Earnings Call
Ptc Therapeutics, Inc. (PTCT)
Earnings Call Transcript - PTCT Q4 2020
Operator, Operator
Thank you for joining us for the PTC Fourth Quarter 2020 Financial Results Conference Call. I would now like to turn the call over to Kylie O'Keefe, Head of Investor Relations. Please proceed.
Kylie O'Keefe, Head of Investor Relations
Good afternoon, and thank you for joining us to discuss PTC Therapeutics' fourth quarter and year end 2020 corporate update and financial results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz; our Chief Financial Officer, Emily Hill; our Chief Development Officer, Matthew Klein; and our Chief Business Officer, Eric Pauwels. 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 our slide posted on 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 any and such risks 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 Form 10-K filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP and 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.
Stuart Peltz, CEO
Thanks, Kylie. And thanks for joining us today. In 2020, we have made significant progress in moving our pipeline forward to bring new therapies to patients on all fronts for research and development through commercial. Despite the COVID-19 pandemic, we initiated five clinical trials, including two registration-directed trials. Let me begin with the Duchenne Muscular Dystrophy franchise, we continue to see strong global growth and geographic expansion. Our DMD franchise sales in 2021 were approximately $331 million. Specifically in the US, the annual revenue of Emflaza totaled $139 million, which is a 38% increase from last year. The annual revenue for Translarna totaled $192 million, and it was driven by geographic expansion, new patients, and label modification. For example, Translarna received marketing authorization in Russia in the fourth quarter. We have also continued to drive additional geographic expansion in Central and Eastern Europe and in Latin America. Even during the turmoil caused by the COVID-19 pandemic, we secured a Brazilian group purchase order for Translarna, and Eric will go into these details shortly. As a reminder, we also recently reported the results from the 045 dystrophin study. We plan to discuss these results along with Translarna's totality of evidence, including existing clinical and real-world data with the FDA. Our goal has always been to bring Translarna to US patients who have long been waiting for this therapy as quickly as possible. Moving to our splicing platform, the approval of Evrysdi in 2020 was an important milestone for PTC partners Roche and the SMA Foundation. Evrysdi is a groundbreaking treatment, which has a benefit for all SMA patients, with particular benefits on durability and broad tissue distribution. As a consequence of the benefits of Evrysdi, it has continued to show strong uptake, and Roche expects that Evrysdi will become the treatment of choice in the US in 2021. With the near-term expected European approval, followed by the Japanese approval, Evrysdi should see continued significant growth this year. Another accomplishment of 2020 with regards to Evrysdi is the royalty monetization deal, which put $650 million on our balance sheet. The structure of the deal allows PTC to receive approximately 60% of the royalty revenue and reverts to 100% once our royalty monetization partner receives $1.3 billion. Our next most advanced molecule from the validated splicing platform is PTC518 for the treatment of Huntington's disease. As a reminder, PTC518 is an orally bioavailable small molecule that crosses the blood-brain barrier and reaches all regions of the brain. Preclinical results demonstrated a dose-dependent reduction in the HTT mRNA and protein in cells of the striatum, cortex, and cerebellum in the HD mouse model. This is critically important as Huntington's disease is a whole-brain disease. HTT reduction is clearly titrating based on PTC518 levels. So the degree of HTT lowering can be tightly controlled. In addition to the whole brain distribution, PTC518 achieved uniform exposure and HTT lowering in all tissues analyzed, showing a near one-to-one ratio between CNS and blood. This is important because it shows the exposure and effect within the brain is analogous to what we see in the blood cell. PTC518 is currently in a single and multiple ascending dose Phase 1 trial in healthy volunteers. We will be measuring both HTT mRNA and protein levels in cells within the blood, allowing us to quickly demonstrate drug activity that results in HTT lowering. This will allow us to select the dose with the desired level of activity. This same approach was successfully used in the risdiplam program, where proof of concept was demonstrated in the healthy volunteer study. We expect the same trajectory in the Huntington's disease program. We are very excited about this program and look forward to the results that are expected in the first half of 2021. Now turning to our virology platform, the second and final stage of the FITE19 registrational trial for COVID-19 has commenced. As a reminder, PTC-299 is an oral small molecule with a dual mechanism of action that demonstrates both antiviral and anti-inflammatory effects. PTC-299 inhibits SARS-CoV-2 viral replication and calms the cytokine storm. PTC-299 functions by targeting a cellular enzyme dihydroorotate dehydrogenase or DHODH. The advantage of targeting the cellular enzyme instead of a viral protein is that it's less likely to elicit drug resistance. Though there have been great strides made in the development of vaccines, the lack of effective COVID-19 treatments has significantly hampered our ability to resume normal life, and therefore the continued focus on developing treatments is key. Now let me turn to our Bio-e platform. We have initiated two registration-directed trials, with particular note, one in mitochondrial epilepsy and one with Friedreich ataxia, and are enrolling patients in both studies. The global prevalence of mitochondrial epilepsy is estimated at 20,000 patients, and the global prevalence of FA is approximately 25,000 patients. Let me now touch on our gene therapy platform. Our initial focus is to launch our first gene therapy for patients with AADC deficiency, which is expected to occur in Europe during the second half of 2021. The BLA submission is also on track for the second quarter of this year. As a reminder, PTC AADC is a transformative gene therapy that has the potential to produce meaningful changes in the AADC deficient patients. PTC-AADC has robust clinical data that demonstrates durability effect for up to 10 years post-treatment, a crucial consideration in a single-dose gene therapy. Now let me discuss our plans for PTC923. As a reminder, there's an estimated global prevalence of 58,000 PKU patients, and the vast majority are not well addressed by current therapies. Therefore, we're excited about the potential of PTC923 as a clinically differentiated therapy to address this high unmet medical need. We will start a registrational trial evaluating the PTC923 for treating PKU called APHENITY, mid this year. Last year, we achieved many important milestones. We anticipate an exciting year in 2021 that will continue to create substantial value for all our stakeholders. I'll now turn the call over to Matt for key updates on our clinical programs.
