PTC Therapeutics, Inc.

Ladies and gentlemen, thank you for standing by and welcome to the PTC first quarter 2022 financial results conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1 on your telephone. If you require any further assistance, please press star 0. I would now like to turn the call over to your host, Kylie O'Keefe. You may begin.

Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics First Quarter 2022 Corporate Update and Financial Results. I am joined today by our Chief Executive Officer, Stuart Peltz, our Chief Operating Officer, Matthew Klein, our Chief Business Officer, Eric Powers, and our Chief Financial Officer, Emily Hill. Today's call will include forward-looking statements based on 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 risk that can materially and adversely affect our business and results of operation. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual reports. on Form 10-K and quarterly report on Form 10-Q 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 is available in today's earnings release. With that, let me pass the call over to our CEO, Stuart Peltz. Stuart?

Thanks, Kylie. Good afternoon and thanks for joining today. I'm excited to share PTC's first quarter results, the first update in what I expect to be a transformative year for the company. Our mission at PTC is to develop therapeutics to help treat patients with rare disorders while producing revenue to provide value for all of our stakeholders. When I founded the company, it was built on the groundbreaking science of RNA biology. By regulating at the RNA level, we realized we could treat diseases of higher medical needs. The company has worked hard to turn these ideas into reality. Over the past 24 years, we have grown into an enduring biopharmaceutical company with a number of commercial products. We are continuing to build a robust pipeline of potential new therapeutics that at steady stage will deliver a new product every two to three years. This will allow us to continue to build into a company with a substantial revenues that bring growing value to all of our stakeholders. Let me start with our commercial portfolio. I'm proud to report that the net product revenue for the first quarter was $130 million, which represents 42% growth over the first quarter of 2021. Our Duchenne muscular dystrophy franchise Net product revenue was $128 million, demonstrating another strong quarter for Translarna and Inplaza. In addition, we recently had the first group purchase order for Tecseti in Brazil, which will be recognized in the second quarter. Eric will go into more detail on our substantial commercial progress later in the call. Evristi sales continue to show strong growth in all regions with substantial growth in Europe. Avrizzi continues to be the most prescribed disease-modifying therapy for SMA, with more than 20% market share in the United States and more than 30% market share in Germany. It is currently approved in 79 countries, and we're excited about the continued rapid update and sustained growth of Avrizzi, which demonstrates the demand across all SMA patients for an effective orally administered therapeutic. We have several exciting near-term value drivers that I'd like now to provide some updates on. For our first gene therapy for AAGC deficiency, we recently announced that we have completed the scientific advisory group and oral explanation meetings with the Committee for Advanced Therapies, or CAT. With the successful completion of these meetings, We now expect a CHMP opinion in May. If approved, PTCAADC would be the first marketed gene therapy administered directly into the brain. We're very proud to have gotten to this point in the European regulatory process and will now focus efforts on submission of the BLA. Turning now to development programs, where we have five ongoing registration-directed trials. The first of these is study 041, the placebo-controlled trial of TransLyna. We expect to report results of study 041 by the end of the second quarter. We also recently received a positive CHMP opinion for the eighth annual renewal for TransLyna in the EU. Turning now to PTC 923 for PKU and the registration-directed affinity study, We're excited by the opportunity in PKU. With a well-established patient population and a high medical need driven by the majority of PKU patients, either therapy naive or poorly controlled on existing therapies. In addition, the affinity study has an enriched population, a biomarker endpoint, and a defined path to registration. Results are expected from this study by the end of the year. For the BioE platform, we expect results from the registration-directed MiDE study of vaticinone in patients with mitochondrial disease-associated seizures in the fourth quarter of this year. We are also excited to announce that we initiated the Cardinal ALS study in PTC 857 in ALS. Moving to our validated splicing platform, we're excited to be following the successful pathway established by Evrizdi with PTC518 in Huntington's disease, or HD. HD is a debilitating disease with no disease-modifying treatments. For PTC518, an oral glycine modifier, we initiated the Phase II Pivot HD study in patients with Huntington's disease in the first quarter of this year, and we look forward to data from the first 12 weeks by the end of the year. From our ecology portfolio, we also recently initiated the Sunrise LMS study of Unespolin and Leomyosarcoma. We are excited to make progress with this platform and will provide additional updates in the next quarter. I'm proud that while PTC has demonstrated success with RNA science, we have worked to grow and diversify the business to increase the strength of the pipeline for continued success that will produce multiple therapies over the next decade. I'll now turn the call over to Matt for more detail on clinical development.

