Ladies and gentlemen, thank you for standing by. Welcome to the PTC First Quarter 2022 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions]. I would now like to turn the call over to your host, Kyle O’Keefe.

You may begin..

Good afternoon and thank you for joining us today to discuss the PTC Therapeutics first 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 Pauwels; 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 Web site 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 results of operations.

For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report 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.

Stu?.

Thanks, Kyle. Good afternoon and thanks for joining today. I'm excited to share PTC's first quarter results, but first an update on what I expect to be a transformative year for the company. On this, PTC has developed 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 unmet medical need. 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 therapeutic that at steady state would deliver a new product every two to three years.

This will allow us to continue to build into a company with 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 Emflaza. In addition, we recently had the first group purchase order for Tegsedi 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. Evrysdi sales continue to show strong growth in all regions with substantial growth in Europe.

Evrysdi 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 uptake and sustained growth of Evrysdi, which demonstrates the demands 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 AADC 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, PTC-AADC will be the first marketed gene therapy administered directly to 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, a placebo-controlled trial of Translarna. We expect to report results of Study 041 by the end of the second quarter. We also recently received the positive CHMP opinion for the 8th annual renewal for Translarna in the EU. Turning now to PTC923 for PKU and the registration-directed APHENITY study.

We're excited by the opportunity in PKU with a well established patient population and a high unmet medical need driven by the majority of PKU patients, either therapy naive or poorly controlled on existing therapies. In addition, the APHENITY 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 Bio-e platform, we expect results from the registration-directed MIT-E study of vatiquinone in patients with mitochondrial disease-associated seizures in the fourth quarter of this year. We are also excited to announce that we initiated the CardinALS study in PTC857 in ALS.

Moving to our validated splicing platform, we're excited to be following the successful pathway established by Evrysdi with PTC518 in Huntington's disease, or HD. HD is a debilitating disease with no disease modifying treatments.

For PTC518, an oral splicing modifier, we initiated the Phase 2 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 oncology portfolio, we also recently initiated the SUNRISELMS study of unesbulin in leiomyosarcoma.

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 diversified 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 APHENITY Phase 3 trial of PTC923 in patients with PKU.

Enrollment in the registration-directed APHENITY trial is ongoing, and we expect to have results by the end of 2022. As a reminder, the APHENITY trial is a six-week placebo-controlled study with the 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, a 15% reduction in phenylalanine levels, will continue to the placebo-controlled phase.

Following completion of placebo-controlled study, all subjects will be eligible to enroll in a long-term extension study. Next, I'll discuss our Bio-E platform from which we currently have two ongoing registration-directed trials with vatiquinone as an additional registration-directed trial with PTC857.

The MIT-E trial, the registration-directed trial of vatiquinone in patients with mitochondrial disease-associated seizures is actively enrolled, 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 vatiquinone.

The study primary endpoint is reduction in the number of observable motor seizures, with secondary endpoints capturing other aspects of disease morbidity. The second vatiquinone registration-directed trial is the Phase 3 MOVE-FA study in patients with Friedreich Ataxia.

The trial includes a 72-week placebo-controlled phase and the primary endpoint is changed from baseline in the modified Friedreich Ataxia 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 in the Bio-e platform, PTC857, we have now initiated Phase 2 registration-directed CardinALS 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 placebo.

The study is planned to enroll approximately 255 patients from study sites worldwide and the primary endpoint is change in ALSFRS score from baseline to 24 weeks. Turning now to our splicing platform, we recently announced the initiation of the Phase 2 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-controlled phase focusing on safety, pharmacology, and pharmacodynamic effects on huntingtin mRNA and protein levels.

After completing the first 12 weeks, all subjects will remain on their initial treatment assignment of either PTC518 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 SUNRISELMS study, which is the registration-directed Phase 2 study of unesbulin in patients with leiomyosarcoma. Leiomyosarcoma, or LMS, is a rare and aggressive cancer that affects 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 79% they offer minimal meaningful efficacy.

