Ladies and gentlemen, thank you for standing by, and welcome to the PTC Fourth Quarter 2020 Financial Results Conference Call. At this time, all participants are in a listen only mode. After the speaker presentation, there will be a question and answer I would now like to hand the conference to your speaker today, Kiley O'Keefe, Head of Investor Relations. Please go ahead, ma'am.
Good afternoon and thank you for joining us to discuss PTC Therapeutics 4th 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 Peltz. 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 any and such risks can materially and adversely affect our business and results of operations.
For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report, 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 and non GAAP financial measures and a reconciliation of GAAP to non GAAP is available in today's earnings release. With that, let me now pass the call over to our CEO. Stuart?
Thanks, Kiley, 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 from research and development through commercial. Despite the COVID-nineteen pandemic, we initiated 5 clinical trials, including 2 registration directed trial with vaticuino. Let me begin with the Duchenne muscular dystrophy franchise. We continue to see strong global growth and geographic expansion.
Our DMD franchise sales in in 2020 were approximately $331,000,000 Specifically in the U. S, the annual revenue of Emflaza totaled $139,000,000 which is a 38% increase from last year. The annual revenue for Translarna totaled $192,000,000 and was driven by geographic expansion, new patients and label modification. For example, Translarna received marketing authorization in Russia in the 4th 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 COVID-nineteen 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 45 dystrophin study. We plan to discuss these results along with Translarna's totality of revenues, including existing clinical and real world data with the FDA. Our goal has always been to bring Translarna to U. S.
Patients who have long been waiting for this therapy as quickly as possible. Moving to our slicing platform, the approval of ARISTI in 2020 was an important milestone for PTC, Our partners Rose and the SMA Foundation. AVIZI is a groundbreaking treatment, which has a benefit for all SMA patients with particular benefits of durability and broad tissue distribution.
As a consequence of
the benefits of Erisi, It has continued to show a strong uptake and Roche expects that RISD will become the treatment of choice in the U. S. In 2021. With the near term expected European approval followed by the Japanese approval of RISD should see continued significant growth this year. Another accomplishment of 2020 with regards to RISD is the royalty monetization deal, which puts $615,000,000 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 $1,300,000,000 Our next most advanced molecule from the validated splicing platform is PTC-five eighteen for the treatment of Huntington's disease. As a reminder, PTC-five eighteen is an orally bioavailable small molecule that crosses the blood brain barrier enriches 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 back HD mouse model. This is critically important As Huntington's disease is a whole brain disease, HTT reduction is clearly titrated both based on PTC-five eighteen levels. So the degree of HTT lowering can be tightly controlled.
In addition to the Whole Brain distribution, PTC-five eighteen achieved uniform exposure and HTT lowering in all tissues analyzers, showing a near one to one ratio between CNS and blood. This is important because it shows the PTC-five eighteen 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 a dose with the desired levels of activity. The same approach was successfully used in the RISD plan program where proof of concept was demonstrated in the healthy volunteer study.
We expect the same trajectory in the Huntington disease program. We are very excited about this program and look forward to the results that are expected in the first half of twenty twenty one. Now turning to our virology platform. The second and final stage of the FIGHT-nineteen trial for COVID-nineteen has commenced. As a reminder, PTC299 is an oral small molecule with a dual mechanism of action that demonstrates both antiviral and anti inflammatory effects.
PTC299 inhibits SARS CoV-two viral replication and calms the cytokine storm. PTC299 functions by targeting a cellular enzyme dihydrooritase 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-nineteen 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 BioE platform.
We have initiated 2 registration directed trials with vityquinone, 1 in mitochondrial epilepsy and 1 in secret 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's 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 Q2 of this year.
As a reminder, PTC AADC is a transformative gene therapy that has the potential to produce meaningful changes in AADC deficient patients. PTC AADC has robust clinical data that demonstrates durability of effect for up to 10 years post treatment, a crucial consideration in the single dose gene therapy. Now let me discuss our plans for PTC-nine twenty three. As a reminder, there is an estimated global prevalence of 58,000 PKU patients and the vast majority are not well addressed by current therapies and therefore we are excited about the potential of PTC-nine twenty three as a clinically differentiated therapy to address this high unmet medical need. We will start a registration of trial evaluating PTC-nine twenty three for treating PKU called Affinity 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. Matt?
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 We're excited to continue to deliver on planned development milestones across our multiple platforms. I would like to start with our BioE 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. Etiquinone, the first compound being developed for the BioE 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 2 vatiquinone registrational trials in mitochondrial epilepsy and Friedreich ataxia. As a reminder, vaticlinone has extensive safety days, particularly in pediatric patients with the longest duration of exposure being over 10 years.