Matt? Thanks, Stu. Our development teams continue to work hard to progress all of our pipeline programs. We have a number of ongoing registration-directed trials that we expect to read out this year and several additional studies being initiated. I'll begin with our Affinity Phase III trial of PTC923 in patients with PKU. Enrollment in the registration-directed Affinity trial is ongoing, and we expect to have results by the end of 2022. As a reminder, the Affinity trial is a six-week placebo-controlled study with a primary endpoint of reduction in blood phenylalanine levels. To enrich the randomized study population for likely PTC923 responders, The study includes a run-in phase during which potential subjects are treated with PTC923 for two weeks. Subjects who demonstrate a response to treatment of 15% reduction in phenylalanine levels will continue to the placebo-controlled phase. Following completion of the placebo-controlled study, all subjects will be eligible to enroll in a long-term extension study. Next, I'll discuss our BioE-Plat. from which we currently have two ongoing registration-directed trials with vitiquinone and an additional registration-directed trial with PTC-857. The MITEI trial, the registration-directed trial of vitiquinone in patients with mitochondrial disease-associated seizures, is actively enrolling, and we expect results by the end of 2022. As a reminder, this study will enroll approximately 60 patients from study sites worldwide. The study includes a four-week run-in phase to ensure patients are having a minimum number of observable motor seizures, followed by a 24-week placebo-controlled phase during which subjects will receive either placebo or vitiquinone. The study primary endpoint is reduction in the number of observable motor seizures, with secondary endpoints capturing other aspects of disease morbidity. The second ptiquinone registration-directed trial is the Phase III MOVE-FA study in patients with phrygiocataxia. The trial includes a 72-week placebo-controlled phase, and the primary endpoint is change from baseline in the modified phrygiocataxia rating scale, or mFARS. This global study is fully enrolled, and we expect results in the second quarter of 2023. Turning to the second compound from the BioE platform, PTC857, we have now initiated Phase II registration-directed cardinal study in amyotrophic lateral sclerosis patients. This trial includes a two-month screening phase to establish a baseline rate of disease progression, followed by a 24-week placebo-controlled phase during which subjects will receive PTC857 or placebos. The study is planned to enroll approximately 255 patients from study sites worldwide, and the primary endpoint is change in ALS FRS score from baseline to 24 weeks. Turning now to our slicing platform, we recently announced the initiation of the Phase II Pivot HD study of PTC518 in Huntington's disease patients. As a reminder, the Pivot HD study consists of two parts, The first part is a 12-week placebo control phase focusing on safety, pharmacology, and pharmacodynamic effects on Huntington mRNA and protein models. After completing the first 12 weeks, all subjects will remain on their initial treatment assignment of either PCC518 or placebo for an additional nine months, during which we will collect blood, CSF, and radiographic biomarker data. The study will initially include two dose levels, 5 milligrams and 10 milligrams. We anticipate data from the 12-week study by the end of this year. I will now turn to our oncology platform and the recently initiated Sunrise LMS study, which is the registration-directed Phase II study of Unespolin in patients with leiomyosarcoma. Leiomyosarcoma, or LMS, is a rare and aggressive cancer found in smooth muscle tissue. It's also one of the most aggressive sarcoma subtypes and has a high risk of recurrence, leading to a poor clinical prognosis. Several chemotherapeutic regimens are utilized for relapsed or refractory LMS, but with an objective response rate of only 7% to 9%, they offer minimal meaningful efficacy. Sunrise LMS is a global placebo-controlled study enrolling patients with relapsed and refractory LMS. Target enrollment is approximately 345 patients, and the primary endpoint is progression-free survival. The Sunrise LMS study is based on the findings from our Phase Ib trial, in which unescolin was found to be well-tolerated and demonstrated a treatment effect in patients with relapsed refractory LMS who had previously completed three, four, or five lines of therapy. In summary, I am proud of our continued progress across the pipeline, and look forward to providing updates on our programs over the course of the year. I will now turn the call over to Eric for an update on our commercial progress.

Eric? Thanks, Matt. The commercial team has kicked off the year with a very strong quarter, building on the momentum that we created last year. So far, 2022 is shaping up to be a transformative year for PTC, and in particular for the customer-facing team, with potential launches in Europe, and other international markets, or PTC-AADC, and in Brazil, the potential approval for the new indication of Weylivra, or familial partial lipodystrophy, or FPL. In addition, we continue the expansion of our geographical footprint for Translarna. Our global DMV franchise continues to deliver robust revenues across all regions. our first quarter revenue for the DMD franchise was $128 million, which is an impressive 42% growth over the first quarter of last year. Let me start with Implaza. Our Implaza net product revenue for the first quarter was $49 million, double-digit growth from the first quarter of last year. Ongoing execution by our Implaza team drove new patient starts, more favorable access, continued high compliance and appropriate weight-based dosing. Now, turning to Translarna. We achieved $79 million in net product revenue for the first quarter. Translarna continues to be robust and globally diversified with growth in long-standing existing markets and new geographical markets. Year-over-year growth was predominantly driven by Brazil, where we completed delivery on the remainder of the Ministry of Health group purchase order that we had partially delivered in the fourth quarter of last year. We are continuing to expand our presence in markets in Asia Pacific as these markets have the potential for continued growth of the brand in the future. Now, moving on to our progress with Tecseti and Rey Libre. Our Latin American team continues to build significant momentum in the region. As Stu mentioned, In Brazil, following the innovative drug classification cortex study, we are excited to have received the first group purchase order from the Ministry of Health, which will be recognized in the second quarter. Now, this is a significant milestone, which reflects the growing number of HATTR patients in Brazil awaiting treatment. Furthermore, patient identification continues to be strong, and we anticipate additional group purchase orders over the course of the year. Finally, the team has submitted the HTA dossier for TEGCETI to CONIPEC, which is the National Commission for the Incorporation of Technology, and has initiated discussions for inclusion of TEGCETI in the essential drug list, which simplifies long-term access. We continue to build our presence in Latin America with ongoing regulatory submissions of Translarna, TEGCETI, and a recent first quarter NDA submission of WeLiever in Mexico. making this our third innovative product to be submitted in this country. As a reminder, last December, we submitted an application to Anvisa in Brazil for approval of WayLever for the treatment of FPL. If approved, WayLever will be the first approved treatment for FPL in Brazil, and this will mark the first approval globally for this indication. We anticipate a decision in the second half of 2022. I will now touch on the preparation for PTC's first gene therapy launch for AADC deficiency. We are very excited about the forthcoming CHMP opinion in May, and our team is ready to execute on the launch of the AADC gene therapy in Europe shortly after potential approval. Expert neurological centers of excellence in key European countries have been identified, qualified, and are ready to treat patients post-approval. Many of these centers are also being prepared to treat AADC deficiency patients via early access programs in the near future. Identification and preparation of additional centers globally are on track, and PTC's efforts to accelerate patient screening and identification activities in enriched high-risk populations continues to progress well. In conclusion, The commercial team is off to a strong start and has set the stage for continued growth across our franchises in 2022. Now, let me turn the call over to Emily for a financial update. Emily?

