Good day, and thank you for standing by and welcome to the PTC First Quarter 2023 Financial Results Call. All participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today’s conference is being recorded.

I would now like to turn the call over to Kylie O'Keefe, Chief Commercial Officer. You may begin. Hello speakers..

Yes. Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' first quarter 2023 corporate update and financial results. I'm joined today by our Chief Executive 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 our current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements.

Our actual results could materially differ from these forward-looking statements, as such statements are subject to risks that can materially and adversely affect our business and 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 filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call.

Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP are available in today's earnings release. With that, let me pass the call over to our CEO, Matthew Klein.

Matt?.

Thanks, Kylie. Good afternoon, and thank you for joining the call. I'm pleased to share PTC's first quarter results and our expectations for continued strong performance and a transformative 2023. PTC is a leader in developing and commercializing innovative therapeutic to treat rare disorders.

I'm incredibly excited to lead PTC into its next quarter century as we continue to utilize pioneering signs, deliver therapies to patients with high unmet medical needs. We had a very productive first quarter, achieving $220 million in total revenue, our highest quarterly revenue ever. This represents 40% growth over the first quarter of 2022.

Our DMD franchise revenues in the quarter totaled $170 million, which represents a 33% increase over the first quarter of 2022. Evrysdi also had a strong first quarter, providing royalty revenue of $31 million. The Evrysdi revenue growth continues to be driven by both therapy naive patients and those previously treated with zolgensma and spinraza.

In addition, U.S growth being driven by patients less than 2 months of age following the recent sNDA approval. This robust first quarter performance puts us in a strong position to achieve our total 2023 revenue guidance of $940 million to $1 billion, which would represent up to 43% year-over-year growth.

In addition, as we previously shared, we expect to use the study results to be reported in the second quarter to inform a strategic portfolio review and likely OpEx reduction, on which we will provide further details once available.

Moving to our pipeline, we remain on track to report results from four clinical studies in the second quarter, three of which are registration directed. Let me provide a brief overview of each study and the results we expect to share. I'll begin with our APHENITY study.

APHENITY is our Phase 3 global placebo-controlled study of sepiapterin in children and adults with PKU. The placebo-controlled portion of the study was 6 weeks in duration with the primary endpoint of reduction in blood phenylalanine levels.

To enrich the randomized population specific care and responders, there was a run-in phase during which all screen subjects received sepiapterin for 2 weeks.

Only those subjects who demonstrate a reduction in phenylalanine levels of 15% or more from baseline in Part 1 were randomized with Part 2 with the primary analysis population consisting of those who had a greater than 30% reduction in phenylalanine levels from baseline during the run-in phase.

At fourth quarter earnings in February, we shared the encouraging data from Part 1 run-in phase, in which approximately two-thirds of treated subjects demonstrated a greater than 30% reduction in phenylalanine levels. The mean phenylalanine reduction for all subjects with at least 30% reduction was 66%.

And the mean reduction for classical PKU subjects was 61%, supporting the concept that a more bioavailable and potent cofactor therapy sepiapterin can provide a clinically meaningful and differentiated response to the full spectrum of PKU patients. We look forward to sharing results in the placebo-controlled portion of APHENITY in May.

Let me now move to the two registration directed trials of vatiquinone. MIT-E is a global registration-directed trial of vatiquinone in patients with mitochondrial disease associated seizures. The study included a 24-week placebo-controlled phase with the primary endpoint being changed from baseline in frequency of observable motor seizures.

The last subject last visit for the placebo-controlled phase occurred in March as planned and we continue to expect results in the second quarter. The MOVE-FA trial is a global Phase 3 registration-directed study of vatiquinone in pediatric and adult patients with pediatric ataxia.

The study includes a 72-week placebo-controlled phase and the primary endpoint is the change in the validated mFARS rating scale from baseline. move FH file is a global phase three registration directed study of the tickler known in pediatric and adult patients with Friedreich ataxia.

The study included a 72-week placebo-controlled phase, with the primary endpoint being changed from baseline in the validated mFARS score. Last patient last visit to the placebo-controlled phase has also occurring and we continue to expect results from MOVE-FA in the second quarter. Moving to our PTC518 Huntington's disease program.

PIVOT-HD is a 12-month placebo-controlled trial that consists of two parts. Part 1 is 12 weeks in duration and focuses on PTC518 pharmacology and pharmacodynamic effects, as well as biodistribution. Part 2 is 9 months in duration and focuses on blood-based, CSF-based and radiographic biomarkers of disease.

The study initially includes two dose levels, 5 milligrams and 10 milligrams, with the ability to include a third dose level of up to 20 milligrams leveraging the titratability of the molecule.

We initially included patients with Phase 2 Huntington's disease, and we recently expanded the trial to include early Phase 3 patients who we study initially at the 5 milligrams and 10 milligram dose levels. We continue to expect interim data from the 12-week portion of the trial in the second quarter of 2023.

These data will include safety, pharmacology pharmacodynamic and biodistribution data from the 5 milligram and 10 milligram dosing. With results of these four studies expected in the next several weeks beginning tomorrow, we will not be discussing these programs until results are reported for each study. Turning to Translarna.

We continue to expect the CHMP opinion for the Type II variation to convert the European conditional marketing authorization to standard authorization in the second quarter. In the U.S., we are preparing a Type C meeting request to review with the FDA, the totality of data collected to date that could support an NDA resubmission for Translarna.

Finally, for Upstaza, as we previously shared, the FDA requested additional bioanalytical data in support of comparability analyses between the clinical and commercial drug path.

We have received initial feedback from the agency on these data and are in the process of responding to additional FDA queries prior to submitting the BLA which could result in a BLA submission occurring in the third quarter of 2023 rather than the second quarter as previously planned.

Overall, I’m incredibly proud about productive and successful first quarter. And we will now hand the call over to Eric to provide an update on our commercial portfolio.

Eric?.

Thanks, Matt. Our global customer facing team is kicked off 2023 with an extremely strong quarter, capitalizing on the significant momentum we created in the second half of 2022. Our team is focused on driving significant growth with our commercial portfolio of products for neurological and metabolic disorders.

We continue to make good progress with the Upstaza launch in Europe. We also have launched Waylivra for familial partial lipodystrophy, FPL in Brazil, following the approval of this new indication in the fourth quarter of last year.

Our strategy and execution of geographic expansion continues to progress in Latin America and our future growth markets in Asia. And we are in a strong position to achieve our 2023 revenue guidance as Matt previously mentioned. Let me start with a DMD. franchise.

Translarna and Emflaza continued to be an important engine for growth, delivering an impressive $170 million in first quarter net revenue, which is up 33% compared to the first quarter of 2022. For Translarna, we achieved $115 million in revenue this quarter. We continue to see strong growth across the major markets internationally.