For the first indication of mitochondrial epilepsy, previous clinical studies demonstrated that ticlinone had a positive effect on seizures and seizure related morbidity across multiple mitochondrial disease subtypes. These results give us confidence that dativequinone has the potential to show clinically differentiated improvement for mitochondrial epilepsy patients. The ongoing mitochondrial epilepsy trial, the MIGHTY trial, is a randomized placebo controlled study enrolling 60 children at centers worldwide. The primary endpoint of the study is 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 Q3 of next year.
We are very excited to bring this therapy to children with mitochondrial disease. The second patikinone 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 II trial, The titquinone treatment demonstrated significant improvement in disease severity compared to a matched natural history cohort over 24 months. These results support that vatiquinone can deliver a meaningful effect to Friedreich ataxia patients. The Phase 3 FA trial, MOVE FA, is a 72 week randomized placebo controlled study.
The primary endpoint of the trial is change from baseline in the modified Friedreich Ataxia Rating Scale or MPARS. 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 U. S. And EU.
We began trial enrollment in Q4 of last year and we anticipate results in 2023. Now let me turn to our PTC-five eighteen PTC-five eighteen 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 eclocks, 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 of a Phase 1 study, but to also establish proof of splicing mechanism and guide dose selection for future studies.
The SED study includes 5 dosing cohorts, each with 6 active and 2 placebo subjects. The MAD study is expected to have 3 to 5 cohorts, each with 6 active and 2 placebo subjects. In the Phase 1 study, we are monitoring drug concentration in both the CSF and blood and will 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 studies. The data from the PTC-five eighteen SAB 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 Q2 of this year. In addition, we are continuing to progress our FA gene therapy program and expect 1st in human dosing before year end. Turning to our PTC299 FIGHT19 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 2nd stage of the study. We have already initiated enrollment in the 2nd stage and data are expected in the second half of twenty twenty one.
In 2021, we look forward to advancing additional programs from our pipeline. We are on schedule to initiate the Phase 3 trial for PTC-nine twenty three in patients with PKU in mid-twenty 21 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 from these programs when available. I'll now turn the call to Eric to provide more detail on our commercial business.
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 mutation DMD patients ages 2 older, We saw revenues of $192,000,000 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 2 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 nonsense 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 2 older. We saw revenues of $139,000,000 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, an increase in 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 $355,000,000 to $375,000,000 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 and Visa 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 for neurological disorder.
There are currently no approved disease modifying therapies available. In clinical trials, PTC AADC gene therapy demonstrated significant and durable neurological PTC is currently preparing for our 1st gene therapy launch for patients with AADC deficiency, which is expected to occur in Europe during the second half of twenty twenty one. As part of these efforts, identification and preparation of for pediatric neurological centers of excellence is underway throughout the U. S, Europe and Latin America. Patient finding activities are also accelerating 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.
Thanks, Eric. In 2020, PTC saw strong continued revenue growth and progress across multiple platforms of 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 4th quarter 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 $380,800,000 in total revenue for the full year 2020 compared to $307,000,000 for the full year 2019. This increase was driven primarily by 3 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 driven by royalties and milestones associated with the U. S. Approval and launch.
Revenue growth was due primarily to our global DMD Translarna net product revenues were $191,900,000 for the year compared to $190,000,000 for the full year 2019. For Emflaza, we reported net product revenues of approximately $139,000,000 for the full year 2020, which compares to $101,000,000 from the prior year. This represents a 38% year over year growth. The total DMD franchise net products revenue was $331,000,000 for 2020. Our 2021 DMD franchise revenue guidance is between $355,000,000 $375,000,000 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 a $650,000,000 cash asset. 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, capping the potential payout to RPI at $1,300,000,000 to retain future upside and the rights to receive the remaining potential regulatory and sales milestones, PTC has retained its ability to receive consistent cash flows in future periods. We recognized $42,600,000 in collaboration revenue in 2020, an increase of $26,900,000 from the prior year. The increase is primarily related to 3 regulatory milestones that were triggered from Roche in 2020.
We also recognized $4,800,000 in royalty revenue in 2020 due to the FDA approval of the RISD in August, as we are entitled to royalties on worldwide annual net sales. Non GAAP R and D expenses were 438,900,000 for the full year 2020, excluding $38,700,000 in non cash stock based compensation expense compared to 236.6 $1,000,000 for the full year 2019, excluding $20,800,000 in non cash stock based compensation expense. This increase in R and D expenditures reflects costs associated with advancing the gene therapy, splicing and BioE platforms, increased investment in research programs and the advancement of the clinical pipeline. Additionally, the increase in R and D Sensus includes one time charges of $53,600,000 related to the acquisition of Sensus Pharmaceuticals and 41 point $4,000,000 related to the MassBio agreement for commercial manufacturing of our lead gene therapy program in AADC deficiency. Non GAAP SG and A expenses were $213,600,000 for the full year 2020, excluding $31,600,000 in non cash stock based compensation expense compared to $181,200,000 for the full year 2019, excluding $21,300,000 in non cash stock based compensation expense.