SUNRISELMS 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 SUNRISELMS study is based on the findings from our Phase 1b trial in which unesbulin 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 for PTC-AADC and in Brazil, the potential approval for the new indication of Waylivra for familial partial lipodystrophy, or FPL.

In addition, we continued the expansion of our geographical footprint for Translarna. Our global DMD 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 Emflaza.

Our Emflaza net product revenue for the first quarter was $49 million, double digit growth from the first quarter of last year. Ongoing execution buyer and Emflaza 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 longstanding 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 Tegsedi and Waylivra. Our Latin American team continues to build significant momentum in the region.

As Stu mentioned, in Brazil, following the innovative drug classification forecast 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 Tegsedi to CONITEC, which is the National Commission for the Incorporation of Technology, and has initiated discussions for inclusion of Tegsedi 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, Tegsedi and a recent first quarter NDA submission of Waylivra 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 Waylivra for the treatment of FPL. If approved, Waylivra will be the first approved treatment for FPL in Brazil, and this will mark the first approval globally for the certification. 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.

We are well positioned for continued geographic expansion. Our growing sales revenue base combined with revenues from respective 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 revenue was 149 million compared to 180 million for the first quarter of 2021. Of this, the DMD franchise produced 128 million in revenue compared to 91 million in the first quarter of 2021.

This includes Translarna revenues of 79 million in the first quarter of this year as compared to 47 million in the first quarter of last year. Emflaza 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 Evrysdi totaling approximately CHF 226 million. In the first quarter of 2021, we reported 7 million in royalty revenue in addition to a 20 million milestone payment that was reported as collaboration revenue.

Evrysdi royalty revenue is up this quarter and this growth is expected to continue as pricing and reimbursement 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 Evrysdi to reach 759.

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 expenses were 60 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.

Operator?.

[Operator Instructions]. Our first question comes from Eric Joseph with JPMorgan..

Good evening, guys. Thanks for taking the question and congrats on the quarter. I guess just one on Translarna and then a couple on the pipeline.

First, just I guess with the performance this quarter's talking about any sort of headwinds related to sales in Russia at all, and are you guiding at this point in terms of how the cadence of revenue performance by proceeding to second quarter with the reiteration of sort of top line from the DMD franchise? And then secondly, as it relates to Study 041, just wondering if you could kind of compare or make the contrast in the primary endpoint being used in this study here compared to DMD? You're looking at slip [ph] or change in six-minute walk distance compared to just change in six-minute walk.

Is it correct to assume that you're taking multiple intervals in between baseline [indiscernible] two weeks? And in that case, how frequently are you assessing six-minute walk distance?.

Yes, thanks for the question. So, obviously, in Russia, it's a volatile situation and we're obviously closely watching as it unfolds. And we plan -- obviously we plan accordingly and helps us best, if necessary, to adjust the business.

But probably, as you know, the sanctions do exclude medicines, and we've been really focusing on the continuity of treatments for the boys and young men who have nonsense mutation Duchenne muscular dystrophy in the region.

So I think the good news is, 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 with our total revenue guidance isn't really affected right now. So it's hard to -- we haven't seen any issues with that.

Matt, do you want to talk about the 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. It obviously not only includes the baseline and final six-minute walk distance, but it also includes information collected 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 this study visit time points that we had previously discussed 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 in 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 they're just giving you a lot more information in the overall analysis..

That's very helpful. Maybe just one follow up on Study 041 as well. In terms of patient demographics by ambulation 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 had baseline originating 350 or other ranges? Thanks.

I guess like, are you -- can you say at this point sort of the average baseline walk distance that you would expect for patients that would be evaluated [indiscernible]? Thanks?.

Matt?.

Yes, 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 as far as exactly what the mean baseline values were, because only two populations of 360 and 180..

Okay, great. Thanks again for taking all the questions..

