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spk37: And thank you for standing by and welcome to the PTC first quarter 2023 financial results call. Ask all participants on a listen only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. 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.
spk39: You may begin. Hello, speakers. Yes.
spk19: Good afternoon, and thank you for joining us today to discuss PTC Therapeutics First Quarter 2023 Corporate Update and Financial Results. I am joined today by our Chief Executive Officer, Matthew Klein, our Chief Business Officer, Eric Powell, 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?
spk35: 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 therapies to treat rare disorders. And I am incredibly excited to lead PTC into its next quarter century as we continue to utilize pioneering science to 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 48% 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. And RISD also had a strong first quarter, providing royalty revenue of $31 million. The RISD revenue growth continues to be driven by both therapy-naive patients and those previously treated with Zolgensla and Spinraza. In addition, U.S. growth is being driven by patients less than two months of age following the recent SNBA 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 affinity studies. Affinity is our phase three global placebo-controlled study of sepiaterin in children and adults with PKU. The placebo-controlled portion of the study was six weeks in duration with the primary endpoint of reduction in blood phenylalanine levels. To enrich the randomized population for sepiaterin responders, there was a run-in phase during which all screened subjects received sepiaterin for two weeks. Only those subjects who demonstrated a reduction in phenylalanine levels of 15% or more for baseline in Part 1 were randomized for Part 2, with the primary analysis population consisting of those who had a greater than 30% reduction in phenylalanine levels for 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, sepiaterin, can provide a clinically meaningful and differentiated response to the full spectrum of PKU patients. We look forward to sharing results from the placebo-controlled portion of Affinity in May. Let me now move to the two registration-directed trials of the tiquinone. MITEI is a global registration-directed trial of the tiquinone 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 three registration-directed study of the tiquinone in pediatric and adult patients with free-type 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 for the placebo-controlled phase has also occurred and we continue to expect results for MOVE-FA in the second quarter. Moving to our PTC518 Huntington Disease Program, PIVOT-HD is a 12-month placebo-controlled trial that consists of two parts. Part one is 12 weeks in duration and focuses on PTC518 pharmacology and pharmacodynamic effects, as well as biodistribution. Part two is nine months in duration and focuses on blood-based, DSS-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 stage 2 Huntington's disease, and we recently expanded the trial to include early stage 3 patients, who we studied initially at the 5 milligram and 10 milligram dose level. 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 mg and 10 mg doses. 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 2 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 transline. Finally, for Stata, as we previously shared, the FDA requested additional bioanalytical data in support of comparability analyses between the clinical and commercial drug products. We have received initial feedback from the agency on new 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 of our productive and successful first quarter, and will now hand the call over to Eric to provide an update on our commercial portfolio.
spk29: Eric? Thanks, Matt. Our global customer-facing team has 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 Upstazer launch in Europe, We also have launched WeLibra 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 the DMV franchise. Translarna and Inflaza continue 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 DMV 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-based dose adjustments on an ongoing basis. The fundamentals of the EMPLASA business continue to be solid. Quarterly net revenue was 55 million. We have seen a significant number of new patient 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 Upstazer commercially in Europe and will 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 Tegceti and WeyLibra in Latin America, where we continue to successfully grow these franchises in Q1. Following WeyLibra'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 WeyLibra for familial chylomicronemia syndrome, which was completed and delivered in Q1. As mentioned in our last call, for Tegceti, 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?
spk24: 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, Eversy 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. And Plaza 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 a $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 non-cash stock-based compensation expense. compared to $127 million for the first quarter of 2022, excluding $13 million in non-cash 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 a $30 million CEPI of Terran 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 non-cash stock-based compensation expense, compared to $59.7 million for the first quarter of 2022, excluding $13.6 million in non-cash 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 31st, 2022. I'll now turn the call over to the operator for Q&A. Operator?
spk37: Anne, thank you. And one moment for Q&A. As a reminder, to ask a question, please press star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1 1 again. Please stand by while we compile the Q&A roster.
spk39: And one moment for our first question.
spk37: And our first question comes from Kristen Kluska from Kantor. Your line is now open.
spk14: 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 patient starts? And is this also related to the specific geographies with more patient ads? 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 in being able to expand your footprint globally? And how do you think you could leverage this, you know, should some of these candidates end up crossing the finish line soon?
spk35: Great. Thank you very much, Kristen, for the questions. We're incredibly proud of the global commercial infrastructure we built 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 nine 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.
spk29: Yeah, 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 prevalence pool that we have on drugs through dose adjustments. That's really important. And, of course, we've been seeing across the board for both in FLASA as well as TransLorna improved and better payer access, and that's really important as well. Now, for TransLorna, we did see $150 million, and 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 sizable 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 reiterating our guidance for the DMV franchise. to 545 to 565 million. So I hope that provides you the color that you need, Kristen.
spk14: Yes, thank you. That's helpful. And then maybe just one quick one on Huntington's disease. You know, an oral drug obviously comes with benefits in terms of compliance and adherence, Thinking about the different therapeutics out there and recognizing the mechanisms are different, how are you thinking about an oral agent's ability to really target the right areas in the brain versus some other routes of administration that are being evaluated?
spk35: Kristen, thank you for the question. We think route of administration and biodistribution are incredibly important elements to the development of a successful therapy for Huntington's disease. the development of PTC518 comes on the heels of the successful discovery and development of a RISD for SMA. And obviously, we've made a number of important learnings about how to design a molecule that can effectively cross the blood-brain barrier and not get efflux and globally by the CMS, which is not only essential for the optimal treatment of SMA, but obviously is similarly critical for Huntington's disease. So, in the design of PTC518, we put to play all of those lessons. have a molecule that's highly selective, highly specific, gets across the blood-brain barrier, and broadly biodistributes to every region of 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's protein that is toxic to cells and leads to 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 being locally delivered in the case of the gene therapy. Obviously, local delivery into the brain gene therapy is something we know a whole bunch about from our successful development of Absteza. And then also has significant advantages over intrathecally administered therapies, which I just can't get all to 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 early by distribute, which we were able to confirm in terms of. The CSF exposure in our phase 1 study will obviously share data again when we do the PIDA-HT readout in the second quarter. And then also, we have other advantages because an oral molecule is titratable. So, we're also going to be leveraging that titratability in our clinical study to identify the optimal dose to achieve the target whole-brain lowering on T2 protein that we think is optimal for disease treatment.
spk14: Great. Thanks. Looking forward to catching up with you once these data read out.
spk39: And thank you. And one moment for our next question. And our next question comes from Brian Abrahams from RBC.
spk44: Your line is now open. Hi, this is Joe. I'm for Brian. Thank you for taking our question. Just on Huntington's, can you tell us more about what which data might be might be shared from the 12 week portion of the study? And it seems like they're 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 desired level of the HTT now down in CSF? Thank you.
spk35: Thanks, Joe, for the question. The PIVOT-HC study is a 12-month placebo-controlled study that's in two parts. Part one is 12 weeks in duration and focuses on PKPD in 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 of 30 to 50 percent of Huntington protein. The second nine months of the study is focused on biomarkers of disease, including Huntington protein levels in the CSS, radiographic markers, including brain volume changes, as well as NFL levels in the plasma and the CSS. The data we plan to share in the second quarter is an interim analysis from the first 12 weeks of PIVIT-HD. We'll be sharing information on the PKPD and blood, so looking at blood, looking at drug levels in the blood, and the reduction in Huntington, Amarni, and protein in the blood, and then looking at the relative exposure of the CSF in the plasma. As you recall from our Phase 1 Healthy Volunteer Study, we were able to confirm that we were getting excellent CNS exposure, and in fact, we're achieving greater exposure in the CSF than in the plasma. So that's a very important finding that we'll seek to confirm the 12-month data. The biomarker data, including the CSF Huntington protein levels, NFL levels, and brain volume changes will come in the readout from the 12-month data. To your second question regarding patient populations, as I shared in answering Kristin's question, the mechanism of the drug is targeting the production of the disease-causing mutant Huntington protein. 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, whether they be juvenile or adult patients, given that the disease cause is 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 in whom we could practically capture clinical effect and in the case of the PhD study, biomarker effect in the time-limited constraints of a clinical trial. So, we put a lot of effort into identifying the attributes of what we thought would be that optimal population. We availed ourselves of the robust Huntington's disease natural history databases and worked closely with Huntington's disease experts and biostatisticians who support these databases 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't practically deliver a benefit. And we certainly don't want patients who are so early in their disease that they're not progressing at all, therefore making it impossible to show that we're slowing disease progression. So we put these attributes to play as our inclusion criteria for the study, and these were essentially stage 2 HD patients. We shared at the JPMorgan conference in January that we were adding additional cohorts of slightly later stage patients. We were now including patients who had a total functional capacity score of 11 and 12, rather than just simply having a TFC score of 13, which would be initially required. The reasons for this were because there were a number of these patients who were identified and pre-screened and prepared to participate in other clinical trials that were no longer being conducted. So we were in a situation where there were patients identified, ready to be in clinical trials, incredibly eager to participate in clinical trials, and whom we obviously believed we could provide benefit with this therapy. So we made the decision to introduce additional dosing cohorts, 5 mg and 10 mg dosing cohorts, in these early stage three patients because this will provide us additional important data on potential benefit of PTC518. And it'll also allow us to test our hypothesis in terms of the optimal population that we initially set out to enroll. So I hope that answers your question on the adjustments or the addition of new patients.
