was wondering if you could talk about your publication plans for the APHINITY sepiapterin data. Will we see that published in a peer-review journal anytime soon? I believe you have the option to go up to a 20 mg dose of PTC518 in PIVOT-HD patients outside the U.S. Where do you stand on implementing that decision?

Matthew Klein (CEO)

Yeah, absolutely. So maybe I'll, I'll take the, I think let me take the second question first, and then I'll, I'll, let Kylie answer the first question second. So on, on 518. So we, as we talked about, we shared the results from the five and 10 mg dose groups, the first cohort of 32 patients in June. You know, those data, from our standpoint, were as good as they can be.

We achieved every objective of that 12-week portion of the study in that first cohort of patients, demonstrating the dose-dependent lowering of huntingtin protein in the blood, seeing the differential exposure of PTC518 in the CSF relative to the plasma at that 10 mg dose, seeing that that ratio is 1.5 to 1, suggesting that we're getting an even greater exposure of 518 in the brain and even potentially higher levels or greater lowering of huntingtin, mutant huntingtin protein in the brain, all of which was very, very important. Of course, the other key point is that we were doing all of this safely. The safety profile of the drug was quite strong in those first 12 weeks. We had no drug-related serious adverse events. There were no NfL spikes.

All very, very important, particularly given concerns that were raised over other HCC lowering therapies that have drawbacks that we've, we've talked a lot about in the past. We said based on those data, we believe we may have the dose levels we need right now to get us where we want to be in terms of the ultimate goal of the program, which is being able to lower brain cell Huntingtin protein levels 30%-50%. And so with the decision, with that, those early data, while we had the ability to go up to 20 mg, the DSMB has supported us starting 20 mg cohorts. The regulatory authorities and local ethics committees have approved us going to 20. We're, we're still in a holding pattern.

We wanna understand a little bit more what the biomarker effects are with the dose levels we have now, five and 10, because those very well may be sufficient to move forward, get us where we wanna be. So we haven't initiated those, the 20 mg dosing yet. We're not sure we're going to need to, and we want to better understand the longer-term biomarker effects of the current dose levels before revisiting that decision. Let me now turn it over to Kylie to answer your question around publication strategy for PKU.

Kylie O'Keefe (Chief Commercial Officer)

Yeah, thanks, Joe. We are absolutely getting the APHINITY study published in a peer review journal. The team is working on that as we speak and is looking to target a high impact journal. And so the timelines for getting that published is obviously driven by the journal of choice. So we're working. This is work in progress. The team is moving through this, and we expect it to be published during 2024, pending the journal chosen.

Matthew Klein (CEO)

Thank you.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Gina Wang of Barclays. Your line is open.

Gena Wang (Managing Director and Senior Equity Research Analyst)

Hi, thank you for taking my questions. So I do have, I think, three quick questions. The first one is, regarding the PKU program. Since, Censa initially was thinking about 505(b)(2), is that because the, lack of confidence of their IP position that this drug will be very different from, Kuvan? That's the first question. And then, you know, related, how confident you are on the IP regarding this is, a new composition or matter. And then, for the PIVOT-HD, I don't know if I missed it. So have you, like, exactly what kind of data you would need in order to remove, FDA clinical hold? So based on, you know, I think your prepared remark, you did mention certain months of, clinical safety data.

When I looked at the press releases, the six months of a clinical safety data demonstrate similar favorable safety profile, could support 12 months dosing, and, what additional data that will require to can dose more than 12 months, and what dose you can dose, like beyond 10 mg. So that's the second question. And quickly, last, last question, regarding the Upstaza in AADC. So if you are using current U.S. data for accelerated approval, what additional study you will need to do, in order to, to get a full approval in the future?

Matthew Klein (CEO)

Great. Thank you very much for the questions, Gina. The first question for, number one, regarding PKU and Censa. Look, I think that was really what, more reflection of Censa being a very small virtual company and probably looking for what they thought at the time would be the quickest and least expensive development path forward. I think, you know, it's, it's not uncommon for a smaller company to think about the development path that way. You know, I think from our, from our standpoint, the, you know, it's very clear this is a highly differentiated therapy that is much more suited to the 505(b)(1) pathway.