And the other question, Eric, you had just in terms of our thinking about revenue growth for Translarna over 2022 would be. So what we think is it's going to be -- last year obviously was driven by geographic expansion, new patient starts, high patient compliance and the expanded age that we got on the label in Brazil.

We also anticipate strong revenue growth for Translarna 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 eligible [ph] patients in the new markets and the ongoing access in the current market. 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 Kluska with Cantor Fitzgerald..

Hi, everyone. This is Rick on for Kristen. Thank you for taking our questions. We just got two for you here.

In the MIT-E trial, can you talk a little bit about the seizure running measurement given that there are multiple types of seizures that 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 a lead in is tailored to the types of seizures that these patients are typically experiencing..

Matt, do you want to take that?.

Yes, absolutely. So the MIT-E trials we talked about is our global study looking at the effects of vatiquinone on mitochondrial disease-associated seizures, which is a highly morbid and common symptom of mitochondrial disease.

About 30% to 50% of all patients with mitochondrial disease have seizures, and these are typically refractory and antiepileptic medications that are commonly given for the simple reason that 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 children. So while you may have some benefit of antiepileptic, it's offset by the increase in 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 and to the primary endpoint is the observable motor seizures for the exact reason you're highlighting, which is you want to make sure that the parents can observe and count them.

And so in the base of what we do to track the seizure changes as we provide patients -- 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 observe 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-month of -- I'm sorry, 24 weeks of either vatiquinone or placebo therapy, and then we'll change -- we'll compare the monthly rate of following placebo or vatiquinone with that baseline frequency.

But again, the primary endpoint will be observable motor seizures and the secondary end points will capture other aspects of seizure technology..

Understood. Thank you for that. And maybe just one more. After recently initiating the Phase 2 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..

Yes, thank you. So we recently initiated this trial. So obviously, what our plans are is it's a yearlong 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, 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 patient -- the treated versus placebo, looking at the level of obviously safety and then looking at the levels of HTT RNA and protein in the cells of the blood, so we'll be able to get that information. And then looking also at biomarkers such as mutant HTT as well as NfL in the CSF..

Thank you..

Our next question comes from Brian Abrahams with RBC Capital Markets..

Hi, guys. Good afternoon. Thanks for taking my questions. My first one is on PTC-AADC. 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 -- these neurological centers that you expect to launch with and the degree to which they've already identified patients, or will kind of initial launch engagement kick off a screening process? And then I have a follow up on Huntington's? Thanks?.

Sure. Thanks for that question. So obviously, we talked about -- we told you that we will be having -- we'll have the CHMP opinion in May.

And just to remind everybody, AADC is obviously an ultra orphan, highly morbid and fatal pediatric disorder where you see patients -- patients they like 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, rollover, stand.

It's 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 looks at -- 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 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 do you want to talk a little more, Matt?.

Sure. Thanks, Brian, for the question. So, obviously, we're optimistic about the positive opinion in May and a lot of that is based on the content of the meetings and 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 -- 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 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 Stu said, be the first ever directly administered therapy to the brain.

I think that's really an important advancement to the entire field of gene therapy that we can now think about marrying a common pediatric and adult neurosurgical procedure, stereotactic guided surgery with the delivery of gene therapy to the exact location in the brain where it's needed most.

I'll use that that it's a segue to our preparations for launch in the surgical and neurology centers of excellence..

Yes. So maybe, as Matt just alluded to, so we were excited about completing these and been working hard to get ready for launch preparation. And so I think there's been -- 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. We've been finding them in all countries. So we're really excited about this.

Eric, do you want to talk a little bit about all the efforts that have been going on?.

Yes, certainly, Stu. The launch preparations in cells are progressing extremely well. 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 in the 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 will 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. So 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 2 study was posted to Clinical Trials 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? Will it get knocked down? 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..

Thanks for the question. I think from the first part of the question, it's really we're looking for reduction.