spk44: Yeah, that was super helpful.
spk39: Thank you, Matt. And thank you. And one moment for our next question.
spk37: And our next question comes from Eric Joseph from JP Morgan. Your line is now open.
spk27: Hi, good evening. Thanks for taking the question. Just a quick one from me on the tiquinone. 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.
spk35: Thank you for the question, Eric. So the protection for particular known is principally going to be under orphan exclusivity. As is always the case, we are exploring other potential ways to strengthen and extend the patent life, obviously in the U.S.
spk38: and Europe as well as in other markets. Okay, great, thanks.
spk27: Maybe just a quick follow-up, if I could, as it relates to MOVE-FA. Can 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 Southland readout? Thanks.
spk35: Yeah, absolutely. So, when we constructed the MOVE-FA trial, we leveraged a number of learnings that we made from our own Phase II trial, as well as a number of the important learnings from other clinical studies. We also were in a position where, given the safety of the ticrinone 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 are usually diagnosed in early adolescence, late childhood, 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 in the last question regarding Huntington's disease, getting that right clinical trial population that'll move enough over the course of the clinical trial for the placebo group puts you in the best position to capture treatment benefits. And so we cut the lower age limit at seven because if patients are younger than seven, 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 means ascertainment of clinical benefits is difficult. So we set the lower age at seven, and then the primary analysis group goes up to 21. Again, we believe that this is a population in whom we can have less of a chance of placebo effect. We're also in a situation where these patients tend to have a greater decline over the course of the clinical trial, which makes it easier to register clinical benefit. And also, as is 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 of the drug and the ability to enroll the younger patients. We're also including additional adult patients. They're not part of the primary analysis population. We previously studied the drug in adults. We believe we can hold benefit for, again, 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 relative to the adult patients. But we would fully expect that with a positive trial, that if we were to move towards approval that we would have a label that would include pediatric and all adult populations. Okay.
spk03: That's great. That's very helpful. Thanks for taking the questions.
spk37: And thank you.
spk39: And one moment for our next question.
spk37: And our line is open. Robin Cornascus from Chewist. You're now available.
spk09: Great. Thanks for taking my question. So I have three of them.
spk10: So the first one is around PKU. So I know the bar, you gave the responder analysis of 30% and the decline, the improvement, the reduction for those lead-in patients. But since the bar for entering phase two is 15%, presumably you're going to get some, you know, lower responders going into this part two. 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 that? So I just wanted you to really flesh it out and set it for expectations for investors. Second question is for FA, given the drug is TID dosing, Do you think the bar for success has to be better than Riatta and maybe flush out, you know, how much that TID dosing might impact the market? And then third, you mentioned like, you know, the range of patients, like you're doing younger patients and you're confident that they might have a lower placebo effect but also maybe progress more rapidly. You know, what's your confidence in that over the timeline? And also, what's your confidence that the decline in the efficacy in that population? Because we've seen decline in rata over time with older patients. What about younger patients, the decline of the efficacy of these drugs? Thank you. Okay.
spk35: Okay, Robin, thank you for those questions. We'll take them in turn. So, the first question is regarding the affinity trial. And so, as we said, we have the run-in phase in which all screen subjects were treated for two weeks of subcutaneous. and we randomized all subjects who had a greater than 15% reduction in fee. However, importantly, the primary analysis population for the trial includes only those subjects who had a greater than 30% reduction during the run-in. So, in terms of the primary analysis and success in the trial, that there'll be no interaction of those who had 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 shared in the past, we had 102 of the 156 subjects who were in the running 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 of 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, to the placebo-controlled phase, look, these patients are treated for two weeks, they're washed out, returned to baseline, and then the same patients are again 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 that historically the placebo patients in PK trials tend not to have very much of any placebo response, that gives us a great deal of confidence to not only achieve the primary analysis success of significant greater reduction in the treatment relative to placebo. But again, you're confident based on the data from Part 1 that we'll be able to demonstrate not only a clinically meaningful response, but one that would strongly differentiate cefutarin for the treatment of PKU. In terms of FA, your first question was regarding the TID dosing, look, we've never seen a problem with compliance with TID dosing. And, you know, it's a breakfast, lunch, and dinner, so it's actually with meals. It's not curate hours, which makes a very big difference. And we believe that there's several other important aspects that differentiate the therapy. I'm going to turn it over to Kylie. I don't know if you want to add anything to that in terms of the effective dosing on the updates.
spk19: Yeah, I think that's well said, Matt. I think there's a number of factors that are taken into consideration, particularly in a disease of high-impact need and progressive diseases like phrygic ataxia. Efficacy, first and foremost, is 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 vitiquinone. 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.
spk35: And then, Robin, in terms of your third question regarding the 7 to 21-year-olds and concerns there, and then why do we think that those patients will move more in the course of the clinical trial and the placebo group? So, the natural history of disease is very clear when you look at age groups and changes in the NFAR 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 a disease course, we're likely to be able to deliver a meaningful benefit. I think that's, you know, well understood reality in treating neurological or neurodegenerative disorders. And in fact, if you look at the RAYADA 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-point placebo-corrected response, which I think lends further support to the notion that if you intervene early, you're going to be able to capture a greater treatment effect on those patients. In terms of reduction in effect over time or still progression over time, look, none of these therapies are curative, but to be able to slow progression and slow progression by a year, by two years, is incredibly meaningful in a slowly progressive disease such as Friedreich's ataxia that is relentless in its progression. So I think we expect there to be a meaningful effect in children that will alter and modify the disease course. One could still expect there to be some progression all the time, but being able to slow the progression of the disease would be an incredibly meaningful impact of the ticket.
spk43: Thanks so much.
spk37: And thank you. And one moment, please. One moment for our next question. And our next question comes from David Leibowitz from Citi. Your line is now open.
spk18: Hi, this is Devanjana 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 OOPS data, like feedback you received, and do you anticipate any additional delays like that could push back the FDA, sorry, the BLA submission beyond third quarter? And one other thing we wanted to know is that, like, you know, given, like, although OMAP and vaticoinone pivotal trials are both using MFRS as endpoint, there are, of course, differences in, like, the patient demographics and time points. So, how should we benchmark vaticoinone results when they come out against OMAP, like, label efficacy? Thanks.
spk35: Thank you very much for the question. So, first time of stasis. As we had 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 product often is different than clinical drug product, and it's important to show the agency that is, you know, apples to apples. The key attributes of the commercial drug product are analogous to the attributes of the clinical drug product. And the agency had asked us 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 cocapsids between clinical product and commercial product. They are quite similar, and we were able to easily provide that data. We have stated that we believe the submission of the 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. submit responses to the queries, we expect to hear back from them, and then be in a position to submit to 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 OMAP and vaticanone, obviously, there's not, the past trial is a bit longer than the OMAP trial, so 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 particular. And obviously, secondary endpoints are really, really important. I mean, I think that's an important part of. The story is also important part of the regulatory pathway and our discussions with the agency have been similar to those that we ought to have. which is they'd like to understand not only the effects on the primary endpoint, but other aspects of disease morbidity, which are captured in some of the secondary inputs.