Thanks, Eric. I am proud to report that PTC has once again delivered excellent results this quarter. With strong commercial performance and a number of potential near-term value drivers expected in 2022, we are looking forward to an exciting year. Our strong global commercial infrastructure continues to support year-over-year revenue growth, and we are well-positioned for continued geographic expansion. Our growing sales revenue base, combined with revenues from expected milestones and royalties, allow us to continue to invest in innovation. I will now turn to the financial results from the first quarter of 2022. Please refer to the press release issued today for additional details. Beginning with our top-line results, in the first quarter of 2022, total revenues were $149 million, compared to $118 million for the first quarter of 2021. Of this, the DMV franchise produced $128 million in revenue, compared to $90 million in the first quarter of 2021. This includes Transbarna revenues of $79 million in the first quarter of this year, as compared to $47 million in the first quarter of last year. and plaza revenues were $49 million in the first quarter of this year, as compared to $44 million in the first quarter of 2021. Total revenue for the first quarter of 2022 also included $19 million in collaboration and royalty revenue, from sales of Everestie totaling approximately $226 million. In the first quarter of 2021, we recorded $7 million in royalty revenue, in addition to a $20 million milestone payment that was recorded as collaboration revenue. Abruzzi royalty revenue is up this quarter, and its growth is expected to continue as pricing and reimbursements come online throughout Europe and other markets outside of the U.S. As a reminder, PTC is eligible to receive a $50 million sales-based milestone payment from Roche, and annual sales of Abruzzi reach $750 million. Non-GAAP R&D expenses were $127 million for the first quarter of 2022, excluding $13 million in non-cash stock-based compensation expense, compared to $121 million for the first quarter of 2021, excluding $14 million in non-cash stock-based compensation expense. Non-GAAP SG&A expense were $16 million for the first quarter of 2022, excluding $14 million in non-cash stock-based compensation expense. compared to $49 million for the first quarter of 2021, excluding $12 million in non-cash stock-based compensation expense. Cash, cash equivalents, and marketable securities totaled $588 million as of March 31, 2022, compared to $773 million as of December 31, 2021. I'll now hand the call over to the operator to start our question and answer session. Operators?

Ladies and gentlemen, if you have a question or a comment at this time, please press the star, then the one key on your touchdown telephone. If your question is unanswered or you wish to move yourself from the queue, please press the pound key. Our first question comes from Eric Joseph with J.P. Morgan.

Good evening. Good evening, guys. Thanks for taking the question. And congrats on the quarter. I guess just one on Translera and then a couple on the pipeline. First, just I guess with the performance this quarter, just talking about any sort of headwinds as it related to sales in Russia at all. And are you guiding at this point in terms of how the cadence of revenue might perform in the second quarter with the reiteration of sort of top line from the DMD franchise? And then secondly, as it relates to study 041, I'm just wondering if you could kind of compare or make the contrast in the primary endpoint being used in this study here compared to ACT-D and D. You're looking at slope of change in six-minute walk distance compared to just change in six-minute walk. Is it correct to assume that you're assessing, you're taking multiple intervals in between baseline and 72 weeks? And in that case, how proven are you assessing six-minute walk distance?

Yeah, thanks for the question. Yeah, so, you know, obviously in Russia it's a volatile situation and we're obviously closely watching as it unfolds. And, you know, we plan, you know, obviously we plan accordingly on how best, if necessary, to adjust the business. But, you know, probably as you know, the sanctions do exclude medicines. And we've been really focusing on the continuity of treatment for the boys and young men who have Nassau's mutation, Duchenne muscular dystrophy in the region. So I think the good news is to date we've been able to ensure continuity of treatment for all the patients. And we've been focusing on that. The other good point, I think, is that we've also been able to be collecting the receivables. And currently, as a consequence of this, in terms of revenues, it's been business as usual. So our exposure and our, you know, with our total revenue guidance isn't really affected right now. So it's hard to, you know, we haven't seen any issues with that. Matt, do you want to talk about the ACT-DMD?