And obviously besides safety, we're also looking at the biomarkers, the reduction in terms of the level of HTT of RNA and protein in the blood and see what happens in the CSF in terms of PK levels as well, so that we will define what those levels are. We saw 2.5 to 3 fold increase in the CSF well into the blood in the Phase 1 studies.

Is that the same that we see in terms of what we did do? And based on those numbers is what we'll look for, how we titrate -- whether we need to or not and what level should we do the titrate of the compound.

In terms of the MRI, Matt, do you want to talk a little bit about that?.

Yes, certainly. Sure. And just to follow up on Stu's point, Brian, so it will be a combination of the safety evaluations in the DSMB and then what we're seeing in terms of the levels of reduction in huntingtin mRNA and protein, as we said all 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 in 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 PK/PD relationship and volumetric MRI will be tracked enough that that's going to really be an endpoint in the second part, right, the nine months [indiscernible] focus on biomarkers..

Really helpful. Thanks, again..

Our next question comes from Joseph Thome with Cowen and Company..

Hi. 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?.

Yes, thanks for that. So with the AADC, as we said, obviously we're in the last throes of completing what we needed with the CAT and the CHMP. So we felt we've gotten that complete and we think that's going to be quite helpful for the FDA.

And so based on that, the next steps -- Matt, why don't you go through what our plans are with the BLA?.

Yes, 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 aligned on this mission 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 a financial question. 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 in to the 2022 financial guidance? And maybe if you could just highlight the ones that we should expect, that would be very helpful? Thank you..

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

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..

Thank you very much. Very helpful..

Yes. On the flipside, I'd just remind you that in our revenue guidance, we have a $50 million milestone from Roche expected for certain Evrysdi, the sales thresholds and there's the potential to reach up to 100 million milestone for additional thresholds..

Okay, that's excellent. Thank you, again..

Thank you..

Our next question comes from Gena Wang with Barclays..

Thank you for taking my questions. I have three questions. The first one is regarding Emflaza. 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 Translarna. What kind of data every year you need to submit to receive renewal in Europe? And my third question is regarding PIVOT-HD trial.

Since you will collect data, huntingtin 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 huntingtin protein in CSF versus blood?.

Great. So I'll take the first one in terms of loss of exclusivity of Emflaza. Yes, you're correct. It's in 2024. Obviously, we're doing some work evaluating our options in order to do that so that -- in order to maintain that.

And obviously we have a number of programs that we're working on to retain patients, which we're obviously optimistic of a lot because we provide patient support services around Emflaza to both the patient and the caregiver communities.

And then we are evaluating all options to defend the Emflaza brand, including leveraging the patient support programs, driving the channel through from the specialty pharmacy partnerships and then levering our key relationships with the contracts and payers.

So you might probably be aware of this, in the rare disease market, patients are actually relatively loyal. The generic pricing discounts are often offset by patient support programs.

In terms of Translarna and what we put in, Matt, why don't you go through that a bit?.

Certainly. Thank you for the questions, Gena. So the annual renewal is based -- 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 forward to continue their 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 when you think about what's occurring within the cell that and obviously right where we're altering splicing.

And if we look at the reduction of both RNA and then the reflexive [ph] of what's going on in the protein, you said 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 -- because of PTC518 is able to go completely to every part of the brain, this is going to be probably the best estimate anyone's ever done in terms of saying, what's the effect and what is the HTT reduction in the CSF 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 volunteers 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 that within the CSF was the consequence of altering the levels of things like HTT that will be secreted due to broken cells, because if you think about it, the reduction could be a consequence of not breaking cells.

So how you're measuring and how fast it goes away might be quite interesting.

Does that help you?.

Yes, that's helpful.

Just wondering like, does that mean -- actually giving 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 that enough..

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 CSF?.

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

Thank you..

Our next question comes from Robyn Karnauskas with Truist..

Great. Thanks for taking my question. All right, okay, a couple. For AADC, can you just first talk a little bit about the patients you've identified, where are they at? Maybe this question's around the launch trajectory and how it can be. So giving that platform would be great. And given so many patients in Asia, maybe give an update.