spk06: Okay. Thanks. Very helpful. Thank you.
spk37: And thank you. And one moment for our next question. And our next question is Joseph Toom from Callen. Your line is now open.
spk31: 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, is it really just a static benefit, or do you want to see a certain proportion of patients under 360 micromole per liter or that have a 70% 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.
spk35: So, thanks for the question, Joe. I'll start, and then I'll let Kylie talk a little bit about the commercial differentiation. So, obviously, a couple of the things that were really impressive from the phase one run-in data. One was the proportion of patients that responded, seeing nearly two-thirds of the patients have over a 30% reduction. is really impressive, and especially when you benchmark it to the KUVAID-Alkma study, where the proportion of responders over 30% was only 20%. The second is the magnitude of the effect, not only in the overall treated 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're able to provide in that running phase a real market reduction in phenylalanine. Our expectation is that the placebo-controlled study would not only provide evidence of clinical benefits sufficient to achieve registration, but also would it be able to provide evidence of differentiation. I'll comment quickly on the regular side, Turn it over to Kylie to comment on the differentiation. So on the regulatory front, we're going to have data from the six-week placebo-controlled study, but obviously we've been patients roll over 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 following positive data.
spk32: Kylie, do you want to end with the commercial differentiation question?
spk19: Yeah, absolutely. Thanks, Matt, and thanks, Jo. I think from that perspective, Jo, it's sort of about looking across the different patient segments that have high medical need in 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's historically been a very difficult to treat patient population. Being able to demonstrate benefit there, I think it's strong. As we've talked about, we have the primary analysis population being in the 30% or greater fee reduction, but those being minimized in 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 that classical PKU population, looking more broadly, I think in those that have already trialed in FEB QVAN, showing a static 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 T reduction will give us an opportunity for a number of different patients in those different segments. I think, obviously, anything higher above and beyond that opens up more and more patients that would be looking to try sepiaptrin.
spk31: Great. Thank you. And then just real quickly on Epstase, I know it was mentioned that several patients were I don't think I saw it in the press release, but are you able to provide some of the revenue for Upstazia this quarter, or if not, are you anticipating breaking that out going forward? Thank you.
spk35: Lawrence, you want to talk a little bit about the launch and progress? Yeah.
spk29: 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 uh germany and france and we um in the quarter and we also um 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 um you know 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 know that 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 now is supporting ongoing price negotiation. And I remind you that sort of Europe is a step-by-step process with access and reimbursement, but we hope to conclude some of those pricing negotiations in the second half of the year. And importantly, we have NICE recommendation in the UK. 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 UK. And as a reminder, I would say that, you know, what we're seeing right now is a really steady cadence of patients. And 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.
spk28: Great. Thank you very much.
spk37: And thank you. One moment, please.
spk39: And one moment for our next question.
spk37: And our next question comes from Kelly Shee from Jefferies. Your line is now open.
spk22: Thank you for taking my questions. For particular in FA, my question is the Phase II study showed a treatment effect at a 2.5 points difference over placebo arm on FARS Neurostar at 24 weeks. And for Phase III, it's 72 weeks and the sidebar at 4.5 points. I'm just curious what data you rely on to model how the treatment effects will trend from 24 weeks to 72 weeks and make this decision on the primary endpoint. Thank you.
spk35: Thank you very much for the question, Kelly. So, a number of important points here that you brought up. So, the phase two study was six weeks in duration and had the difference that you noted, and part of that magnitude of that difference was driven by a placebo effect that was present even after six months. And this is something that was important lesson we learned. And if you look at the REATA data as well, you still see a persistent placebo effect at six months that had that study only been six 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 control phase was to allow for complete washout of any placebo effect and allow for the placebo patients to more closely mimic the natural history of the disease, which is on average a two and a half point loss on the MPAR score per year. So you would expect that based on natural history, the change in the placebo group should be closer to three and perhaps even higher. The magnitude of treatment benefits was based on the hypothesized treatment benefit was based on the long term extension of the phase two study. Now, we did do the six week 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 sex match natural cohort, natural history cohort. The magnitude, the difference between those two groups, between the natural history and the natural history cohort and the treated cohort was actually much more marked. There was a 4.8 point worsening and a 1.8 treatment benefit. So, the difference over the 18 to 24 months was 6.6. So, we're starting to see a magnitude of effect from the Phase 2 study that's greater than what you've mentioned as a hypothesized effect, 4.5. So, we believe that 4.5 estimate and powering on that difference puts us in a strong position to capture significant benefit in this study.
spk22: Super 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 label in both mild and classic PKO patients? Or this might require expanded enrollment?
spk35: Yes, it's a good question. We have 15 patients who were in that greater than 30% reduction, and we had previously shared that we had five additional classical patients who had between 15% to 30% reduction in the running phase with a mean reduction of 22%. So, you're seeing pretty meaningful reductions now across 20 patients, which in classical PKU is a lot. I would also say, a couple things to keep in mind. One is that we also have capped 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 with classical PKU is not only the threshold response of having a greater than 30% reduction, but also the absolute change in fenylalanine. 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 IQ. So if you think about a 15 or 20% reduction in phenylalanine levels for a classical PKU patient, obviously those could be quite meaningful when one considers the benefits of reducing the overall So, we believe that the data set we're generating will have not only a number of sufficient number of patients with classical to be included in the label, but the magnitude of affecting and recording these patients is also quite important and impactful.
spk21: Terrific. Thank you.
spk37: Danielle, if your phone's on mute, could you please unmute it?
spk33: Yeah, 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 C 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 guess May and maybe June for the others. Thanks so much.
spk35: Thanks for the questions, Alex. So let me take the second question first. We've been able to provide the specific guidance for PKU with readouts in May, and obviously the others we've not provided more specific timing because we don't have the more specific timing beyond second quarter at this time. In regards to your first question and the Type C meeting for TransLARN, 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 the Type C meeting to review with them the totality of data from TransLARN, including mechanistic data, district and data, 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 request and the briefing book. We're going to be able to include not only the mechanistic data they asked for, but the data that we've collected in the three placebo-controlled trials, and then there's over 700 boys. where we've been able to demonstrate consistent clinically meaningful benefit in these boys. And when you think about what the FDA really needs to see in this data package, it's that we're having a clinically meaningful effect. It's not due to chance and the. Consistency of effect that we're seeing across the three studies, the volume of data that we collected in over 700 boys, the ability to look across these three studies and see statistically significant benefit across a number of the key endpoints of the disease, the safety of the drug, as well as the context of the disease, which is non-sense mutation, DMD remains significant on that medical need. So we look forward to putting together all these data in a briefing package. We're also conducting some additional analyses to address some of the previous concerns that the agency has raised so we can come in to the agency at the right time and have a robust discussion about a path to NDA resubmission.
spk07: Great. Thanks so much.
spk37: And thank you. And one moment, please. And our next question comes from Joe Swartz from SBB Securities. Your line is now open.
spk16: Great. Hi, this is Will on for Joe today. Thank you for taking our questions. So to start, I just want to pivot back to the 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 RIADA's OMAVA LOCKS alone. So, in this event, how are you thinking about next steps on the regulatory side? And I have a quick follow-up. Thank you.
spk35: So, Will, thanks for the question. We believe that we will have sufficient power to detect the difference that was recorded in the REATA study. So, we don't see that as a risk here if we capture the same magnitude effect in similar variants.
spk00: Okay, great.
spk16: And then, I guess, following up here, you know, has the agency provided you guys with any specific guidance in terms of what they want to see, either from an efficacy standpoint or a stats perspective? And how is your thinking, if at all, changed on this since the approval of Omad Valoxelone? And kind of, you know, any insight into the agency's views here would be helpful.
