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 speakers' presentation, there will be a question and answer session. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker for today, Tali 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' Q2 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 Powells 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 operations.
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 10 ks 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, Kiley, and thanks for joining us today. As we close out the first half of twenty twenty one, 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 fewer 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 a sustained 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 vaccine, 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're continuing 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 IVRISD. Based on this impressive growth, we will be raising our 2021 DMD franchise revenue guidance The $370,000,000 to $390,000,000 and Emily will go into this in more detail later in the call.
So let me start with the DMD franchise. Our commercial team has been working hard to make our therapies accessible to DMD patients around the globe. As a result, Translarna saw an impressive 36% year over year growth. I'm very proud that the growth continues almost 7 years post launch, both in existing geographies and with continued geographic expansion. Emflaza 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 AVRISD. Ovirzbee continues to see a strong update in the U. S. With 1800 SMA patients now on treatment, representing almost 20% market share in less than a year post launch.
Auryxia 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, a RISD was approved in Japan this quarter and we will receive a $10,000,000 milestone payment from Roche upon the first commercial sale. I also wanted to touch on the recent positive results from the SMA studies, which I find to be quite remarkable.
The rainbow FISH study using the AVIZVI in presymptomatic infants Diagnosed with SMA demonstrated that a RISD treated infant achieved the same developmental milestone as healthy children. Interim data from the JEWELFISH study, which is assessing the RYSI in SMA patients Previously treated with other therapies, including Zolgensma and SPINRAZA demonstrated overall stabilization in motor function after switching to a RISD. This shows the benefit of a RISD in the broad and Energous Real World SMA Population. Turning to PTC-five eighteen and our Huntington's disease program. In the Q2 of this year, We were excited to release the preliminary results from our Phase 1 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 PTC5180. The results also demonstrated a target mRNA lowering of 40% to 50%, Even in the lowest multiple ascending dose cohorts, we are in the process of completing the Phase 1 trial. This includes additional protein sampling, our food effect cohort and the CSF pharmacology cohort. We plan to release the results of these additional cohorts in the Q3 of this year as well as share 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 exacerbate multiple disease states. Deron that can modulate this process with the valuable therapies to treat a wide variety of diseases. We have 2 important ongoing trials with vaticlinone, Our first compound from our BioE platform that is a 15 leboxygenase 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 Our 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 neurogenitive We are pleased to have completed the Phase 1 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 3 registration directed study APHINITY in September of this year. PKU is a large orphan indication with an estimated 58,000 patients globally.
The vast majority of patients are not well controlled with existing therapies, highlighting the substantial unmet medical need. Study startup activities are well underway and we are utilizing our global infrastructure to focus on sites both in the U. S. 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 PTC-nine twenty three 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 to see HMT opinion in the Q4. Turning to the U.
S. As we have previously shared, we were conducting additional surgeries in advance the BLA submission, we're happy to announce that the 3rd 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 CRO. 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. Unestilin, previously PTC596, Is in clinical trial for 2 niche solid tumors, CIPG and LMS. CIPG is a rare pediatric brain tumor and LMS is a rare adult solid tumor in muscle. Both have high unmet medical needs with few beneficial to no treatment options. Results are anticipated in the second half Of 2021 for the 2 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 therapies to patients in need. With that, I'll turn the call over to Matt for an update on development. Matt?
Thanks, Hugh. 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 PTC-five eighteen Huntington disease program. As Stu mentioned, we shared the initial results from our PTC-five C-five eighteen Phase 1 healthy volunteer study in the Q2 of this year. As we reported, PTC-five eighteen treatment resulted in the desired dose dependent lowering of HTT mRNA levels in both the SAD and NAD 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 Q3 of this year. Given that we have achieved our key objectives for the PTC-five eighteen Phase 1 study, Planning for the Phase II trial is underway and we expect to initiate the trial by the end of this year. The Phase II study will be conducted in HD patients I 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 2 ongoing registration directed trials with beticlinone, our lead compound from the BioE platform, and we recently completed the Phase 1 healthy volunteer study of PTC-eight 57, the 2nd compound to the platform. Both the MITEI trial, our Phase twothree trial in children with inherited mitochondrial disease and epilepsy And MOVE FA, our Phase 2 trial in Friedreich 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-eight fifty seven, a 15 lipoxygenase inhibitor being developed for adult neurodegenerative diseases.