We anticipate non GAAP R and D and SG and A Expenses for the full year 2021 to be between $725,000,000 $755,000,000 excluding approximately $100,000,000 in estimated non cash stock based compensation expense. Cash, cash equivalents and marketable securities totaled $1,100,000,000 as of December 31, 2020, compared to $686,600,000 as of December 31, 2019. I'll now hand the call over to the operator to start our question and answer session. Operator?
Thank you. Our first question comes from Eric Joseph with JPMorgan. Your line is now open.
Good evening. Thanks for taking the questions. Just a couple from me, first with PBC PTC AADC assuming a positive CHMP decision. Perhaps you could just sort of Walk us through the initial launch strategy in Europe. And of the 200 patients that you're anticipating to identify that launch, what countries I guess how should we be thinking about
this?
Their regional distribution, what proportion are in Europe. And then Also, I guess, just thinking about the risk benefit just thinking about the age of pre vessel patient population here as well, can you talk a little bit about the Risk benefit profile as it varies by age, is there any Challenges with putemix, stereotactic delivery in older juveniles compared to what's been described today in infants? Thanks.
Yes. Thanks, Eric, and Thanks for the call. Maybe I'll start and then I'll I'll turn it over to Eric, who could talk to you more about the commercial planning. So I thought I'd start just by saying just to remind everyone That the AADC treatment that we have for gene therapy Actually, we think it's really a transformative gene therapy that really can make very meaningful Differences in the lives of patients with AADC deficiencies. And that is just to remind you, it's an ultra orphan highly morbid of VEGAL pediatric disorder.
And much like when you think about SMA, in the severe form of these patients, They really are developmentally arrested and are unable to hold their head up, roll over, sit, stand and move and They can die within a few years of life. There's really no approved therapies and nothing really for And I think in the clinical trials, we showed that there was really transformative Changes in these patients were patients that were developmentally arrested like this, they all improved and we had patients that went from Not being able to move to be capable of rolling, sitting, standing and walking. So we saw Substantial progression as a consequence of this. So really highly transformative results, Clinical data for 5 years, 5 years showing improvement up to 10 years of which we I can continue to follow them and we saw this in all pediatric age groups that we mentioned, including older children and adolescents. So we saw a very nice benefit as a consequence of it.
We didn't see any really Anything from the standpoint of surgeries of challenges related as a consequence to the surgeries. So we think the content it's a highly valuable product we believe because of we think it's one of the best packages, Our clinical package is because of durability, the ability to see a biomarker where you can see changes in Dopamine levels that we continue to see. And so I think that's actually was really is really powerful. And so what we've been working on in terms of the launch is obviously Getting ready to identify getting ready and identifying patients, getting centers of excellence. And so, Eric, why don't you talk through A bit about the potential launch and what we're doing for launching that.
Yes, sure. Eric, thanks for the question there. First of all, most importantly, we have a number of key activities that Stu outlined in preparing that regional rollout. So those included an increase in disease educational programs who are driving genetic testing. We now have 60 screening programs now in over 20 countries, the vast majority in Europe as well as LatAm, in other Central and Eastern Europe and other places where we know there will be access and reimbursement for gene therapy products and ultra rare disease products.
We've done a number of things in terms of global country and specific webinars and the virtual symposium. So The level of the preparation in the marketplace has been extremely, I would say, aggressive in terms of how and where we're preparing In terms of our patient finding activities and education, and as Stu mentioned, one of the key areas as well is making sure that those sites, The centers of excellence are prepared to not only treat the patients, but also follow them. And we've been Doing that in many of the key areas. The regional rollout is going to be specific as you would expect with first Launches in Germany, but we will immediately, roll out a number of early access programs and take full advantage of the mechanisms by which European as well as Latin American and other areas of the world will have once the final opinion and approval comes from Europe. So we would anticipate Germany, of course, and then early access programs in countries like France, Italy, Spain, Northern Europe and Scandinavia and others.
And we'll take full advantage of early access programs in Latin America as well based on the European approval. We're very confident at this point and we're most importantly, I would say, I'm excited that the We've seen an acceleration of patient finding since we've implemented a large number of these programs and We're anticipating to have 300 patients addressable at the time of launch, and these will be in countries we have access and reimbursement to gene therapy. Great. That's helpful. I'll hop back into you, please.
Thank you. Our next question comes from Gena Wang with Barclays. Your line is now open.
Hi. How are you guys doing? This is David on for Gena. Thank you for taking my questions. I have a few questions around the for
the dominant disease program PTC-five eighteen.
First question is just around the dose. So can you discuss what dose levels you're testing in healthy volunteers? And what's the half life and dosing frequency?