And there were some large government orders contributing to our revenue in Latin America, Central and Eastern Europe and the Middle East regions. Given unpredictable government ordering patterns in these markets, we expect to see ongoing lumpiness in quarterly revenue throughout the year.

We remain confident that we will achieve our 2023 DMD franchise revenue guidance of $545 million to $565 million as our growth fundamentals remain solid with continued new patient starts, high compliance, low discontinuation and proper weight base dose adjustments on an ongoing basis.

The fundamentals of the Emflaza business continued to be solid, Quarterly net revenue was $55 million.

We have seen a significant number of new patients start forms in the first quarter, which will provide important momentum as we progress through the year along with continued high compliance, appropriate weight based dosing and broader insurance access. Now turning to Upstaza.

The first and only gene therapy approved to be infused directly into the brain. We continue to see the transformative effects as new patients have been treated in Europe this quarter, including our first cross border commercial patient.

We see the steady rollout of Upstaza commercially in Europe and we'll leverage early access programs and cross border treatment in other international markets. Importantly, patient identification continues to accelerate and new treatment centers of excellence are being opened in markets internationally.

Additionally, market access discussions are progressing well with Germany and France. And we have received positive final guidance from NICE in England and Wales for AADC patients 18 months and older. We expect to treat more patients in more countries in Europe and other international markets throughout 2023.

Now moving to Tegsedi, and we would lever it in Latin America, where we continue to successfully grow these franchises in Q1. Following Waylivra's approval for familial partial lipodystrophy by ANVISA in December last year. We officially launched this new indication in Brazil, and have already generated our first prescriptions.

We also received our first group purchase order for Waylivra for familial chylomicronemia syndrome, which was completed and delivered in Q1. As mentioned in our last call, for Tegsedi, we received our second group purchase order from the Brazil Ministry of Health.

In conclusion, the first quarter was our strongest quarter ever at PTC and an excellent start to 2023 with substantial progress across all our commercial products, and in all major regions, setting us up to achieve our 2023 revenue guidance. Now, let me turn the call over to Emily for a financial update.

Emily?.

Thanks, Eric. I'll take a few minutes to review our first quarter financial results. Please refer to the earnings press release issued this afternoon for additional details. Beginning with top line results, total revenues for the first quarter were $220 million.

This consisted of net product revenue across the commercial portfolio of $187.6 million, Evrysdi royalty revenue of $30.8 million and manufacturing revenue of about $2 million. Translarna net product revenues in the quarter were $115.1 million, reflecting strong growth across all geographies.

Emflaza had net product revenues of $54.6 million, representing 12% growth in the quarter compared to the first quarter of 2022.

As Matt mentioned, the first quarter performance puts us in a strong position to achieve 2023 total revenue guidance of $940 million to $1 billion, including $100 million milestone expected whenever it surpasses $1.5 billion in annual revenue.

Non-GAAP R&D expenses were $179.8 million for the first quarter of 2023, excluding $15.3 million in noncash stock-based compensation expense, compared to $127 million for the first quarter of 2022, excluding $13 million in noncash stock based compensation expense.

The year-over-year increase in R&D expenses reflects additional investment in research programs and advancement of the clinical pipeline, as well as the $30 million sepiapterin clinical development milestone paid predominantly in common stock. Non-GAAP SG&A expenses were $73.4 million for the first quarter of 2023.

Excluding $13.5 million in noncash stock-based compensation expense, compared to $59.7 million for the first quarter of 2022, excluding $13.6 million in noncash stock-based compensation expense.

Cash, cash equivalents and marketable securities totaled approximately $286.3 million as of March 31, 2023, compared to $410.7 million as of December 31, 2022. I will now turn the call over to the operator for Q&A.

Operator?.

Hi, good afternoon. Thanks for taking my questions. The first one is for your DMD portfolio.

Could you talk specifically about what's been the biggest driver in new patients starts? And is this also related to the specific geographies with more patient adds? And then just kind of on top of that bigger picture question here, given you have a few registrational trials on deck, what's been the biggest learning factors and being able to expand your footprint globally, and how do you think you can leverage this should some of these candidates end up crossing the finish line soon?.

Great. Thank you very much Kristin for the questions that we are incredible proud of the global commercial infrastructure rebuilt and the ability to continue to grow. So DMD franchise revenue year-over-year being that we've been on the market now for almost 9 years. So that's really a tremendous accomplishment.

And obviously, there have been a number of key learnings in building that infrastructure that will come into play as we look forward to launching new products.

Let me turn the call over to Eric, who can give some more color on the global franchise?.

Yes, thanks for that, Kris -- Kristen, thanks for the question. I think we're really pleased with the fundamentals and the execution across all geographies. I mean, we achieved $170 million of sales, and that's the highest ever for our DMD franchise. To your question about what's driving growth, we see growth in a lot of different areas.

Of course, geographic expansion has helped with new patients, but also early diagnosis of patients, and the rapid time from the time they're diagnosed to commercial treatment, and the execution that our commercial team has been able to work on.

In addition to that, we're also focusing on maintaining, if you will, the ambulant, as well as a non-ambulant patient prevalent pool that we have on drugs, two dose adjustments, that's really important. And of course, we've been seeing across the board for both Emflaza as well as Translarna, improved and better paid payer access.

And that's really important as well. Now for Translarna, we did see $115 million, and that that is also from growth from all of our major markets. And that's incredibly important. But we also did receive some large government orders from our CIS region, our Central and Eastern Europe, Brazil, and from the Middle East.

The timing and the size of those orders, sometimes are a little hard to predict. And that creates some levels of lumpiness. But the most important thing is that these sizeable orders have confirmed that there is underlying growth fundamentals. And so we have a very strong base of new patients, as well as existing patients that we're managing.

We are expecting orders, government orders like this in the second half as well. And as Matt reiterated, we are rewriting our guidance for the DMD franchise to $545 million to $565 million. So I hope that provides you the color that you need, Kristen..

Yes, thank you. That's helpful. And then maybe just one quick one on Huntington's disease. In oral drug obviously comes with benefits in terms of compliance and adherence.

But thinking about the different therapeutics out there and recognizing the mechanisms are different, how are you thinking about an oral agents ability to really target the right areas in the brain versus some other routes of administration that are being evaluated?.

Yes, Kristen, thank you for the question. We think route of administration and biodistribution are incredibly important elements to the development of a successful therapies for Huntington's disease. And obviously, the development of PTC518 comes on the heels of the successful discovery and development of Evrysdi for SMA.