I am pleased to share that we have completed the Phase 1 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-eight fifty seven forward to Phase 2. Through its activity at 15 lipoxygenase, PTC-eight fifty seven targets the pathway of oxidative stress and inflammation known as ferroptosis, 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 3 registration directed trial, the APHINITY study with PTC-nine twenty three this quarter. As a reminder, Affinity is a double blind, placebo controlled study with a run-in phase to identify subjects who respond PTC-nine twenty three treatment. These responders will then be randomized to receive either PTC-nine twenty three or placebo for 6 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 Q4 of 2022. Turning now to our gene therapy platform. As Stu noted, The 3rd cannula surgery in support of the AADC BLA submission has been completed. We plan to align with the FDA on the DAT package And then to submit the BLA by the end of the year.
As a reminder, the surgeries were conducted to gain experience The intended commercial cannula in delivering our gene therapy product. 1 of the innovative aspects of our AADC gene therapy program is that the gene therapy product is delivered directly to the protein, the area of the brain key to disease pathology. In order to achieve this direct delivery into the brain tissue, neurosurgeons use a Stereotech surgical procedure that relies on an MRI based Google map that provides a direct path for the surgeons to safely reach the containment to deliver the gene therapy. Let me now provide a quick update on emvodestat, previously PTC299, currently in a Phase twothree trial for COVID-nineteen, the FIGHT-nineteen study. Enrollment is ongoing in this trial and we expect this study to be completed by the end of this year.
As a reminder, invotistat is also being studied in 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 41. 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 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 DMD franchise. With our key focus on patients, our team was instrumental is delivering another highly successful quarter for commercial revenue. You're seeing incredible progress In our DMD franchise with year over year growth in both Emflaza and Translarna resulting in a 36% growth for the franchise.
New patient starts, continued high adherence and fewer discontinuations have sustained the growth of Emflaza. In this quarter, we achieved $49,000,000 in revenue, which is a 36% increase over the Q2 of 2020. Strong execution supported by new data recently presented by Doctor. 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 $53,000,000 in revenue this quarter, a 36% growth over the Q2 of 2020. This sustained performance was driven by growth due to expansion of the patient base, continued high compliance and broader access in existing geographies as well as continued geographic expansion. As an example of geographic expansion, following the approval of Translarna 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 Q2 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 infrastructure in additional markets such as Japan, Mexico.
We are making continued progress with reimbursement for Translarna And we're pleased in extending the managed access agreement in England. In Latin America, we continue to see increases in DMD patients and are making good progress towards securing a group purchase order for Translarna in Brazil in the second half of twenty twenty one to treat both new and existing BMD patients. Now turning to TEGSEDI and WAYLIVRA, Disease awareness and patient identification continues to be the focus in Latin America and our teams have made substantial progress Despite the ongoing COVID-nineteen challenges in the region, in Brazil, our discussion on pricing for TEGSEDI continues. During this process, we continue to provide medical education, genetic testing and patient program support to make TEGSEDI available in multiple countries within Latin We are pleased that we now have some of the first patients benefiting from the treatment with WAYLIVRA in Latin America through early access pathways. We are preparing for a launch in Brazil.
However, due to COVID delays at Avisa, WAYLIVRA registration is now anticipated in Q4. NVISA 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 lead 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 and enriched high risk populations. Significant progress has been made with the identification and preparation of expert pediatric neurological centers of excellence throughout the U. S, 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 2021 revenue guidance to $370,000,000 to $390,000,000 I will now turn the call over to Emily for financial update. Emily?
Thanks, Eric. In the Q2 of 2021, we continued to strong commercial performance and demonstrated progress across our pipeline. We remain in a healthy financial position with 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 Emflaza to date, We are pleased to raise revenue guidance for the DMD franchise for 2021 to $370,000,000 to $390,000,000 from the original 2021 revenue guidance of $355,000,000 to $375,000,000 The press release issued earlier this afternoon summarizes the details of our Q2 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 $117,000,000 for the Q2 of 2021, a 55% increase over the Q2 of 2020. This revenue includes $103,000,000 in net product sales and $14,000,000 in royalty revenue from our partnered Energousie program.