Matthew Klein, Chief Development Officer
Thanks, Stu. I want to build on Stu's comments on our development team's achievements in 2020. We have worked hard at PTC to navigate the many challenges of the past year and are excited to continue to deliver on planned development milestones across our multiple platforms. I'd like to start with our Bio-e platform. This platform focuses on diseases of oxidative stress by targeting a special class of enzymes called oxidoreductases. Oxidoreductases are a family of enzymes that perform important electron transfer reactions and are known to have important biological functions. Particularly known, the first compound being developed for the Bio-e platform targets the oxidoreductase 15-lipoxygenase. 15-lipoxygenase is a key regulator of inflammation and oxidative stress pathways and has been implicated in a number of CNS diseases. As Stu mentioned, we have initiated two vatiquinone registrational trials in mitochondrial epilepsy and Friedreich ataxia. As a reminder, the vatiquinone has extensive safety data, particularly in pediatric patients, with the longest duration of exposure being over 10 years. For the first indication, mitochondrial epilepsy, previous clinical studies demonstrated vatiquinone had a positive effect on seizures and seizure-related morbidity across multiple mitochondrial disease subtypes. These results give us confidence that vatiquinone has the potential to show clinically differentiated improvement for mitochondrial epilepsy patients. The ongoing mitochondrial epilepsy trial, the MIT-E trial, is a randomized, placebo-controlled study enrolling 60 children at centers worldwide. The primary endpoint of the study is a reduction in observed motor seizures, with secondary endpoints capturing other aspects of seizure activity and seizure-related morbidity. Enrollment is underway and data are expected in the third quarter of next year. We are very excited to bring this therapy to children with mitochondrial disease. The second particular known registrational trial is in Friedreich ataxia, which is a rare, inherited progressive neuromuscular disease that affects the nervous system and heart. In a previous Phase 2 trial, particularly known treatment demonstrated significant improvement in disease severity compared to a Natural History cohort over 24 months. These results support that vatiquinone can deliver a meaningful effect to Friedreich ataxia patients. The Phase III FA trial MOVE-FA is a 72-week randomized placebo-controlled study. The primary endpoint of the trial is change from baseline on the modified Friedreich ataxia rating scale, or mFARS. The key secondary endpoint is the change from baseline in activities of daily living, as assessed by the FA-ADL scale. This endpoint strategy was developed in consultation with regulatory authorities in the US and EU. We began trial enrollment in the fourth quarter of last year and we anticipate results in 2023. Now let me turn to our PTC518 vatiquinone disease program. PTC518 is an orally bioavailable small molecule developed from our splicing platform that was designed specifically to treat Huntington disease. Given the need to effectively target every region of the brain, the molecule is designed to cross the blood-brain barrier and avoid efflux, a significant advantage for treating neurodegenerative disease. The Phase 1 healthy volunteer trial is underway and includes both single ascending and multiple ascending dose regimens. As a reminder, this healthy volunteer trial is designed to not only capture key safety and pharmacology data typical to Phase 1 study, but also to establish proof of splicing mechanism and guide dose selection for future studies. The SAD study includes five dosing cohorts, each with six active and two placebo subjects. The MAD study is expected to have three to five cohorts, each with six active and two placebo subjects. In the Phase 1 study, we are monitoring drug concentration in both the CSF and blood and we'll be measuring levels of HTT mRNA and protein in the cells of the blood. This ability to gain key proof of splicing mechanism data is similar to what we were able to accomplish in the risdiplam Phase 1 healthy volunteer study. The data from the PTC518 SAD and MAD studies are expected in the first half of this year. Now turning to our gene therapy platform, we remain on schedule for the CHMP opinion on the PTC-AADC MAA and for the BLA submission to the FDA in the second quarter of this year. In addition, we are continuing to progress our FA gene therapy program and expect first in human dosing before year-end. Turning to our PTC299 FITE19 clinical trial; we recently announced that enrollment of the first stage of the study was completed. As planned, the DSMB reviewed the interim safety data and unanimously recommended continuing with the second stages of the study. We have already initiated enrollment in the second stage and data are expected in the second half of 2021. In 2021, we look forward to advancing additional programs through our pipeline. We are on schedule to initiate the APHENITY Phase 3 trial for PTC923 in patients with PKU in mid-2021, with data expected by the end of 2022. As Stu mentioned, despite existing therapies, PKU remains a high unmet medical need. To summarize, we look forward to building on the successful execution of our clinical development programs in 2021 and sharing important updates in these programs when available. I'll now turn the call to Eric to provide more detail on our commercial business.