Yes. So Thanks. Thanks for that. And just to remind everybody, that We have PTC-five eighteen, the role of this is to cause splicing to induce an intron into the RNA so that there's a premature stop codon, so that it will then be it would get Prematurely stopped, so you don't make the protein and the RNA is rapidly degraded. And then So that's so 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 is as well one of the major characteristics is it's not an efflux Out of the brain. And just for everyone, the reason that that is so critical of a property is that many things It can pass the blood brain barrier, but the brain protects itself and moves out many things that are potential that they think Potentially toxic to it and so that e flux, so there's many pumps that do that. We've made sure that PTC-five eighteen could pass the blood drainage 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 Great. 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 HCT lowering can be tightly controlled.
And I think that really distinguishes 518 because of the it achieves uniform exposure And that the Huntington lowers in all cells of the tissues analyzed, and in all cells within the brain. And therefore, it shows a near one to one ratio between the PTC-five eighteen levels that are observed in brain cells and again 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 and brain. So we have a very good measurement to show that's 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 And based on our understanding of the experience that we've seen in splicing that the kind of that what we did It is obviously screened from the molecules for specificity in biodistribution. So we selected really date the molecule on that.
Then We moved into the clinic and 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 identified what we think is the right dose, start low and continue to move up to be within regions that we We predict to see HTT lowering and choose it based on that. So that's how we chose the doses to go into humans and have the and look for what levels were changed. David, that help you?
Yes, that's very helpful. And just a 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 a dose for the Huntington disease patients in your next trial.
Yes. So the way we think about this is, we're going to do a single ascending dose and multiple ascending dose. And so we'll be able to know what exposure gives us a targeted number to be able to move forward. And so and that's the beauty. The beauty of the fact it's really, really great that we're capable of identifying Knowing what the dose is, characterizing the exposure and then measuring the level of RNA changes in the RNA over And both doing that in a single ascending dose and a multiple ascending dose, we get a very good characteristic of What's the dose that gives us steady state level of reduction?
And that's actually so we can actually and I think that's one of the major advantages That we have is that we have a small molecule to where we know the exposure in the blood and in the brain and we've shown That what you see in the blood is equal to what you see in the brain that we've seen that across all of the animals, including non human primates. So we're very comfortable knowing that. So as what we're doing is as we measure in people, we'll be measuring the levels of of drug and then the reduction of HTTRNAs in the blood. So we'll have a very good dose response level That we can prove we can type, that we can define what dose we want. So we're probably starting to think about looking at Probably a 50% reduction within that.
But and then we'll look for that in terms of Clinical benefit. I think there's results out there when you look at clinical data in terms of some SNPs that you see in patients where If you lower 50%, they have a substantial improvement in terms of 9 years greater without disease demonstration. So there's pretty good clinical data that suggest that a 50% will have a benefit. But we're also at the We also have the capability, that as we learn more, should we go lower or not, we could titrate that. But I think we're starting to look when we can go lower if we think it's correct to do so, but we're starting to think to look at the reduction And starting that looking at a 50% level, but we'll be able to identify if we can go lower and even further, what would be the dose that we We'll be able to define that dose.
Does that help you, David?
Yes, absolutely. Very helpful. Thank you, Steve. I'm going to hop back on the queue.
Thank you.
Thank you. Our next question comes from Alethia Young with Cantor. Your line is now open.
Hey, guys. This is Lee on for Alicia. Thanks for the update. Just wanted to follow-up On the Song Genesys program, the Phase 1 study, can you just give us a quick update on where you are in the trial now? And have you moved to the net portion of the study?
So you want to know right. So as we've Talked about, in terms of the trial, we've obviously been doing the trial, we're looking at both the SAD, The single ascending dose and they're going into the multiple ascending dose trial. So we've obviously been doing Both of those. So we're in the we said that we'd have it by within the first half of the year. So it's underway And that we've been moving forward.
And so just to remind everyone, it's right where it's designed to capture obviously the safety and pharmacological data. And so what I said is there's in the single ascending dose study includes up to 6 cohorts, Each with 6 patients who have active 6 with active drugs who have placebo. The MAD study is expected, where we'll have it could be up to 5 cohorts, again with 6 Subjects that can have active drug, while 2 would have placebo. And so things have been dosed and moving forward without any issues. We're actually pretty excited about it.
And just to remind everyone that in the Phase 1 study, what we're monitoring is obviously The drug concentration in the blood, the levels of the HCT messenger RNA and ultimately protein in blood cells, We will have one cohort that will measure PTC5818 blood levels as well as blood levels in the CSF. Now as a reminder, these are healthy volunteer studies and the subjects don't have Huntington disease. So we don't expect to have In the sense, the proteins of interest that people have talked about in the CSF as CSF. The purpose is to do exploratory PK measurement studies in the CSF and to be able to correlate that with the blood. And at the end of the day, I think what you'll see is that we're going to show proof of splicing mechanism Determine the pharmacokinetic characteristics of PTC-five eighteen, be able to define the dose and be able to say what dose Exposure levels that allow us to target, the level of HTT reduction that we're shooting for and to know if we wanted to go higher, what dose So these and I think these results are going to be really analogous to what we're able to accomplish when we The SMA trial, the RISD plan, in the healthy volunteer subjects, which worked out really beautifully.