Turning now to more detail on the success of the DMD franchise. Translarna net product sales were $53,000,000 compared to $39,000,000 in the Q2 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. Emflaza net product revenue for this quarter was 49,000,000 as compared to $36,000,000 in the Q2 of 2020. Moving on to an update on EVRISD.
Our partner Roche has reported year to date sales of CHF 243,000,000 which is approximately US265 $1,000,000 As a reminder, In exchange for $650,000,000 upfront cash added to our balance sheet, PTC also retains approximately 50% 7% of Evryndzi royalty until Royalty Pharma receives a return of $1,300,000,000 after which 100% of the royalties revert back to PTC. As part of this royalty monetization transaction, PTC also retained sales and regulatory based cash milestones. Following the approval of the VIRISI in Japan this quarter, we anticipate a near term $10,000,000 milestone payment upon the 1st commercial Japanese sale. Non GAAP R and D expenses were $112,000,000 for the Q2 of 2021, excluding $13,400,000 in non cash stock based compensation expense compared to $168,000,000 for the Q2 of 2020, excluding $8,600,000 in non cash stock based compensation expense. The relative decrease in research and development expense is primarily related to one time charges in the Q2 of 2020 of $53,600,000 for our Censa merger as well as $41,200,000 for our commercial manufacturing service agreement with MassBiologics.
Non GAAP SG and A expenses were $56,600,000 for the Q2 of 2021, excluding $12,300,000 in non cash stock based compensation expense compared to $45,300,000 for the Q2 of 2020. Excluding $8,300,000 in non cash stock based compensation expense. Cash, cash equivalents and marketable Securities totaled $947,100,000 as of June 30, 2021 compared to $1,100,000,000 as of December 31, 2020. I'll now turn the call over to the operator for Q and A. Operator?
Thank
Please standby while we compile the Q and A roster. Our First question comes from the line of Eric Joseph with JPMorgan. Your line is open.
Good evening. Thanks for taking the question. Nice quarter. Just on the D and D franchise performance, with guidance now raised Here, we're looking at the midpoint that actually seems to imply a flat to down trajectory for the second half. So I'm just wondering if Kind of talk us through any risks that you're anticipating with respect to ongoing performance of either Translarna or Emflaza And wondering whether this second quarter results reflect any advanced purchasing or first stocking?
Can I have a follow-up?
Yes. Thanks, Eric, for the call. Eric, why don't you take this?
Sure, Eric. First of all, I think we had a terrific Q2. We had $53,000,000 in sales for Translarna, that's 36% increase over last year. And with Emflaza, Identically, 36% growth. We had $49,000,000 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. We're very proud of the work that the European team has done after 7 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 It's really a lot of the new patients are coming in from Russia, from Central and Eastern Europe, Middle East and our business in Latin America continues To be solid, despite some of the COVID challenges that we have and we expect right now, orders in Latin America In particular in 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 Translarna. On the Esuazza front, We had one of our best quarters ever and we continue to see new patient growth. We also see that compliance with Emflaza is Extremely high. And more importantly that the data that's being generated now, new data, Real more 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 Emflage. 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. It would be right now on the upper end, we'd 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 second question on emvodestat. The FIGHT-nineteen trial is focused on hospitalized But I'm just trying to get a sense of how you're 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 a patient
Yes. Thanks. Thanks for that question. And particularly, we're excited about this. Just to remind Everybody, the PTC299 is a RO small molecule, and that so it certainly can't 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 And that is a dual mechanism. And that is that because of its mechanism first of 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-two 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 on the whole, we think That this will certainly have a possibility in the outpatient SADI 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're certainly think that it has the capability to They use in both and it's simple to take. You can get 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 Alethia Young with Cantor Fitzgerald. Your line is open.
Hi, congratulations on all the progress. This is Nina on for Alethia and thanks for taking the question. We were wondering for the Huntington's update end of the 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?