Sure. Eric, thanks for the question. To answer your question regarding the use of the model for study 041, it's exactly to do as you mentioned. not only includes the baseline and final six-minute walk distance, but it also includes information collected at all the other time points, which makes it a much more robust approach to data analysis. That's typically why one would use a model of that sort. The other thing it does, given that I think you asked about having the study visit time points, being that we had previously discussed that as a result of COVID, some of the visits occurred outside of the window, By using a model, you can also not only include the specific observation, but also at the time at which an observation was made. And so the benefit of a model is that you not only have information on walk distance, but also the time at which that distance was collected. So again, just giving you a lot more information in the overall analysis.

That's very helpful. Maybe just one follow-up on study 41 as well. In terms of patient demographics by angulation at baseline, I know you're stratifying for different ranges in six-minute walk distance at baseline, 300 to 350, 350 to 400, and so on. Are there any quotas associated with those? Ranges like, are you seeking to accrue a certain proportion of patients that that baseline of between 3 to 53 to 50 or other other ranges? Thanks. And I guess, like, are you can you stay at this point sort of the average baseline. Walk distance that you would expect for patients that would be evaluating the modified intent to treat group. Thanks.

Matt? Yeah, sure.

So the overall study population, as we've talked about in the past, is 360 boys, and then there is that modified population you mentioned that has the specific walk distance, and that would be 185 boys. We're not commenting on exactly what the mean baseline values were, but those are the two populations, the 360 and the 185.

Okay, great. Thanks again for the questions.

And the other question you had is just in terms of how we're thinking about revenue growth for TransLondon over 2022. We think, you know, so what we think is it's going to be, you know, last year obviously was driven by geographic expansion, new patient starts, high patient compliance and expanded the expanded age that we got on the label in Brazil. We also anticipate strong revenue growth for Transline of Franchise in 2022. That's going to be driven by the acceleration of the footprint in new markets, optimizing our presence in the current markets, and then driving access for all LZO patients in the new markets and the ongoing access in the current markets. That's our focus. So we plan, we think this is going to be another strong year for the franchise.

Your next question comes from Kristen. Let's go with character Fitzgerald.

Hi, everyone. This is Rick on for Kristen. Thank you for taking our questions. We've just got two for you here. In the MITEI trial, could you talk a little bit about the seizure run-in measurement, given that there are multiple types of seizures the patients can have, some of which are more observable than others. How are you measuring seizure activity? We'd be interested to know how this approach during the lead-in is tailored to the types of seizures that these patients are typically experiencing.

Matt, do you want to take that?

Yeah, absolutely. So the MITEI trials we've talked about is our global study looking at the effects of etiquinone on mitochondrial disease-associated seizures, which is a highly morbid and common a symptom of mitochondrial disease. About 30 to 50 percent of all patients with mitochondrial disease have seizures, and these are typically refractory to anti-epileptic medications that are commonly given for the simple reason that common anti-epileptics don't target the energetic pathways that are causative of seizures in mitochondrial disease patients. In fact, many of them actually heighten oxidative stress, which is what's causing seizures in these So while you may have some benefit of the anti-epileptic, it's offset by the increased oxidative stress exacerbating the seizure pathology. And as you pointed out in your question, these children do have multiple seizure types, but the focus for the run-in phase into the primary endpoint is the observable motor seizures for the exact reason you highlighted, which is you want to make sure that the parents can observe and count that. And so what we do to track the seizure changes is we provide the parents with a diary. They undergo extensive training with the seizure diary, including a vocabulary list in which we capture the different types of seizures they observed in their children, and we highlight that we are counting the observable motor ones, the ones they see that involve motor activity. And so these are calculated during the run-in phase, We're requiring a minimum of six observable motor seizures. That will then serve as a baseline comparison following the six months of either, I'm sorry, 24 weeks of either retiquinone or placebo therapy, and then we'll compare the monthly rate of following placebo or retiquinone with that baseline frequency. But again, the primary endpoint will be observable motor seizures, and the secondary endpoints will capture other aspects of seizure pathology.

Understood. Thank you. Thank you for that. And maybe just one more. After recently initiating the Phase II Pivot HD trial, is there anything you can say about ongoing enrollment pace or performance of clinical sites versus expectations? We'd really be interested in getting an idea of how the early stage of trial enrollment has gone. Thank you.

Yeah, thank you. So, you know, we recently just initiated this. this trial. So, obviously, you know, what our plans are is it's a year-long trial that's broken up into a 12-week part and then going on for the rest of the year. And what we said is our anticipation is that we'll have the results from the 12-week portion by the end of the year. Now, that's going to be looking at looking at patient, you know, treated versus placebo, looking at, you know, the level of, you know, obviously safety, and then looking at the levels of HTT RNA and protein in the blood, in the cells of the blood, so we'll be able to get that information, and then looking also at biomarkers like such as mutant HTT as well as NFL into the in the CSF.

