PTC Therapeutics, Inc.

Ladies and gentlemen, thank you for standing by, and welcome to the PTC second quarter 2021 financial results. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask the question during this session, you will need to press star then 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star then 0. I will now like to hand the conference over to your speaker for today, Kyle E. O'Keefe, Senior Vice President of Global Commercial and Corporate Strategy. You may begin.

Good afternoon, and thank you for joining us today to discuss the PTC Therapeutics Second Quarter 2021 Corporate Update and Financial Results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz, our Chief Development Officer, Matthew Klein, our Chief Business Officer, Eric Powers, and our Chief Financial Officer, Emily Hill. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements. Our actual results could materially differ from these forward-looking statements, as such statements are subject to risks that can materially and adversely affect our business and results of operation. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10Q and annual report on Form 10K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP to non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's earnings release. With that, let me pass the call over to our CEO, Stuart Peltz.

Stuart? Thanks, Kylie, and thanks for joining us today. As we close out the first half of 2021, I'm proud to say that a lot of progress has been made in all facets of our business. And I'll go into this in more detail shortly. However, before I do, I'd like to take a moment to reflect on our strategic plan at PTC and measure how we're doing. At PTC, our mission is to provide innovative treatments to patients with debilitating diseases that have few or no treatment options. The foundation of our strategy is to have a sustained pipeline so that we may continue to produce commercial treatments. that will drive revenue and create value for all stakeholders over both the short term and long term. We all know the importance of having a deep pipeline to balance the innate challenges of the drug discovery and development process. We're all working towards building a steady state number of therapeutic programs so that the successful programs move forward. This approach will allow us to have the same pipeline of potential new therapies that reach commercialization and substantially grow our revenue base. Though many of us have been fortunate to have access to COVID vaccines, we recognize that the pandemic is still very much a reality in many parts of the world. This brings additional challenges with potential impact across multiple aspects of our business. However, we'll continue to manage through these challenges as they arise. I want to emphasize the impressive revenue growth that we have seen this quarter, which is driven by the strength in our DMD franchise and the incredible uptake of IRISD. Based on this impressive growth, we'll be raising our 2021 DMD franchise revenue guidance to $370 to $390 million. And Emily will go into this in more detail later in the call. So let me start with the DMV franchise. Our commercial team has been working hard to make our therapies accessible to DMV patients around the globe. As a result, TransLinda saw an impressive 36% year-over-year growth. I'm very proud that the growth continues almost seven years post-launch, both in existing geographies and with continued geographic expansion. Impraza is also continuing to deliver strong revenue, with an increase of 36% over the same period of last year. Eric will discuss the success of the commercial franchise in more detail shortly. Now let me turn to the splicing platform, starting with Avrizzi. Avrizzi continues to see a strong uptake in the U.S. with 1,800 SMA patients now on treatment. representing almost 20% market share in less than a year post-launch. Evrizdy is also now approved in 53 markets outside of the U.S., and we are starting to see an early adoption in these markets and expect this growth to continue as we conclude on additional pricing and reimbursement discussion. As anticipated, Evrizdy was approved in Japan this quarter and and we will receive a $10 million milestone payment from Roche upon the first commercial sale. I also wanted to touch on the recent positive results from the SMA study, which I find to be quite remarkable. The Rainbow Fish study using Avrizzi in pre-symptomatic infants diagnosed with SMA demonstrated that Avrizzi-treated infants achieved the same developmental milestones, as healthy children. Interim data from the jewelfish study, which is assessing of RISD in SMA patients previously treated with other therapies, including Zolgentema and Spinraza, demonstrated overall stabilization and motor function after switching to a RISD. This shows the benefit of a RISD in the broad and heterogeneous real-world SMA population. Turning to PTC518 and our Huntington's disease program, in the second quarter of this year, we were excited to release the preliminary results from our phase one healthy volunteer study. As a reminder, the results from this study demonstrated a dose-dependent lowering of Huntington mRNA even after only a single dose of PTC518. The results also demonstrated a target mRNA lowering of 40 to 50% even in the lowest multiple ascending dose cohort. We are in the process of completing the phase one trial. This includes additional protein sampling, a food effect cohort, and a CSF pharmacology cohort. We plan to release the results of these additional cohorts in the third quarter of this year, as well as sheer details on our next clinical study, which we are planning to initiate before year end. I will now turn to our BioE platform. This is an exciting and novel science platform to identify new therapies that result as a consequence of excess electrons, usually produced from the mitochondria during electron transport. This triggers oxidative stress and causes havoc within the cell that results in and exacerbates multiple disease states. Drugs that can modulate this process would be valuable therapies to treat a wide variety of diseases. We have two important ongoing trials with vatiquinone. Our first compound from our BioE platform that is a 15-laboxygenase inhibitor, which is the key regulator of this pathway. The first is in mitochondrial epilepsy, and the second is in Friedreich ataxia. These two trials are registration-directed and therefore our potential near-term value drivers. We also have a second-generation 15-lipoxygenase inhibitor, PTC-857, with pharmacokinetic properties well-suited for a range of adult neurodegenerative diseases. We are pleased to have completed the Phase I Healthy Volunteer Study for PTC-857, and Matt will share the results later in the call. Turning now to our PKU program, which is another important near-term value driver. We're excited as we plan to initiate the Phase III Registration-Directed Study Affinity in September of this year. PKU is a large orphan indication within an estimated 58,000 patients globally. The vast majority of patients are not well-controlled with existing therapies, highlighting the substantial unmet medical needs. Study startup activities are well underway, and we are utilizing our global infrastructure to focus on sites both in the US and globally. PKU is a unique development and commercial opportunity in the rare disease world, as it has a well-defined patient population, well-known centers of excellence, and an expedited path to commercialization. We look forward to the potential of bringing PTC923 as a clinically differentiated therapy to the PKU community. Moving to our gene therapy platform and our AADC program, as a reminder, the CHMP imposed a clock stop to allow for the pre-approval inspection. This process is still ongoing, and we expect the CHMP opinion in the fourth quarter. Turning to the U.S., as we have previously shared, We were conducting additional surgeries in advance of the BLA submission. We're happy to announce that the third surgery has recently been completed and will now align with the FDA prior to the BLA submission, which we plan to submit by the end of this year. I want to take this moment to discuss our gene therapy manufacturing facility in Hopewell, New Jersey. We have a 220,000 square foot fully functional, well-equipped, and validated facility for the development and manufacture of the gene therapy products in our pipeline, thereby minimizing our reliance on external CROs. As we have excess capacity and retain the relevant manufacturing expertise, we have a unique opportunity to potentially create a revenue stream by entering into development and manufacturing service agreements with other companies. utilizing this facility and our expertise to produce high-quality plasma DNA and AAV vectors. Lastly, I wanted to highlight the potential upcoming milestones from our oncology platform. Unescolin, previously PTC-596, is in clinical trial for two niche solid tumors, DITG and LMS. DIPG is a rare pediatric brain tumor, and LMS is a rare adult solid tumor in muscle. Both have high medical needs with few beneficial to no treatment options. Results are anticipated in the second half of 2021 for the two clinical trials, and with positive results, we have the potential to initiate registration-directed trials. We look forward to sharing the results shortly. As you can see, we are continuing to make progress across our commercial and clinical efforts. I'm proud of our progress, driven by our people and their strong commitment to our mission to deliver therapy to patients in need. With that, I turn the call over to Matt for an update on development. Matt? Thanks, Stu.