So we're on track to share the data for PTC-five eighteen for the both the single ascending dose and the multiple ascending dose And expect to have that within the first half of this year. And of course, we're planning to have A deep dive that we'll have we will talk further with you so you can see Much of the data that of the science and the data that we have in the preclinical studies, ahead of that. Okay.
So I
wouldn't mind quite excited.
Okay. Thanks for the color. And then my second question is just on AADC. Just wondering for you to file BLA in the 2nd quarter, What are the remaining stats? And in terms of the cannular study, can you just give us an update on where you are right now.
Sure. I just want to remind you, obviously, we've already talked a bit about it. Already, both in the durability and the 10 year post treatment follow-up, we know about this And just to remind everyone in the EU, the MAA is moving forward. We expect a CHM opinion in the Q2 of this year. Matt, you want to talk a little bit about where we are right now?
Yes, sure. Yes, sure. Thanks, Steve. As we've talked about before, one of the gating factors key gating factors to the submission of the 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 that 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 2 of those studies 2 of those surgeries already. The procedures went Well, there were no complications from the surgery and recoveries on schedule. And again, just as a reminder, these surgeries are to evaluate the safety of the cannula given We already have extensive safety and efficacy data that Stew 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'll align with the FDA and move forward with the BLA submission.
Okay, great. Thank you.
Thank you. And our next question comes from Robin Karnauskas with Chua Securities. Your line is now open.
Hi, thanks everyone for taking our questions. This is Min on for Robin. So I guess back on Huntington's, When you present the data, are we going to get data from all the dose cohorts? Or will it be whatever the trial has enrolled And that's what you can present, so maybe possibly just a few cohorts from the SAD study. I guess just the first question around there.
Yes. So I think what we've said in the past, we're going to have both Obviously, what we have, we're on track to share the data for both the SAD and M and D studies within the first half of the year. And what we were planning to have is a deep dive ahead of that. So if we get to that point When we get to that point, we would have by the end of the year both the SAD and the MAD data on that. We'll share the dose levels with you at that time.
I see. And then I guess last question, where do you have an idea or a sense where the therapeutic dose may be and where that may fall in? And then sorry, one more question as well. Yes, I guess that one first. Any idea for whether the therapeutic dose may fall within the You know, MAD or SAD study?
Yes. I think we're again, we're Based on the data and based on what we're doing, we had a pretty good indication of what we thought that would be in terms of defining the dose. And so, it's been moving forward. So I think we'll be in pretty good shape where we'll be able to have A dose response curve in terms of measuring both the splicing and where the dose is. So we'll know We'll be able to give you a pretty accurate prediction of what dose gives a particular exposure that leads to That leads to in the sense of if we want to say a 30% or 50% or 70% reduction of I think we'll be in a pretty good position to be able to tell you that, and then and to be able to move forward based on that.
And Between the SAD and MAD, we're going to have a very good picture in terms of both safety as well as the dose, the exposure and And the level of traction by the and I said it's First half by the first half at the end of the first half of this year.
Got it. That's helpful. And then sorry, last question. Regarding your comments around titration, I guess, will you have enough, I guess, enough Sense to know whether there's more safety risk 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 risk that this trial may not be able to measure should you push beyond 50%?
Well, no. Well, so I think what we're shooting for right now is around that. My point the way I think about this is that There's plenty of data in terms of people that either want a Lille or as a consequence of that people are There are no safety findings that we see of that. So I don't think there's going to be a risk in terms of that. In terms of going lower, There isn't really a lot of data beyond that.
We clearly know that it's important during early embryonic development, But there isn't a lot of data that said after that, what is the how low can you go? I could tell you from As a geneticist point of view, when you look at the level of most things That when you say how much do you normally need, I mean, if you have like some of the factors, if you have 10% of them, You're pretty much normal. So the question is at what level, how far can you go where you don't see any effect? And so I think There are some ways where we're thinking of being able to test that in animal models that have Human HTT, where we can actually use titration of our compound to reduce it to the level of interest And we might be able to do some animal studies to be able to define that. And the reason we would be able to do that with 5/18 with Humanized HTT mouse is that we're really capable of doing uniform exposures that continually reduce levels versus if we want 50% down, we could see 50% down in virtually every tissue in the body and certainly Within the brain, that will include the cortex, striatum, cerebellum and every other tissue within the brain.
So we know that from the work we've done. And so we've been working with the groups to be able to build that mouse. And if So we're obviously shooting for 50% right now. And I think that's a target that I think we'll certainly be able to achieve.
Great. Thank you so much, Sue.
Thank you. Our next question comes from Joel Beatty with Citi. Your line is now open.
Hi, thanks for taking the questions. First, are there ways to assess using biomarkers in the clinical data For PTC-five eighteen, if you're generating uniform knockdown throughout the body or how important is it to assess that clinically?