And then I have a follow up..

So I'll ask Eric to comment here. But obviously, we found patients in every country that we looked at around the globe. So that there is -- there's a misinterpretation sometimes on thinking that this is higher in Asia, which it could be the 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 we've been -- and the patient identification has been ramping up. Obviously, as we said, we've done over 100 programs and we've become learning how to find them. So we're accelerating and finding them as well.

Eric, do you want to talk a little bit more about patient identification findings?.

Yes, sure. Thanks for the question, Robyn. Patient finding has been something that we've been really good at. And we've been seeing 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 -- 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 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 be 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..

Breaking it down though, can you just help us a little bit though to 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 at this, like, how is it speeding up?.

So I think one of the -- you have to remember that you got to -- when you have a new disease that people just misdiagnose and either thrown into CP clinics or refractory epilepsy clinics or other places, you sort to 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 did a lot. We used many different countries to test many different things. And in a sense laboratories to find what's the best way to find patients and then everybody would start using the best practices over all of them.

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, we're getting patients ready upon approval to line up for the surgeries. So that's been our goal..

That's perfect. I'm trying to be really mindful, because I know other people are asking questions and trying to be like so efficient. I guess a quick question on PKU. I mean, [indiscernible] talked about how far the PKU centers are really struggling. They're backed up.

How confident are you that you actually can continue to enroll in time? And like given that back up 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 in from LatAm, Brazil.

Can you give some clarity around 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 -- Matt, maybe you want to talk a little bit about the clinical trials of PKU and how they have been going?.

Yes, sure. So, Robyn, we're not seeing what you've mentioned. And I will say that, 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 positive access to centers. It will be an enrollment challenge at this point..

So we haven't seen that.

And then your last -- Robyn, your last question was, are you sort of asking about lumpiness of --?.

Yes. You talked about orders from Brazil as well. So we just want to make sure we model it correctly. Could you give us a little more granularity on how do we model these orders? Do they come in exactly in the first quarter? Then explain the second quarter, how do we think about that for LatAm? Thanks..

Sure.

Emily, do you want to go through?.

Yes, sure. 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 guidance, 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'm [indiscernible] question. Thanks..

Thank you..

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

Hi, everyone. This is Alex on for Danielle. Couple from us on Translarna and Study 041.

Have the EMA -- like have the regulators given any indication one way or another whether market access is contingent upon Study 041 hitting stat sig? And how much is EMA putting -- are they putting into this drive registry? And if you can just remind us about the exact timeline of regulatory actions following top line data readout, that would be great? Thanks..

Yes, thanks for the question.

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 walking years better in terms of getting off the ground, much better pulmonary function.

So those -- when you think about it, those are the long-term consequences that you hope that critical endpoint meet. And the beauty of a STRIDE registry is showing us that Translarna is having a profound effect on the 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 STRIDE registry and the totality of the data is what we think is critical.

Did that help you?.

Yes. But 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 sig.

Is that what I'm reading?.

Yes, until we turn over the cards and see the data, it's hard to say exactly but we anticipate that even if it's not -- we're hoping for perfection, but if there's imperfection, we still think that this data -- if you think about this data when look into totality, the data Study 041 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 favors Translarna over placebo.

And then you couple that with the STRIDE results showing real world effect, we certainly anticipate that this -- 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..

Hi. 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 50% 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? Is this a tool indicative of using a lower magnitude of fee reduction than you first expected? Thanks..

Matt, do you want to take that?.

Sure. Colin, 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 to effect. That change was administrative.

It has nothing to do with anything we're going to be seeing in the trial, because we weren't actually not looking at any data yet or observing anything in the trial.

I think it'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'd like to 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 as we continue to execute and deliver on all fronts. As we've discussed today, we've already progressed a number of key milestones and we'll continue to do so throughout the year.

We're excited about the upcoming potential CHMP opinion for AADC 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 does conclude today's presentation. You may now disconnect and have a wonderful day..