Eric Pauwels, Chief Business Officer
Thanks, Matt. We are very excited with the progress of our late-stage clinical pipeline, which is poised to potentially deliver multiple innovative neurology therapies that we can leverage with our global commercial footprint and existing expertise in rare diseases. As Stu highlighted, the DMD franchise had strong growth in 2020, with both Emflaza and Translarna generating significant revenue. Despite the challenges of the pandemic, we continue to see year-over-year growth of the DMD franchise. For Translarna, the only treatment for nonsense mutations DMD patients ages two and older, we saw revenues of $192 million in 2020. The growth was due to the ongoing expansion of the patient base, high compliance, recent label updates allowing broader access, and continued geographic expansion. With the recent approval of Translarna in Russia in Q4 2020, we are excited to bring this therapy to nonsense mutation DMD patients and expand the use of Translarna globally, which is now available in over 50 countries. In Latin America, we continue to see good progress. As a reminder, last October, we entered into a purchase agreement with Brazil's Ministry of Health to supply Translarna for both new and existing patients. This order was important given the governmental administrative delays in Brazil hit exceptionally hard by the pandemic. The agreement specified two shipments; we are excited to announce that both shipments were received by Brazil's Ministry of Health last year, including the last shipment in Q4 2020, to ensure continuity of the growing base of Brazilian non-sense mutation DMD patients. We continue to see further growth coming from new patients in the region and expect the next Brazil order in the second half of this year. Now moving on to Emflaza, which is the first and only corticosteroid approved for all DMD patients ages two and older. We saw revenues of $139 million in 2020, which is a 38% year-over-year growth, driven primarily from new patient starts, a reduction in bridge and PAP free of charge programs, and increasing compliance and lower treatment discontinuations. Importantly, we continue to see strong new prescription growth into 2021, supported by publications of Emflaza's real-world clinical benefit over prednisone, which is now driving patients to seek switching treatment from their healthcare providers. We expect the DMD global franchise growth to continue in 2021 with geographic expansion for Translarna and new patients for both Emflaza and Translarna. Based on this, our revenue guidance for the DMD franchise for 2021 is $355 million to $375 million. Now switching to Tegsedi and Waylivra; we continue discussions with CMED for pricing of Tegsedi in Brazil. During this process, we continue to provide medical education, genetic testing, and patient program support as needed. For both Tegsedi and Waylivra, we continue to engage in patient finding in Latin America, with ongoing success in these programs. We also continue to engage in early access programs in the region, as we await a decision on the Waylivra ANVISA filing in Brazil, which is expected in Q3 2021. Now moving on to AADC; PTC-AADC is a transformative gene therapy that has the potential to produce meaningful changes in AADC patients. As a reminder, AADC deficiency is a highly morbid and fatal pediatric neurological disorder. There are currently no approved disease-modifying therapies available. In clinical trial, PTC-AADC gene therapy demonstrated significant and durable neurological and muscular improvements shown to continue for up to 10 years after treatment. PTC is currently preparing for our first gene therapy launch for patients with AADC deficiency, which is expected to occur in Europe during the second half of 2021. As part of these efforts, identification and preparation of expert pediatric neurological Centers of Excellence is underway throughout the US, Europe, and Latin America. Patient finding activities are also accelerated with over 60 screening programs in over 20 countries to identify 300 patients by the time of launch. I continue to take pride in our global customer-facing teams as they ensure continuity of access to PTC products for rare disease patients in need. We continue to expand our commercial expertise with the upcoming launch for AADC deficiency in neurology, and build on our success in translating groundbreaking science to transform the lives of rare disease patients worldwide. Now, let me turn the call over to Emily for a financial update.