I want to start by emphasizing the continued progress our development teams have made across all our programs. First, I'll start with our splicing platform and our PTC518 Huntington Disease Program. As Stu mentioned, we shared the initial results from our PTC518 Phase 1 Healthy Volunteer Study to the second quarter of this year. As we reported, PTC518 treatment resulted in the desired dose-dependent lowering of HTT mRNA levels in both the SAD and MAD cohorts. We are in the process of completing additional cohorts to provide data on HTT protein levels and CSF biodistribution. Results from these cohorts will be released in the third quarter of this year. Given that we have achieved our key objectives for the PTC518 Phase 1 study, planning for the Phase 2 trial is underway, and we expect to initiate the trial by the end of this year. The Phase 2 study will be conducted in HD patients, and will focus on demonstrating dose-dependent reductions in HTT mRNA and protein levels. We will provide more details on the study design once it is finalized. Next, I would like to highlight the progress we have made in programs for our BioE platform. We have two ongoing registration-directed trials with baticrinone, our lead compound from the BioE platform, and we recently completed the Phase I Healthy Volunteer Study of PTC857, the second compound from the platform. Both the MITEI trial, our Phase 2-3 trial in children with inherited mitochondrial disease and epilepsy, and MOVE-FA, our Phase 3 trial in phrygic ataxia, are global studies that are actively enrolled. As Stu noted, these programs are near-term value drivers, and we remain on schedule to have data readouts with the MITEI study in Q3 2022 and the MOVE-FA study in 2023. Turning now to PTC 857, a 15-hypoxygenase inhibitor being developed for adult neurodegenerative diseases. I am pleased to share that we have completed the Phase I Healthy Volunteer Study and that PTC-857 was found to be well-tolerated with no reported serious adverse events. PTC-857 also demonstrated predictable pharmacology, and we were able to achieve the desired plasma exposure levels consistent with the levels at which we observed efficacy in our preclinical studies. We are now positioned to move PTC 857 forward to phase two. Through its activity at 15 lipoxygenase, PTC 857 targets the pathway of oxidative stress and inflammation known as ferruptosis, a pathway key to CNS disease pathogenesis in ALS, Parkinson's disease, and other neurodegenerative disorders. Our preclinical program has demonstrated that PTC 857 provides potent protection against oxidative stress and inflammation-based cell injury and death in a series of CNS disease in vitro and in vivo test systems. Turning now to our PKU program, we are on schedule to initiate our Phase III registration-directed trial, the Affinity Study, with PTC923 this quarter. As a reminder, Affinity is a double-blind, placebo-controlled study with a run-in phase to identify subjects who respond to PTC923 treatments. These responders will then be randomized to receive either PTC923 or placebo for six weeks. This approach of enriching the study population with responders increases the probability of success of the trial. Following the efficacy study, all subjects will be eligible to enroll in a long-term open-label extension study. We plan to have data from the efficacy trial in the fourth quarter of 2022. Turning now to our gene therapy platform, As Stu noted, the third cannula surgery in support of the AADC BLA submission has been completed. We plan to align with the FDA on the data package and then to submit the BLA by the end of the year. As a reminder, the surgeries were conducted to gain experience with the intended commercial cannula in delivering our gene therapy product. One of the innovative aspects of our AADC gene therapy program is that the gene therapy product is delivered directly to the botanist. the area of the brain key to disease pathology. In order to achieve this direct delivery into the brain tissue, neurosurgeons use a stereotactic surgical procedure that relies on an MRI-based Google map that provides a direct path for the surgeon to safely reach the containment to deliver the gene therapy. Let me now provide a quick update on embodistat, previously PTC299, currently in a phase 2-3 trial for COVID-19. the FITE-19 study. Enrollment is ongoing in this trial, and we expect this study to be completed by the end of this year. As a reminder, Embodistat is also being studied as an ongoing trial in patients with acute myeloid leukemia. Finally, I would like to remind you of our ongoing placebo-controlled trial with Translarna for Duchenne muscular dystrophy, study 041. This global study is a 72-week randomized placebo-controlled trial that incorporates many of the key learnings we have made from our previous DMD trials. This study is fully enrolled, and we expect to have results in Q3 2022. In summary, we are continuing to move our development programs forward with many important milestones in the near future. I will now turn the call over to Eric for an update on our commercial business.