Yes. I think clinically, I mean the biomarker that we're choosing Is looking at a reduction of Huntington levels within the blood, which We've done extensive analysis in both mouse, rat and non human primates and we've been able to show that the reduction there goes along 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 obviously, So everyone knows that HTT is an intracellular protein, right? So we're looking when we do the analysis, we're 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 when we looked in mouse models.
So we know we'll be able to do that direct correlation based on the blood and what we see, the reduction in protein and RNA levels. Does that help you, Joel?
Yes, great. And then maybe switching gears for RISD, could you remind us what additional potential zones remain?
Any what?
Milestone payments.
Oh, milestone. Oh, yes, sure. Emily thought she was going to talk today, but I'll give I'll pass it to Emily.
Thank you so much. Thanks, Joel, for the question. I appreciate
So you are correct. We have retained all of our milestones for EVERTI with the after the royalty monetization, and we do have about $300,000,000 in milestones remaining largely sales based and Regulatory, the most real term, near term milestones, upcoming are about $55,000,000 in total $20,000,000 would be in the first commercial sale in the EU, dollars 10,000,000 for the commercial sale in Japan and then a potential $25,000,000 sales based milestone upon Roche hitting $500,000,000 in sales.
Great. Thank
you.
Thank you. Thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is open.
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 2 MAD cohorts versus just running 3?
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.
Yes. Thanks, Brian. So the Obviously, what we're when we think about the drug concentration within blood and the levels that we'll see And the reduction that we'll see in the HTM RNA and protein within the cells, we're also taking the CSF that will What we anticipate is the level that we see in blood and the CSF level would be equal and that's similar to what We've done in non human primate. So we think that's going to be very telling to us. And so we'll be able to just confirm the ratio that we've seen previously.
So I think that's good. At least we'll You don't have a potential to see that, so that's what's going to help us in terms of defining what The exposure is in terms of and what that would be. And so that's the way one could look at that in terms of to make sure that you see The correct level and that could be done elsewhere as well. But I think that's a really important way for us to be able to be sure in terms of the PK And then equating the PK to reduction of RNA and protein. You bring up actually a pretty good point in terms of the When you think of RNA and protein, a lot depends on the half life of the protein and the RNA.
And so we'll be able to get a pretty good handle on that in The multiple ascending dose and looking to what happens with both the RNA level. And what we're obviously trying to do is In the multiple ascending doses, they reach steady state and then they'll be able to monitor the HD RNA and proteins. And so we know that the in some ways they have HD has A leaky blood brain barrier. I think that's what you're referring to. So But so I think that's something that we'll have to take into consideration as we monitor The PK of them in patients.
Got it.
And thanks so much.
Yes, okay. And I would just make the other point. We don't have issues with ePlex, so that shouldn't
Thank you. Our next question comes from the line of Vincent Chen with Bernstein. Your line is open.
Thank you very much for taking the questions and congrats on the 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 PTC-five 180s? Which ones and how much were they modulated? And then the second question is, thinking about the ongoing study, how many doses do the Mad, healthy volunteers, yes.
And what's your sense for how much of run out is needed to assess the risk of off target toxicities?
Yes. So I think Could you just say the first question one more time?
Sure, sure. In the preclinical RNA Seq experiments that you did, How many other RNA splicing events were identified that were modulated by PTC-five eighteen? Which ones were they? And how much were they modulated?
Yes. So maybe it's worth talking a little bit about how we optimize the compounds in general. I think that's actually An important point. So when we the way we do the optimization and looking for In selectivity, selectivity is a pretty important point for us. And so we begin when we do the high throughput Screening with the small molecules, we screen them in the Huntington in fibroblast for them and then we Optimize those molecules for efficacy, which also include selectivity in pharmaceutical So we look very much so for us to select for molecules that may start out to be less selective, But build in select as much selectivity as we can.
So at the end of the day, we found we've identified these molecules and We spent a lot of time to show that they really do have favorable properties, a safety window that we've seen In the animal model, strong potency, and the ability and a pretty selective ACT that alters the select. We learn a lot about the mechanism and the specificity of that. And just contrast that with, for instance, the competitor molecule that was for 1 molecule and then the others. I can tell you that, for instance, The specificity of our molecule versus SMA is substantially different than Selectivity that's built in is far more selective for SMA than for HD than SMA. And That was a consequence of really spending the time to build in the selectivity within the molecule to be able to do that.
And that's really a consequence of both understanding The specific sequences, the differences between them, understanding how the U1 there works, where we can build in The selectivity in the RNA. See, I think in the deep dive that's coming up, we'll spend some more time on the question that you're And probably we'll be discussing that more during the deep dive time.
I see. That's very helpful. And 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 about splicing toxicities, how quickly would you expect those to show up and how much run out do you need?