And obviously, we've made a number of important learnings about how to design a molecule that can effectively cross the blood and barrier, not at flux and globally by distribute CNS, which is not only essential for the optimal treatment of SMA, but obviously is similar. Similarly critical for Huntington's disease.

So in the design of PTC518, we put to play all of those lessons have a molecule is highly selective, highly specific gets across the blood brain barrier, and blood by distributes every region in the brain, which is incredibly important given that Huntington's disease is a full brain -- whole brain disease.

So the mechanism drug, obviously is targeting the cause of the disease, which is the production of the mutant Huntington protein that is toxic to cells and leasing neurodegeneration. And so what we're able to do with our splicing molecule is essentially decrease the production of the disease causing toxic protein.

And therefore having the ability to get to every region of the brain which contributes to disease is an incredibly important advantage of PTC518 over other therapies that are limited in their biodistribution by means of either being locally delivered in the case of a gene therapy, obviously, local delivery to the brain and gene therapy, something we know a whole bunch about from our successful development of Upstaza.

And then also has significant advantages of [indiscernible] administrated therapies which are just can't get all the locations in the brain that are contributing to disease.

So in this case, we have an oral molecule that was designed to get across the blood brain barrier or thereby distributed which we were able to confirm in terms of the CSF exposure in our Phase 1 study and we will obviously share data again and when we do the PIVOT-HD readout in the second quarter, and then also, we have other advantages because of all milestones titratable.

So we're also leveraging our titratability in our clinical study to identify the optimal dose to achieve the target whole brain Huntington protein that we think is optimal for disease treatment..

Great, thanks. Looking forward to catching up with you once these data read out..

And thank you. And One moment for our next question. And our next question comes from Brian Abrahams from RBC. Your line is now open..

Hi, this is Joan for Brian. Thank you for taking our question. Just on Huntington's, can you tell us more about what which data might be shared from the 12-week portion of the study? And it seems like there may have been some changes in your target population to include earlier Huntington's patients.

Can you share your thinking around it? And if it speaks to any possible changes in your thinking around desire level of the HTT knockdown and CSF? Thank you..

Thanks, Joe, for the question. So, the PIVOT-HD study is a 12-month placebo controlled study that is in two parts. Part one is 12 weeks in duration, it focuses on PK PD in the blood, as well as biodistribution. Looking at the relative exposure in the CSF and in the plasma.

These are important data points to inform optimal dose that gets us towards the target reduction in the brain and 30 to 50% of Huntington protein.

The second 9 months of the study is focused on biomarkers of disease including Huntington protein levels and CSF, radiographic markers, including bringing volume changes as well as NFL levels in case and the CSF. The data we plan to share in the second quarter is an interim analysis from the first 12 weeks of PIVOT-HD.

We will be sharing information on the PK/PD in a blood. So looking at blood, looking at drug levels in the blood and the reduction in Huntington mRNA protein one and then looking at the relative exposure of the CSF in the plasma. As you recall from our Phase 1 healthy volunteers study, we're able to confirm that we were getting excellent CNS exposure.

And in fact, achieving greater exposure in the CSF than in the plasma. So that's a very important finding that will seek to confirm the trove of data of the biomarker data including the CSF, Huntington protein levels, NFL levels, and brain volume changes will come up in the readout from the 12-onth data.

To your second question regarding patient populations. As I shared, answering Kristen's question, the mechanism of the drug is targeting the production of the disease causing mutant Huntington protein. That is by leveraging splicing, we're able to introduce a stop codon that effectively decreases the production of that disease causing protein.

Obviously, that holds promise for the full spectrum of HD patients, and whether they be juvenile or adult patient, given that the disease causes the same in all cases. However, it's obviously incredibly important in conducting a clinical trial that we try to include the right study population to whom we could practically capture clinical effects.

And in the case of the PIVOT-HD study, biomarker effect, along the -- in the time limited constraints on a clinical trial. So we put a lot of effort into identifying the attributes of what we felt would be that optimal population.

We availed ourselves and the robust Huntington disease natural history database is to work closely with Huntington's disease experts in biostatisticians, who support these databases, to come up with what we thought were the essential attributes of a study population that would likely to decline over the course of a clinical trial.

Obviously, we want patients who are not so advanced in their disease, that by targeting the upstream cause of the disease, we can practically deliver a benefit. And we certainly don't want patients who are so early in disease, that they're not progressing at all right. Therefore, making it impossible to show that we're slowing disease progression.

So we put these attributes can play at our inclusion criteria for the study, these were essentially Stage 2 HD patients. We shared at the JP Morgan conference in January, that we were adding additional cohorts on slightly later stage patients.

We were now including patients with who had a total functional capacity score of 11 and 12, rather than just simply having a TFC score of 13, which was initially acquired.

The reasons for this were because there were a number of these patients who were identified some pre-screened and prepared to participate in other clinical trials that were no longer being conducted.

So anyway, a situation where there are patients identified but it could be in clinical trials, incredibly eager to participate in clinical trials and whom we obviously believe we could have provided benefit with this therapy.

So maybe decision to introduce additional dosing cohorts, 5 milligrams, 10 milligram dosing cohorts in these early Stage 3 patients, because this will provide us additional important data on potential benefit of PTC508. And will also allow us to test our hypothesis in terms of the awful population that we initially set out to enroll.

So I hope that answers your question on the adjustments or the addition of the patient..

Yes, that was super helpful. Thank you, Matt..

And thank you. And one moment for our next question. And our next question comes from Eric Joseph from JP Morgan. Your line is now open..

Hi, good evening. Thanks for taking the question. Just a quick one from me, on particular known and if you could just briefly talk about the patent estate for the compound? I guess what claims are covered on IP where you maintain exclusivity? And then for what duration? Thanks..

Yes, thank you for the question, Eric. So the protection for vatiquinone is principally going to be under orphan exclusivity, as is always the case, we're exploring other potential ways to strengthen and extend the patent life, obviously, in the U.S and Europe as well as in other markets..

Okay, great. Thanks. And just a quick follow-up if I could. As it relates to MOVE-FA, could you just talk about sort of the range of patients entering by age, and I guess within that patient ages that will comprise the primary analysis for mFARS on the soft line reading. Thanks..

Yes, absolutely. So when we constructed the MOVE-FA trial, we leveraged a number of learnings that we'll need from our own Phase 2 trial, as well as another of the important learnings from other clinical studies.

We also were in a position were given the safety of the tip and the large volume of exposure in children, this opened up the opportunity to enroll the full spectrum of FA patients in terms of age. And so in this trial, our primary analysis population consists of patients aged 7 to 21.

Now, the majority of FA patients will usually diagnosed in early adolescence, late childhood or early adolescence. And the idea here is if you look at the natural history of disease, the younger patients tend to have a more uniform and more rapid decline.