Emily Hill, CFO
Thanks, Eric. In 2020, PTC saw strong continued revenue growth and progress across multiple platforms of our pipeline. We are executing on a number of fronts to deliver on many potentially value-creating milestones this year. The press release issued earlier this afternoon summarizes the details of our fourth quarter and year-end 2020 financial results. I will take a few minutes now to review these financial results and our 2021 guidance. Please refer to the press release for additional details. Starting with our top line results, we reported $380.8 million in total revenue for the full year 2020 compared to $307 million for the full year 2019. This increase was driven primarily by three factors: Emflaza growth due to both new patient starts and high compliance; Translarna driven by broader access, geographic expansion, and label updates, as well as Evrysdi driven by royalties and milestones associated with the US approval and launch. Revenue growth was due primarily to our global DMD franchise. Translarna net product revenues were $191.9 million for the year, compared to $190 million for the full year 2019. For Emflaza, we reported net product revenues of approximately $139 million for the full year 2020, which compares to $101 million from the prior year. This represents a 38% year-over-year growth. The total DMD franchise net product revenue was $331 million for 2020. Our 2021 DMD franchise revenue guidance is between $355 million and $375 million, and this guidance does not reflect any other anticipated revenue contribution. The royalty purchase agreement with RPI has allowed PTC to diversify its market risk of having a future royalty stream currently tied to one product by transforming its potential future cash flows into $650 million cash assets. This has created real value for PTC's financial position as the cash is being invested to support PTC's research and development platforms and patient care initiatives. Additionally, by retaining the majority interest in the future royalties due from Roche, tapping the potential payout to RPI at $1.3 billion to retain future upside, and the rights to receive the remaining potential regulatory and sales milestone, PTC has retained its ability to receive consistent cash flows in future periods. We recognize $42.6 million in collaboration revenue in 2020, an increase of $26.9 million from the prior year. The increase is primarily related to three regulatory milestones that were triggered from Roche in 2020. We also recognize $4.8 million in royalty revenue in 2020, due to the FDA approval of Evrysdi in August, as we are entitled to royalties on worldwide annual net sales. Non-GAAP R&D expenses were $438.9 million for the full year 2020, excluding $38.7 million in non-cash stock-based compensation expense, compared to $236.6 million for the full year 2019, excluding $20.8 million in non-cash stock-based compensation expense. This increase in R&D expenditures reflects costs associated with advancing the gene therapy, splicing, and Bio-e platform, increased investment in research programs, and the advancement of the clinical pipeline. Additionally, the increase in R&D expenses includes one-time charges of $53.6 million related to the acquisition of Censa Pharmaceuticals and $41.4 million related to the MassBio agreement with commercial manufacturing of our lead gene therapy program in AADC deficiency. Non-GAAP SG&A expenses were $213.6 million for the full year 2020, excluding $31.6 million in non-cash stock-based compensation expense compared to $181.2 million for the full year 2019, excluding $21.3 million in non-cash stock-based compensation expense. We anticipate non-GAAP R&D and SG&A expenses for the full year 2021 to be between $725 million and $755 million, excluding approximately $100 million in estimated non-cash stock-based compensation expense. Cash, cash equivalents, and marketable securities totaled $1.1 billion as of December 31, 2020, compared to $686.6 million as of December 31, 2019. I'll now hand the call over to the operator to start our question-and-answer session.
Operator, Operator
Our first question comes from Eric Joseph with JP Morgan.
Eric Joseph, Analyst
Good evening. Thank you for answering my questions. First, regarding PTC-AADC, assuming a positive CHMP decision, could you explain the initial launch strategy in Europe? Of the 200 patients you expect to identify at launch, how should we consider the regional distribution? What proportions will be in Europe? Additionally, could you discuss the risk-benefit profile, particularly in relation to age? Does it vary by age, and are there any challenges with stereotactic delivery in older juveniles compared to what has been described for infants? Thank you.
Stuart Peltz, CEO
Thank you, Eric, and thank you all for joining the call. I'll begin and then hand it over to Eric, who will discuss our commercial planning in more detail. I want to remind everyone that our AADC treatments represent a truly transformative gene therapy that can significantly enhance the lives of patients with AADC deficiency. This is a very rare and serious pediatric condition, akin to severe cases of SMA, where patients experience developmental delays, unable to hold their heads up, roll over, stand, or move, often resulting in a short life span. Currently, there are no approved treatments or disease-modifying therapies available for these patients. In our clinical trials, we have observed remarkable improvements among these patients, with changes from being developmentally arrested to gaining the ability to roll, sit, stand, and even walk. We've seen significant progress over five years, and even after ten years of follow-up, improvements have persisted across all pediatric age groups, including older children and adolescents. The results have been highly transformative, with a strong clinical data package demonstrating durability and observable changes in dopamine levels. We consider this product to be of great value, and we are focusing on identifying patient populations and establishing centers of excellence for our product launch. Now, I'll turn it over to Eric to delve deeper into our launch plans.
Eric Pauwels, Chief Business Officer
Thank you for the question. First and foremost, we have several key activities in place for the regional rollout that Stu detailed. These include an increase in disease education programs focused on genetic testing, and we now have 60 screening programs across more than 20 countries, primarily in Europe and Latin America, as well as parts of central and eastern Europe where we expect access and reimbursement for gene therapy and ultra-rare disease products. We've also conducted numerous global webinars and virtual symposiums. The level of preparation in the marketplace has been very proactive regarding our patient identification and education efforts. Additionally, one critical area is ensuring that our centers of excellence are ready not only to treat patients but also to follow up with them. We've made significant strides in this regard. Our regional rollout will specifically begin with commercial launches in Germany, followed by several Early Access Programs in countries like France, Italy, Spain, Northern Europe, and Scandinavia, as well as in Latin America, contingent on European approval. We are confident in this approach and excited to report an acceleration in patient identification since launching these programs. We expect to have around 300 patients ready for treatment at the time of launch in regions where gene therapy access and reimbursement are available.
Operator, Operator
Our next question comes from Gena Wang with Barclays.
Unidentified Analyst, Analyst
This is David on for Gina. Thank you for taking my questions. I have a few questions regarding the Huntington disease program PTC518. First, can you discuss what dose levels you are testing in healthy volunteers? Additionally, what is the half-life and dosing frequency?
Stuart Peltz, CEO
Yes, thanks for that. Just to remind everybody that we have PTC518, the role of this is to cause splicing to induce an intron into the RNA so that there's a premature stop going on, so you don't make the protein and the RNA is rapidly degraded. And so that we designed this, it's an orally bioavailable small molecule that crosses the blood-brain barrier; it reaches all regions of the brain. And I think most importantly, as well, one of the major characteristics is, it's not an efflux out of the brain, and that just for everyone, the reason that is so critical of a property is that many things can pass the blood-brain barrier, but the brain protects itself and moves out many things that are potentially toxic to it. And so, we've made sure that PTC518 passes the blood-brain barrier and stays within, and that's a critical property. So that, and therefore, you know the level of what you see in the blood is what you see in the cells within the whole brain. And so, what we've shown in animal models, that HTT reduction was clearly titrated based on its exposure level, so that the degree of HTT lowering can be tightly controlled. And I think that really distinguishes PTC518 because of that it achieves uniform exposure. And that the Huntington lower is in all cells of the tissues analyzed and then all cells within the brain. Therefore, it shows a near one-to-one ratio between the PTC518 levels that are observed in brain cells in all parts of the brain. And what we see in the cells of the blood, that's because it passes the blood-brain barrier. And so we see the same levels in blood-brain, so we have a very good measurement to show is indeed the case. So when we think about the trials that we did, it was based on, obviously, working on what the levels that we saw in the mouse rat and non-human primate. Based on our understanding of the experience that we've seen in splicing, that what we did is obviously screen for the molecules for specificity in bio-distribution. So we selected the molecule on that, then we moved in the clinic. The levels that we did is based on the results that we saw in the animal models and the predictions of what we would see in people is how we chose the levels of drug that we would begin with. So I think that's how we did this, where we identify what we think is the right dose, start low and continue to move up to be within regions that we were predicting the CHTT lower rate.
Unidentified Analyst, Analyst
Yes, that's very helpful. And just to follow up on that, Stu, I guess the question is what level of HTT reduction are you looking for in healthy volunteers to enable you to select dose for the Huntington's disease patients in your next trial?
Stuart Peltz, CEO
We plan to conduct both a single ascending dose and multiple ascending doses to determine the exposure that allows us to move forward with our goals. This approach enables us to identify the appropriate dose based on measured RNA changes over time. By analyzing both types of dosing, we aim to establish a dose that maintains a steady state level of reduction. One of our advantages is the ability to accurately measure the small molecule's exposure in both the blood and the brain, as we've observed that blood levels correspond with brain levels across various animal models, including non-human primates. As we collect data from participants, we will monitor drug levels alongside reductions in HTT RNAs in the blood, which will help us define our dose-response curve. We're considering aiming for approximately a 50% reduction, as prior clinical data indicates that achieving this level can lead to notable improvements in patients, potentially extending their disease-free period. However, we remain flexible and may adjust our targets based on what we learn, starting with a focus on that 50% reduction while also exploring whether lower doses may be beneficial.
Operator, Operator
Our next question comes from Olivia Young with Cantor.
Li Watsek, Analyst
Hey, guys, this is Li on for Olivia. Thanks for the update. Just wanted to follow up on the Huntington program, the Phase 1 study. Can you just give us a quick update on where you are in the trial now? Or have you moved to the next portion of the study?