spk35: Yeah, 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 those are really the buzzwords that FDA likes to see for clinical benefit, it typically wanted to have a key secondary endpoint that more directly assesses feel or function, move along with the primary endpoint so that you can contextualize appropriately contextualize the recorded changes and as far as being clinically meaningful. Obviously, that was a source of a lot of the discussion that went on over from the time Ray Adder shared their data in October 2019 until NDA approval. And I think that some of the back and forth was based on the fact that their key secondary endpoint, which was the clinical low blood pressure scale, did not achieve statistical significance. So, be that as it may, The approval of the FDA on essentially a statistically significant end bars 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 we believe, anyway, that being able to achieve statistically significant effects on the MPHARs, particularly in a longer study of 72 weeks relative to 48 weeks, and in a larger patient population that we have in MOVE-FA relative to the MOXIE study, would put us in a strong position. Nonetheless, we did spend a lot of time planning our key secondary endpoint for this study, which is the FA activities of daily living scale, which is something that I The agency has shared that they believe adequately captures field of function . We selected this as the key secondary endpoint because if you look at the natural history data, MFAR's changes tend to move along with changes in the ADL scale. They tend to move similarly and across as the disease progresses. And in fact, if you look at the results of the MOXIE study, the one secondary endpoint on which There was nominal statistical significance. It was the ADL scale. Unfortunately, I believe 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 MPHAR is the benchmark that's now been set for approval, but we'll also obviously be looking to see if we can capture secondary endpoint benefit as well.
spk39: Very helpful. Thank you.
spk17: Our next caller is Jeff Hung with Morgan Stanley. Jeff, your line is open. Please go ahead.
spk26: Thanks for taking my questions. For Mighty, can you remind us of why the study was powered for a 40% placebo-adjusted difference in seizure reductions when 20 to 25 reduction can be important? You know, would you consider the study a 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.
spk35: Thanks for the question, Jeff. The powering of the MITEI study was based on a couple things. Obviously, on the placebo side, we tried to hypothesize a change in observable motor seizure frequency that was consistent with the placebo response that's been shown in other pediatric epilepsy syndrome trials. And there's not been any previous placebo-controlled trials in children with mitochondrial disease with seizures, but we believe the hypothesized effect of placebo effects 10% was reasonable, given what we've seen in other studies, which is generally ranging between 3% and 19%. On the efficacy side, a 50% reduction. So first let me say we absolutely agree, given the refractory nature of these seizures, their highly morbid nature, the fact that they can be life-threatening in many cases, I think most KOLs and they're going to agree that a 20 to 25% reduction would be clinically leading for this population. That 50% hypothesis is driven a bit by the previous seizure reductions we've quantified in other studies, particularly in the treatment series of children with pompous cerebellar hypoplasia type six, which tends to be one of the most virulent mitochondrial disease associated seizures subtypes. So again, we believe that we 20 to 25% would be incredibly meaningful, but again, the numbers are based on our previous experience as well as the experience of others.
spk26: Great, thanks. And then for PTC 518, did the FDA specify where the additional data for supporting dosing and duration needed to come from geographically? I know that you've been enrolling patients outside the U.S. and 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 made care at the end of the study if more patients end up coming from other geographies. Thanks.
spk35: Yeah, so just as a reminder, Jeff, the FDA asked for additional data to support the dosing and duration proposed in the PIVOT-HD study was based on non-clinical data. This was based on data from toxicology studies, the same toxicology studies that were used to support the approvals of the conduct of the study and 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 PIV-HC study. Obviously, as the study has only been conducted in countries outside of the U.S., they naturally understand that those data are going to come from patients outside of the U.S. And so we will plan, as we do this first interim data cut, to use those data to take those data to the agency and continue discussions about opening enrollment again 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 the data looked at whether they were collected in the U.S. or elsewhere.
spk37: Okay.
spk26: Thank you.
spk37: And thank you. And one moment for our next question. One moment. And our next question comes from Gina Wang from Barclays. Your line is now open.
spk20: Thank you. Very quick few questions. First one is regarding the full data sets. We see each individual data set is press release and the conference call in the second quarter. And the second question is regarding affinity trial in PKU Med-IR. Some patients had prior KUVA experience. I know you cannot comment on the percentage of patients, but would these are KUVA non-responders in the study or simply just KUVA experienced patients? And then lastly, very quickly on PIVOT-HD, what is your bar for blood hunting team knockdown levels?
spk35: Tina, thank you for the questions. Unfortunately, I didn't clearly hear your first question. I heard the second and third. Would you mind repeating the first question?
spk20: Sure. First question is basically for the four data sets, would you report individually with press release and a conference call in second quarter?
spk35: Yes. So, as we've guided that the data from Affinity will be in May, the others need to occur in the second quarter. We haven't given details yet on the exact nature of whether they'll be all releases and calls. So we haven't made those decisions yet. And we plan to share the data as they become available. There's not a plan now to batch 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 were then washed out from KUVAN and then . Obviously, will give us the opportunity to understand in specific subjects. What was their sort of effect relative to what we observed to this, that the terror effect during the London phase, and we'll plan to break up some of those data. In with the data release when available. So, to directly answer your question, it's a mix of folks who've been on. in the past and failed, and others who were taking it and washed out to come into the affinity 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 percent. We're in a difficult position. Obviously, we can't directly measure changes in neuronal Huntington protein levels because we simply can't biopsy brain 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 can easily access. And that was one of the nice findings, some important findings from phase one 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 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 what we saw in 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 to plasma was 2.7 to 1. So we were getting twice as high exposure in the brain to the blood. So therefore, we said at 5 and 10 milligrams, if those exposure ratios hold, we could very well be at the necessary dose level to achieve the desired 30 to 50% lowering. So we'll look at when we get the PIVOT-HC data at the levels of reduction recording in the blood at 5 and 10 milligrams. We'll also look at the relative exposure from the blood to the brain and use those data to help guide the decision of whether we want to start dosing in that higher dose level of 20 milligrams. which, based on the Phase I data, would represent roughly 50% reduction in the blood. And therefore, if we were closer to a one-to-one ratio of blood and brain exposure, would suggest that we're achieving roughly 50% reduction in the brain. I know those are a lot of numbers and a little complicated, but does that answer your question?
spk34: Very helpful. Thank you.
spk37: 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.
spk13: Hi, this is Yihan for Colin. Thanks for taking our question and congrats on the quarter. So the first question is for the Translator, 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 queue. 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 our current guidance. Can we have more color on that? And the second cue, just a very quick clarification question. So for the UPS visa, 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.
spk35: Thank you, Yihao, for the question. Let me first say on Translator Review, we're 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 and Emily to provide additional cover. a color on the Translarna franchise.
spk29: As we mentioned earlier, Translarna continues to grow, and it's growing in all major markets. So we're seeing growth, particularly as we're adding new patients, managing the prevalence pool, and particularly working on dosing adjustments and high compliance. We have compliance rates in many countries at 90%. We've seen a lot of the geographic expansion take hold over the last three to four years as we've developed these in places such as 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 for 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. that we will continue to get those orders in the second half because some of these, we're adding new patients every quarter, especially seeing from these geographic expansion markets. So this strong performance that we've seen across TransLarnac is going to continue. We'll have some lumpiness in the quarters, 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 load discontinuation, are incredibly important. We're not going to change the guidance at this point in time, and we'll just continue to provide updates 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.
spk35: and then uh i'll just also that's why we don't typically give quarterly guidance we tend to give annual guidance for for just that reason uh on regarding the bla i will say that uh as we commented before they had the fda had asked for additional data in support of comparability analyses we provided those data and they've come back with a follow-up with follow-up questions that we're now in the process of answering and we'll send back in shortly uh and again we 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, the query responses.
spk11: Okay, thank you.
spk37: And thank you.
spk39: And one moment for our next question.
spk37: And our next question comes from Cade Cruz. Your line is now open.
spk02: Hi, this is Cade 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.
spk35: absolutely thank you questions but i'll start okay and i'll turn it over to emily uh so first uh regarding our facts look as we mentioned in the prepared remarks and as we've talked about previously we've been building our r d uh and commercial infrastructure uh over the past several years uh and quite proud of what we've achieved obviously the performance of the commercial performance in the in the first quarter is incredibly progressive incredibly impressive And it's clearly a result of the infrastructure that we've created. And we're now well positioned to launch additional products on positive data. We've also said that when we turn over the cards of 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'll be reduction in OpEx. And therefore, we will come back once that analysis is 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 further on OPEX and on stocking?
spk24: Yeah. On OpEx, obviously, put it 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.
spk39: And thank you.
spk37: I would now like to turn the call back over to Chief Executive Officer Matthew Klein.