Obviously, we're in a position to have the resources to do the necessary studies and not have to rely on another NDA and incur that risk of, of having a stay based on the, launch of the therapy following approval. As we talked about, not only do we have a great deal of confidence in how differentiated sepiapterin is and its ability to meet the persistent large unmet medical need for PKU patients, and as we've heard from physicians, including Ania Muntau on our Commercial Day time this summer, a desire for physicians to even switch patients who may be served to some extent on Kuvan to sepiapterin, because of what we've been able to show in terms of the large magnitude of clinical benefit. We've also talked about the IP here. We obviously have orphan, designation.

We also have some potential patent extensions that we believe will extend the orphan exclusivity out several years. Your second question on PIVOT-HD. As we had talked about in the past, in our discussions with the agency, they've said that what they wanted to see additional evidence that we can dose at the dose levels we intended in PIVOT-HD. Those additional data could take the form of non-clinical data. It could also take the form of clinical data.

We had made the decision, since we were able to conduct this trial in many countries outside of the U.S. and enroll the study outside the U.S., that we would conduct the study, collect the clinical data in the study, and then provide those data as we had them to FDA, in order to fulfill that need of demonstrating that PTC518 can be demonstrated safely. So once we had the 12-week data, we took those data that we presented, and obviously, since all patients aren't enrolled at the same time, we had some data beyond 12 weeks. We provided all of that to the agency, and that was clinical data.

It included clinical laboratories, it included the NfL levels, that we had shared at the earnings, adverse event reports, the lack of serious adverse events, the DSMB minutes, letters from the DSMB chair, all of which were shared with the FDA. As I mentioned in the prepared remarks during our discussion in the meeting, the FDA indicated that those data that we had at that point could be sufficient, for 12-week dosing in five and 10 mg, if that's what we wanted to start now. But obviously, the goal here is to think about longer-term dosing, as your question suggested, and they said what they would like to see is data at the 6-month time point. So basically, a little bit longer than three months to support the duration of dosing that we had proposed in PIVOT-HD.

For right now, quite simply, doing the timing math, it's very possible by the time we got that data sent it to the FDA, got the review, got sites ready, up and running in the U.S., it might very well be that we'll be done with enrollment in PIVOT-HD. We're extremely close right now to completing enrollment in the stage two patients, and enrollment is moving very quickly overall for the study, particularly after the gene data release, when we were able to provide a lot of comfort to physicians and patients that, unlike other Huntington's disease therapies, we were able to achieve our objectives and do so safely. So there's been a lot of interest in that study. There's obviously a lot of interest in the United States for patients and physicians.

So we we would love to be able to open sites here, but if the study is fully enrolled, then we'll look to start phase III here and be able to offer the opportunity for patients to participate in the PIVOT-HD in the PTC518 development. Your third question was regarding Upstaza and accelerated approval and confirmatory study. So we are using the existing clinical study now in the U.S., and we have the endpoint that we're using to support the accelerated approval, is an early endpoint of biochemical changes. Then you'll have a longer-term extension component of that study, which will collect long-term clinical data to provide the clinical evidence necessary to support the full approval. So this is really an example where we will have the study ongoing.

It's going to be a long-term study that's going to look at the acquisition of developmental motor milestones over time, much in the way that we've been able to show previously in the clinical studies of Upstaza that were done previously, where over time, we're able to show that these children develop the ability to first lift their head and be able to sit, crawl, and walk independently. That obviously takes many years, which is why, in many ways, this is a very good setup for an accelerated approval, where we have biomarker evidence, dopamine increases, which is obviously likely to predict long-term clinical benefit of the acquisition of dopamine-related motor milestones.