So as we talked about the last question in part of Huntington's disease, getting that right clinical trial population that will move enough over the course of the clinical trials randomized to the placebo group, puts you in the best position to capture treatment benefits. And so we cut the lower age limit is 7, because if patients are younger than 7.

First of all, there's very few of them. But second of all, it's harder for those young children to comply with a number of the study assessments. So that makes ascertainment or clinical benefit difficult. So we set the lower age at 7, and then the primary analysis group goes up to 21.

Again, we believe that this is a population in whom one we can have less of a chance to the placebo effect. We're also in a situation where these patients tend to have a greater decline over the course of the clinical trial, and which makes it easier to register clinical benefit.

And also, as it's commonly the case, in neurodegenerative disorders, if you're going to intervene, it helps to intervene earlier in the disease, you have a better chance of affecting disease progression if you act earlier. And so we were able to do that, again, given the safety which are on the billion younger patients.

We are also including additional adult patients, it's not part of the primary analysis population.

We previously studied the drug in adults, we believe we can hold benefit for patients of all ages, and the opportunity to enroll adult patients will give us a chance also to look at the relative benefits in the pediatric patients, relatives and those old patients but we would fully expect that with a positive trial, and if we can move towards approval that we would have a label that would include pediatric and all adult population..

Okay, that's great. That's very helpful. Thanks for taking the questions..

And thank you. And one moment for our next question. And our line is open. Robyn Karnauskas from Truist. You are now available..

Great. Thanks for taking my questions. So I have three of them. So the first one is around PKU. So I know the bar, you gave the responder analysis of 30% and a decline -- the improvement, fee reduction for those lead in patients.

But since you -- the bar for entering Phase 2 is 15%, presumably you're going to get some lower responders going into the Part 2 that might actually reach the 30% at the end of the Part 2 Phase.

And I was just wondering, how do you set the expectations for Part 2? Do you think it'll look as good as just the lead in phase, considering there may be some slower responders entering them.

So I just want you to really flesh it out and set expectations for investors? Second question, is for FA, given the drug is TID dosing? Do you think the bar for success has been better than Reata? And maybe flush out, how much that TID dosing might impact the market? And then third, you mentioned like the range of patients like the -- you're doing younger patients and your confidence that they might have a lower placebo effect, but also maybe progress more rapidly.

What's your confidence in that over the timeline? And also, what's your confidence of the decline in the efficacy in that population? Because we've seen decline and we're out over time with older patients. What about younger patients, the decline of the efficacy of these drugs? Thank you..

Okay. Okay, Robyn, thank you for those questions. Let's take them in turn. So the first question is regarding the APHENITY trial. And so as we said, we have the run-in phase in which all screen subjects were treated for 2 weeks [indiscernible] account. And we randomized all subjects who had a greater than 15% reduction.

However, importantly, the primary analysis population for the trial includes only those subjects who had a greater than 30% reduction during the run.

So in terms of the primary analysis, and success on the trial there'll be no interaction of those, like 15% reduction, or between 15% and 30% reduction during the run-in versus those that had 30% reduction.

And just to give you a few of the numbers, as we've shared in the past, we had 102 of 156 subjects who were in the run-in phase had over 30% reduction. And there were additional 13 subjects who had between 15% and 30%.

That's important because what you're basically seeing is that those who responded to the drug, by and large, the vast majority had a tremendous response of over greater than 30% response. And as we shared, the mean reduction in all comers was 66% from baseline. So really impressive reductions in those numbers.

To answer your question also about what we would expect to see in terms of reduction in the patients as they move from the run-in phase, the -- to the placebo-controlled phase these patients are treated for 2 weeks, they're washed out and turn to baseline and then the same patients are getting treated with the same drug.

So those who get randomized to active, we fully expect to see similar magnitude of reduction. And obviously those who were randomized to placebo given with historically the placebo patients and PKU trials tend not to have very much any placebo response.

That gives us a great deal of confidence to not only achieve the primary analysis, the success of significant greater reduction in the treatment relative to placebo, but again, confident based on the data from Part 1 that we'll be able to demonstrate not only clinically meaningful response, but one that was struggling differentiate stepping accounts for the treatment of PKU.

In terms of FA, your first question was regarding the TID [ph] dosing. Look, we've never seen a problem with compliance with TID dosing. And it's a breakfast, lunch and dinner. So it's actually with meals and snack curate hours, which makes a very big difference. And we believe that there's several other important aspects of differentiate the therapy.

Let me turn it over to Kylie, I don't know if you want to add anything to that in terms of the effective dosing update?.

Yes, I think that's well said, Matt. I think there's a number of factors that are taken into consideration, particularly in disease of high unmet need and progressive diseases like Friedrich ataxia. Efficacy, first and foremost, obviously, a key priority.

And so it'll be interesting to see as we come out of the MOVE-FA study where both our primary and secondary endpoints land. In addition to that safety is obviously really important. And so there's a number of key differentiation factors from a safety point of view that we've seen with to and then obviously dosing comes into play.

And as Matt said, with dosing around meals, it's easy to comply and adhere to, particularly in the younger ages where we see our differentiation where parents are obviously providing the tablets to these kids as they're eating the meals.

So across the board, from the discussions we've had both with KOLs and with patients, there's not been any concerns raised around that, Robyn..

Yes, And then, Robyn, in terms of your third question regarding the 7 and 21 year olds and concerns there, and then how to -- why do we think that those patients will move more in the course of a clinical trial in placebo group. So the natural history of disease is very clear when you look at age groups, and changes in the mFARS score over time.

The patients who are diagnosed earlier and are younger at the time of disease presentation tend to have a more uniform and greater magnitude of decline over the course of the study. In terms of the concept that by interviewing early or in disease course, we're likely to be able to deliver a meaningful benefit.

I think that's well understood reality in treating neurological or neurodegenerative disorders.

And in fact, if you look at the Reata data, it was in their young -- they had patients 16 to 45, and those in the 16 to 17 year old cohort, those younger patients, where they had the greatest, over five points placebo corrective response, which I think lends further support to the notion that if you intervene early, you're going to be able to capture later treatment effects on those patients.

In terms of reduction in effect over time, or still progression over time. But none of these therapies are curative, but to be able to slow progression and slow progression by a year or by 2 years is incredibly meaningful. And a slowly progressive disease, such as Friedrich ataxia, that is relentless in [indiscernible] progression.

So I think we expect there to be a meaningful effect in children that will alter and modify the disease course. They -- one could still expect to gain some progression all the time, but being able to slow the progression of disease would be incredibly meaningful impact of particular..

Thanks so much..