Eric? Thanks, Matt. Once again, I'm extremely proud of the strong execution from our global customer-facing team. and the continued remarkable growth of our global DMV franchise. With our keen focus on patients, our team was instrumental in delivering another highly successful quarter for commercial revenue. We have seen incredible progress in our DMV franchise with year-over-year growth in both Enflaza and TransLarna, resulting in a 36% growth for the franchise. New patient starts, continued high adherence, and if and fewer discontinuations has sustained the growth of Implaza. In this quarter, we achieved $49 million in revenue, which is a 36% increase over the second quarter of 2020. Strong execution, supported by new data recently presented by Dr. Craig McDonald at the PPMD meeting, continues to support clinical differentiation over prednisone, and is helping drive new prescriptions from patient switches. Turning to TransLarna, we achieved $53 million in revenue this quarter, a 36% growth over the second quarter of 2020. This sustained performance was driven by growth due to expansion of the patient base, continued high compliance, and broader access to the existing geography, as well as continued geographic expansion. As an example of geographic expansion, following the approval of TransLarda in Russia, we are pleased to announce that we have successfully launched and patients are now receiving treatment. The launch in Russia and continued growth in other key markets have been one of the major drivers for revenue growth in the second quarter of 2021. Ongoing geographical expansion in Central and Eastern Europe, Latin America, the Middle East, and Asia-Pacific continues to be a focus for us, including expanding our footprint and infrastructure in additional markets such as Japan and Mexico. We are making continued progress with reimbursement for Transwarner, and we are pleased in extending the managed access agreement in England. In Latin America, we continue to see increases in newly diagnosed DMD patients and are making good progress towards securing group purchase order for Translana in Brazil in the second half of 2021 to treat both new and existing DMV patients. Now, turning to Tecseti and Reliever, disease awareness and patient identification continues to be the focus in Latin America, and our teams have made substantial progress despite the ongoing COVID-19 challenges in the region. In Brazil, our discussion on pricing for Tecseti continues. During this process, we continue to provide medical education, genetic testing, and patient program support to make Tecseti available in multiple countries within Latin America through early access programs to bring this important treatment for HHTR amyloidosis patients. We are pleased that we now have some of the first patients benefiting from the treatment with Waylibra in Latin America through early access pathways. We're preparing for a launch in Brazil. However, due to COVID delays at Anvisa, waiver registration is now anticipated in Q4. Anvisa has announced the establishment of a task force to address the backlog of pending applications with a priority for rare disease applications. I will now touch on the preparation for PTC's first gene therapy launch. As a reminder, PTC-AADC is a transformative gene therapy that has the potential to produce meaningful changes in AADC deficiency patients. Preparations are progressing well, and we anticipate launch to occur in Europe shortly after final EMA approval. PTC continues to accelerate patient screening activities with over 100 at-home and saliva-based genetic testing programs in over 20 countries, initiated in enriched high-risk populations. Significant progress has been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the US, the EU, and Latin America to ensure treatment center readiness at the time of launch. And we remain confident to achieve our goal of 300 patients identified globally by launch. We generated another strong and sustained performance in Q2, and I continue to take great pride in our accomplishments from global customer-facing teams and their ability to flawlessly execute against their strategic priorities. With that, I am pleased to announce that PTC is raising our 2021 revenue guidance to $370 to $390 million. I will now turn the call over to Emily for a financial update. Emily?