So obviously for the multiple ascending dose, that's a 14 day dosing period followed by 28 days of observation. And so that's what we do in terms of defining the dose. But Jim, I got to remember also that we're also doing completing the long term safety toxicity studies that will help us. And I just I don't want anyone in the community in the to the folks that are listening to think There's something different about splicing toxicity versus any other toxicity, whether it's off target for .:] Splicing or other molecule or some other function, the key is, we spent a lot of time looking for selectivity and specificity. And then we look at toxicity could be for off target and it could be for whatever the reason is.
And So that's why we do those studies to look for the off target toxicities. But I don't think you can make the argument there's something unique about these To be able to identify the toxicities, understand the risks to be able to move forward. I think this is a very Standard and step wide approach that and the targeting of splicing is no different than doing kinases, Flasitases, transcription factors, other things that other people do. I wouldn't try and make it to something special here versus other things.
I see. I think that yes, yes, very helpful. Thank you for the color and congrats again on all the progress.
Thanks a lot. I appreciate it.
Thank you. Our next question comes from the line of Raju Prasad with William Blair. Your line is open.
Hi, there. This is Sami on for Raju. Thanks for taking my question. I was curious if there's any update on your Angelman syndrome gene therapy. And I believe previously you said that the Angelman program and Frederick's ataxia The gene therapy programs were delayed because of COVID.
I'm just wondering if that's still the case or if there's any other behind the scenes things going on? And then just secondly, how are you thinking in terms of the FDA's recent guidance for gene therapies for CNS diseases, how are you thinking about that guidance influencing those trial designs? And do you plan on using the same endpoints that will be used for the vitaquinone trial for Frederick's ataxia? Thank you.
Sure. So yes, you're right. We've talked about this in the past. And I do think So one of the things that happened during the pandemic is that there are really COVID related delays that push programs out. But we're really working hard and we're progressing on the FA gene therapy program and this effect The human dosing before year end.
Similarly, we're pushing hard on the Angel Mick syndrome. I don't think we actually gave Particular timelines on that, but there have been some that we're moving forward on that and we'll probably talk more about that We'll talk through over time as And so maybe, Matt, do you want to add any other color to this?
Yes, sure. Thanks for the questions, Sami. So on the I think you had some questions about our Friedreich ATAXA gene Therapy program and the recent FDA guidance. Maybe I'll just tackle the guidance first. Quite frankly, not a lot of surprises there.
It's sort of read Very standard FDA guidance for the development of therapies for nerdy and nerve diseases. I think they're obviously communicating the need to have rigorous control groups Even for gene therapy and they obviously also wanted to spend a lot of time talking about the importance of device and device comparability and using Making sure that your product works well with the device and having consistency throughout the development program. So all things that, one, not really different from general Guidance around CNS drug development and then second, with specifics of gene therapy, it's all things that we've learned and become quite familiar with A long way with our experience gauging therapy development. And I think the other thing that we're obviously Having our programs, which is very important is we're taking a targeted CNS approach and one of the few benefits to One is that we're able to deliver the gene therapy product to the specific anatomic areas where the pathology of the disease really results from. So For example, in our AADC program, we're delivering our gene therapy products to the containment, which is really the key area of dopaminergic neuron function.
In future ataxia, we're delivering our gene therapy precisely expediently inclusive of cerebellum. Obviously, the cerebellum is a key component of Ataxia, which is obviously a key component of the phlegic ataxia disease. And so by doing targeted gene therapy, not only does It allows us to have lower doses, which obviously lowers risk and exposure to the vectors and obviously it also lowers on manufacturing burden. Switching now to your questions regarding the Friedreich ataxia gene therapy program, I think we're actually incredibly excited to be able to We're developing 2 therapies for frigid ataxia. We have our oral small molecule, eptiquinone, which has Broad distribution of CNS and other organ systems as well as our gene therapy program, which is delivering tritaxin targeted mutant nucleus.
I think these are really complementary approaches. I think while Friedreich ataxia has a great deal of pathology resulting From the Genentate Nucleus, it's also a whole brain disease and a whole body disease as the heart, for example, is a significant source of disease morbidity and mortality So we view our approaches as incredibly complementary and we're excited to be able to offer both of these therapies in a complementary way. In terms of the development itself and endpoint selection, I think one of the great advantages of working at Friedreich Ataxia is the well established natural history. The community as well as a very rigorous natural history, particularly around the disease rating scale that was developed by the community as well as the activity of the daily living So as we think about gene therapy, the gene therapy development program, obviously, we're looking to those where there's Significant natural history, so we can really appreciate the impact of the gene therapy on a long term objective of the disease. But Obviously, in our first in human studies, we'll also be exploring other endpoints that are both biomarkers, biochemical mediators, imaging modalities and also other clinical endpoints that would be important to the disease and that would certainly capture the ability
Thank you. Our next question comes from the line of Danielle Brill with Raymond James. Your line is open.
Hi, guys. This is Anil Gautaulin on for Daniel. Taking the question. On the Slide 18, I had a question on 5 18, how uniform was the HTT reduction in animal models for a given dose? And is the reduction affected by the length of nucleotide repeats or any other factors that you could identify?
Yes, sure. Thanks for the question. So actually that's the beauty, the fact that One thing that I think really distinguishes PTC-five eighteen is that it really achieves uniform So when we look for instance, for HTT lowering in the cells and tissues analyzed, We'll see if we see a 50% reduction in blood, we saw in animal models a 50% reduction within the brain and the So it's amazingly Uniform. And that's good, right? And that's a demonstration of really, as I said, we had a one to one Ratio in terms of what we saw lowering in the blood within the brain, but that's true within all tissues as well.
So and that actually turns out to be, I think, very important because I know people have talked about Huntington in terms of Australia and But I think when you look, you see that Huntington disease is a whole brain disease. So it's very important to emphasize that Based on our preclinical results that we'll see a dose dependent reduction of the HCT mRNA and protein in all cells within the brain. That includes the striatum cortex and cerebellum. And so it gets everywhere. And then again, I think a really critical point is that and this is I think a real and this was true for SMA, I think it's That will be true here and you as well is that we have the ability to measure the reduction based on exposure Since we can determine that within the blood and that that same ratio that we see in the blood occurs in other tissues as well.
Right. Thank you. That's helpful. But in terms of the
like the HTT gene itself and the variation in the nucleotide Within HTT, does that have any effect on HTT reduction?
No, no. For a given dose?
Yes, that's near that's in a different location. The way this is working is, there's a It's within an intron of the pseudo exomes, the piece of the RNA within the intron that gets That normally doesn't get spliced in, but because of the molecule, it does get spliced into the mRNA and that leads to, Again, premature termination and rapid degradation of the RNA, that's not in the CAGR team and it doesn't matter As a consequence of that, so there is no issue with that and therefore And that's the beauty of this. This will be good for all patient types. And obviously, in the long run was You can see because it's orally bio available that the advantage here is that we would anticipate over time That it would be for patients, while we'll be looking initially at those that are manifesting symptoms, but you can imagine over time we would be able to do that for patients before they have symptoms because it's so easy to take. So I think that's important.
So at the end of the day, the answer to your question is that, Pseudo Exxon Corporation occurs Regardless of the degree of HGT expansion.
Okay. Thank you very much.
Sure.
Thank you. Our next question comes from the line of Joseph Fone with Cowen and Company. Your
Just one on the BioE platform, Curious with PTC 857, after you see these healthy volunteer data, maybe what are you looking for and kind of when Can we see that advancement into a potential GVA Parkinson's study? And then as 857 and abatiquinone both target 15 LO, can Can you kind of tell us what are the differences that make 857 maybe more amenable to the Parkinson's disease indication? Thanks.
Yes, sure. So I think part of what we're doing, it does have different properties. And 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. And for indications like GBA, what you said, Parkinson's, obviously, it's a different it's in a different Number of patient population versus 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 that there's a different value for the size of the patient population. And so we thought it was important to have On molecule. Matt, you want to talk a little bit of where we're at in terms of the trial and what we're thinking about?
Yes, absolutely. Joseph, thanks for the question. So as you mentioned, we've been studying 857 In the Phase 1 study, which was a single ascending and multiple ascending dose studies, fairly standard healthy volunteer studies where the focus has really been Safety and pharmacology, we completed the dosing in those studies and we're in the process of doing the analysis. And
Really what
we're looking for here is understanding the pharmacology, making sure that it's that the molecules behaving in humans as we've been able to model it from the preclinical studies And also identifying the dose level that gets 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 we've seen now as a bit of background, 857 targets 15 lipoxygenase, which is a key governor of a number of Pathways which independently are known to be important in Parkinson's disease pathology such as microglial activation, alpha synuclein oxidation, aggregation, glutathione, depletion and with the base oxidative stress. And so what we're able to do by targeting 15 LO is affect simultaneously all four of those pathways. So we do have an extensive amount of preclinical work demonstrating effect. And again, what we want to see in the Phase 1 study is identifying a dose level that brings us that 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.
Yes.
Yes. Thanks, Matt. And I think the really important point here as well is that, oxidative stress, right, Really extra electrons that cause oxidative stress, there's multiple diseases that we can go in as Matt has said. And so Having another molecule to go into other indications, with different properties, we think that's going to be valuable.
Great. Thank you so much.
Thank you. I'm not showing any further questions. I will now turn the call over to Stuart Peltz for closing remarks.
Well, thanks a lot for joining us today. And As many of you may be aware, the 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 And it serves as a report and reminder to us that we do this work ultimately to benefit the patients. And I Hope that you see just how strong our execution has been in 2020 and how this sets up For us, for 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, you can see by the question, The interest in the Phase 1 Huntington's disease readout and we look forward to sharing that