And thank you. And one moment, please. One moment for our next question. And our next question comes from David Lebowitz from Citi. Your line is now open..

Hi. This is Debanjana [ph] on behalf of David. So thanks for taking our call.

The first thing we wanted to ask was like if you could share any further details on the nature of FDA queries regarding data like feedback you received? And do you anticipate any additional delays like that could push back by FDA -- sorry, the BLA submission beyond third quarter.

And one of the thing we wanted to know is that like even like although [indiscernible] trials are both using [indiscernible] as endpoint. There are, of course, differences in like the patient demographics and time points. So how should we benchmark [indiscernible] on results when they come out against the OMAP? Like label efficacy? Thanks..

Thank you very much for the question. So first time [indiscernible] as we have previously shared, the agency had requested that we provide some additional data on comparability between the clinical drug product and the commercial drug product, as is commonly the case in drug development, and particularly the case in gene therapies.

The manufacturing process for a gene therapy drug product can evolve over the course of development. And the process used to generate commercial drug products often is different than clinical drug product. And it's important to show the agency that is, apples-to-apples.

The key attributes of the commercial drug products are analogous to the attributes of the clinical drug product and the agent data assets to provide some additional data essentially analyze additional samples of the clinical drug product to demonstrate that it's comparable to the commercial drug product, which we were able to do.

They have come back and asked for some additional questions around one specific area, which is differences in empty fill capsids between clinical product and commercial products. They are quite similar, and we were able to easily provide that data. We have stated that we believe the submission of BLA could be delayed to Q3 of this year from Q2.

And that's simply because of the potential cadence of interactions back and forth between the agencies.

We are going to make responses to their queries, we expect to hear back from them and be in a position to submit the BLA, but we just wanted to communicate that it's possible given the cadence of the back and forth with the agency, that the submission could be delayed until the third quarter.

Regarding differentiation between [indiscernible] and vatiquinone, obviously, there's not -- as trial is a bit longer than the [indiscernible] trials, that's going to allow for the possibility of capturing a longer term impact on patients. Obviously, the patient populations are slightly different.

But nonetheless, we'll be able to look over the longer term over all different age groups and appreciate the relative benefits of vatiquinone. And obviously, secondary endpoints are really, really important. I mean, I think that's an important part of the FA story. It's also important part of the regulatory pathway.

And our discussions with the agencies have been similar to those that we ought to have, because they'd like to understand that all in the effects on the primary endpoint, but other aspects of disease morbidity, which are capturing some of the secondary endpoints..

Okay. That’s very helpful. Thank you..

And thank you. And one moment for our next question. And our next question is Joseph Thome from Cowen. Your line is now open..

Hi, there. Good afternoon and thank you for taking our questions. The first one on the PKU trial.

When you think about what constitutes success here, it's really just aesthetic benefit, or do you want to see a certain proportion of patients under 360 micromoles per liter? Or that have a 30% reduction from baseline or what have you? And do you have the sufficient safety database to file off this program if the study works? And then I have one quick follow-up..

So thanks for the questions. I'll start and then I'll let Kylie talk about the commercial differentiation. So obviously, a couple of the things that were really impressive from the Phase 1 run-in data.

One was the proportion of patients and respondents seeing nearly two-thirds of the patient have over 30% reduction is really impressive, and especially when you benchmark it to the Kuvan all-comer study where the proportion of responders over 30% was only 20%.

The second is the magnitude of the responders, not only in the overall treating patients who had over 30% reduction, which was 66% but in the classical PKU patients who had an average reduction of 61%.

And that's really impressive, and again, says that regardless of your disease severity, we are able to providing in that run-in phase of real market reduction in phenylalanine.

Our expectations about the placebo-controlled study would not only provide evidence of clinical benefit sufficient to achieve registration, but also would it be able to provide evidence and differentiation. I'll comment quickly on the regulatory [indiscernible] then turn it over to Kylie to comment on the differentiations.

On the regulatory front, we're going to have data from the 6-week placebo-controlled study, but obviously we've been patients rollover from the placebo-controlled study into a long-term open-label extension study, which is going to provide data not only on durability effect, but obviously longer term safety, which we believe, along with all the other data collected to date would put us in position to be able to submit -- file positive data.

Kylie, do you want to -- the commercial differentiation question..

Yes, absolutely. Thanks, Joe. I think from that perspective, Joe is sort of about looking across the different patient segments that have high unmet medical need and PKU, which we've talked about in the past. I think having an ability to demonstrate benefit in classical PKU is extremely important.

And Matt just touched on that, I think that historically been a very difficult to treat a patient population being able to demonstrate benefit there. I think, its strong. As we've talked about, we have the primary analysis population being in the 30%, or greater fee reduction.

But those things the [indiscernible] 15% or greater, and I think even in that 15% to 30% population showing benefit in classical PKU is going to be a powerful differentiation.

Outside of those that classical PKU population, looking more broadly, I think, in those that have already tried it and said to them, showing us that the benefit, I think will be key, and even looking at those that are poorly controlled over time and ultimately well controlled.

I think looking at a 40% plus greater fee reduction will give us an opportunity, number of different patients in those different segments. I think obviously anything higher above on that opens up more and more patients that would be looking to try sepiapterin..

Great. Thank you. And then just real quickly on Upstaza. I know as much as several patients were treated, I don't think I saw it in the press release but are you able to provide some of the revenue contribution for Upstaza this quarter, or if not, are you anticipating bringing that out going forward? Thank you..

Eric, you want to talk a little bit about the launch in progress?.

Yes, well, we haven't actually broken out specific patient numbers or revenue. But we're really pleased with the way the launch is progressing. It's going according to plan. And what we see is patients are being treated in the transformative effects.

We actually have treated patients in both Germany and France, and we -- in the quarter, and we also have treated our first cross border patient which came from the Middle East and was treated in Europe. So proof-of-concept of treating cross border patients commercially was achieved.

We continued our patient finding activities, and we've been able to continue to find patients in the first quarter, and new patients in all major geographies, where we've -- we know there is access for gene therapy.

So the surgical centers as well, we've been working very closely with them, and establishing them in key countries, particularly multiple centers in Europe. And we anticipate having centers in the Middle East and Brazil, during the course of the year to set up and take full advantage of what I call early access programs as well.

On the payer engagement side, it's gone extremely well. We've had strong HTA assessments in Germany and France, which is -- which now supporting ongoing price negotiation. And I remind you, that sort of Europe is a step by step process with access and reimbursement.

So we hope to conclude some of those pricing negotiations in the second half of the year. And importantly, we have nice recommendation in the U.K. And that's important for patients in England and Wales who will have access to the treatment soon. And we anticipate treating these patients in the coming weeks or months in the U.K.