Thank you.

Our next question comes from RBC Capital Markets.

Hey, guys. Good afternoon. Thanks for taking my questions. My first one is on GTA ADC. It sounds like you've had some productive discussions with CHMP. I was wondering if you could maybe elaborate a little bit more about the meetings, your confidence in a positive recommendation there. And then I guess as we think about the launch preparation that you discussed a bit, can you elaborate a little bit more on maybe just the numbers of centers, of these neurological centers that you expect to launch with and the degree to which they've already identified patients or will the kind of initial launch engagement kick off a screening process? And then I have a follow-up on Huntington's. Thanks.

Sure. Yeah, thanks for that question. So obviously we talked about, we told you that we will be having our, we'll have the CHMP opinion in May. And just to remind everybody, you know, AADC is obviously an ultra-orphan, highly morbid and fatal pediatric disorder where you see patients, you know, patients that they lack dopamine And as a consequence, their growth arrested where you can see in the severe form of patients, they're unable to hold their head up, sit, roll, roll over, stand. It's, you know, much like you've seen in the severe type SMA patients, quite similar to that. And as we said in our recent disclosure, we announced that we completed, we've been working with the CAT, which is the Committee for Advanced Therapies, and that's the committee that's of the CHMP that does, that looks at, you know, looking at gene therapy. So we recently said that we had both a scientific advisory group meeting as well as an oral explanation, and that we successfully completed those, and that as a consequence of that, we anticipate that they'll be sending their final opinion in May. So we felt good about it. Maybe Matt, do you want to – Matt was there leading the charge, so you want to talk a little more, Matt?

Yeah, sure. Thanks, Mark, for the question. So, you know, obviously we're optimistic about the positive opinion in May, and a lot of that's based on the content of the meetings. I think a lot of A lot of the meeting discussion focused on details around the label, which obviously gives us a sign that we're near the end of the process and heading towards a positive opinion. And obviously we look forward to this being, being able to bring this therapy to patients. The data collected to date are very compelling and the ability to show that we've been able to provide treatment to kids who have no motor activity, provide the gene, and now they're in many cases able to sit, stand, walk, and perform as as healthy children might at that age. I think the other important part of the data is the durability, which was really an important part of the package. So we have follow-up data from six, seven, eight, nine, even up to 10 years showing durability of motor benefit and other benefits of the drug. I think we're also really excited that this would, as you said, be the first ever direct administering therapy to the brain. I think that's really exciting. an important advance to the entire field of gene therapy that we can now think about marrying a common pediatric and adult neurosurgical procedure, stereotactic biotic surgery, with the delivery of gene therapy to the exact location of the brain where it's needed most. I'll use that then as a segue to our preparations for launch and the surgical and neurology centers at Exxon.

Yeah. So maybe, you know, as Matt just alluded to, So we were excited about completing these and have been working hard to get ready for launch preparation. And so I think we've been doing this for quite some time, both getting the neurosurgical centers ready as well as for patient identification and really doing a lot of screening. As everyone knows, this is a relatively new disease, so you have to identify the patients, and we've been looking. now and finding patients and that's been accelerating as well. We've done over 100 different screening programs in 20 different countries and been finding them in all countries. So we're really excited about this. Eric, you want to talk a little bit about all the efforts that have been going on?

Yes, sir. Certainly, Stu. I mean, the launch preparations themselves are progressing extremely well. I mean, we've been focusing on accelerating disease education, patient identification, and that's been going on already for a number of years. But to your point, Brian, preparation of surgical treatment centers has been really an important part of our most recent efforts. And in particular, we've been working with many of the top key opinion leaders, both pediatric neurologists as well as neurosurgeons, in preparation for that. So to answer your question really simply, we are looking to ensure that there are multiple centers in each of the main countries that will be ready, that are ready now, and will continue to be ready. And we're going to continue to expand in each one of these major markets to ensure that we have as many centers over time. One of the things that we do know is that as we find patients and as we treat them, and the more we provide disease awareness and education, When a treatment is available and the families and the patients see this, we certainly will have more and more demand, and we'll continue to expand, if you will, the neurological centers that we have, not only in Germany, in France, in Italy, of course, UK, Northern Europe, and many of the other markets that will have early access programs. We certainly are going to do as many centers as possible. We'll have multiple centers in each of the main countries at the time of launch.

That's super helpful. Thanks. And then maybe just a quick one on 518. The Phase II study was posted to ClinTrials this morning, and I guess we're curious what the DSMB is going to be looking for to make the recommendation to escalate to the 20 milligram dose for Part B. Is that just safety, or will it be... at knockdown and is there a goal there? And I know also you guys have talked about volumetric MRI as a potential endpoint that could be used for accelerated approval. We didn't see that listed in the posting. Wasn't sure if that was just because that's something that'll be in Part B or if there's been any change to the endpoints you view as being key there for accelerated approval. Thanks.