Thanks, Eric. In the second quarter of 2021, we continued to see strong commercial performance and demonstrated progress across our pipeline. We remain in a healthy financial position with a robust cash balance and another year-over-year increase in revenue from the BMD franchise. We have been working strategically to advance key platforms and look forward to a number of upcoming milestones from our pipeline. In light of the consistent strong performance of Translarna and M-Plaza to date, we are pleased to raise revenue guidance for the DMD franchise for 2021 to $370 to $390 million from the original 2021 revenue guidance of $355 to $375 million. The press release issued earlier this afternoon summarizes the details of our second quarter 2021 financial results. I will take a few minutes now to review these financial results. Please refer to the press release for additional details. Beginning with the top-line results, revenues were $117 million for the second quarter of 2021, a 55% increase over the second quarter of 2020. This revenue includes $103 million in net product sales and $14 million in royalty revenue from our partner diversity program. Turning now to more detail on the success of the DMD franchise. Transvarna net product sales were $53 million, compared to $39 million in the second quarter of 2020. A key driver of this growth has been through geographic expansion, particularly in Russia and the Central and Eastern Europe, Middle East, and North Africa region. MFLAZA net product revenue for this quarter was $49 million, as compared to $36 million in the second quarter of 2020. Moving on to an update on Evrisdy, our partner Roche has reported year-to-date sales of approximately 243 million Swiss francs, which is approximately 265 million U.S. dollars. As a reminder, in exchange for 650 million upfront cash added to our balance sheet, PTC also retains approximately 57% of Evrisdy royalties until royalty farmer receives a return of 1.3 billion. after which 100% of the royalties revert back to PTC. As part of this royalty monetization transaction, PTC also retains sales and regulatory-based cash milestones. Following the approval of the Brizzy in Japan this quarter, we anticipate a near-term 10 million milestone payment upon the first commercial Japanese sale. Non-GAAP R&D expenses were 112 million for the second quarter of 2021, excluding 13.4 million in non-cash stock-based compensation expense, compared to 168 million for the second quarter of 2020, excluding 8.6 million in non-cash stock-based compensation expense. The relative decrease in research and development expense is primarily related to one-time charges in the second quarter of 2020, of $53.6 million for our CENSA merger, as well as $41.2 million for our commercial manufacturing service agreement with MassBiologics. Non-GAAP SG&A expenses were $56.6 million for the second quarter of 2021, excluding $12.3 million in non-cash stock-based compensation expense, compared to $45.3 for the second quarter of 2020, excluding $8.3 million in non-cash stock-based compensation expense. Cash, cash equivalents, and marketable securities totaled $947.1 million as of June 30, 2021, compared to $1.1 billion as of December 31, 2020. I'll now turn the call over to the operator for Q&A. Operator?

Thank you. Ladies and gentlemen, as a reminder to ask the question, you will need to press star then 1 on your telephone. To withdraw your question, press the pound key. Again, that's star 1 to ask the question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Eric Joseph with JP Morgan. Your line is open.

Good evening. Thanks for taking the question. Nice quarter. Just on the DMT franchise performance, with guidance now raised here, if we're looking at the midpoint, it actually seems to imply that a flat-to-down trajectory for the second half, so I'm just wondering if you could kind of talk us through any risks that you're anticipating with respect to ongoing performance with either Translana or Inflaza, and wondering whether the second quarter results reflect any advanced purchasing or stocking, and if I have a follow-up.

Yeah, thanks, Eric, for the call. Eric, why don't you take this?

Sure. Eric, you know, first of all, I mean, we had a terrific Q2. We had $53 million in sales for TransLarna. That's a 36% increase over last year. And within Plaza, identically, 36% growth. We had $49 million of revenue in the quarter. I think when you look at our revised guidance, I think our guidance right now reflects that we're growing in all major markets. uh we're very proud of the the work that the european team has done after seven years especially northern and southern europe where they have the largest base of patients and we've been able to maintain that high base large base of patients with high compliance rates minimizing dropouts but where we're seeing growth right now is really a lot of this the new patients are coming in from russia from central and eastern europe middle east and and our business in latin america continues to be to be solid despite some of the COVID challenges that we have. And we expect right now orders in Latin America, and particularly Brazil, significant orders which you already know can be somewhat lumpy. We anticipate those to happen in the second half of the year. So, I mean, overall, I think we're very confident. We have a strong continued growth at Transvarna. On the Implaza front, we had one of our best quarters ever. And we continue to see new patient growth. We also see that the compliance with Inflaza is extremely high. And more importantly, that the data that's being generated now, new data, real-world data, and switching data, we're seeing not only new patients, but we're seeing an increased amount of patients that are actually switching from prednisone to Inflaza. And that's really a very important sign. So overall, I think our guidance Where we're looking at right now is very strong continued performance, and it would be right now on the upper end would be at least about 17% increase year over year. And that's pretty in line with what we think we can achieve, and the business right now has a good tailwind.

Okay, great. And just a second question on Invotastat. The Fight 19 trial is focused on hospitalized patients, but I'm just trying to get a sense of – How are you thinking about the market opportunity in view here, assuming success? Do you see potential for its use in the outpatient setting? Do you have the regulatory flexibility to do that? Or do you need to conduct a separate trial for outpatient use? Thanks.

Yeah, thanks for that question. Particularly, we're excited about this. Just to remind everybody that PTC299 is a small molecule. And that so it certainly can be used in the outpatient setting, right? So we think right now we're doing a hospital trial, but it certainly could be used. And I think it has the advantage in that it's a dual mechanism. And that is that because of its mechanism, first of all, it's a cellular mechanism, so it won't have the issue. We don't anticipate as much of an issue with the SARS-CoV-2 mutating. And it targets the DHODH. cellular enzyme. And second of all, I think by targeting this, it's less likely to elicit drug resistance as a consequence of that. So we so so on the whole, we think that that this will certainly have a possibility in the outpatient setting. And we'll have to discuss with the FDA based on the results from the current trial is successful. If and when successful, how can we use it in both the in-hospital as well as patient setting? So we certainly think that it has the capability to be used in both. And it's simple to take. You can get it, you know, obviously you get a prescription and you can take it as soon as you get COVID.

Okay, got it. I appreciate that. Thanks for taking the questions. Thank you.

Thank you. Our next question comes from the line of Alethea Young with Cantor Fitzgerald. Your line is open.