And as a reminder, I would say that, what we're seeing right now is a really steady cadence of patients. And where the overall cadence of those patients that are being treated means that there will be more patients treated in Europe. And as the year goes by, we're going to see patients via early access in the Middle East, Britain, Brazil.

So, so far, I would say we're really pleased with the progress..

Great. Thank you very much..

And thank you. One moment, please. And One moment for our next question. And our next question comes from Kelly Shi from Jefferies. Your line is now open..

Thank you for taking my questions. So, Vatiquinone, I would say, my question is that the Phase 2 study showed the treatment effect at a 2.5 point difference over placebo arm on mFARS Neuro start at 24 weeks. And the first -- for our Phase 3 is to 72 weeks and you said about 4.5 points difference.

I'm curious what data you will rely on tomorrow how the treatment effect new trend from 24 weeks to 72 weeks and make this desire on the primary endpoint. Thank you..

Thank you very much for the question, Kelly. So a number of important points here and that you brought up so being the face you study was 6 weeks in duration and had the difference that you noticed. And part of that magnitude of that difference was driven by a placebo effect that was present even up to 6 months.

And this is something that was important lesson we learned and if you look at the realty data as well, you still see a persistent placebo effect in 6 months that had that study only been 6 months in duration, they would not have achieved statistical significance as they did. More time is needed for that placebo effect to abate.

So our selection of the 18 months duration or 72 week duration of the placebo-controlled phase was to allow for complete washout of any placebo effects and allow for the placebo patients to more closely mimic the natural history of the disease, which is on average a 2.5 point loss on the MMR score for year.

So you would expect them based on natural history. The change in the placebo group should be closer to three and perhaps even higher. The magnitude of treatment benefit was based on -- hypothesized treatment benefit was based on the long-term extension of the Phase 2 study.

Now we did do the 6 weeks placebo portion, right but all patients were continued to be treated for an additional 18 months which allowed them for a comparison of 18 to 24 months of treatment with an age stage and [indiscernible] natural cohorts -- natural history cohort.

The magnitude of the difference in between those two groups, between the natural history and the natural history cohort and treated cohort was actually much more market. There was a [indiscernible] 8 point -- 1.8 treatment benefits. So the difference over the 18 and 24 months was 6.6.

So we're starting to see a magnitude for those facts came from the Phase 2 study that's greater than what you mentioned as a hypothesize effect. 4.5. So we believe that 4.5 estimating power while that difference puts us in a strong position to capture significant benefit in the study..

Very helpful. And I also have a quick follow-up in PKU, if I may? Do you think 16 classic patients are sufficient to ensure a broad level in both mild and a classical PKU patients? Or this might require expand data enrollment..

Yes, it's a good question. We have 15 patients who are in that greater than 30% reduction. And we have previously shared that we have five additional classical patients who have between 15% to 30% reduction in the run-in phase with the mean reduction of 22%.

So you're seeing pretty meaningful reduction now across 20 patients which in classical PKU is a lot. I would also say, keep -- a couple of things to keep in mind. One is that we also capture the number of classical PKU patients, so you're seeing a good proportion of those treated, who are having those meaningful levels of reduction.

The other important thing to think about classical PKU is not only the threshold response of having a greatest 30% reduction, but also the absolute change in phenylalanine. When you think about PKU, it's that levels of phenylalanine that are most significant in terms of the clinical effects of the disease, including cognitive effects.

And it's well-known that reductions in phenylalanine by even 100 points can impact on. So if you think about a 15% or 20% reduction in phenylalanine levels for classical PKU patients, obviously those could be quite meaningful when one considers the benefits of reducing the overall level of phenylalanine.

So we believe that the dataset we're generating will have not only a number -- sufficient number of patients with classical PKU to be included in the label. But the magnitude of effect in quarters patients is recorded in these patients and it's also quite important and impacts them..

[Indiscernible]. Thank you..

Danielle, if your phone is on mute, could you please unmute it?.

Yes, hey, sorry. This is Alex on for Danielle. Just a couple quick ones from us. Just to clarify, my audio went out. Just wondering what was up with the FDA Type 2 meeting request for Translarna. Has that been requested or scheduled? And then secondly, just curious about the order of the upcoming readouts. We're trying to back into it a little bit.

Is it fair to assume that PKU will come first? We were trying to get May, and maybe June for the others. Thanks so much..

Yes, thanks for the questions, Alex. So let me take the second question first. We've been able to provide the specific guidance for PKU was readout in May, and obviously the others, we've not provided more specific timing, because we don't have a more specific timing beyond second quarter at this time.

In regards to your first question, and it ties to TBD for Translarna as we had previously shared, we had a meeting with the FDA, a clarification meeting, following up the written response only that we had received from them in the fall.

In that meeting, the agency suggested that we request a Type C meeting to review with them the totality of data from Translarna, including mechanistic data, dystrophin data and the data that we've generated over the clinical studies done to date, and then be able to have a robust discussion on the totality of data and its potential to support an NDA resubmission.

So obviously there's a lot of data to be presented. We're in the process of preparing that meeting requests and the briefing book.

We're going to feel we're going to be able to include not only mechanistic data they asked for, but the data that we've collected in the three placebo-controlled trials and then it's over 700 boys [ph] where we've been able to demonstrate consistent clinically meaningful benefit in these boys.

And when we think about what the FDA really needs to see in this data package, it's that we're having a clinically meaningful effect that's not doing the change.

And the consistency of the effect that we're seeing across the three studies, the volume of data that we've collected in over 700 boys, the ability to look across these three studies and see the historically significant benefit across a number of the key endpoints of the disease, the safety of the drug as well as the context of the use, which is non-consultation DMD remains a significant unmet medical need.

So we look forward to putting together all these data in a briefing package, we're also conducting some additional analysis to address some of the previous concerns at the agency wave. So we can come in to the agency at the right time and have a robust discussion about a past NDA resubmission..

Great, thanks so much..

And thank you. And one moment, please. And our next question comes from Joe Schwartz from SVB Securities. Your line is now open..

Great. Hi, this is Will on for Joe today. Thank you for taking our questions. So to start, I just want to pivot back MOVE-FA study. And based on the powering it looks like there is the potential for the study to miss on statistical significance, while also showing a benefit over reorders on [indiscernible].

So in this event, how are you thinking about next steps on the regulatory side? And I have a quick follow-up. Thank you..

So Well, thanks for the question. We believe that we will have sufficient power to detect the difference that was recorded in the Reata study. But we don't see that as our year if we capture the same magnitude and effect in similar areas..

Okay, great.