Operator (participant)

Thank you. Thank you. One moment, please. Our next question comes from the line of Paul Choi of Goldman Sachs. Your line is open.

Paul Choi (Biotechnology Equity Research Analyst)

Good afternoon, and thank you for taking our questions. Two questions for me. First, on the commercial side, with the approval of vamorolone today, can you maybe just comment on how you're thinking about the impact to Emflaza, and would you maybe consider pulling back on salesforce resourcing for that product starting next year ahead of your expected loss of exclusivity? And then on the pipeline side, can you maybe comment on what you would intend to present in terms of your PIVOT-HD update next year? Should investors, you know, continue to expect plasma Huntingtin updates and neurofilament changes, or would you perhaps present some details on other endpoints, including clinical endpoints? Thank you very much.

Matthew Klein (CEO)

Thanks, Paul, for the question. Let me, let me grab the second one first, and then I'll, I'll turn the other question over to, to, Kylie. So first, in terms of, the 518 data. So the 12-month data that we said in the call that we would share in the first half of 2024, that'll be data from the biomarker portion, right? We talked about PIVOT-HD as being a 12-month placebo-controlled study in two parts. The first part, the 12 weeks, focuses on pharmacodynamic and pharmacokinetics as well as safety. And then in that second portion, at the 12-month time point, we would have data, further data on neurofilament levels, now less about safety, but maybe more about recording treatment benefit, CSF, Huntingtin protein, mutant Huntingtin protein levels, volumetric changes on MRI.

We also will have some clinical data at that time point, which are not main endpoints at the 12 months, but obviously, we're collecting this data. I think we would certainly share the biomarker data, share what clinical data we have with the obvious caveat that even at 12 months, it's very hard to have interpretable clinical effect on things like the UHDRS scale or even the total motor score or some of the different modalities tests, just given the rate of progression of the disease and the sensitivity of those instruments to change over a short period of time. So the analysts will have those data. The main focus will be the biomarker data, obviously, concerning safety.

We will also, when ready, have data on the additional subjects who are going to hit the 12-week time point and then ultimately hit the 12-month time point. We haven't given a timeline for that. The timeline will be given. Obviously, the data point I think most are interested in, which is that 12-month data point for the initial cohort of subjects, on whom we shared the 12-week data. So in terms of your question on vamorolone and Emflaza, Eric, do you want to take it?

Eric Pauwels (Chief Business Officer)

Yeah, thanks for the question, Paul. I think with Emflaza, you know, we know that Emflaza has been currently on the market for more than six years. It is currently the standard of care. We've established Emflaza as a standard of care because there's been a number of publications, and there's also a lot of scientific evidence that it has actually preserved greater motor function than prednisone.

Eric Joseph (VP and Equity Research Analyst)

And, we know that the data has continually supported that, and we have very, very strong relationships with each one of the healthcare providers, in terms of showing them the evidence, but also providing patient support. We understand that the community wants options, but we know that right now we have been focused on, and our field force has been focused on not only growing the brand this year, but also we have a number of strategies that will also protect the brand, following loss of exclusivity. Because we don't necessarily see this as being a falloff, because of a generic or even a competitor. And we have a number of key strategies right now, and a lot of them are centered around leveraging our patient support programs.

Eric Pauwels (Chief Business Officer)

Because we have that direct line with patients, and we have more patients on Emflaza than any other DMD treatment. We can continue to leverage that support. And through that process, we'll continue to work with our specialty pharmacies. We'll be targeting key relationships with payers, to obviously continue to, if you will, foster brand loyalty. So while the vamorolone is an additional option, we also know that clinically it hasn't been differentiated like Emflaza, and that we have a very strong and loyal customer base.

Paul Choi (Biotechnology Equity Research Analyst)

Okay, thank you for taking our questions.

Operator (participant)

Thank you. One moment, please. Our next question comes from the line of Tazeen Ahmad of Bank of America. Line is open.