Yes, sure. So as we've said before, The Phase 1 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 biosdistributes to the body and through the brain where we have a ratio of lowering and peripheral blood cells of 1:one with cells inside the brain. So 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 1, the biodistribution of the molecule and 2, the fact that it is An oral molecule that's been designed that e flux from 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 at the dose of the lowering of mRNA in the peripheral blood cells in both the SAD and M18 cohorts. And the CSF cohort we referred to is a pharmacology cohort.
What we're going to look at in the CSF, some 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 Sure, not only does it cross the blood brain barrier, but then it doesn't get deep flux. That means once it gets across the blood brain barrier, it stays in. And that's incredibly important for its bio distribution throughout All regions of the brain. But 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 cohort, Lining up the levels of drug in the plasma with the levels of drug in CSF and being able to check that box that we're getting the desired and designed CNS 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 LacaDeflux that we've seen in the preclinical studies in the animal models We're a key design feature of the market.
Thank you. Our next question comes from the line of Tazeen Ahmad 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 found. I think the last count was somewhere in the 200.
Was curious if you have any updated numbers on the addressable patient population that you could identify today? And then I have follow-up.
Okay. Yes, thanks for the question. Eric, you want to take it?
Yes, Tazeen, right now we're still doing a lot of work, as I mentioned earlier. Our plans are Our plans are really continuing to aggressively look at and pursuing patient finding. We're not at this point in time, we're not We compared to the combined 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 And at that time, we'll be providing the number of patients. But you have to be really, really get to 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 In screening patients in very high risk population, 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 announced 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, reimbursement amongst There it is, 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, we have treated patients in the U. S, in Europe, and Asia and we're really expanding the, If you will, the pediatric neurological centers of excellence. So 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 56,000 patients. Is that still your view?
Yes, Eric.
We currently yes, our current what we've seen not only in the published literature and 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 It's not sort of a simple product that you're going to use like a tablet in the 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 going to 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 U. S. Is finding patients saliva programs that we're using are simple and easy to use. And we're finding patients in Many of the countries where we know that gene therapies are currently being reimbursed and that's really important.
Okay. So there The beauty is we're finding them everywhere as well in many different countries. So I think we're in pretty good shape. That still gives us the confidence that there's about 5,000 patients there.
Okay. Thank you. Then if I could squeeze one in on Huntington's. Just to clarify, are you planning on showing knockdown for wild type by the end of this year?
So in the with that, we're looking at both. We don't discriminate between wildtype and mutant. So yes, you'll be seeing the overall 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
Okay. But will you be specifically highlighting what the wildtype knockdown is?
I think We'll be showing we'll be able to say what the wild type knockdown is based on the overall there's no differentiation between the 2 in that sense.
Okay, got it.
We're expecting $49,000,000 to $50,000,000 So it's a one to one ratio.
Okay, got it. Thank you.
Thank you. Our next question comes from the line of Brian Abrahams 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 accumulation of mutant Huntington over time. And do you have any data from animal models or preclinical models that might tell us whether 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, right, in animal models that show The lowering of HTT results in improvements in animals. So I think I don't think you have A rapid reduction in that sense is causing any sort of unusual consequence that I know of at least And the animal studies. Thanks.
Thank you. Our next question comes from the line of Payton Bostat with Cowen. Your line is open.
Hi, guys. This is Paige on for Joe. Thanks for taking my question and congrats on the strong quarter. I was wondering if you could provide a little more And on why ALS is 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 If you think about 857 and the whole BioE platform and knowing that Really in terms of excess electrons that leads to oxidative stress and turns on inflammation causes aggregation. It's a key so the fifty 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 up. But I guess the important point is that could be used in a wide it happens in all of the neurodegenerative diseases As well as many other things. So you can go through a multiples of them and our notion was to look at a number of them And maybe Matt will go through the and that's the idea, we will be doing that. But Matt, why don't you go through as to why we're Keep clean up ALS as the first example.