And then I guess following up here, has the agency provided you guys just any specific guidance in terms of what they want to see either from an efficacy standpoint or a staff perspective? And how is your thinking if at all changed on this since the approval of omaveloxolone and kind of any insight into the agencies and views here would be helpful?.

Yes, sure.

It's an interesting question, Will, because historically the agency has very much wanted to not only see a significant effect on the mFARS scale, but given that it's a composite scale that doesn't clearly communicate the impact of a therapy on how a patient feels or functions in everyday life, which is really -- those are really in the buzzwords that FDA likes to see for clinical benefit.

Typically wanted to have a key secondary endpoint that more directly assesses feel or function moves, along with the primary endpoints so that we can contextualize -- appropriately we contextualize and recorded changes in ours as being clinically meaningful.

Obviously, that was a source of a lot of the discussion that went on from the time writers share their data in October 2019 to NDA approval. And I, I would I think that some of the back and forth was based on the fact that a key secondary endpoint, which was a clinical global impression scale, did not achieve physical significance.

So be that as it May, the approval of the SBA on essentially a statistically significant mFARS change set a threshold that we believe others can now follow.

I think while it's unclear and challenging, sometimes to predict how the FDA will act or the reasoning behind their decision, they tend to be quite consistent when they set a precedent for approval. So I think it's clear.

I think it is -- we believe that being able to achieve a statistically significant effects on the mFARS, particularly in a longer study, was 72 weeks relative to 48 weeks and in a larger patient population that we had MOVE-FA relative to the [indiscernible] study would put us in a strong position.

But nonetheless, we did spend a lot of time planning, a key secondary endpoint for this study, which is the FA activities of daily living scale, which is something that the agency has shared that they believe adequately capture scalar function in everyday life.

We selected this as the key secondary endpoint, because if you look at the natural history data, and bars changes tend to move along with changes in the ADL scale there, they tend to move similarly and across as the disease progresses.

And in fact, if we look at the results of the MOXIe study, the one secondary endpoint on which there was statistic -- nominal statistical significance, it was the ADL scale, unfortunately, that was listed as the last of several secondary endpoints in the MOXIe study.

So, again, just to answer your question, I think the statistical significance on mFARS is the benchmark that's now been set for approval. But we'll also obviously be looking to see if we can capture secondary endpoints benefit as well..

Very helpful. Thank you..

Our next caller is Jeff Hung with Morgan Stanley. Jeff, your line is open. Please go ahead..

Thanks for taking my questions. For, MIT-E, can you remind us of why the study was hard for 40% placebo adjusted difference in seizure reductions when 20% to 25% reduction can be important? Would you consider the study success if you see a 20% to 25% reduction? Or do you need to see a 40% reduction? And then I have a follow-up..

Thanks for the question, Jeff. So, the power in MIT-E study was based on a couple of things.

Obviously, the placebo side we tried to hypothesize change in observable motor seizure frequency that was consistent with the placebo response that’s been showing other pediatric epilepsy syndrome trials and there's not been any previous placebo-controlled trials in children with mitochondrial seizures, but we believe the hypothesize effect and placebo effect of 10% was reasonable, given what's been seen in other studies, which is generally ranging between 2% and 18%.

On the efficacy side, a 50% reduction. So [indiscernible] we absolutely agree, given this -- to the refractory nature of the seizures, they're highly morbid nature, the fact that they can be life threatening in many cases, I think most KOL and [indiscernible] would agree that a 20% to 25% reduction would be clinically meaningful as population.

50% hypothesis are driven by the previous seizure reductions we've quantify them in other studies, particularly in the treatment series and children with Pontocerebellar hypoplasia Type 6, which seems to be one of the most virulent mitochondrial disease on seizure subtypes. So again, we believe that we -- 20% to 25% would be incredibly meaningful.

But again, the numbers are based on that previous experience as well as the experience of others..

Great. And then for PTC518, did the FDA specify where the additional data for supporting dosing and duration needed to come from geographically? I know you've been enrolling patients outside the U.S. And I just wanted to see if FDA had given any indication on whether they wanted data from patients in the U.S. for additional data.

And if they make care at the end of the study if more patients end up coming from other geographies. Thanks..

Yes. So just as a reminder, Jeff, the FDA asked for additional data to support the dosing and duration of proposed in the PIVOT-HD study was based on nonclinical data.

This is based on data from a toxicology study, the same toxicology studies that were used to support the approvals on the conduct of the study in the other geographies around the world where the study is being conducted. It was the FDA uniquely had asked for additional data to support the dosing and duration.

And they said those data could be clinical data that were collected as part of the instead. Obviously, as the study has only been conducted in countries outside of the U.S., they would naturally understand that those data are going to come from patients outside of the U.S.

And so we will plan as we do first interim data cuts to use those data to take those data to the agency and we continue discussions about opening enrollment to get in the U.S.

But in terms of the patients coming from outside of the U.S., they naturally expect that, and there shouldn't be any other impact on how these data looked at whether they were collected in the U.S. or elsewhere..

Okay. Thank you..

And thank you. And one moment for our next question. One moment. And our next question comes from Gena Wang from Barclays. Your line is now open..

Thank you. Very quick few questions. First one is regarding the full data sets, we see each individual data sets in this press release and the conference call in the second quarter? And the second question is regarding APHENITY trial in PKU some patients had a prior Kuvan experience.

I know you cannot comment on the percentage of patients, but would these are Kuvan responders in the study or simply just Kuvan experienced patients? And then lastly, very quickly on PIVOT-HD.

What is your Huntington knockdown level?.

Gena, thank you for the question. Unfortunately, I didn't clearly hear your first question. I heard the second and third.

Would you mind repeating the first question?.

Sure.

First question is basically for the four data sets, will you report individually with press release and conference call in second quarter?.

Yes. So as we've guided, that the data from APHENITY will be in May, the other feed to occur in the second quarter, we haven't given details yet on the exact nature of whether there'll be all releases and calls so we have to make those decisions yet. And we plan to share the data as they become available.

There's not a plan now to match them in any way. On your second question, we do have patients who entered the study who had previously been treated with Kuvan who are Kuvan failures. We have patients in the study who were on Kuvan when they came into the study who have been washed out from Kuvan.

And then that obviously will give us the opportunity to understand in specific subjects. What was there sort of Kuvan effect relative to what we observed to the sectarian effect during the run phase, and we'll plan to break out some of those data with the data release when available.

So to [indiscernible] answer your question, it's a mix is folks who've been on Kuvan the past and failed and others who were taking it and washed out to come into the APHENITY study.

On the PIVOT-HD study in terms of magnitude of Huntington reduction, as we've talked about the goal of this program is to achieve a lowering of Huntington protein in the brain of 30% to 50%. And we're in a difficult position, obviously, we can't directly measure changes in neuronal Huntington protein levels because we simply can't biopsy lean tissue.