Hi. Congratulations on all the progress. This is Nina. I'm for Alethea, and thanks for taking the question. We were wondering for the Huntington's update end of year if you could just share how much and what information we should get or expect around CSF. Thanks.

Sure. Matt, do you want to take that?

Yeah, sure. So as we've said before, the phase one study, the key objective of that study was to demonstrate dose-dependent lowering of Huntington mRNA and protein in peripheral blood cells. We're in a unique opportunity with an oral molecule that broadly distributes through the body and through the brain where we have a ratio of lowering in peripheral blood cells of one to one with cells inside the brain. what we're able to do is able to look at blood cells peripherally and get a read on what's going on in the brain. And that's really a function of, one, the biodistribution of the molecule, and, two, the fact that it is an oral molecule that's been designed not to efflux from the CNS and really penetrate all regions of the brain equally, which obviously is incredibly important in Huntington's, which is a total brain disease. And so that's what we were able to show so far with the data we've read out of that dose-to-pandemic lowering of mRNA in peripheral blood cells in both the SED and MAD cohorts. And the CSF cohort we referred to is a pharmacology cohort. What we're going to look at in the CSF and healthy volunteers is making sure we get the biodistribution to the CNS that we anticipate based on all the work we've done before. One key element of the design of this molecule was to ensure not only does it cross the blood-brain barrier, so that it doesn't get efflux. That means once it gets across the blood-brain barrier, it stays in. And that's incredibly important for its biodistribution throughout all regions of the brain. Well, the way we can tell whether or not that's happening is by measuring drug levels in the CNS, in the CSS specifically, and comparing those levels to the peripheral plasma levels. So that's exactly the readout that we'll be getting from the CSF COPLIN. Lining up the levels of drug in the plasma with the levels of drug in CSS and being able to check that box that we're getting the desired and designed CNF penetration. So specifically, you'll be getting a readout of drug levels in the CSF and being able to check that key box that we're getting the biodistribution lack of efflux that we've seen in the preclinical studies in the animal models and where key design feature of the molecule.

Okay, thank you. Thank you. Our next question comes from the line up with Bank of America. Your line is open.

Hi, good afternoon. Thanks so much for taking my questions, guys. I just have a couple. One on AADC. This is a program where I think you guys have been engaged in patient finding efforts for a while. It's been a few quarters since we've gotten an update on how many patients you've found. I think the last count was somewhere in the 200s. I was curious if you have any updated numbers on the addressable patient population that you could identify today. And then I have follow-ups.

Okay. Yeah, thanks for the question. Eric, do you want to take it? Yeah.

You know, right now we're still doing a lot of work, as I mentioned earlier, to You know, our plans are really continuing to aggressively look at and pursuing patient finding. You know, we're not, at this point in time, we're not going to be prepared to provide numbers of patients, but we're well on track right now to achieving our goal, which is to have 300 addressable patients between now and the time when we have our first launch. Now, we're anticipating our launch, the first country launch to be in Germany, and that would be following EMEA approval, and at that time we'd be providing the number of patients. But you have to be really, really, you have to understand that this is an ultra-rare disease. And what we've done is we've really casted the net pretty widely now. So we have 100 programs right now where we have been screening patients in very high-risk populations, particularly like in the cerebral palsy and the epilepsy centers. And we've casted our nets geographically to over 20 countries. And those 20 countries really represent areas where we can get access and reimbursement. But keep in mind, when we announce the number of patients at the time of launch, that will be the number of patients globally. And then, of course, that will be sequenced according to market access and reimbursement amongst various countries in Europe and in early access programs across the globe. So really focusing on that. We're focusing on not only just patient finding, but making sure that our centers are ready. And we have centers right now that have, as Matt said, who have treated patients in the U.S., in Europe, in Asia, and we're really expanding the, if you will, the pediatric neurological centers of excellence to make sure that when we have these patients, they'll be able to be treated as quickly as possible.

Okay. And in terms of your total addressable population that you think exists, I think your last guidance was somewhere between 5,000 and 6,000 patients. Is that still your view?

Yeah, Eric?

We currently, yes, our current, what we've seen not only in the published literature and the work that we've done in terms of screening programs, particularly in the rich population, suggests that that is a sort of global number. Now remember, this treatment is not sort of a simple product that you're going to use like a tablet, an oral, or even an infusion. So this is going to require stereotactic approach, surgery, and follow-up. So the intervention and the treatment of the patient is gonna be slightly more complicated than sort of your average treatment that we would do. So in terms of how and what we believe the number of patients that exist, I think it's incredibly important to know that we have made important strides in finding these patients through these genetic testing programs. The Pinpoint Program in the US is finding patients, saliva programs that we're using, are simple and easy to use. And we're finding these patients in many of the countries where we know that gene therapies are currently being reimbursed, and that's really important.

Okay. So there are 5,000 of these there. And, you know, the beauty is we're finding them everywhere as well in many different countries. So I think we're, you know, we're in pretty good shape. That still gives us the confidence that there's about 5,000 patients there.

Okay. Thank you. And then if I could squeeze one in on Huntington's. Just to clarify, are you planning on showing knockdown for wild types by the end of this year?

So we're looking at both. We don't discriminate between wild type and mutant. So yeah, you'll be seeing the levels reflect the overall levels of the RNA that we see since it's both of them, both wild type and mutant are seen. So you'll you get that as well as protein level reduction from both of them.