Sure. Thanks for the question. I think from the first part of the question, it's really we're looking for a reduction in obviously besides safety and safety, we're also looking at the biomarkers, the reduction in terms of the levels of HTT of RNA and protein in the blood and see what happens in the CSF so that in terms of PK levels as well, so that we will define what those levels are, right? We saw two and a half to three-fold increase. in the CSF levels of the blood in the Phase I studies, is that the same that we see in terms of what we then do? And based on those numbers, what we'll look for, how we titrate, whether we need to or not, and what level should we do to titrate the compound. In terms of the MRI, Matt, you want to talk a little bit about that?

Yeah, so short and just to follow up on Stu's point, Brian, so it will be a combination of the safety evaluations and the DSMV and what we're seeing in terms of the levels of reduction in Huntington mRNA and protein, as we said, along targeting at 30% to 50% reduction range. So how close are we with the first two doses? And then do we need to titrate the molecule and go to additional dose? And then, of course, marry that with the safety evaluation from the DSMB. In terms of clinicaltrials.gov, you're correct. What's listed there is for that first 12-week portion focusing on the pharmacology and PKPD relationship and volumetric MRI. We'll be tracking that, but that's going to really be an end point in the second part, right, the nine months continuing people-controlled focus on biomarkers.

Really helpful. Thanks again.

Our next question comes from Joseph Tomey with Cowan & Company.

Good afternoon, and thank you for taking the questions. Maybe one on AADC in the U.S. Maybe what remains to be done ahead of submitting that BLA? Have you been able to meet with the FDA and have them sign off on those surgeries that were completed last year?

Yeah, thanks for that. So with the AADC, as we said, obviously we're in the last rows of completing the uh what we needed with the uh with the cat and the chmp so we felt we we've gotten that completed we think that's going to be uh quite helpful for the fda and so based on that um the next steps matt why don't you go through what where our plans are with the bla yeah absolutely joe thanks for the question as you said we wanted to

get to the finish line in Europe and obviously be able to leverage all the learnings we've made in the regulatory interactions with Europe and really use those to enhance further the package for the FDA. And as you said, the plan will be to meet with the agency, align on the submission package, and move forward. The meeting request has been submitted. We'll look forward to meeting with the agency and then moving forward with the next step.

Perfect. That makes sense. And maybe more financial questions. I know a lot of the acquisitions that you did over the past couple of years had some pretty attractive upfronts, but then came with some milestone payments on enrollment or successful data or approval. So are some of those milestones baked into the 2022 financial guidance? And maybe if you could just highlight the ones that we should expect, that would be very helpful. Thank you.

Yeah. Yeah, sure. So, yes, they are baked in. And Emily, you're on.

Yeah, thank you. Thanks for the financial question. We do have a payment due for success in AADC, and that's $70 million expected in 2022. And then for PKU, we also expect to pay a $30 million developmental milestone for the completion of enrollment of the clinical trial in 2022. Perfect.

Thank you very much. Very helpful.

Yeah, on the flip side, I'd just remind you that in our revenue guidance, we have a $50 million milestone from Roche expected for certain adversity sales thresholds, and there's the potential to reach up to 100 million milestones for additional thresholds.

Perfect. Thank you again. Thank you. Our next question comes from Gina Wang with Barclays.

Thank you for taking my questions. I have three questions. The first one is regarding Inflaza. I just want to clarify that seven-year orphan drug exclusivity should be expired in 2024 and also even assuming additional six months extension based on the label expansion to younger patients and also no more protection after 2024. So that's the first question. My second question is regarding Translana. what kind of data every year you need to submit to receive a renewer in Europe. And my third question is regarding PIVOT-HD trial. Since you will collect data regularly, Huntington protein data, both in the blood and the CSF. And based on what you've learned so far, do you expect similar percentage reduction in Huntington protein in CSF versus blood?

Great. So I'll take the first one in terms of loss of exclusivity. of the FLASA, that's, yes, you're correct, it's in 2024. Obviously, we're doing some work evaluating our options in order to do that, so that we, you know, in order to maintain that. And obviously, we have a number of programs that we're working on to retain patients, which we're, you know, obviously optimistic about because we provide patient support services around Inflaza to both the patient and the caregiver communities. And then I was evaluating all options that defend the Inflaza brands, including leveraging the patient support programs, driving the channel pull-through from the specialty pharmacy partnerships, and then levering our key relationships with the contracts and payers. So, you know, you might probably be aware of this, and in the rare disease market, patients are actually relatively loyal in that generic pricing discounts are often offset by patient support programs. In terms of TransLarn and what we put in, Matt, why don't you go through that a bit?

Yes, certainly. Thank you for the questions, Gina. The annual renewal includes safety data that's collected from our post-marketing safety registry as well. We include data from the stride registry to provide evidence of clinical benefit. So it's basically information that continues to support a favorable benefit-risk balance, which is obviously the key of what the European authorities are looking for to continue the renewal.