So what we're doing to understand and guide dosing is a couple of things. First, we're obviously looking at the changes in blood levels of Huntington protein because that's a compartment that we could easily access.

And that was one of the nice findings some important findings from Phase 1 that we were able to record evidence of target engagement and dose-dependent splicing activity with dose-dependent reduction in Huntington mRNA and protein in the blood that gives us a very good window into the target engagement and splicing activity.

Now the next important element is the relative exposure of drug between the blood and the brain, which we can measure by looking at blood levels of drug and measure by looking at CSF levels of drug. We know that splicing activity is directly related to exposure.

So by understanding what the reduction is in the blood at a certain exposure relative and then understanding the relative exposure between the blood and the brain, can give us an estimate of what is going on inside the brain cells.

So the decision to start with 5 and 10 milligrams in the Phase 2 study was based on a stalling Phase 1 in terms of blood Huntington protein lowering, which what we saw in the MAD was roughly 40% reduction at 15 milligrams and roughly 60% reduction at 30 milligrams. We noted that the ratio of free drug in the CSF plasma was 2.7:1.

So we're getting twice as high exposure in the brain to the blood. So therefore, we said that 5 and 10 milligrams, if those exposure ratios hold, we could very well be at the necessary dose level to achieve the design 30% to 50% lowering.

So we will look at when we get the APHENITY data at the levels of reduction of recording in a blood at 5 and 10 milligrams.

We will also look at the relative exposure from the blood to the brain and use those data to help guide the decision on whether we want to start dosing in that higher dose level of 20 milligrams, which based on the Phase 1 data represent roughly 50% reduction in the blood, and therefore, if we were closer to a 1:1 ratio of blood and brain exposure would suggest that we're achieving roughly 50% reduction in the brand.

I know there were a lot of numbers a little complicated, but does that answer your question?.

Very helpful. Thank you..

And thank you. And one moment for our next question. And our next question comes from Colin Bristow from UBS. Your line is now open..

Hi. This is Yihan on for Colin. Thanks for taking our question and congrats on the quarter. So the first question is for the Translarna. It seems to have a very big beat this quarter. And you just noted the government order would continue to be expected in the second Q.

Just wondering about this government order in terms of the longer time and also because you didn't really update your DMD guidance. Just wondering if we should potentially expect more revenue for this whole year versus your kind of guidance. Can we have more color on that? And the second Q, just a very quick clarification question.

So for the Upstaza BLA filing delay in the third quarter, you previously said you have already provided the additional requested data to FDA is that correct? Thank you so much..

Thank you, Yihan for the question. Let me first say on Translarna revenue. We are incredibly excited about the performance in the first quarter. As Eric stated in the prepared remarks, we remain on target to meet franchise guidance this year. But let me turn it over to Eric to provide additional color on the Translarna franchise and revenue..

Hey, Yihan, as we mentioned earlier, Translarna continues to grow and it's growing in all major markets. So we are seeing growth, particularly as we are adding new patients, managing the prevalence pool and particularly working on dosing adjustments and high compliance. We have compliance rates in many countries of 90%.

We've seen a lot of the geographic expansion take hold over the last 3 to 4 years as we have developed these in places such as the Central and Eastern Europe, in the Middle East, our CIS region and, of course, in Latin America. So many of these orders that come in are central government orders, and it's four new patients as well as the existing ones.

And so it's kind of hard to predict the timing and the size of some of these larger orders. We anticipate that we will continue to get those orders in the second half because some of these -- we are adding new patients every quarter, especially seeing from these geographic expansion markets.

So this strong performance that we've seen across Translarna is going to continue. We will have some lumpiness in the quarter, but we anticipate government orders to continue because the base that we have, including new patients that are coming in and managing the compliance and the low discontinuations are incredibly important.

We're not going to change the guidance at this point in time, and we'll just continue to provide an update as we see these orders coming in. But I'd like to reiterate that we have a 545 to 565 DMD franchise right now that we are very confident in achieving this year..

And then I'll just say this why we don't typically give quarterly guidance. We tend to give annual guidance for just that reason. Regarding the BLA, I will say that as we commented before, the FDA had asked for additional data and supportive comparability analyses.

We provided those data, and they've come back with a follow-up with follow-up questions that we are now in the process of answering and we'll spend back in shortly.

And again, the timing -- the potential delay in submission from the second quarter to third quarter is just a possibility based on the potential cadence of responses from the agency to the query responses..

Okay. Thank you..

And thank you. And one moment for our next question. And our next question comes from [indiscernible]. Your line is now open..

Hi. This is [indiscernible] on for Paul Choi. Thanks for taking our questions. Two quick ones for us. First, we wanted to see what the impact of inventory or stocking was throughout the quarter. And then second, we noticed you took out your full year operating expense guidance.

We wanted to see what the rationale was for removing that and how to think about go-forward operating expenses as the pipeline progresses here? Thanks so much..

Yes, thanks for your questions. Well, I'll start, [indiscernible], and then I'll turn it over to Emily. So first, regarding OpEx, look, as we mentioned in the prepared remarks and as we've talked about previously, we've been building our R&D and commercial infrastructure over the past several years. and quite proud of what we have achieved.

Obviously, the performance -- the commercial performance in the first quarter is incredibly impressive and is clearly a result of the infrastructure that we've created, and we are now well-positioned to launch additional products on positive data.

We've also said that when we turn over the card to these clinical trials, we'll then be in a very good position to do a strategic portfolio review, which we plan on doing as a result of which we expect that there will be a reduction in OpEx, and therefore, we will come back once that analysis performed and share any changes to the operating expenses.

Obviously, we'll undertake this review of the portfolio, clearly guided by return on investment and probability of success and ensuring that we focus on things that we think will bring success and the revenue growth we desire to achieve over the coming years. Emily, do you want to comment on OpEx further on OpEx and on stocking..

Yes. On OpEx, obviously, put at best, we look forward to after the readout of data analyzing our program priorities and looking for opportunities to narrow our OpEx guidance. On the revenue side, there was no stocking.

We saw some large government orders, as Eric has pointed out, which contributed to the growth in the first quarter and put us in a position to reiterate both our DMD franchise guidance as well as our overall revenue guidance for the year..

And thank you. I would now like to turn the call back over to Chief Executive Officer, Matthew Klein..

Well, I want to thank everyone for joining the call today. I'm incredibly pleased with the productive and successful first quarter that we have, and we look forward, of course, to sharing the upcoming study readouts with you all as soon as they've come to [ph]. So thank you all again for joining the call, and have a good evening..

This concludes today's conference call. Thank you for participating. You may now disconnect..