spk35: 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 become available. So, thank you all again for joining the call, and have a good evening.
spk37: This concludes today's conference call. Thank you for participating.
spk39: You may now disconnect. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you.
spk23: music music you Thank you.
spk37: Good day, and thank you for standing by, and welcome to the PTC first quarter 2023 financial results call. Ask all participants on a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you'll need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1-1 again. 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.
spk19: Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' first quarter 2023 corporate update and financial results. I am joined today by our Chief Executive Officer, Matthew Klein, our Chief Business Officer, Eric Powell, 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?
spk35: 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 therapies to treat rare disorders. And I'm incredibly excited to lead PTC into its next quarter century as we continue to utilize pioneering science to 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 48% 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. And RISD also had a strong first quarter, providing royalty revenue of $31 million. The RISD revenue growth continues to be driven by both therapy-naive patients and those previously treated with dolgenza and spinerosis. In addition, U.S. growth is being driven by patients less than two months of age following the recent SNBA 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 op-ex 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 affinity study. Affinity is our phase three global placebo-controlled study of sepiaterin in children and adults with PKU. The placebo-controlled portion of the study was six weeks in duration with the primary endpoint of reduction in blood phenylalanine levels. To enrich the randomized population for sepiaterin responders, there was a run-in phase during which all screened subjects received sepiaterin for two weeks. Only those subjects who demonstrated a reduction in fentanyl alanine levels of 15% or more for baseline in Part 1 were randomized for Part 2, with the primary analysis population consisting of those who had a greater than 30% reduction in fentanyl alanine levels for 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, sepiaterin, can provide a clinically meaningful and differentiated response to the full spectrum of PKU patients. We look forward to sharing results from the placebo-controlled portion of Affinity in May. Let me now move to the two registration-directed trials of the tiquinone. MITEI is a global registration-directed trial of the tiquinone 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 three registration-directed study of the tiquinone in pediatric and adult patients with retrypotaxia. The study included a 72-week placebo-controlled phase with the primary endpoint being change from baseline in the validated mFARS score. Last patient, last visit for the placebo-controlled phase has also occurred and we continue to expect results for MOVE-FA in the second quarter. Moving to our PTC518 Huntington Disease Program, PIVOT-HD is a 12-month placebo-controlled trial that consists of two parts. Part one is 12 weeks in duration and focuses on PTC518 pharmacology and pharmacodynamic effects, as well as biodistribution. Part two is nine 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 stage 2 Huntington's disease, and we recently expanded the trial to include early stage 3 patients, who we studied initially at the 5 milligram and 10 milligram dose level. 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 doses. 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 2 variation to convert the European conditional marking authorization 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 TransLogin. Finally, for STAVA, as we previously shared, the FDA requested additional bioanalytical data in support of comparability analyses between the clinical and commercial drug products. We have received initial feedback from the agency on new 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 of our productive and successful first quarter, and will now hand the call over to Eric to provide an update on our commercial portfolio. Eric?
spk29: Thanks, Matt. Our global customer facing team has 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 products for neurological and metabolic disorders. We continue to make good progress with the Upstazer launch in Europe, We also have launched WeLibra 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 the DMD franchise. Translarna and Inflaza continue 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 DMV 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-based dose adjustments on an ongoing basis. The fundamentals of the EMFLAZA business continue to be solid. Quarterly net revenue was 55 million. We have seen a significant number of new patient 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 Upstazer commercially in Europe and will 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 Tegceti and WeyLibra in Latin America, where we continue to successfully grow these franchises in Q1. Following WeyLibra'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 WeyLibra for familial chylomicronemia syndrome, which was completed and delivered in Q1. As mentioned in our last call, for Tegceti, 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?
spk24: 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, Eversy 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. And Plaza 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 a $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 non-cash stock-based compensation expense. compared to $127 million for the first quarter of 2022, excluding $13 million in non-cash 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 CEPI of Tarrant 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 non-cash stock-based compensation expense, compared to $59.7 million for the first quarter of 2022, excluding $13.6 million in non-cash 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 31st, 2022. I'll now turn the call over to the operator for Q&A. Operator?
spk37: And thank you. And one moment for Q&A. As a reminder to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please stand by while we compile the Q&A roster. And one moment for our first question. And our first question comes from Kristen Kluska from Cantor. Your line is now open.
spk14: 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 patient starts? And is this also related to the specific geographies with more patient ads? 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 in being able to expand your footprint globally? And how do you think you could leverage this, you know, should some of these candidates end up crossing the finish line soon?
spk35: Great. Thank you very much, Kristen, for the questions. We're incredibly proud of the global commercial infrastructure we've built 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 nine 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.
spk29: Yeah, 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 the non-ambulant patient prevalence pool that we have on drugs through dose adjustments. That's really important. And of course, we've been seeing across the board for both MFLASA as well as TransLorna, improved and better payer access, and that's really important as well. Now for TransLorna, we did see $150 million, and 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 sizable 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 reiterating our guidance for the DMV franchise. to 545 to 565 million. So I hope that provides you the color that you need, Kristen.
spk14: Yes, thank you. That's helpful. And then maybe just one quick one on Huntington's disease. An 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 agent's ability to really target the right areas in the brain versus some other routes of administration that are being evaluated.
spk35: Kristen, thank you for the question. We think route of administration and biodistribution are incredibly important elements to the development of a successful therapy for Huntington's disease. Obviously, the development of PTC518 comes on the heels of the successful discovery and development of a RISD for SMA. And obviously, we've made a number of important learnings about how to design a molecule that can effectively cross the blood-brain barrier and not get deflux and globally by the CNS, which is not only essential for the optimal treatment of SMA, but obviously is similarly critical for Huntington's disease. So, in the design of PTC518, we put to play all of those lessons. have a molecule that's highly selective, highly specific, gets across the blood-brain barrier, and broadly biodistributes to every region of 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's protein that is toxic to cells and leads to 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 being locally delivered in the case of the gene therapy. Obviously, local delivery into the brain and gene therapy is something we know a whole bunch about from our successful development of Obstetza. And then also has significant advantages over intrathecally administered therapies, which I just can't get all to 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 where they by distribute, which we'll be able to confirm in terms of The CSF exposure in our phase 1 study will obviously share data again when we do the PIT-HD readout in the second quarter. And then also, we have other advantages because an oral molecule is titratable. So, we're also leveraging that titratability in our clinical study to identify the optimal dose to achieve the target whole-brain lowering on T2 protein that we think is optimal for disease treatment.
spk14: Great. Thanks. Looking forward to catching up with you once these data read out.
spk39: And thank you. And one moment for our next question. And our next question comes from Brian Abrahams from RBC.
spk37: Your line is now open.
spk44: Hi, this is Joe. I'm for Brian. Thank you for taking our question. Just on Huntington's, can you tell us more about 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. share your thinking around it and if it speaks to any possible changes in your thinking around desire level of the HTT now down in CSF. Thank you.
spk35: Thanks, Joe, for the question. So, the PIVOT-HT study is a 12-month placebo-controlled study that's in two parts. Part one is 12 weeks in duration and focuses on PKPD 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 of 30 to 50 percent of Huntington protein. The second nine months of the study is focused on biomarkers of disease, including Huntington protein levels in the CSF, radiographic markers including brain volume changes as well as NFL levels in the plasma and the CSF. The data we plan to share in the second quarter is an interim analysis from the first 12 weeks of PIVIT-HD. We'll be sharing information on the PKPD in the blood, so looking at blood, looking at drug levels in the blood and the reduction in Huntington, Amarni, and protein in the blood, and then looking at the relative exposure of the CSF in the plasma. As you recall from our phase one healthy volunteer study, we were able to confirm that we were getting excellent CNS exposure. And in fact, we're achieving greater exposure in the CSF than in the plasma. So that's a very important finding that we'll seek to confirm in the 12-week data. The biomarker data, including the CSF hunting and protein levels, NFL levels, and brain volume changes will come in the readout from the 12-month data. To your second question regarding patient populations, as I shared in answering Kristin'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, whether they be juvenile or adult patients, given that the disease cause is 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 in whom we could practically capture clinical effect, and in the case of the PHD study, biomarker effect in the time-limited constraints of a clinical trial. So we put a lot of effort into identifying the attributes of what we thought would be that optimal population. We availed ourselves of the robust Huntington's disease natural history databases and worked closely with Huntington's disease experts and 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't practically deliver a benefit. And we certainly don't want patients who are so early in their disease that they're not progressing at all, therefore making it impossible to show that we're slowing disease progression. So we put these attributes to play as our inclusion criteria for the study, and these were essentially stage 2 HD patients. We shared at the JPMorgan conference in January that we were adding additional cohorts of slightly later stage patients. We were now including patients who had a total functional capacity score of 11 and 12, rather than just simply having a TFC score of 13, which would be initially required. The reasons for this were because there were a number of these patients who were identified and prescreened prepared to participate in other clinical trials that were no longer being conducted. So we were in a situation where there were patients identified, ready to be in clinical trials, incredibly eager to participate in clinical trials, and whom we obviously believed we could provide benefit with this therapy. So we made the decision to introduce additional dosing cohorts, 5 mg and 10 mg dosing cohorts, in these early stage 3 patients, because this will provide us additional important data on potential benefit of PTC518, and it'll also allow us to test our hypothesis in terms of the optimal population that we initially set out to enroll. So I hope that answers your question on the adjustment or the addition of new patients.