And then your third question was HD blood and CSF, right? Yes. So I think it's an interesting question from the point of view of when you think about, you know, what's occurring within the cell that, you know, obviously right where you're altering splicing, if we look at the reduction of both RNA and then the the reflects of what's going on in the protein, you think you have a good sort of juxtaposition of seeing how much, what's the exposure and what's the reduction, right? So you see that quite nicely. However, when you think about what's going on in the CSF and the biomarkers, I think it's almost a different measure because you're not measuring what's within the cell, right? You're measuring what's outside the cell. And so we know there's probably a small amount of HTT that gets secreted and that the rest of it is probably a consequence of broken cells, right, that lead to the amount of HTT within the CSF. So the interesting question becomes, what are the changes that would occur? And so we'll monitor that. And I think this will be, you know, because of, PTC, you know, 518 is able to go completely through, you know, to every part of the brain, this is going to be probably the best estimate anyone has ever done in terms of saying what's the effect and what is the HTT reduction in the CFS mean and how fast does it go down. What we're going to learn also from this is the exposure level of the drug. within the CSF and see if it maintains the same of what we saw in healthy subjects or is it different than what we see versus HTT patients. So we're going to learn a lot there in terms of really in a very careful way where you can actually know the level of exposure, know within the CSF what's the consequence of altering the levels of things like HD, you know, be secreted or due to broken cells. Because if you think about it, the reduction could be a consequence of not breaking cells. So, you know, how you're measuring and how fast it goes away might be quite interesting. Does that help you?

Yes. Yes, that's helpful. Just wondering, like, you know, does that mean we actually, given the lower baseline in the CSF, should we actually see more sensitive change in the CSF versus blood?

What do you mean lower? We don't have any.

Oh, like, sorry, because in the CSF, you only have a broken protein released from the cell. versus in the blood, you collect all the protein inside the cells. So then the protein baseline level will be much higher in the blood versus in the CSF.

That's right. So what we're looking for is the percentage change that occurred as a consequence of that. So you normalize the change of that that you'll see in the HTT, and you'll normalize in cells, and then you'll normalize that to what you see in the CSF.

Thank you.

Our next question comes from Robin Karnak, is with Truist.

Great, thanks for taking my question. All right, okay, a couple. For AATC, can you just first talk a little bit about the patients you've identified, where are they at? I think there's questions around the launch trajectory and how quick it can be So giving that platform would be great. And given so many equations in Asia, maybe give an update and then have a follow-up.

Right. So I'll ask Eric to comment. Eric and Connie can. But obviously we found patients in every country that we looked at around the globe. So that there is the notion, I think people, there's a misinterpretation sometimes on, I'm thinking that it's higher in Asia, which, I mean, there could be founder's effect, but it's clearly found everywhere. It's clearly found everywhere within the world. There's no country that we haven't found it in. And the patient identification has been ramping up. Obviously, as we said, we've done over 100 programs, and we've begun learning how to find them, so we're accelerating in finding them as well. Eric, do you want to talk a little bit more about patient identification and finding?

Yeah, sure. Thanks for the question, Robin. You know, patient finding has been something that we've been really good at, and we've been in good progress every quarter as we've been focusing now across multiple geographies. And over the past couple of years, as Stu mentioned earlier, we've had hundreds of screening programs now in more than 20 countries. These 20 countries right here are really the focus of ours because we know they're going to be countries that will have access mechanisms for reimbursement to gene therapy and also have centers of excellence which can perform the treatment. So it's incredibly important that we focus our screening there. We're pleased with the type of patients that we've been screening. We've been finding patients all ages. So in terms of just, you know, very early in terms of few months up to their teens. So we've seen patient identification across the board in all patient types as well as, you know, age and severity. We're finding these patients primarily now in these high-risk population groups, particularly in cerebral palsy and epilepsy centers. And a lot of our focus has been on the key markets as well where we have been testing or been doing a lot of testing in these centers and finding patients. Another thing I'd like to highlight, too, is the earlier comment about centers of excellence. These neurological centers of excellence are also playing a very important role. And where we are sequencing the launch, as I mentioned, in Germany, France, southern Europe, northern Europe, where we have early access programs and access mechanisms, as soon as we are treating patients, there is a strong interest in screening and identifying even more. So we have very active key opinion leaders in these countries. So to Stu's point earlier, there is no specific market where we found more or less. We've been finding patients in all the key geographies and we're very pleased with that. And I think what's

Breaking it down, though, can you just help us a little bit, though, feel a little bit better about, given that you're launching slowly in different countries, like where you're finding the patients? And you've been working so hard to find them. I think that's where people are trying to go with. It's like, you know, how is it speeding up?

So I think one of the – well, you have to remember that you've got to – when you have a new disease that – that people just misdiagnose and need to throw them into CP clinics or refractory epilepsy clinics or other places, you sort of have to turn over and you need to sort of figure out the right algorithm to find those patients, right? And so that's why when we say we have done over 100 different programs is because we use many different countries to test many different things And in a sense, laboratories define what's the best way to find patients, and then everybody would start using the best practices over all of that. So when we say we found patients in every country, we're talking about over 20 countries that we've been searching in, and we found them in all of those countries. So when it comes to getting ready for a launch, you know, we're getting patients ready upon approval, you know, to line up for the surgeries. So that's been our goal. That's perfect.

Yeah. I'm trying to be really mindful because I know other people are asking questions and trying to be so efficient. I guess a quick question on PKU. I mean, Byron talked about how hard these PQ centers are really struggling. They're backed up. How confident are you that you actually can continue to enroll in time? And I think you know, like given that backup and the inability to treat patients, how do you feel about that? And I'll just add one other question for Emily. Emily, you gave a lot of color around buy-ins from Latin and Brazil. Please give some clarity around, you know, how we should model. You did a great job saying it, but just help us model the first quarter and second quarter a little bit more clearly. Thank you.

So maybe on the first point with PKU, I think from our point of view, I think things have been moving well. Matt, maybe you want to talk a little bit about the clinical trials at PQE and how they've been going. Yeah, sure.

So, Robin, we're not... Seeing what you've mentioned, and I'll say that, you know, once again, we're leveraging our global infrastructure with study sites around the world, and quite frankly, a lot of pull from investigators to participate in the trial. And so our teams have done a really good job in terms of projecting and managing enrollment flow. So we're not seeing problems with access to centers being an enrollment challenge at this point.

So we haven't seen that so far. And then your last, Robin, your last question was, are you sort of asking about lumpiness?

Yeah, we've talked about orders from Brazil as well. So we just want to make sure we model it correctly. It could just give us a little granularity on how do we model, you know, these orders. Did they come in exactly in the first quarter? Did they blend into the second quarter? How do we think about that for Latin? Thanks.

Emily, you want to go through?

Yeah, sure. I mean, we don't give quarter-by-quarter guidance exactly because of that lumpiness, so it is hard to give additional color for modeling purposes. I will say that we contemplate that lumpiness when we give our annual guidance, and we remain confident in our annual guidance for both the DMD franchise and the other revenues we've included.

Okay, great. Thank you guys so much. Sorry to be so quick. I want to make sure I want to ask this question. Thanks.

Thank you. Our next question comes from Danielle Brill with Raymond James.

Hey, everyone. This is Alex on for Danielle. A couple from us on Translarna and Study041. Have the EMA, like, have the regulators given any indication one way or another whether market access is contingent upon Study041 hitting stat sigs? And how much is EMA putting, you know, weight are they putting into the stride registry? And if you could just remind us about the exact timeline of regulatory actions following top line data readout, that would be great. Thanks.

Yeah, thanks for the question. And I think we've been saying this for quite some time, that we believe that the EMA really looks at the totality of the data and includes not only the trials and the totality of the data and the results that we have in the trials, but also the results of the registry where we're seeing comparison at five and a half years greater walk in years better in terms of getting off the ground much better pulmonary function. So those are, you know, when you think about it, those are the long-term consequences that you hope that clinical endpoints will meet. And the beauty of the stride registry is showing us that the transline is having a profound effect on these kids looking at endpoints in terms of how patients function, feel, and survive. So I think the combination of the trial data sets that we have as well as the SRED registry and the totality of the data is what we think is critical. Does that help you?

Yeah. I mean, just to pin you down a little bit, if you're saying that you think that you have a potential to still access the market if study 041 does not hit stat C? Is that what I'm reading?

Yeah, I mean, you know, until we, you know, turn over the cards and see the data, it's hard to say exactly, but we anticipate that even if it's not, if, you know, we're hoping for perfection, but if there's not, if there's imperfection, we still think that this data, or if you think about this data, when looking at the totality of the data of study 07, study 2041, that everything, when you look at the six-minute walk test, you look at the time function test, the NSAA, falls, all the measurements that we did, it always favored Translano or placebo. And then you couple that with the dried results showing real-world effects, we believe, you know, we would, we certainly anticipate that this, you know, we plan to have this, that this will remain on the market.

All right. Great. Thank you.

Our next question comes from Colin Bristow with UBS.

Hey, good afternoon, and congrats on all the progress. Just one on 93 and PKU. So the open label extension criteria was recently, I guess, updated or relaxed to allow patients with 15% or greater reductions in fee levels versus previously being greater than or equal to 30%. So I just wanted to touch base on this, and can you explain the rationale behind And is this at all indicative of you seeing a lower magnitude of fever reduction than you had first expected? Thanks.

Matt, you want to take that?

Sure, Colin. Yeah, the purpose of the long-term extension is really just to allow patients in who were in the first part of the trial, and it's allowing us to collect long-term safety data to build up the safety dossier and also obviously look at magnitude of effect. change was administrative has nothing to do with anything we'd be seeing in the trial because we're actually not looking at any data yet or observing anything in the trial. I think that's just intended to allow for as many patients as possible to enter into that follow-up period, even if they maybe didn't meet the criteria to be randomized, that we could actually put them in if we want to bolster the number of patients we're collecting long-term safety data on. Okay, great. Thank you.

And I'm not showing any further questions at this time. I'll turn the call to Stuart Peltz for any closing remarks.

Okay. Well, thank you for joining us today. I'm proud of our strong financial performance this quarter, you know, as we continue to execute and deliver on all fronts. As we've discussed today, we've already progressed a number of the key milestones and will continue to do so throughout the year. We're excited about the upcoming potential CHMP opinion for AABC gene therapy, as well as the results from a number of registration-directed trials anticipated this year. We're well-positioned to continue our mission of bringing life-changing therapies to patients, and I look forward to providing updates on all our progress as the year goes on. Thanks for tuning in.

Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.