Stuart Peltz, CEO
We have been conducting the trial, focusing on both the single ascending dose (SAD) and moving into the multiple ascending dose (MAD) phase. We mentioned that we would have updates by the first half of the year, and everything is progressing well. The study is designed to capture safety and pharmacological data. In the single ascending dose study, there are up to six cohorts, each consisting of six patients receiving active drug and placebo. The MAD study may include up to five cohorts, with six subjects on active drug and two on placebo. We are advancing without any issues and are excited about the progress. In the Phase 1 study, we are monitoring drug concentration in the blood, the levels of HTT messenger RNA, and ultimately the protein in blood cells. One cohort will measure PTC518 blood levels and levels in the cerebrospinal fluid (CSF). It's important to note that these studies involve healthy volunteers who do not have Huntington's disease, so we do not expect to see the proteins of interest in the CSF. The aim is to conduct exploratory pharmacokinetic measurement studies in the CSF and correlate those results with the blood data. Ultimately, we aim to demonstrate proof of the splicing mechanisms, determine the pharmacokinetic characteristics of PTC518, define the necessary dose, and identify exposure levels needed to achieve our target HTT reduction. We believe these results will be comparable to what we accomplished with the SMA trial using risdiplam in healthy subjects. We are on track to present data for both the SAD and MAD studies within the first half of this year, and we plan to hold a deep dive to discuss the preclinical data in detail prior to that.
Li Watsek, Analyst
Okay, thanks for the color. And then my second question is just on AADC, just wondering for you to file BLA in the second quarter. What are the remaining steps? And in terms of the cannula study, can you just give us an update on where you are right now?
Stuart Peltz, CEO
Sure. I just want to remind you obviously, we've already talked a bit about it. Again, we think this is a transformative gene therapy, and that we've seen what it does for patients already, both in the durability and the 10-year post-treatment. Follow-up we know about this quite well. And just to remind everyone, the EU and MAA are moving forward to expect a CHMP opinion in the second quarter of this year. Matt, do you want to talk a little bit about where we are right now?
Matthew Klein, Chief Development Officer
Yes, sure. Yes, so thanks Stuart. As we've talked about before, one of the gating factors to this mission BLA was conducting additional surgeries with the cannula we intend to use commercially. And that cannula is CE Marked in Europe for the delivery of gene therapy, which is why obviously; it wasn't an issue with the MAA submission. It's been used in many gene therapies before, and it was just a matter of us getting experience demonstrating the safety of the cannula delivering our specific gene therapy to our intended patient population. And so we've actually completed two of those studies or two of those surgeries already. The procedures went well, there were no complications from the surgery, and recovery is on schedule. And again, just as a reminder, these surgeries are to evaluate the safety of the cannula given that we already have extensive safety and efficacy data that Stu mentioned accumulated over a number of years with the gene therapy product. We plan to conduct one additional surgery, and then once those data are collected, we will align with the FDA and move forward with the BLA submission.
Operator, Operator
Our next question comes from Robyn Karnauskas with Truist Securities.
Minh Vong, Analyst
Hi, thanks, everyone, for taking our questions. This is Minh on for Robyn. And so just back on Huntington's when you present the data, are you going to get data from all the dose cohorts or will it be whatever the child has enrolled. And that's where you can present so maybe passages just few cohorts from the SAD study? I guess it's the first question around there.
Stuart Peltz, CEO
We are on track to share data for both the SAD and MAD studies within the first half of the year. Ahead of that, we plan to provide an in-depth analysis. By the end of the year, we will have both the SAD and MAD data available, and we will share the dose level with you at that time.
Minh Vong, Analyst
I see. And then for my last question, do you have any insights on where the therapeutic dose may be and where it might fall? Also, one more question: any idea where that therapeutic dose may fall within the MAD or SAD study?
Stuart Peltz, CEO
Yes, I believe that based on the data and our ongoing work, we had a strong indication of what we anticipated regarding the dose definition. We've been making progress, and I think we will be in a good position. We'll have a dose response curve that measures both the splicing and the dosage. We will be able to accurately predict the dose corresponding to a specific exposure, which will indicate whether we're targeting a 30%, 50%, or 70% reduction of HTT. I feel confident that we will be able to provide that information and proceed accordingly.
Minh Vong, Analyst
Got it. That's helpful. And then sorry my question regarding your comments around titration, I guess, will you have enough, I guess enough sense to know whether there's more safety risks that would come on with going with a greater than 50% reduction? I guess, how do you know there won't be any longer-term safety risks that the child may not be able to measure should you push beyond 50%?
Stuart Peltz, CEO
I believe our current goal is to reach a certain level, and there's a substantial amount of data regarding individuals with one allele. We have not identified any safety concerns associated with this, so I don't foresee any risks. However, there isn't much data available for lower levels. It's clear that certain factors are crucial during early embryonic development, but we need to understand how low we can go after that. Typically, if you have around 10% of certain factors, you function normally. The critical question is determining the threshold where there are no observable effects. We are considering testing this in animal models with human HTT to titrate our compounds and assess the reduction levels. With our humanized HTT mouse model, we can achieve consistent exposures to lower the levels effectively. We have seen that we can achieve around a 50% reduction in nearly all body tissues, including different parts of the brain. Our prior work supports this capability, and if we can move forward with our molecule development, we should gather data that will help us understand whether we can go lower without compromising safety. Our target remains a 50% reduction, which I believe we can accomplish.
Operator, Operator
Our next question comes from Joel Beatty with Citi.
Joel Beatty, Analyst
Hi, thanks for taking the questions. First, are there ways to assess using biomarkers in the clinical data for PTC518, if you're generating uniform knockdown throughout the body, or how important is it to assess that clinically?
Stuart Peltz, CEO
Yes, I think clinically, I mean, the biomarker that we're choosing is looking at the reduction of Huntington levels within the blood with which we've done extensive analysis in both mouse, rat, and non-human primates. We've been able to show that the reduction there goes along with the reduction that we've seen in other tissue types. So that's going to be a pretty good biomarker, and that's in the set, obviously, just so everyone knows that HTT is the intracellular protein. Right. So we're looking, when we do the analysis, we're looking directly within the cells and the blood cells are good marker for the level of reduction that we've seen there. We've seen in all other tissues, where we worked in mouse models. So we know we'll be able to do that direct correlation based on the blood. What we see the reduction in protein and RNA levels. Does that help you, Joe?
Joel Beatty, Analyst
Yes, great. And then maybe switching gears for Evrysdi. Could you remind us what additional potential milestone payments?
Stuart Peltz, CEO
What?
Joel Beatty, Analyst
Milestone payments?
Stuart Peltz, CEO
Oh, milestone, yes, sure. Emily, I thought you were going to speak today. But I'll pass it to Emily.
Emily Hill, CFO
Thank you very much. I appreciate your question, Joel. You are right. We have maintained all of our milestones for Evrysdi, especially after the royalty monetization, and we still have about $300 million in milestones remaining. The most immediate milestones we are anticipating involve approximately $55 million in total for 2021. This includes $20 million for the first commercial sale in the EU, $10 million for the commercial sale in Japan, and a potential $25 million sales-based milestone contingent upon Roche achieving $500 million in sales.
Operator, Operator
Our next question comes from the line of Brian Abrahams with RBC.
Brian Abrahams, Analyst
Hi there. Thanks so much for taking my questions. A few on the Huntington's program. Given what's known or not known about HTT protein turnover, in the context of the timeframe of the study, I was wondering how you guys are thinking about looking at mRNA versus protein changes? What's going to guide your decision as to whether to move into those additional two MAD cohorts versus just running three? And then as you sort of look past the study, how do you think about how the blood-brain barrier properties in Huntington's patients might impact the overall plasma to CSF ratio? And how you might be thinking about dose adjusting when you go into patients? Thanks.
Stuart Peltz, CEO
Yes, thanks, Brian. When we consider the concentration of the drug in the blood and the expected reductions in HTT mRNA and protein within the cells, we anticipate that the CSF levels will be comparable to what we observed in non-human primates. This will provide us with valuable insights to confirm the previously observed ratios. It will help us define the exposure levels effectively. It's crucial for us to ensure that we are accurately measuring the pharmacokinetics and relating that to the reduction of RNA and protein. You raised a good point regarding RNA and protein, as it heavily depends on their half-lives. We will gather significant data through the multiple ascending doses to assess both RNA levels and work towards achieving a steady state. This will allow us to model HD RNA and proteins effectively, particularly in the first half of the year.
Vincent Chen, Analyst
Thank you very much for taking the questions on congrats on progress. A couple more for you on Huntington's disease. The first is in your preclinical RNA-seq experiments, how many other RNA splicing events were identified that were modulated by PTC518? Which ones and how much were modulated? And then the second question is thinking about the ongoing study, how many doses do the MAD healthy volunteers get? And what's your sense for how much run out is needed to assess the risk of off-target toxicities?
Stuart Peltz, CEO
Yes, could you repeat the first question one more time?
Vincent Chen, Analyst
Sure. In the preclinical RNA-seq experiments that you did, how many other RNA splicing events were identified that were modulated by PTC518? Which ones were they and how much were they modulating?
Stuart Peltz, CEO
Yes, it's important to discuss how we optimize our compounds. During the optimization process, selectivity is a key focus for us. We begin by conducting high-throughput screening of small molecules in Huntington fibroblasts and then refine these molecules for efficacy and potency, considering selectivity and pharmaceutical properties. We aim to enhance selectivity in molecules that initially exhibit lower selectivity. Ultimately, we have identified several molecules and dedicated significant time to ensure they possess favorable traits, including a safety window observed in animal models, strong potency, and notable selectivity for HTT. Our understanding of the mechanism and specificity has improved significantly. For example, when comparing our molecule's specificity to a competitor's, our selectivity for SMA and HD is much higher due to the effort we put into building selectivity into the molecule. In the upcoming RNA-seq deep dive, we will address your questions in more detail.
Vincent Chen, Analyst
Actually that's very helpful. I guess the second question was simply how many doses do the healthy volunteers in the multiple ascending dose study get? And what's your sense for how much run out you would need to assess the risk of off-target toxicities? If I think of splicing part of disease how quickly would you expect those to show up and how much run out do you need?
Stuart Peltz, CEO
For the multiple ascending doses, we are conducting a 14-day dosing period followed by a 28-day observation period. While we define the dose this way, it's important to emphasize that we are also completing long-term safety and toxicity studies. I want to clarify that there is nothing inherently different about splicing toxicities compared to other toxicities, whether they involve splicing targets or other molecules. We have invested considerable effort in ensuring selectivity and specificity. Toxicity can arise from off-target effects for various reasons, which is why we conduct these studies to identify and understand any off-target toxicities. However, I don't think one can claim these toxicities are unique compared to those seen with other drugs, and that is precisely why we perform safety toxicology experiments to identify toxicities and assess risks to enable progression. This is a standard stepwise approach; targeting splicing is no different from targeting kinases, phosphatases, transcription factors, or other areas of research. I wouldn’t suggest that there’s anything particularly special about this compared to other domains.
Operator, Operator
Our next question comes from the line of Joseph Thome with Cowen & Company.
Joseph Thome, Analyst
Hi there, thank you for taking my question. I have one about the Bio-e platform. After reviewing the healthy volunteer data for PTC857, what are you looking for next? When might we see progress into a potential GBA or Parkinson's study? Also, since both 857 and vatiquinone target 15-LO, could you explain what differences might make 857 more suitable for the Parkinson's disease indication? Thanks.
Stuart Peltz, CEO
Yes, sure. So I think part of what we're doing, it does have different properties. In terms of that probably would be an advantage for something that we're taking long-term for a lot of people, again, it's an orally bioavailable molecule. For indications, like GBA, as you said, Parkinson, it's a different, it's in a different number of patient populations versus a vatiquinone and where that's going now. So we thought it'd be best to have a different molecule with perhaps different properties. And so that's sort of in the sense it has different value for the size of the patient population. And so we thought it was important to have another molecule. Matt, do you want to talk a little bit about where we're at in terms of the trial and what we're thinking about?
Matthew Klein, Chief Development Officer
Yes, so Joseph, thanks for the question. As you mentioned, we've been studying 857 in the Phase 1 study, which was the single ascending and multiple ascending dose studies, fairly standard, and healthy volunteer studies where the focus has really been safety and pharmacology, we completed the dosing in those studies. We are in the process of doing the analysis. What we're looking for here is understanding the pharmacology, making sure that the molecule is behaving in humans as we've been able to model what's in the preclinical studies, and also identifying the dose level that gives us the exposures that we saw to be efficacious in all the preclinical work that we've done. So we want to walk away from this study with the dose level that we know is safe that has predictable pharmacology and would be consistent with delivering the exposure that's necessary to achieve the preclinical effects you've seen now as a bit of background; 857 targets 15-lipoxygenase, which is a key governor of a number of pathways, which independently have known to be important in Parkinson's disease pathologies, such as microglial activation, alpha-synuclein, oxidation, aggregation, glutathione depletion, and with the base of oxidative stress. What we're able to do in targeting 15-LO is affect simultaneously all four of those pathways. We have an extensive amount of preclinical work demonstrating effect. What we want to see in the Phase 1 study is identifying that dose level that brings a side exposure that matches up with what we've seen in the preclinical studies and then we'd be in a position to move forward with the next stage of development.
Stuart Peltz, CEO
Yes. Thanks, Matt. I think the really important point here as well is that oxidative stress, right, really extra electrons cause oxidative stress; there are multiple diseases that we can go into 857. So having another molecule to go into other indications with different properties, we think it's going to be valuable.
Operator, Operator
Thank you. I'm not showing any further questions. I will now turn the call over to Stuart Peltz for closing remarks.
Stuart Peltz, CEO
Well, thanks. Thanks a lot for joining us today. As many of you may be aware, Rare Disease Day is upcoming this Sunday, and this is oftentimes where we take stock of where we've been and where we're going as a company. It serves as a report and reminder to us that we do this work, ultimately, for the benefits of patients, and I hope that you see just how strong our execution has been in 2020, and how this sets up for really many value-creating milestones in 2021. So we're excited about the programs that we have, and we look forward to, in particular, I know everyone's been interested to see by the question, the interest in the Phase 1 Huntington's disease readout, and we look forward to sharing that with you within the second quarter. Again, thank you for joining us. Have a good evening.
Operator, Operator
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.