Okay, but will you be specifically highlighting what the wild-type knockdown is?

I think we'll be showing, you know, we'll be able to say what the wild-type knockdown is based on the overall. There's no differentiation between the two in that sense. Okay, got it. Because the X49 is 50, so it's a one-to-one ratio.

Okay, got it. Thank you.

Thank you. Our next question comes from the line of Brian Abrams with RBC Capital Markets. Your line is open.

Hi, this is Steve on for Brian. Thanks for taking our question. Another one on Huntington's. I'm curious what is known about how the neuron adapts to accumulation of mutant Huntington over time, and do you have any data from animal models or preclinical models that might tell us whether A rapid depletion of the mutant protein could cause any inflammation or dysregulated protein turnover.

Thanks. We don't have any. I think there's been several studies that show in terms of clinical benefit in animal models that show the lowering of HTT results in improvements in animals. So I don't think you have a rapid reduction in that sense that's causing any sort of unusual consequence that I know of, at least, in the animal studies. Thanks.

Thank you. Our next question comes from the line of Peyton Bonstadt with Cowan. The line is open.

Hi, this is Peyton on for Joe. Thanks for taking my question and congrats on the strong quarter. I was wondering if you could provide a little more background on why ALS was chosen for PTC 857 instead of some of these other CNS disorders or neurodegenerative disorders and any timeline on when you'll release more details on the trial design. Thanks.

Sure. So maybe I'll start and then pass it on to Matt. I think the, you know, if you think about 857 and or the whole BioE platform and knowing that, really, in terms of, you know, excess electrons that leads to oxidative stress and turns on inflammation, causes aggregation. It's a key. So, the 15-lipoxygenase is a key mediator in this process. And then when you're, in a sense, when the system of stopping of electrons gets overwhelmed, This is sort of the emergency response system that ultimately turns on the inflammatory response and fixing. So it's a real problem that it gets turned on and doesn't get turned off. But I guess the important point is that can be used in a wide, it happens in all of the neurodegenerative diseases as well as many other things. So you can go through multiples of them. And our notion was to look at a number of them And maybe Matt will go through the, you know, and that's the idea. We will be doing that. But Matt, why don't you go through as to why we're picking up ALS as the first example.

Yeah, sure, Stu. As Stu mentioned, the entire preclinical program has been based on the understanding that targeting 15-life oxygenase and its pathway of oxidative stress and inflammation is critical in a number of different situations. neurodegenerative disease pathologies, so including ALS, including Parkinson's disease and others. So what we've done is looked at a number of different in vivo and in vitro models of a number of different diseases and have been able to show strong efficacy across all of these models, some that are generic to neurodegenerative disease and others that are disease-specific. So we arrive now with the Phase I data in hand and the ability to move to Phase II, and our selection of starting first with ALS is based on the fact that right now we have three months, we have tox studies to support three-month dosing. And when we think about neurodegenerative disease development, one of the key, two of the key considerations actually are, one, having it, being able to dose for long enough to see change, so rate of progression of the disease, and then also being able to, of course, identify the right patients that are going to change over time in a trial so that you're able to show benefit. One of the key advantages of ALS is that Unfortunately, it's a rapidly progressive disease, and despite there being two approved therapies, there's still a significant unmet need. The disease is still rapidly progressive and fatal, with the majority of patients dying between 18 and 36 months following diagnosis. But over the course prior to that ultimate demise of the patient with ALS is a rapid decline in neurological function, neuromuscular function, and respiratory function, all of which are readily measurable. We also have an ALS, a validated endpoint, the ALS-FRS, which is known to change over a three-month period of time and allows us, based on use of both the placebo group as well as robust natural history data, able to show in a three-month treatment study with PTC-857 that we can have an impact on the disease. So what we have here is a disease in ALS where our preclinical work was understood about the pathogenesis of the disease and the importance of our target pathway of 15-like oxygenase in that disease, we have an opportunity in a three-month study to show a treatment effect that can then inform a then definitive registration-directed study. So just to summarize, basically the selection of ALS as the first indication is basically where we are in terms of the toxicology program, having the three-month data complete and being able to do three months of dosing to be able to have an ALS to do these, where in that period of time, we can collect the necessary data to show PKPD effect and then be able to move on to efficacy. So right now, we're in the process of designing that trial. It's going to include probably elements of a run-in phase to establish a baseline rate of progression of disease, and at least within the three-month treatment window, but we're still sorting out the exact details. There'll be a placebo and dose groups as well. We'll use very standard ALS endpoints. Obviously, I mentioned the validated ALS F-ORIS. which is a validated endpoint for which has been used for approval previously, as well as other important biomarkers that can give us key indications of pharmacodynamic effects that are particularly relevant to both the disease of ALS and the mechanism of action of PPC8x7. And we plan to begin that trial in the first quarter of 2022, and we'll provide more details on the full study design once it's ready.

Thank you. That's very helpful. Well, just one more quick kind of follow-on question to that. Will you plan on going into other indications, or will you wait until this trial is done with the data? Thanks.

Our goal will be, this is, I think it's more of a timing issue than anything else because of, you know, having short versus long-term toxicology. And I think we've said that the adult neurodegenerative indication was the GPA, Parkinson's disease, and ALS. This is more of a matter of timing to get into them.

Okay, thank you. That was very helpful.