spk44: Yeah, that was super helpful.
spk35: Thank you, Matt.
spk39: And thank you. And one moment for our next question.
spk37: And our next question comes from Eric Joseph from J.P. Morgan. Your line is now open.
spk27: Hi, good evening. Thanks for taking the question. Just a quick one from me on the tiquinone, 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?
spk35: Thanks. Thank you for the question, Eric. the protection for particular known is principally going to be under orphan exclusivity as is always the case we are exploring other potential ways to strengthen and extend the patent life how they stay in the us and europe as well as another market okay great thanks maybe just a quick follow-up if i could um as it relates to move fa um can you just talk about sort of the
spk27: the range of patients entering by age and, I guess, within that, patient ages that will comprise the primary analysis for MFARS on this hotline readout. Thanks.
spk35: Yeah, absolutely. So, when we constructed the MOVE-FA trial, we leveraged a number of learnings that we made from our own Phase II trial, as well as a number of the important learnings from other clinical studies. We also were in a position where, given the safety of the tiquinone 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 FDA patients are usually diagnosed in early adolescence, late childhood, 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 in the last question regarding Huntington's disease, getting that right clinical trial population that'll move enough over the course of the clinical trial for the placebo group puts you in the best position to capture treatment benefits. And so we cut the lower age limit at seven, because if patients are younger than seven, 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 means ascertainment of clinical benefits is difficult. So we set the lower age at seven, and then the primary analysis group goes up to 21. Again, we believe that this is a population in whom 1, we can have less of a chance of placebo effect. We're also in a situation where these patients tend to have a greater decline of the cost of the clinical trial, which makes it easier to register clinical benefit. And also, as is commonly the case in neurodegenerative disorders, if you're going to intervene. It helps 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 of the drug and the ability to enroll the younger patients. We're also including additional adult patients. They're not part of the primary analysis population. We previously studied the drug in adults. We believe we can hold benefit for, again, 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 relative to the adult patients. But we would fully expect that with a positive trial, that if we can move towards approval that we would have a label that would include pediatric and all adult populations. Okay.
spk03: That's great. That's very helpful. Thanks for taking the questions.
spk37: And thank you.
spk39: And one moment for our next question.
spk37: And our line is open. Robin Cornascus from Chewis, you're now available.
spk09: Great. Thanks for taking my question. So I have three of them.
spk10: So the first one is around PKU. So I know the bar, you gave the responder analysis of 30% and the decline, the improvement, the reduction for those lead-in patients. But since the bar for entering phase two is 15%, presumably you're going to get some, you know, lower responders going into the part two. 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 that? So I just wanted 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 to be better than Riatta and maybe flush out, you know, how much that TID dosing might impact the market? And then third, you mentioned like, you know, the range of patients, like you're doing younger patients and you're confident that they might have a lower placebo effect but also maybe progress more rapidly. You know, what's your confidence in that over the timeline? And also, what's your confidence that the decline in the efficacy in that population? Because we've seen decline in rata over time with older patients. What about younger patients and decline of the efficacy of these drugs? Thank you. Okay.
spk35: Okay, Robin, thank you for those questions. We'll take them in turn. So, the first question is regarding the affinity trial. And so, as we said, we have the running phase in which all screen subjects were treated for two weeks of sedation. And we randomized all subjects who had a greater than 15% reduction in fee. However, importantly, the primary analysis population for the trial includes only those subjects who had a greater than 30% reduction during the run-in. So, in terms of the primary analysis and success in the trial, that there'll be no interaction of those who had 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 shared in the past, we had 102 of the 156 subjects who were in the running 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 of 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, look, these patients are treated for two weeks, they're washed out, returned to baseline, and then the same patients are again 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 that historically the placebo patients in PK trials tend not to have very much of any placebo response, that gives us a great deal of confidence to not only achieve the primary analysis success of significant greater reduction in the treatment relative to placebo. But again, you're confident based on the data from Part 1 that we'll be able to demonstrate not only a clinically meaningful response, but one that would strongly differentiate cefutarin for the treatment of PKU. In terms of FA, your first question was regarding the TID dosing. Look, we've never seen a problem with compliance with TID dosing. And, you know, it's a breakfast, lunch, and dinner, so it's actually with meals. It's not Q8 hours, which makes a very big difference. And we believe that there's several other important aspects that differentiate the therapy. I'm going to turn it over to Kylie. I don't know if you want to add anything to that in terms of the effective dosing on the updates.
spk19: Yeah, I think that's well said, Matt. I think there's a number of factors that are taken into consideration, particularly in a disease of high-impact need and progressive diseases like phrygic ataxia. Efficacy, first and foremost, is 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 vaticanone. 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.
spk35: And then, Robin, in terms of your third question regarding the 7- to 21-year-olds and concerns there, and then why do we think that those patients will move more in the course of the clinical trial and the placebo group? So, the natural history of disease is very clear when you look at age groups and changes in the NFAR 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 a disease course, we're likely to be able to deliver a meaningful benefit. I think that's, you know, well understood reality in treating neurological or neurodegenerative disorders. And in fact, if you look at the RAYADA data, it was in their young, they had patients 16 to 45. And in the 16 to 17-year-old cohort, those younger patients, where they had the greatest, over five points, placebo-corrected response, which I think lends further support to the notion that if you intervene early, you're going to be able to capture a greater treatment effect on those patients. In terms of reduction in effect over time or still progression over time, look, none of these therapies are curative, but to be able to slow progression and slow progression by a year or by two years is incredibly meaningful in a slowly progressive disease such as Friedreich's ataxia that is relentless in its progression. So I think we expect there to be a meaningful effect in children that will alter and modify the disease course. One could still expect there to be some progression over time, but being able to slow the progression of the disease would be an incredibly meaningful impact of the ticket.
spk43: Thanks so much.
spk37: And thank you. And one moment, please. One moment for our next question. And our next question comes from David Leibowitz from Citi. Your line is now open.
spk18: Hi, this is Devanjana 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 OOPS data, like, feedback you received. And do you anticipate any additional delays, like, that could push back the FDA, sorry, the BLA submission beyond third quarter? And one other thing we wanted to know is that, like, you know, given, like, although OMAP and vaticoinone pivotal trials are both using MFARs as endpoints, there are, of course, differences in, like, the patient demographics and time points. So, how should we benchmark vaticoinone results when they come out against OMAP-like label efficacy? Thanks.
spk35: Thank you very much for the question. So, first, I'm going to stay with that. As we had 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 product often is different than clinical drug product. And it's important to show the agency that, you know, apples to apples. The key attributes of the commercial drug product are analogous to the attributes of the clinical drug product. And the agency had asked us 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 product. They are quite similar, and we were able to easily provide that data. We have stated that we believe the submission of the 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. submit responses to the queries, we expect to hear back from them, and then be in a position to submit to BLA, but we just wanted to communicate that it's possible, given the cadence of the back and forth with the agencies, that the submission could be delayed until the third quarter. Regarding differentiation between OMAD and vaticanone, obviously, there's not, the past trial is a bit longer than the OMAD trial, so 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 the tiquinone. And obviously, secondary endpoints are really, really important. I mean, I think that's an important part of the FA story. It's also an important part of the regulatory pathway, and our discussions with the agency have been similar to those that Reata which is they'd like to understand not only the effects on the primary endpoint, but other aspects of disease morbidity, which are captured in some of the secondary inputs.