Yes, sure, Stu. As Stu mentioned, The entire preclinical program has been based on the understanding that targeting 15 lipoxygenase and its pathway of oxidative stress and inflammation It's critical in a number of different neurodegenerative disease pathology, so including ALS, including Parkinson's disease and others. So what we've done He's looked at a number of different in vivo and in vitro models on a number of different diseases and have been able to show strong efficacy across all of these models, Some that are generic, generic generic disease and others that are disease specific. So we arrived now with the Phase I data in hand and ability to move to Phase II And our selection of move starting first with ALS is based on the fact that right now we have 3 months we have tox studies to support 3 month dosing. And when we think about neurodegenerative disease development, 1 of the key 2 of the key considerations actually are 1, 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 the trial so that you're able to show benefit.
One of the key advantages of ALS Unfortunately, it's a rapidly progressive disease and despite there being 2 approved therapies, there's still significant unmet need. The disease is still rapidly progressing and fatal with the majority of patients dying between 18 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 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 3 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 3 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 the TNF oxygenase In that disease, we have an opportunity in a 3 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 based where we are in terms of the Based where we are in terms of the, toxicology program being having the 3 months data complete and being able to do 3 months of dosing To be able to have an ALS and do these work 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 other than the 3 month treatment window, but we're sorting out the exact details. There'll be a placebo and dose groups as well. We use very standard ALS endpoints.
Obviously, I mentioned the validated ALSFARIS Scale, which is a validated endpoint, which has been used for approval previously, as well as other important biomarkers that give us key indications of Our pharmacodynamic effect particularly relevant to both the disease of ALS and a vector of action PTC 8% and we plan to begin that trial in the Q1 of 2022 and we'll provide more details on the full study design once it's ready. Thank you. That's very helpful.
Yes.
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 Having short versus long term toxicology and we've always I think we've said that the adult neurodegenerative is indication With the GPA, Parkinson's disease and ALS, this is more of a matter of timing to get into them.
Our next question comes from the line of Danielle Brill with Raymond James. Your line is open.
Hi, this is Alex on for Danielle. Thanks for taking the question. I was hoping to see if you could provide any color on your plans for the 518 Huntington's Phase 2 Patient pool, we've been hearing from KOLs that the patient pool should be as early stage Huntington's disease as possible to capture benefit. Is this feasible to address in Phase 2? And if not, could you share your thoughts on how you're approaching the enrollment criteria for the patient pool in Phase 3 trial?
Thanks.
Sure. I mean, I'll make a general statement and I'll pass it to you. Obviously, the In any of these diseases that are either neuromuscular and neurodegenerative where they where you see it, they always want Yes, as early as possible. But still, but be in the range of while you're in early That there is some decline that you can measure, right? So that at the end of the day, if you come in too early, The decline takes too long for a clinical trial time.
So they have to hit the right patient population choosing the right endpoints 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'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 It includes an 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 and Matt has been doing and his team has been doing a lot of thinking about that. So I'll pass if there's anything else that you want to talk about.
Yes. I just want to say, I think the point that you raised us and To reinforce this concept of the Goldilocks population where we're sure that we have a population Early enough in disease that you have, 1, the ability to affect the disease progression, especially if our overall approach is acting upstream of the disease with ophthalmology, we 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, 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. So during the duration of the trial, you have a placebo group that And absence of therapy is going to decline enough that you can show a clinical benefit. And so we've been spending a lot of time availing ourselves of The existing databases like the Pingrol HD database, over 20,000 patients we work on in house and have teams and external KOLs is well working with us and looking very carefully at the important factors like age, CAG repeat and a number of different I'd like to really find one that population that's going to move, Goldilocks population as you said and second, The appropriate endpoints actually measure those changes over time.
So what you're going to see from us as this work goes continues in our Phase II trial 1st and foremost, obviously, the goal of the Phase II trial is to be able to demonstrate the effect of Huntington's mRNA and protein lowering in Huntington's disease patients. We'll obviously be enrolling patients that based on our work, we believe are reasonable to show that in, but we'll also have changes in other measures These importantly things like radiographic changes is what we want to look at as biomarkers and diseases both blood based on radiographic to be able to then tie into Demonstrating the benefit of reduction in htmRNA and protein. So obviously to do that, we want to make sure we're good at night in the graft and again help the right patients who are going to Change over time so that we can show a benefit in those patients.
But then the other thing, maybe I'll make also a bit. I think there's some interesting Things going on and based on the experience with the Alzheimer's, experience with the FDA, If 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's a monogenetic disease. You know you're targeting the precise Protein that's mRNA that's involved in the process. You know that it's due to the mutant amnizase.
The natural history data shows that reduced levels of immune 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 and You've heard probably Novartis talk about it as well, that they've had a discussion with both the EMA and FDA. So if that's the case, we're in a very good position to see if we Could work with that endpoint for a potentially 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 the question. Thank you. Thank you.
Our next question comes from the line of Gena Wang with Barclays. Your line is open.
Hi, this is Sheldon on for Tina. Thanks for taking our question. I have a couple of 518s for Huntington. I think in the past you mentioned that beyond the 15 mg and 30 mg max doses, you have another 2 to 3 doses. Could you comment on in the 3Q data updates, how many dose levels would include and if you can share what those there are?
And my second question is from this healthy volunteer trial to the Phase II trial, how would you define 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 milligram 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 of 15 30 milligrams, We were even at the 15 milligram dose, we're able to get to somewhere between 40% 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% reduction.
So Clearly, we're able to be able to titrate the level of HCT mRNA, depending on the exposure of that. The other things I think, what we're doing Is really doing as we said, looking at FoodFX, going FoodFX looking at CSF In order to really in a sense, we've already in the range of where we are thinking about The dose that we want, which was somewhere between 15 milligrams to 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 HTT, in the HD patient, just to make sure that the exposure And reduction that we see 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 what we're trying to do is obviously achieve the desired lowering at the lowest dose that makes us comfortable that we're in Therapeutic that were in the therapeutic range where efficacy is and we already know that with the 15% 15 milligram dose range.
That help you?
Yes. For the CSF cohort, Will that cover only one dose level or will they cover multiple dose level in that cohort?
It's we're only doing one dose level, right, Matt?
Yes. You may really only need one dose. This is Simple pharmacology, we basically need the 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 models. 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 the human.
Our next question comes from the line of Raju Prasad with William Blair. Your line is open.
Hi, there. This is Sami on for Raj. Congrats on the quarter and thanks for taking our questions. 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 type ventral 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 butamen? 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.
Yes. Thanks for the question. So that was done in the Clinical in a university setting where they you said in sustained. So, I think if you look at the results that we've had where we're it's underway in terms of what we've shown, Going into the retainer, the really profound results that we saw in a much larger number of patients That was that were looked at for 5 years in a clinical setting as well as 5 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 that we saw durable neurological and neuromuscular improvement Again, up for 10 years?
And I think we are the only therapy for AADC. 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 uniquely positioned to make sure that PTC ABC is available to all AADC patients Around the world that need this, I think, transformative therapy. And I think When we thought of the reason we like to putainum is that obviously all patients showed improvement We have many patients to 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 selective 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 at the pace, it's transformative. It's where the dopamine neurons are And it's shown to be quite active in the big data. So we feel pretty good where we're at and then we're doing all the other necessary regulatory events No requirements to bring a gene therapy to patients.
Got you. Thank you. And just a Separate thoughts. 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 regenitis disorders, so could you remind us what those candidates are and your
What our the oncology program that we're working on is there's It's for 2 compounds. 1 is called yanesplillin, which is previously 596 And then evotestat, which is PTC299 and you heard a little bit about that with the COVID-nineteen, but this included trials for AML. We are planning a deep dive update on the programs actually quite shortly and sharing the results of these programs as well. PGC on the unisexelim is in clinical trials for DIPG and LMS. DITG 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 higher met 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 twenty twenty one for the clinical trials. And so I think we're quite excited about that. And with positive results there, we have the potential To initiate registration directed trials following these results. And so we're and then with emvodastat, It's in AML and we also expect results by the end of 2021. So these are 2 additional programs and molecules So we have not talked much about what we're going to be starting.
We're now getting into position to talk about them and have some data I think it would be quite exciting.
Great. Thank you. I look forward to seeing that data.
Yes. Me too.
Thank you. I'm showing 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 2nd 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 development team that has made substantial progress across the full pipeline, and we're excited to continue to share These updates with you as they become available. Also the in addition to that, I think the present Perseverance and execution of the global commercial team has resulted in PTC raising Our 2021 revenue guidance for the DMD 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. You may now disconnect.