Thank you. Our next question comes from the line of Danielle Brill with Raymond James. Your line is open.

Hi, this is Alex. I'm for Danielle. Thanks for taking our question. I was looking to see if you could provide any color on your plans for the 518 Huntington's Phase II patient pool. We've been hearing from KOL that the patient pool should be as early stage Huntington's disease as possible to capture benefit. Is this feasible to address in Phase II? And if not, could you share your thoughts on how you're approaching the enrollment criteria for the patient pool in Phase II trial? Thanks.

Sure. I mean, I'll make a general statement on that. You know, obviously the, in any of these diseases that are either neuromuscular or neurodegenerative where they, where you see a, they always want to get in as early as possible. But still, but be in the range of while you're in early that you, that there's some decline that you can measure, right? So that at the end of the day it isn't, if you come in too early, the decline takes too long for clinical trial charges because they have to hit the right patient population, choosing the right endpoint in the range that you think. It's very much like a Goldilocks, right? Too early doesn't help you and too late doesn't help you. So you have to find the right patient population. And that takes a fair amount of looking at the natural history and trying to define what What's the right patient population and what's the right outcome for that particular population? And can you see it in a given amount of time that you're going to do the experiment that you have high confidence? And then define the patient as the inclusion exclusion criteria that gets you the patient population that you have some confidence in will be declining. So that's the philosophy of what we're taking. Matt and his teams were doing a lot of thinking about that. So I'll pass if there's anything else, Matt, you want to talk about.

Yeah, I just want to say I think the point that you raised, Allison, is to reinforce this concept of the Goldilocks population where we're sure that we have a population that's early enough in disease that you have, one, the ability to affect the disease progression, especially if our overall approach is acting upstream of the disease pathology. You want to make sure that you're early enough that you can actually affect the disease progression, but also make sure that you can still have a meaningful amount of change in an untreated group, right, because the key here is to be able to show benefit over placebo. And to do that, that's really a matter of math, but during the duration of the trial, you have a placebo group that, in absence of therapy, is going to decline enough that you can show clinical benefit. And so we've been spending a lot of time availing ourselves of the existing databases like the Conroll HD database, over 20,000 patients we've worked on in-house and have teams and external KOLs as well working with us on looking very carefully at the important factors like CAGE, CAG repeat, and a number of different endpoints that are collected to really find, one, that population that's going to move, that Goldilocks population that Steve said, and second, the appropriate endpoints to actually measure those changes over time. So what you're going to see from us is As this work goes, continues in our phase two trial, is first and foremost, obviously the goal of the phase two trial is to be able to demonstrate the effect of Huntington mRNA and protein lowering in Huntington disease patients. We'll obviously be enrolling patients that based on our work, you know, we believe are reasonable to show that in, but who will also have changes in other measures of disease. Importantly, things like radiographic changes. Because what we want to look at is biomarkers of disease, both blood-based and radiographic, to be able to then tie into demonstrating the benefit of reduction in the HTTM RNA and protein. So obviously, to do that, we want to make sure we're delighting the graft templates and again have the right patients who are going to change over time so that we can show a benefit in those patients.

But on the other hand, maybe I'll make also a bit, I think there's some interesting things going on and based on the experience with Alzheimer's experience with the FDA, we do plan to discuss with them a pathway for accelerated approval focusing on a relevant biomarker. I mean, if you think about the plaque in Alzheimer's that was used, here you have, I think, even a better case for it. It's a monogenetic disease. You know you're targeting the precise protein or mRNA that's involved in the process, you know that it's due to the mutant honey. There's natural history data that shows that reduced levels of the mutant protein extend the time before you see the onset of the disease. So there certainly is a possibility of being able to at least have a discussion with the FDA you've heard probably Novartis talk about it as well, that they've had a discussion with both the EMA and the FDA. So, you know, if that's the case, we're in a very good position to see if we, you know, could work with that endpoint for a potential accelerated approval. And then what we've been talking about could certainly be done for the second study.

Great, thanks so much for the color. Thanks for taking our question. Thank you.

Thank you. Our next question comes from the line of Gina Wang with Barclay. Your line is open.

Hi, this is Sheldon for Gina. Thanks for taking our question. I have a couple of 518s for Huntington. I think in the past you mentioned that beyond the 15 and 30 max doses, we have another two to three doses could you comment on in the 3Q data updates how many of those levels would include and if you can share what those are. And my second question is, from this healthy volunteer trial to the Phase II trial, how would you define the optimal therapeutic window? Thanks.

Sure. So what we've talked about in the past was In the single ascending dose, we went up to 135 milligrams, and the results got down to around 50% of the RNA level, which in a way probably in 90 to 135 equates to 100% reduction of the HTT. In the multiple ascending dose at 15 and 30 milligrams, we were even at the 15 milligram dose, we were able to get to somewhere between 40 and 50% reduction after 14 days of treatment. So we were... So it shows you really quite nicely that 15 milligrams, which is the lowest dose that was in our trial, got to that, and 30 milligrams got to between 60 and 70 percent reduction. So clearly, you know, we're able to be able to titrate the level of HTC mRNA depending on the exposure of that. The other things I think what we're doing is really, as we said, looking at food effect, looking at CSF in order to, you know, really, in a sense, we've already in the range of where we are thinking about the dose that we want, which is somewhere between 15 and 30 milligrams, because that gives us already the 50% reduction. that we'll probably start with in terms of reducing. So I think we're in a pretty good position, and the next steps there will be really to reproduce and begin to look at the biomarker as a consequence of, look at the biomarker of HD, HTT in the HD patient, just to make sure that the exposure and reduction that we see is is doing well. And then also what we said is that we're looking at CSF and the CSF is so that, and that's just a PK study. So we know that would just define and ensure that what we see in the blood is equivalent to what we've seen in the CSF. So I think, you know, what we're trying to do is obviously achieve the desired lowering at the lowest dose that makes us comfortable that we're in the therapeutic that were in the therapeutic range where efficacy is. And we already know that with the 15%, 15 milligram dose range. Does that help you?