Tazeen Ahmad (Managing Director in US Equity Research)

Okay, thanks so much for taking my questions. A few quick ones from me, if I may. So, to keep with the topic of the approval for Catalyst Pharma, how, if in any way, does that change your strategy for how you might want to look beyond the loss of exclusivity for Emflaza next year and beyond? And then second question, as it relates to sepiapterin milestone agreements with Censa, I believe you've already paid them $30 million for completing phase III enrollment. I guess, what other milestones should we anticipate either this year or next? And then lastly, to clarify on the conditional approval for Translarna, and I'm sorry if it was answered earlier, is there a set amount of time for which a conditional approval would need to be renewed on a go-forward basis? Thanks.

Matthew Klein (CEO)

Sure. Thanks for the question, Tazeen. Let me take, let me take the third one, and then I'll, I'll pass to the team for the other two. So the, so the conditional authorization, obviously, there's always comes with a specific obligation to collect additional data. So that's less of a time-based, specific time-based element, but rather the time is necessary for that data collection effort. Obviously, there have been therapies that have had conditional authorization for many, many years, even beyond a decade. So, you know, for us, what we would do is look forward to the opportunity to keep the, the therapy on the market and then continue to collect the data necessary. We do also have the, the obligation to submit for annual renewals, which we've been through before.

That's what we've done for the past several years, to show that we're, one, collecting the data that we've agreed to as part of the specific obligation, and then also providing any necessary updates, particularly around safety, to the therapy that might emerge. Obviously, the safety story on Translarna is quite robust, and we've clearly been able to show that it is a therapy that is safe for the long term, just as we've been able to show the benefit long term through the STRIDE registry. In terms of your questions on Emflaza's strategy and as well as milestones, Kylie, do you want to take Emflaza?

Kylie O'Keefe (Chief Commercial Officer)

Yeah, absolutely. So on the Emflaza front, Tazeen, I think what we continue to do is see Emflaza as a standard of care across all DMD patients. And we have been able to demonstrate the benefit of Emflaza in a number of different milestones, and we continue to believe that that's not going to shift in the near term. I think from a loss of exclusivity perspective, we have a number of strategies that we're looking at to be able to preserve the business. And again, that doesn't shift based on the vamorolone approval. We have good, strong relationships across our customer base and with patient advocacy groups, and we will continue to leverage those relationships as we move forward. On the milestone question, Tazeen,

Tazeen Ahmad (Managing Director in US Equity Research)

Yeah, sorry. Are you able to provide any color on the specific strategies that you're going to use for Emflaza?

Kylie O'Keefe (Chief Commercial Officer)

Yeah, absolutely. So there's four main pillars that we're focused on with regards to protecting the business. So one is ensuring that we have an enhanced patient support program, which is really, really important for particularly DMD patients and those in Medicaid, as an example. And then also partnering with specialty pharmacies, partnering with payers, and partnering with manufacturers to be able to ensure that we're doing the best for the patients and protecting the business. So they're some of the key strategies that we're looking at, as well as a Dispense as Written program that the team is working on as we speak.

Tazeen Ahmad (Managing Director in US Equity Research)

Okay, thank you.

Operator (participant)

Thank you.

Kylie O'Keefe (Chief Commercial Officer)

In just to answer the last question, Tazeen, around the milestones for Censa. So you are correct. We obviously had paid the $30 million in equity in 2023. We don't expect any additional milestones for Censa in 2023, but we had shared in the Q that we expect $65 million worth of regulatory success-based milestones for Censa in the next twelve months, so in 2024. And we haven't broken out the specifics around that.

Operator (participant)

Thank you. I'm showing no further questions at this time. Let's turn the call back over to Dr. Matthew Klein, Chief Executive Officer, for any closing remarks.

Matthew Klein (CEO)

Great, thank you. Thank you all for joining the call today. We look forward to a strong closeout in 2023 as we get ready for what's clearly also going to be a busy 2024, and we'll look forward to sharing updates with you as they become available. Thank you all again, and have a good evening.

Operator (participant)

Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.