spk06: Okay. Thanks. Very helpful. Thank you.
spk37: And thank you. And one moment for our next question. And our next question is Joseph Toom from Callen. Your line is now open.
spk31: Hi there. Good afternoon, and thank you for taking our questions. Maybe the first one on the PKU trial. When you think about what constitutes success here, is it really just a static benefit, or do you want to see a certain proportion of patients, you know, under 360 micromole per liter or, you know, that have a 50% 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.
spk35: So, thanks for the question, Joe. I'll start, and then I'll let Kylie talk a little bit about the commercial differentiation. So, obviously, a couple of the things that were really impressive from the phase one run-in data. One was the proportion of patients that responded, seeing nearly two-thirds of the patients have over a 30% reduction. is really impressive, and especially when you benchmark it to the KUVAID-Alkma study, where the proportion of responders over 30% was only 20%. The second is the magnitude of the effect, not only in the overall treated 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're able to provide in that running phase a real market reduction in phenylalanine. Our expectation is that the placebo-controlled study would not only provide evidence of clinical benefits sufficient to achieve registration, but also would it be able to provide evidence of differentiation. I'll comment quickly on the regulatory front, but then turn it over to Kylie to comment on the differentiation. So, on the regulatory front, We're going to have data from the six-week placebo-controlled study, but obviously we've been patients roll over 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 following positive data.
spk32: Kylie, do you want to answer the commercial differentiation question?
spk19: Yeah, absolutely. Thanks, Matt, and thanks, Joe. I think from that perspective, Joe, it's sort of about looking across the different patient segments that have high medical need in 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's historically been a very difficult to treat patient population. Being able to demonstrate benefit there, I think it's strong. As we've talked about, we have the primary analysis population being in the 30% or greater fee reductions but those being minimized in 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 trialed in FEB QVAN, showing a stat-seq 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 C reduction will give us an opportunity for a number of different patients in those different segments. I think obviously anything higher above and beyond that opens up more and more patients that would be looking to try sepiaptro.
spk31: Great, thank you. And then just real quickly on Upstazer, I know it was mentioned that 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 Upstazer this quarter, or if not, are you anticipating breaking that out going forward? Thank you.
spk35: Mark, do you want to talk a little bit about the launch and progress?
spk29: Yeah, 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 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. You know, 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 that 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 now is supporting ongoing price negotiation. And I remind you that sort of Europe is a step-by-step process with access and reimbursement. But we hope to conclude some of those pricing negotiations in the second half of the year. And importantly, we have NICE recommendation in the UK. 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 UK. And as a reminder, I would say that, you know, what we're seeing right now is a really steady cadence of patients. And 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.
spk28: Great, thank you very much.
spk37: And thank you. One moment please.
spk39: And one moment for our next question.
spk37: And our next question comes from Kelly Shi from Jefferies. Your line is now open.
spk22: Thank you for taking my questions. My question is, the Phase II study showed a treatment effect at a 2.5 points difference over placebo arm on FARS Neurostar at 24 weeks. And for Phase III, it's 72 weeks, and the sidebar at 4.5 points. I'm just curious what data you rely on to model how the treatment effects will trend from 24 weeks to 72 weeks and make this decision on the primary endpoint. Thank you.
spk35: Thank you very much for the question, Kelly. So, a number of important points here that you brought up. So, the phase two study was six weeks in duration and had the difference that you noted, and part of that magnitude of that difference was driven by a placebo effect that was present even after six months. And this is something that was important lesson we learned. And if you look at the REATA data as well, you still see a persistent placebo effect at six months that had that study only been six 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 control phase was to allow for complete washout of any placebo effect and allow for the placebo patients to more closely mimic the natural history of the disease, which is on average a two and a half point loss on the MPAR score per year. So you would expect that based on natural history, the change in the placebo group should be closer to three and perhaps even higher. The magnitude of treatment benefits was based on, the hypothesized quantitative treatment benefit was based on the long-term extension of the Phase II study. Now, we did do the six-week placebo portion, right, but all patients were continued to be treated for an additional 18 months, which allowed then for a comparison of 18 to 24 months of treatment with an age, stage, and sex-matched natural cohort, natural history cohort. The magnitude, the difference between those two groups, between the natural history and the natural history cohort and the treated cohort was actually much more marked. There was a 4.8 point worsening and a 1.8 treatment benefit. So, the difference over the 18 to 24 months was 6.6. So, we're starting to see a magnitude of effect from the Phase 2 study that's greater than what you've mentioned as a hypothesized effect, 4.5. So, we believe that 4.5 estimate and powering on that difference puts us in a strong position to capture significant benefit in this study.
spk22: Super 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 label in both mild and classic PKO patients? Or this might require expanded enrollment?
spk35: Yes, it's a good question. We have 15 patients who were in that greater than 30% reduction, and we had previously shared that we had five additional classical patients who had between 15% to 30% reduction in the running phase with a mean reduction of 22%. So you're seeing pretty meaningful reductions now across 20 patients, which in classical PKU is a lot. I would also say, a couple things to keep in mind. One is that we also have capped 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 with classical PKU is not only the threshold response of having a greater than 30% reduction, but also the absolute change in fenylalanine. 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 IQ. So if you think about a 15 or 20% reduction in phenylalanine levels for a classical PKU patient, obviously those could be quite meaningful when one considers the benefits of reducing the overall So, we believe that the data set we're generating will have not only a sufficient number of patients with classical PKU to be included in the label, but the magnitude of effect recorded in these patients is also quite important and impactful.
spk21: Terrific. Thank you.
spk37: Danielle, if your phone's on mute, could you please unmute it?
spk33: Yeah. 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 C 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 guess May and maybe June for the others. Thanks so much.
spk35: Yeah, thanks for the questions, Alex. So let me take the second question first. We've been able to provide the specific guidance for PKU with readouts in May, and obviously the others, we've not provided more specific timing because we don't have the more specific timing beyond second quarter at this time. In regards to your first question and the types to be used for transwine, 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 the Type C meeting to review with them the totality of data from TransLARN, including mechanistic data, district and data, and the data that we 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 request and the briefing book. We're going to be able to include not only the mechanistic data they asked for, but the data that we collected in the three placebo-controlled trials, and then there's over 700 voids where we've been able to demonstrate consistent clinically meaningful benefit in these voids. And when you 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 due to chance. And the consistency of effect that we're seeing across the three studies, the volume of data that we collected in over 700 boys, the ability to look across these three studies and see statistically significant benefit across a number of the key endpoints of the disease, the safety of the drug, as well as the context of the disease, which is non-sense mutation DMD remains a significant medical need. So we look forward to putting together all these data in a briefing package. We're also conducting some additional analyses to address some of the previous concerns that the agency has raised so we can come in to the agency at the right time and have a robust discussion about a path to NDA resubmission.
spk07: Great. Thanks so much.
spk37: And thank you. And one moment, please. And our next question comes from Joe Stuart. From SBB Securities, your line is now open.
spk16: Great. Hi, this is Will on for Joe today. Thank you for taking our questions. So to start, I just want to pivot back to the 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 Riatta's OMAVA locks alone. So in this event, how are you thinking about next steps on the regulatory side? And I have a quick follow-up. Thank you.
spk35: So, Will, thanks for the question. We believe that we will have sufficient power to detect the difference that was recorded in the REATA study. So, we don't see that as a risk here if we capture the same magnitude of effect in similar areas.
spk00: Okay, great.
spk16: And then, I guess, following up here, you know, has the agency provided you guys with any specific guidance in terms of what they want to see, either from an efficacy standpoint or a stats perspective? And how is your thinking, if at all, changed on this since the approval of OMAV-Oxalone? And kind of, you know, any insight into the agency's views here would be helpful.
spk35: Yeah, 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 those are really the buzzwords that FDA likes to see for clinical benefit. It typically wanted to have a key secondary endpoint that more directly assesses feel or function, move along with the primary endpoint so that you can contextualize, appropriately contextualize the recorded changes as far as being clinically meaningful. Obviously, that was a source of a lot of the discussion that went on over from the time Ray Adler shared their data in October of 2019 to NDA approval, and I think that some of the back and forth was based on the fact that their key secondary endpoint, which was the clinical global impression scale, did not achieve statistical significance. So, be that as it may, the approval of the FDA on essentially a statistically significant NBARs 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 we believe, anyway, that being able to achieve a statistically significant effect on the mFARS, particularly in a longer study of 72 weeks relative to 48 weeks, and in a larger patient population that we have in MOVE-SA relative to the MOXIE study, would put us in a strong position. Nonetheless, we did spend a lot of time planning our 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 captures field of function in any good light. We selected this as the key secondary endpoint because if you look at the natural history data, MR's changes tend to move along with changes in the ADL scale. They tend to move similarly and across as the disease progresses. And in fact, if you look at the results of the MOXIE study, the one secondary endpoint on which there was nominal statistical significance, it was the ADL scale. Unfortunately, I believe 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 MPHARs is the benchmark that's now been set for approval, but we'll also obviously be looking to see if we can capture secondary endpoint benefit as well.
spk17: Very helpful. Thank you. Our next caller is Jeff Hung with Morgan Stanley. Jeff, your line is open. Please go ahead.
spk26: Thanks for taking my questions. For MITEI, can you remind us of why the study was powered for a 40% placebo-adjusted difference in seizure reductions when 20 to 25 reduction can be important? You know, 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.
spk35: Thanks for the question, Jeff. So, the powering in the MITEI study was based on a couple things. Obviously, on the placebo side, we tried to hypothesize a change in observable motor seizure frequency that was consistent with the placebo response that's been shown in other pediatric epilepsy syndrome trials. And there have not been any previous placebo-controlled trials in children with mitochondrial disease with seizures, but we believe the hypothesized placebo effect of 10% was reasonable given what's been seen in other studies, which is generally ranging between 3% and 19%. on the efficacy side of 50% reduction. So first let me say we absolutely agree given the refractory nature of these seizures, their highly morbid nature, the fact that they can be life-threatening in many cases, I think most KOLs agree that a 20% to 25% reduction would be clinically leading for this population. That 50% hypothesis is driven a bit by the previous seizure reductions we've quantified in other studies, particularly in the treatment series of children with Ponticerebral or hypoplasia type 6, which tends to be one of the most virulent mitochondrial disease-associated seizures subtypes. So again, we believe that we 25% would be incredibly meaningful, but again, the numbers are based on our previous experience as well as the experience of others.
spk26: Great, thanks. And then for PTC 518, did the FDA specify where the additional data for supporting dosing and duration needed to come from geographically? I know that you've been enrolling patients outside the U.S. and 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 may care at the end of the study if more patients end up coming from other geographies. Thanks.
spk35: Yeah, so just as a reminder, Jeff, the FDA asked for additional data to support the dosing and duration proposed in the PIVOT-HC study was based on non-clinical data. This was based on data from the toxicology studies, the same toxicology studies that were used to support the approvals of the conduct of the study and 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 duration, and they said those data could be clinical data that were collected as part of the PIV-HC study. Obviously, as the study has only been conducted in countries outside of the U.S., they naturally understand that those data are going to come from patients outside of the U.S. And so we will plan, as we do this first interim data cut, to use those data to take those data to the agency and continue discussions about opening their moment again 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 the data looked at whether they were collected in the U.S. or elsewhere.
spk37: Okay.
spk26: Thank you.
spk37: And thank you. And one moment for our next question. One moment. And our next question comes from Gina Wang from Barclays. Your line is now open.
spk20: Thank you. Very quick few questions. First one is regarding the full data sets. We see each individual data set with press release and the conference call in the second quarter. And the second question is regarding Affinity Trial in PKU Med IRA. Some patients had prior KUVA experience. I know you cannot comment on the percentage of patients, but would these are KUVA non-responders in the study or simply just KUVA experienced patients? And then lastly, very quickly on PIVOT-HD, what is your bar for blood hunting team knockdown levels?
spk35: Gina, thank you for the questions. Unfortunately, I didn't clearly hear your first question. I heard the second and third. Would you mind repeating the first question?
spk20: Sure. First question is basically for the four data sets, would you report individually with press release and a conference call in second quarter?
spk35: Yes. So, as we've guided that the data from Affinity will be in May, the others need to occur in the second quarter. We haven't given details yet on the exact nature of whether they'll be all releases and calls. So we haven't made those decisions yet. And we plan to share the data as they become available. There's not a plan now to batch 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 were then washed out from KUVAN and then . Obviously, will give us the opportunity to understand in specific subjects. What was their sort of effect relative to what we observed to this, that the terror effect during the London phase, and we'll plan to break up some of those data. In with the data release when available. So, to directly answer your question, it's a mix of folks. There's folks who've been on. in the past and failed, and others who were taking it and washed out to come into the affinity 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 percent. We're in a difficult position. Obviously, we can't directly measure changes in neuronal Huntington protein levels because we simply can't biopsy brain 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 can easily access. And that was one of the nice findings, some important findings from phase one 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 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 Slicing 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 what we saw in phase 1 in terms of blood hunting and 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 to plasma was 2.7 to 1. So we were 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 desired 30 to 50% lowering. So we'll look at when we get the PIVOT-HC data at the levels of reduction recording in the blood at 5 and 10 milligrams. We'll also look at the relative exposure from the blood to the brain and use those data to help guide the decision of whether we want to start dosing in that higher dose level of 20 milligrams which, based on the phase one data, would represent roughly 50% reduction in the blood. And therefore, if we were closer to a one-to-one ratio of blood and brain exposure, would suggest that we're achieving roughly 50% reduction in the brain. I know those are a lot of numbers and a little complicated, but does that answer your question?
spk34: Very helpful. Thank you.
spk37: 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.
spk13: Hi, this is Yihan for Colin. Thanks for taking our question and congrats on the quarter. So the first question is for the Translator, 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 queue. 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 our current guidance. Can we have more color on that? And the second cue, just a very quick clarification question. So, for the APHISA 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.
spk35: Thank you, Yihao, for the question. Let me first say on Translator Review, we're 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 and Emily to provide additional color on the TransLorna franchise.
spk29: Hey, as we mentioned earlier, TransLorna continues to grow, and it's growing in all major markets. So we're seeing growth, particularly as we're adding new patients, managing the prevalence pool, and particularly working on dosing adjustments and high compliance. We have compliance rates in many countries at 90%. We've seen a lot of the geographic expansion take hold over the last three to four years as we've developed these in places such as 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 for 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. that we will continue to get those orders in the second half, because some of these, we're adding new patients every quarter, especially seeing from these geographic expansion markets. So this strong performance that we've seen across TransLarnac is going to continue. We'll have some lumpiness in the quarters, 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 load discontinuation, are incredibly important. We're not going to change the guidance at this point in time, and we'll just continue to provide updates as we see these orders coming in. But I'd like to reiterate that we have a 545 to 565 DMV franchise right now that we are very confident in achieving this year.
spk35: And then, I'll just also, that's 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 in support of comparability analyses. We provided those data, and they've come back with a follow-up, with follow-up questions that we're now in the process of answering, and we'll send back in shortly. And again, we, 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, the query responses.
spk11: Okay, thank you.
spk37: And thank you.
spk39: And one moment for our next question.
spk37: And our next question comes from Cade Cruz. Your line is now open.
spk02: Hi, this is Cade 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.
spk35: Yeah, absolutely. Thank you for your questions. I'll start, Kay, 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've achieved. Obviously, the performance, the commercial performance in the first quarter is incredibly impressive. And it's clearly a result of the infrastructure that we've created. And we're now well positioned to launch additional products on positive data. We've also said that when we turn over the cards of 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'll be reduction in OpEx. And therefore, we will come back once that analysis is 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 further on OPEX and on stocking?
spk24: Yeah. On OpEx, obviously, put it 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.
spk37: And thank you. I would now like to turn the call back over to Chief Executive Officer Matthew Klein.
spk35: 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 become available. So thank you all again for joining the call, and have a good evening.
spk37: This concludes today's conference call. Thank you for participating. You may now disconnect.
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