Yeah. For the CSF cohort, will that cover only one dose level or will it cover multiple dose level in that cohort?

We're only doing one dose level, right, Matt?

Yeah, we really only need one dose. This is simple pharmacology. We basically need a single dose level, obviously based on the dose proportionality we've seen throughout the, not only the SAD and MAD work done to date, but all the preclinical pharmacology. I think one thing you can say that, One thing that translates very well in neurodegenerative diseases is the pharmacology models from preclinical to clinical, right? So what we've learned about the biodistribution and what we've learned about the predictive pharmacology, we're able to assess a single dose level and verify at a single dose level in a human.

Very helpful. Thanks.

Thank you. Our next question comes from the line of Raju Prasad with Gwen Blair. Your line is open.

Hi there. This is Samyane Faraj. Congrats on the corridor and thanks for taking our question. There was recently a paper published in Nature Communications that came out of an academic center in which they used an AADC gene therapy that was administered to the substantia nigra and ventral tegmental area. And that ultimately led to some pretty compelling improvements in motor function. Just kind of wanted to get your guys' thoughts on targeting these midbrain regions as opposed to the butane. And if you would consider conducting a post-approval study examining the administration of PTC, AADC to them, and then I have a follow-up.

Yeah. Yeah, thanks for the question. So that was done in a clinical setup. at a university setting where they use that in suspension night. Um, and so, um, you know, I think if you look at the results that we've had, where we're, it's underway in terms of the, of what we've shown, but, you know, going into the routine of the, the really profound, uh, results that we saw in a much larger number of patients that was going, that were looked at for five years in a clinical setting, as well as, um, five years after. So we have up to 10 years of continued results. And I think you can, I think what we can see is that there, you know, that we saw durable neurological and neuromuscular improvement, again, up for 10 years. And I think we are the only therapy for ADC that's an active regulatory process with the EMA that we submitted in 2020. And we also plan to submit the BLA by the end of the year. So I think that we're, you know, we're uniquely positioned to make sure that PTC-ADC is available to all ADC patients around the world that need this, I think, transformative therapy. And I think, you know, when we thought of the reason we like to retain them is that, obviously, all patients showed improvement, and we have many patients that show that. And then the other thing that I think is, An issue is that the midbrain is a much deeper structure that we think is less safe to get to. So, I mean, the selection of the choice of that was based on a number of factors. And I think results of that have really shown that it's really, I think, quite efficacious, transformative, It's where the dopamine neurons are, and it's shown to be quite active in the . So we feel pretty good where we're at, and then we're doing all the other necessary regulatory requirements to bring a gene therapy to patients.

Gotcha. Thank you. And just a separate thought. I felt like we haven't heard too much about your oncology pipeline before, and it's a little divergent from your other therapies, which mainly target rare genetic disorders. So could you remind us what those candidates are and your clinical development strategy for them?

Sure. Yeah, thanks for that question. So the oncology program that we're working on is – There's, it's for, it's for two compounds. One is called your Nespalin, which is, is previously 596. And then Invotastat, which is a PTC 299. And you heard a little bit about that with the COVID-19, but it's included trials for AML. And we are planning a deep dive update on the programs actually quite shortly and sharing the results of these programs as well. PGC on Unespalin is in clinical trials for DIPG and LMS. DIPG is a rare pediatric brain tumor. It's estimated to have about 300 patients per year that are diagnosed in it in the U.S. LMS is a rare adult solid tumor in muscles with an estimated 4,000 patients diagnosed per year in the United States. Both of these programs have high medical needs with really few beneficial to no treatment options. And so these programs have been ongoing. So it's very much reminiscent of a rare disorder, a rare disease approach. We anticipate having the results of these in the second half of 2021 for the clinical trials. And so I think we're quite excited about that. And with positive results here, we have the potential to initiate registration-directed trials following these results. And so we're, and then with Embodistat, it's in AML, and we also expect results by the end of 2021. So these are two additional programs and molecules that we have not talked much about what we're going to be starting. They're now getting into position to talk about that and have some data. I think it would be quite exciting.

Great. Thank you. I look forward to seeing that data.

Yeah, me too.

Thank you. I'm sure no further questions in the queue. I would now like to turn the call back over to management for closing remarks.

Thank you. So thanks for joining us today. as we shared our second quarter highlights. I believe the progress that we've made in this quarter is really a result of the dedication of our people. And while the pandemic is ongoing, I really am continually impressed by the development team that has made substantial progress across the food pipeline. And we're excited to continue to share these updates with you as they become available. Also, in addition to that, I think the perseverance and execution of the global commercial team has resulted in PTC raising our 2021 revenue guidance for the DMV franchise. And we look forward to the continued execution of this in the second half of this year. So thanks for joining and look forward to talking to you all soon.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation.