PTC Therapeutics, Inc. (PTCT) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the PTC518 Data Release Conference Call. [Operator Instructions] After the speakers' presentation there'll be a question-and-answer session. [Operator Instructions] Please be advised that today's conference may be recorded. I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Senior Vice President of Global, Commercial and Corporate Strategy. Please go ahead.

Good morning, everyone, and thank you for joining us. Today we'll be discussing the results of our PTC518 program in Huntington's disease. Joining me on today's call is our Chief Executive Officer, Dr. Stuart Peltz; and our Chief Development Officer, Dr. Matthew Klein. As a reminder, slides are available in the Investors section of the website for you to follow along during the presentation today. I will now pass the call over to our Chief Executive Officer, Stuart Peltz. Stuart?

Thanks, Kylie, and thank you all for joining us today. I'm excited to share some updates with you today on our Huntington's disease program and the development candidate PTC518. First, let me remind you that today's presentation will include forward-looking statements and I refer you to our SEC filings. We were founded over 23-years ago, based on being the first company tackling RNA Biology. One focus was on targeting splicing as a therapeutic target. These efforts were fruitful, showing that the modulating splicing with small molecules can be successfully accomplished with the receipt of the first commercial product from this pipeline. Our ability to modulate splicing has evolved over the last 2 decades, such that it is now the most efficient and sophisticated splicing platform. These efforts have allowed us to have a robust set of programs based on the splicing platform with the next most advanced compound being PTC518 to treat Huntington's disease. Based on the success of Evrysdi for treating SMA, we defined a roadmap to identify and develop Evrysdi. So the pathway began by understanding that we wanted to identify selective oral small molecule that penetrated the blood-brain barrier. We knew that it should have broad tissue distribution not be highly efflux, so that there is sufficient concentration in the brain and that we define the ratio between the blood and brain. Because healthy subjects of both copies of SMN gene, we could also show proof of splicing mechanism in cells of the blood in the Phase 1 trial for risdiplam. This was key because it gave us confidence that we had a non-target drug to move forward and demonstrate clinical benefits that ultimately led to the Evrysdi approval. As you can appreciate, we utilized the same approach to identify a candidate for a drug for Huntington's disease and we have designed PTC518 to retain these pharmacokinetic properties and to also to be highly selective for the target splicing site in the HTT gene. As you know, we have been conducting a Phase 1 study healthy volunteer trial with PTC518. Earlier this year, we showed preliminary results demonstrate PTC518 showed dose-dependent HTT mRNA lowering from both the single ascending dose and the initial multiple ascending dose cohorts. We're excited to share additional Phase 1 studies, showing substantial protein lowering. We will also show that based on the CSF pharmacology results, PTC518 crosses the blood-brain barrier. Matt will then share with you the design of our Phase 2 biomarker trial, which we believe can rapidly progress with a possibility to bring this therapy to HD patients as quickly as possible. Now let me turn to Huntington's disease. Huntington disease is a monogenetic disorder. It's a progressive neurodegenerative disorder that is debilitating and leads to movement, psychiatric and cognitive decline overtime. There are an estimated 135,000 patients worldwide and no approved disease modifying therapies and the phenotype often occurs during the prime of their lives. Huntington's disease, this was called the triplet nucleotide repeat disease. In the case of Huntington's disease, and have multiple copies of the CAG repeat within the gene. This mutation results in a gain of function. We need to RNA and protein aggregates. The greater the number of CAG repeats, the more rapid the outset, it's a devastating disease. The CAG repeats cause a gain of function mutation. Therefore, the more HTT gene expression there is, the greater the disease burden. Our approach is to reduce these burden by targeting HTT expression through splicing modulation, leading to less HTT production. I just described the goal -- that the goal of our therapeutic approaches to reduce the levels of HTT mRNA protein. There is a large body of published results demonstrating that animal studies using HD model system that show that a reduction in mutant HTT leads to a significant reduction in the Huntington's disease phenotype. Furthermore, human natural history studies have shown that HD patient we view they are only one copy, that have mutations that lower Huntington's disease gene expression levels also have better outcome, showing the delay in disease onset. There are also many animal model on human case studies that support the fact that reduction of the wildtype HTT protein is well tolerated, as Huntington disease is the monogenetic gain of function disorder in which higher mutant HTT expression causes greater disease. We're confident the HTT lowering approach. We are directly targeting the well understood reasons why patients have the disease. The way PTC518 reduces HTT levels is quite remarkable. As you see here, this is the HTT pre-mRNA with 2 exons, 49 and 50 flanking the infra. In the absence of the molecule, the HTT pre-mRNA splices normally generating a full length HTT mRNA. In the presence of PTC518, a pseudo exon continue the premature stop codon is activated and then the splicing to the HTT mRNA. The resulting transcript is rapidly degraded leading to lower levels of the mutant HTT transcript and preventing the production of the mutant HTT protein. From our experience, we learned that there are specific characteristics or properties that are required to create a successful orally bio-available splicing modifier and we work hard to optimize our molecules that have these characteristics. We have shown that in preclinical studies, PTC518 has demonstrated all of these characteristics. It penetrates the blood-brain barrier and selectively reduces HTT mRNA and protein in both the CNS and periphery in a dose-dependent manner. It is reversible, titratable and not effluxed. So uniformly distributed throughout all key regions of the brain, showing reduction of HTT mRNA and protein. I'll now take a moment to review the Phase 1 healthy volunteer study, both the preliminary and recent results. As a reminder, the key objectives of the Phase 1 healthy volunteer study are to establish a target dose range of PTC518 for subsequent studies that reduced HTT mRNA and protein. This is why the study consisted of a single and multiple ascending dose cohort. We have already shown results from the single dose and initial multiple of dose portions of the study, demonstrating a dose-dependent reduction in HTT mRNA levels and safety and tolerability. Today, we'll add the results showing that the HTT protein in mRNA are reduced, and that the PTC518 is in the CSF showing that it passes the human blood-brain barrier and we're able to -- it will be able to reach all parts of the brain. I just wanted to remind you of the preliminary results of the single ascending dose and initial multiple ascending dose that demonstrated the PTC518 exhibited dose-dependent lowering of the HTT mRNA. We were delighted to achieve the target level of 30% to 50% lowering in the lowest dose tested both in the SAD and MAD cohorts. It is important to think about what a reduction of 50% in mRNA level means in terms of the steady state within the cell. The half-life of HTT mRNA is about 24 hours. So after one day of no new HTT mRNA is made, this should be a 50% of the baseline. This tells us that PTC518 essentially inhibits the production of all new mRNA. So at the higher levels of drug in the SAD was that the remaining 50% of the mRNA was a customers of the previous synthesize RNA and splice mRNA that was produced prior to PTC518 treatment. The preliminary results from so far were very exciting and the PTC518 was able to promote a 50% or greater reduction of HTT mRNA levels. PTC518 was well tolerated, demonstrated predictable pharmacology and showed a dose-dependent lowering of HTT transcript. Before I share the new results, I first wanted to take a minute to review how to think about mRNA in protein degradation kinetics that lead to a steady state levels of RNA and protein. Let's start with them treat itself, with our steady state levels of mRNA and protein. This is because the amount of mRNA and protein being made, matches the amount that has been degraded. So the mRNA and protein levels are the same overtime. Now let's say PTC518 would lead to inclusion of the pseudo exon into the transcript resulted in rapid decay of HTT mRNA. In this case, the concentration of PTC518 added or reduced the HTT mRNA to approximately 50%. We know the half-life of HTT mRNA is about 24 hours. A day after drug treatment, the amount of transcript that is present is regulated by how much of the drug was used. In this case, 50% of newly synthesize our mRNA is inhibiting. In the case of the original HTT mRNA that was made before PTC518 addition, about half of it will be degraded. In this case, after a day, half of HTT RNA would have decayed, so that the overall change in level would be 75%. After a few days, all of the original HTT mRNA would have decayed. Then only the newly synthesize HTT mRNA produced in the presence of the drug would be present and would come to the steady state level that is 50% of the HTT transcript present prior to drug treatment. The HTT protein levels depend on how much mRNA produce. Therefore, reducing the mRNA by 50%, we call the 50% production of the HTT protein, however the HTT protein has a longer half-life, approximately 5 to 7 days. So it will take longer to get to the new steady state level. Finally, after all the previously produced HTT protein is degraded, a new steady state is reached where 50% of the pre-treated mRNA and protein level are present in the cell and are at steady state. So while the timing may be different of reaching steady state, the levels of protein in mRNA will settle at the same level. In order to look at the changes in protein levels, we needed to complete the multiple ascending dose cohort with a longer duration. In this case we treated healthy subjects for 21-days and then modern mRNA and protein levels. Based on these results, we also can accurately model, what the steady state of both the HTT mRNA and protein will ultimately be. Now let's turn to the data. We have modeled the rate of mRNA and protein decay based on their half-life, which shows the predictive time to reach steady state after PTC518 treatment at 30 milligrams daily dose. For HTT mRNA, the half-life is about 24 hours. The mRNA reaches steady state after approximately 5 days. For HTT protein the half-life is much longer, about 5 to 7 days. So it should take about 6 weeks to reach the steady state. The light [grey] data points are based on our model that protects both the time and HTT mRNA and protein level based on the respective half-life. Now let's turn to the results seen in the 21 days duration cohort of the multiple ascending dose. As you can see, the trajectory of mRNA protein lowering is very predictable and follows the expected time for us. mRNA level rapidly decrease and reached steady state at about 4 to 5 days of treatment. As predicted the rate of protein lowering is slower, which you can see after 21 days of treatment is approximately 40% HTT lower rate. If we were to dose for longer, we anticipate the steady state HTT protein level, which reached the same level of reduction of HTT mRNA, which would take about 6 weeks. This confirms the level of mRNA and protein reduction will be equivalent at steady state. These are really good results that put us in a really good position for the next step. We have demonstrated a PTC518 versus splicing of the pseudo exon to create a dose-dependent reduction of both HTT mRNA and protein. Now let's switch gears and talk about the PTC518 levels in the CSF. One of the questions were commonly asked is how do we know the drug crosses the blood-brain barrier. To accomplish this, we measure PTC518 levels in the CSF in a cohort of human subject. This will determine how much PTC518 crosses the blood-brain barrier completes the levels of the blood. As you can see, there's a good correlation between PTC518 levels in the CSF and in free plasma, which is similar to the non-human primates, we've already shared in the HTT tag. The 2 subjects in this cohort received 30 milligram daily dose. It is clear that the results demonstrate the PTC518 efficiently crosses the blood-brain barrier at significant level giving us confidence that PTC518 will be well distributed in the brain -- in all brain tissues. Now I'd like to briefly turn now to the food effect cohort, the final component of the Phase 1 study. The results show the food affect cohort demonstrated that PTC518 showed increased exposure, when taken with the fat meal. These findings will be considered in the dosing regimen for the Phase 2 study. So we've now successfully completed all facets of the Phase 1 healthy volunteer study and are excited to have met all of our objectives. Analogous to the path we use towards an Evrysdi approval in SMA, we've shown that PTC518 can reduce levels of HTT mRNA and protein in a dose-dependent manner. We have not only also shown that PTC518 passes the blood-brain barrier, it is also formed a substantial level of PTC518 in the CSF. It is also well tolerated. PTC518 should predictable pharmacology such that we can provide a dose that leads to a defined exposure that leads to a defined reduction in HTT mRNA and protein. These results are key to success of the PTC518 program. These are important results that help us set up for the next set of trial. As Matt will tell you, the goal of our next step is to outline the clinical path that we think will rapidly bring PTC518 to patients with Huntington's disease. The first of these next step is to initiate the Phase 2 study in Huntington's disease patients and I'll pass to Matt to provide more details on this. Matt will also describe for you potential pathway to rapidly accelerate this program. Matt?

Thanks, Stu. Now that we have successfully completed all the objectives of the Phase 1 study, we are moving full speed ahead with initiating the Phase 2 study. I will take you through some of the key elements of the Phase 2 study, which we plan to initiate before the end of 2021. The key objectives of the phase 2 study are to demonstrate safety, tolerability and pharmacology of PTC518 as well as decreases in Huntington mRNA and protein levels in Huntington's disease patients. In addition, we plan to study the effects of PTC518 on a number of blood based, CSF based and radiographic biomarkers of disease that could potentially allow us to pursue an accelerated approval pathway. The FDA approval of Biogen's Aduhelm demonstrates the openness of the agency to utilize the established accelerated approval pathway for severe neurodegenerative disorders like Huntington's disease. Therefore, we are ensuring that our Phase 2 HD trial protocol contains the necessary design elements and endpoints that could provide biomarker data to support accelerated approval. In addition, we are also designing this protocol to provide information necessary to support a longer duration Phase 3 efficacy trial regardless of whether the Phase 2 trial is the part of the clinical data approval pathway or as a confirmatory trial following an accelerated approval. As shown on Slide 27, the Phase 2 study will be a double-blind, multiple dose, placebo controlled study, consisting of a 12-week, placebo-controlled phase, followed by a one-year open label extension. We are planning to enroll approximately 100 to 150 subjects, who will be randomized to receive placebo for once daily dosing with one of 2 dose levels of PTC518. After 12 weeks, placebo subjects will be randomized to receive one of the 2 dose levels for the remainder of this study. In addition, we will consider the addition of a third dosing arm, either higher or lower than the initial 2 dose levels based on HTT lowering and biomarker effects in the initial 2 dosing cohorts, leveraging the titrate ability of PTC518. As I mentioned earlier, we plan to initiate the trial by year-end 2021 and as in all of our clinical studies, we will be including study sites both in the US and internationally, leveraging our global infrastructure in KOL network. Our endpoint strategy was developed to meet the overall objectives of the Phase 2 study. The primary endpoint of the study will include measurements of PTC518 safety and tolerability in HD patients as well as percent HTT protein lowering in the blood. We will also include a number of disease relevant endpoints that will provide important evidence of pharmacodynamic effect and potentially support the accelerated approval pathway, including HTT protein reduction in CSF, neurofilament light chain levels in the CSF and plasma and preservation of brain volume as assessed by MRI images. In addition, we will also collect clinical outcome data including assessments of motor and cognitive function. It's well understood the key element in neurodegenerative disease drug development is identifying the optimal clinical trial competition. The so-called Goldilocks population, that is not too advanced in the disease such that demonstrating disease modification is not feasible and not too early in the disease such that subjects do not exhibit enough signs of disease topology to allow for demonstration of improvement. This is not a new concept to us. We learned the importance of selecting the right population that would allow for demonstration of meaningful clinical benefit in a reasonable timeframe through our working Duchenne muscular dystrophy. Now, let me tell you how we're doing this in our Huntington's disease program. We took advantage of the extensive HD natural history databases that are available, including the 20,000 patient low HD database and the track HD database, which includes biomarker and radiographic data in HD patients. We worked with externally HD experts and also brought the databases in-house, so that our own teams could conduct analysis to identify the optimal patient and disease characteristics of this Goldilocks population. We also utilized the natural history databases to identify biomarker and clinical endpoints that could be used in the Phase 2 and Phase 3 study. Let me provide a few key learnings from these efforts. First, we made a very important observation that focusing on the total functional capacity scale or TFC as has been done in a number of HD trial, will likely lead to enrollment of the study population that is too far advanced to be able to show meaningful clinical benefit in the time course of the clinical trial. Why? Because by the time TFC scores decline, patients are at the fifth percentile of the total motor scale and SDMT cognitive scale and have lost significant straight on volume. That is pretty far advanced, making it really difficult to demonstrate meaningful modification of disease. We're looking at the TFC instrument itself, there are items such as ability to hold the job and ability to comb your hair. By the time in HD patient loses the ability to do these things, the disease is so advanced, it will be quite challenging to restore these abilities. Therefore, as I think most disease experts would agree, a clinical trial of a potentially disease modifying drug should enroll earlier stage patients. So how did we identify these earlier stage patients? We look at trajectories of disease progression as a function of age, CAG repeat as well as other potential prognostic criteria and use these analysis to define the specific attributes of HD patients that would yield the Goldilocks study population. The study inclusion criteria would then develop from these predicted parameters to ensure study subjects are at the appropriate stage of disease. The key inclusion criteria are shown on this slide and include age of 25-years and older, CAG repeats of 42 to 50 inclusive and the requirement to be ambulatory at the time of enrollment. In addition, we are including specific criteria with defined score ranges around clinical, cognitive and radiographic parameters to ensure patients are added earlier stage of disease. We are also including a specific criterion related to the pin score, which is a validated predictor of disease progression that will help ensure we are enrolling subjects that are not too early in disease progression and are at a higher risk of declining over the course of the clinical trial. So in summary, we have successfully achieved all of the objectives of the Phase 1 PTC518 study. Today, we provide a key additional data demonstrating that at steady state we can achieve a defined ratio of mRNA to protein and demonstrated CSF exposure levels, consistent with what is needed to ensure that we achieve the desired broad brain bio distribution of PTC518. With the success of Phase 1, we are now moving full speed ahead into Phase 2. Phase 2 trial will include a number of innovative aspects with regard to patient inclusion criteria and will include a panel of biomarker entrance that it could allow us to pursue an accelerated approval. We look forward to updating you as we continue the important work to bringing this potentially transformative therapy to patients. Thank you for your attention. We will now pass the call back to the operator to open the line to questions. Operator?

[Operator Instructions] Our first question comes from Alethia Young with Cantor.

And congrats on this update on the data with the protein. Maybe 2 from me. I just wanted you to kind of compare contrast like how these detailed Phase 1 data match up versus like the antisense approach. Do you think they're differentiated? And then can you give us any color on kind of any conversations you've had with the agency around thinking about some of the novel markers for potential kind of later stage development?

Yes. Yes, Thanks, Alethia, for the question. Yes, I think there is a couple of really key considerations. And so, I'll start by reminding that PTC518, we designed this as an orally bio-available of small molecule that passes the blood-brain barrier. We've shown that it reaches all aspects of the brain, which I think is a key differentiator in the sense of licenses in the blood to get to the whole brain. So that is, I think one of the most important thing. The other thing we did is that we worked hard to make sure that it wasn't effluxed out of the brain, so that, right, which often happens with many molecules as they're pumped out. PTC518 is able to stay in the brain. So this is a critical property and so that we made. And then we also have these advantage of when we measured the levels of 518 in blood, we have -- we can know what the concentration is in the brain as well, so I think that's really quite nice. And then the other thing is, obviously, that the molecule is titratable. So we can define the exposure levels we can titrate to where we want to get too, so you know you're able to define the dose that causes the reduction in HTT protein. And that we get uniform exposure into the lower's, really the HD levels, are in tissues that we analyze. So we're in a very good position there and that we know that we get into the brain, right. So I think those are really important points that I think we emphasize and we've seen these results both in, not only what you're seeing here but in animal models as well. So that's actually important as well. And so the other point of this is that differentiated in terms of the mechanism of action. So we use and that's occurring pseudo exon in an interim. And so we can induce that to come in which causes [indiscernible] and promote rapid degradation prevention of that. The other, I think also key is that we can monitor the level and so we can look to see not only one, what's the exposure levels with consequence of lowering, what is a lowering of these 2 key and we could do that in healthy volunteer. We spend let's says the setup be ready to be able to do that in HTT patients. So I think that really does put us in a really good position. So I think those are [Technical Difficulty]. And what was the second question?

Any conversations with regulators about the Phase 2 or regulatory endpoint?

Yes, Matt, you want to go through our process?

Yes, absolutely. So thanks for the questions, Alethia. So right now we're focused on getting the IND cleared and moving forward with the Phase 2 study. We're confident that all of the elements of the design that we have described today will be able to conduct in the trial, and again we have pay particular attention in this protocol to not only gain the essential safety pharmacology data, but also to be able to take those key biomarker data, which over the course of that, all the placebo controlled phase, but also the long-term open label extension, but give us a really solid collection of data that could provide surrogate endpoints that could potentially provide the basis for an accelerated approval. And so as we move forward in the trial, we will continue to interact with the agency at that -- those elements as we collect data throughout the trial.

Our next question comes from Eric Joseph with JPMorgan.

Just perhaps a clarification question first and can you -- are you going to note that those levels for which you booked at protein lowering in CSF distribution. I'm curious whether you evaluated those higher than 30 megs in the non-portion and the extent to which you're confident from a safety and tolerability standpoint, should you need to dose escalate in the Phase 2 Huntington study?

Yes, yes. Thanks. So that as we see in the CSF in healthy volunteers, where we were limited really by the number of patients that we get. So that was the only dose that we do, but you can see in the blood we were able to get -- you can see the RNA levels went down to about 65% within that range. So we think we're actually in a good position there. And we'll be able to obviously modulate and measure the HTT levels and I think we've said all along, we're trying to suit somewhere between 30% to 50% in terms of the HTT level reduction of that, and I think we're really in a good shape. I think that's a Phase 1 study shows us that we're able to get even beyond the 50%, really quite well. So we anticipate that doses will be -- that will be well within our ability to actually reduce HTT. And I think the other aspect of this is that -- that's really important is that we were monitoring this as we go along and we can actually titrate up or down the dose based on what we guess. So I think this is actually very encouraging and we're seeing -- and with regard to safety, we've been able to do this within the safety margins that we've been able to see. So I think we're in a pretty good position in terms of being ready and getting the right dose in the Phase 2 trial. Matt, you want to add anything else?

Eric, just to follow up on Stu's comment, we looked at dose levels 30 milligrams in the CSF as well as 13 over the course of the dosing cohorts. So those are levels consistent with where we've also observed the mRNA and protein reduction and obviously these are dose levels that are at the lower end of the range that we've included in the Phase 1 study. So we don't have concerns around tolerability, safety, further doses that were used in the Phase 2 trials you mentioned.

Got it. Okay. And then actually the CSF evaluation, right. The confidence on efflux not being initiated that based on. I'm just curious to know how that -- other that ACH is conduct a unity ACH CSF concentration at multiple points over the 2 week treatment period. I guess the level of -- the developed exposure that we see right now, do you expect that to reflect any state with longer-term courses of the treatment?

Yes. So the CSF levels were taken at 7 days after exposure was the 30 milligram dose that's what we're seeing. And I think what's -- there were multiple time points that we took after that, you can see really quite nicely when you look at the ratio of blood to CSF. We're in a very good position and that really I think is demonstrating that what we've seen before in terms of the molecule, not efflux, we'll be able to get to concentration that we want to get through not only in the blood, but also in the CSF and that's what this is demonstrating. And I think this is a really an important point here is that, we're able to show that we are able to get the drug levels to where we want to be able to get. And that -- therefore we will be actually sitting all areas within the brain, which I think it's going to be a major advantage for program and that it gets to all regions and therefore we'll see a totality of the effect of reducing HTT RNA and protein themselves. So this is really I think an exciting part of what we're showing in the Phase 1 trial.

Our next question comes from Robyn Karnauskas with Truist Securities.

So just a couple more. I'm just looking at this trial versus the ASO approach. So I think in the uniQure trial, they're looking at early patients, but it's -- with the of TFC of 9 to 13 and you're talking about being ambulatory. So can you help us understand how your patient population might compare to that population? And with regard to regulatory strategy, I think they're also going after -- they sort of said that like they're going to potentially be able to file a conditional approval based on about 26 patients treated, 13 in the open label -- another open label controlled arm. So I'm sorry, I'm losing my voice. So basically, on a shorter population, but they are doing at blinded, right. Sorry, it's gene therapy not ASO, sorry, I'm having a rough morning. Basically my bottom line is like, how are you really compare -- how does your trial compared to that? What are your thoughts on conditional approval? And then, how do you really think about, what you would need for -- ability to get approved on conditional approval. I know they're doing a natural history study. Would that be something you'd have to do as well so that you do have these biomarkers? Sorry about my voice.

No, no, no. Thanks a lot. And I think this is -- I'll start with the second one first and then I'll ask Matt go through a bit of the trial design. But I think, in terms of the approval pathway, I think, to us some of a game changer was the Biogen result with ADUHELM in terms of being able to get an accelerated approval, and therefore the openness of the FDA in terms of using biomarkers and potential as the means of doing that. And in a way I can't think of a better example than the monogenetic disorder for Huntington's disease where we can monitor the levels of Huntington's protein within the blood and demonstrated the reduction, but also see and looking at biomarkers internally in terms of both the Huntington levels in the CSF as well as looking at biomarkers and success in neurofilament and then we'll be looking at other clinical markers as well, but I think those are 2 important biomarkers, where we can see where the levels are, and then move from there. So I think while we'll be doing a 12-week study, we'll be looking at this as well beyond the 12-weeks and have an extension that would go on beyond that as Matt has talked about. So I think that's key to this. And so looking obviously, having the biomarker to be able to look at that have a placebo effect, I think that's the objective measure that actually we were doing and to have a placebo will actually be helpful for that. So as I said, we will be continued to treat up to one year. So we'll have long-term retention and safety data and we'll continue to harvest the biomarker data of that, that I think will support the treatment benefit, especially when we compare to natural history trajectory. And there's a lot of natural history that we've been looking at as well. So we're bullish about the ability. We're in a very good position to be able to produce that data and then I'll -- let me pass this to Matt in terms of the comparison of the trial design.

Yes, sure. So thanks for the question, Robyn. So one really key point here is that the TFC criterion of 9 to 13 is actually quite [ valid ]. And that was really one of the big "Ahas" we had when we looked very carefully at the natural history academy. So if you take 13 as the sort of starting point for TFC the highest possible score, as you start to see the TFC decline, you're at a stage of disease where you are down to the 5th percentile in terms of total motor score and cognitive function. For example, striatal volume is also down at the 5th percentile of that trial. So you're really pretty far advanced in the disease. We believe it, as many others do, that if you're really going to have an effective study design for a disease-modifying agent, particularly one like we have, the PTC518, which is uniquely in the neurodegenerative disease able to get to that because of the disease upstream to the disease pathology, you really want to be earlier in the disease course. You want to be at a point where you can practically demonstrate that you can preserve motor function, that you can preserve cognitive function and importantly from a biomarker standpoint, that you can preserve brain volume. As Stu mentioned, these biomarkers, including volumetric analysis of the brain which is a lot of natural history, would be a very important surrogate that would certainly meet. We believe the statutory requirement of likely to predict clinical benefit in terms of an accelerated approval. So [ it's imperative ] to make sure that we were developing a set of criteria that would ensure that we would enroll earlier stage patients. And then also with the use of the PIN score, which is this predictive algorithm that was a validated report of literature of 2017 by Jeff Meischen, Trinity University [indiscernible] natural history work on HT. That PIN score we apply in this particular case predicts patients who are likely to progress and decline in terms of motor function, cognitive function and radiographic brain volume over the course of the clinical trials. So we are using that as a strategy to enrich our population that would -- that would likely decline in the absence of therapy so that we can have that as a basis of comparison to the treatment effect of PTC518, both in terms of biomarkers and of course ultimately in terms of clinical benefit.

Okay. If I could just ask one quick follow-up. So just to be clear, post-approval, you think you would not only have to have the CSF but also the brain volume, in your filament, all those things to different biomarkers potentially, you don't know yet, but that could be a potential. I just want to clarify. And second, when we do see the 4 patients from uniQure, they're going to meet early, and when you're thinking about how your drug would be at that time point, can we glean anything potentially about how much better response you might feel you would have given you could have more broader distribution. I know everyone's going to ask you that so I might as well ask you on the call today.

Yes, I think in terms of accelerated approval, I think we're in a position where we believe there are several different potential surrogate endpoints, right. I think if you think about CSF, HTT levels for instance, CSF is acellular space. Our Huntington protein that gets us to the CSF is likely due to neuronal cell damage and spillages for CSF, right? Usually, you don't have neurons or other cells in the CSF. And so being able to demonstrate a decline or lowering of protein in the CSF is a surrogate of neuroprotection, protecting neurons, injured neurons dying and that's HTT protein with CSF. So we believe that is a very important biomarker, given what we've been able to show in terms of correlation of peripheral and central HTT low, we believe that's potentially valuable surrogate endpoint and of course, being able to preserve brain volume, I think, we all would agree that disease where loss of brain volume correlates with clinical decline, being able to preserve brain function was likely to predict that it's going to have a long-term clinical benefit. So we're confident in that.

Yes. And I think the other point that's important in terms of the -- what you're talking about with the uniQure readout, I think what's interesting I think there has been -- you have to remember they've seen uneven distribution in the sense only if their pig model and that led to somewhat of a disconnect between what we're seeing in the brain versus the CSF. So again, it's all -- it often -- as it often does and comes back to be not only have a drug that's selective and capable of lowering of HTT RNA protein levels, but it's also key to distribute throughout the brain and if we can get to all aspects of the brain, it becomes more difficult to see what happens to that. So the readout will be interesting from their point of view, but not necessarily predictive of what will happen here.

Our next question comes from Tazeen Ahmad with Bank of America.

I think most of them have already been answered. But can you maybe still give us a little bit more color on the NfL biomarker? I know there's been a lot of discussion on it, and -- even on this call already, but really what would be convincing evidence on NfL and what has FDA told you about the use of that biomarker, especially for the study?

Yes. So from the point of view of what we think the NfL is, it's a marker of injury, right? So you -- it tends to go up when there is injury and obviously some of that. So I think that's a marker reduction is considered to be important in terms of maybe lowering the injury and data. In terms of the discussions I think Matt -- as Matt talked about we'll be having those discussions over time. So we haven't really had a precise discussion yet in terms of what the [ NfL disease ]. However, we do know the NfL has concerns that correlate with disease progression. So by reducing it, you would anticipate that you would -- you're having effect on the disease.

Okay. And has FDA opined on this as well with you?

Matt, you want to comment?

Yes. Today, as we said, we are in regulatory interactions now and are focused on getting the trial up and running. I think in terms of regulatory viewpoints as surrogates, I think the FDA, when you have discussions that are consistently reverting towards already said in terms of the statutes which is, they want to be able to demonstrate that something likely to be suggested clinical benefit. So as we collect data and put the story together, that's obviously going to be the bar that we'll need to clear in terms of the accelerated approval. And importantly, we're in a position to have a constellation, obviously, has been different as we talked about, rather than many potential biomarkers that could demonstrate the possibility of predicting clinical benefits. So I think that puts us in a very, very good position in being able to collect data that could be used [indiscernible].

Our next question comes from Danielle Brill with Raymond James.

Stu, I guess, first, I'm curious why you conducted 21-day MAD study if HTT protein halfway its 5 to 7 days and what gives you confidence that the safety profile, and I guess, protein reduction will remain stable and clean after the 6 weeks of dosing when study states reach? And then I guess maybe just for some more specifics on the 10 HD score, sorry if I missed this, so what is the range scores that you're including at baseline service of that Phase 2 study?

Sure. So on your first question, which is the 21-day cohort, we did that really because we were in the Phase 1 unit and therefore we were limited by their availability to go beyond that. But I think we felt really that -- so we pushed it as far as 21 days and that we thought that that would give us the duration needed to reach a target lowering that we'd be comfortable that we would see, and you can see we reached the lowering of 40% within that timeframe. So and then when you look at where that tag and where we would predict based on the model, it's just right on top of it. So I think we're in a really good position there. And then, obviously, we will be going into HTT patients in Phase 2 so, and that's going to be going out to 3 months and you can see the RNA levels were quick within those 21 days. So approximately 65% the model looks like it's going to go right down to the same number. So we're pretty comfortable that we can get to that level within that. And so, Matt, do you want to comment a little bit for the Phase II and safety?

Yes, sure. So in terms of the Phase II and Phase III and on the PIN scores, so we're comfortable to see that, Danielle, the exposure levels that we are achieving for the protein lowering level, we're seeing appropriate safety margins for the doses that were used in the Phase II study to achieve the desired protein levels. And we don't have concerns there at this time. And then in terms of the PIN score. So the PIN score is prognostic index that was developed by HD researchers and the initial validation was published back in 2017 on movement disorders and what they basically did was develop the prognostic index based on several important factors in the disease including cognitive function scores, motor scores, agency, CAG, the peak line and we were able to develop an equation basically that would predict later loss of function disease. Now, what we did, and again, by having a multivariate equation, we were able to put in several different predictors together that improved their ability to more precisely predict patients at risk of later stage progression. But we did for this trial, we worked with the same group and we found that this PIN is also an effective index for evaluating the risk of progression earlier in the disease. So not to decline late stage, but it also was able to predict the likelihood of declining through that -- those earlier stages of disease, which is really, really want to be in the clinical trial. So what we did is work with them to develop a range of scores that will -- that we're going to put into our inclusion criteria that I'm sure that we're enrolling a population that is a greater risk of decline of motor function and cognitive function. And this really, we believe is a very powerful enrichment criteria that will allow us to evaluate 518 in a population that's symptomatic, but earlier in disease progression and therefore better suited to benefit from the HTT lowering compounds like PTC518. Those -- the criteria we're not giving -- we're not sharing a specific scores right now, I think, for obvious competitive reasons, but obviously what we posted on clinical trials that delve in the inclusion criteria go up as we given at the start of trial.

Our next question comes from Joseph Thome with Cowen and Company.

Maybe first one just on the CSF exposure. In the non-human primates, it does look pretty 1:! and then the humans. It almost looks like you're getting more exposure in the CSF than plasma. Is this expected? Is this just due to noise because it was 2 patients here? Maybe any additional information there? And then on the second part, maybe just a little bit more on how you devise the model here. Is this based on animal studies? And I guess, in a BACHD mouse, did you see similar kinetics that you're bringing down mRNA first and then the Huntington follows?

Yes. No, I think the -- I think as a consequence of really developing the molecule, so that it did influx, we're seeing -- you can see as, as I said, we're getting very good levels of drug within the brain. There's -- and so it's clear that it's -- I think that's 518 efficiently crosses the blood-brain barrier, really quite significant levels, not efflux and really gives us confidence that we can achieve the target within the brain. And that we're going to -- obviously, what we'll be doing is to monitor the blood CSF relationship as we go forward in the Phase II trial. Obviously, one of the important points is that we could take advantage of the titrate mobility of 518 as we monitor the biomarker. So I think we could be in a very good position, not only to look at what low level -- what levels we reduced it in the blood, but the consequence of all 3 reductions of HTT and the CSF as well as the NfL. and therefore, we can actually go -- have a pretty good ways of saying so we try and go higher or lower. So I think that's where we are right now, and we'll take advantage of that. We take advantage of the fact that it's titratable and the biomarkers as we make decisions, as we go forward on that. And then what was the second -- Matt, what was the second question?

The second one was just on the kinetics of the model. Could you show a similar kinetics on the BACHD mouse? You can treat them longer than the healthy volunteers?

Oh, yes, yes. We've done a lot of work in terms of looking at and look at both the half-life of the [Technical Difficulty] we're basically the same both in the BACHD as well as what we see in human. So we're pretty confident of this model. And what's beautiful is that you could see the data points reflect what happens within the model. So I think we're in a good position in terms of knowing exactly what we need to do there based on not only the data and how it fits, but also what we were seeing in the animal model studies. So the molecule itself is behaving beautifully as we anticipated.

Our next question comes from Colin Bristow with UBS.

A couple of quick ones. If you go to the subpart age pathway, how many patients worth of safety data and what duration would you expect to have at the time of filing? And then just, obviously, we've not seen evidence that synthetically reducing HTT as a benefit on disease course. And just in the context that you're lowering wild type, and there's some conflicting natural history data. How do you see this in the context of FDA's willingness to allow this as a surrogate?

Sure. Let's sort of take it from the notion of -- let's start with the notion of, first of all, that we're dealing with HT Huntington's disease, which is a monogenetic disorder as a consequence of the age, of having the CAG repeats, right, in the early part of the gene. And we know it's actually due to that, right? So it's pretty clear, and it's again a function mutation that leads to aggregation and neurodegenerative death. So it's a pretty good position that having more -- and there's data when you look at both the animal models, a large number of animal models, which I think clearly show that a reduction of HTT improves the outcome of that. And -- so, I think that's -- we're pretty confident of that. And then, if you look at the -- in human data, SNPs, where you see reductions of HTT production in Huntington's patients, there's an elongation prior to disease outcome studies. So there's lots of data that demonstrates that. So when you contrast that with even in Alzheimer, in terms of plaque, where the data is not nearly as strong, it was still utilized as a biomarker. So I think there's pretty good precedents that HTT -- mutant HTT causes the disease and then lowering it would be important. And then from a safety database point of view, Matt, why don't you talk about our [ 13 range ] talk about moving forward with the FDA.

Yes, absolutely. So Colin, obviously, the high hurdle here is being able to collect the biomarker data that would stand for the accelerated approval. Over the course of the 12-week placebo-controlled phase and the year-long open-label extension with the 100 to 150 patients, we will have a substantial safety sampling that we believe could be included in an application for accelerated approval. And of course, we can continue to treat those patients while they're continuing to grow the safety database from the study as well as if needed to, if the agency wanted us to include additional patients for safety, we can certainly do that. So I think we'd be in a position with the patients treated in this study with the duration of the open-label extension to have a volume of safety data that it's not sufficient, could easily be supplemented to provide additional safety data as part of the filing over time.

So, we think it's a potential game changer if we can use the accelerated pathway in terms of getting it to patients quickly and then do an outcome study subsequent to that, that really, I think would be beneficial, obviously, for the patient to be able to get it earlier.

Our next question comes from Gena Wang with Barclays.

First, I just wanted to confirm, 30-milligram dose was used for both Slide 17 and 19?

So, Matt, you want to?

Yes. That was the dose we used for the CSF as well as the protein.

Okay. Good. So also, did you show plasma -- drug ratio in BACHD mouse model and how that compare to non-human primates?

They were in the non-human primate and mouse, they were all approximately similar.

Okay. So roughly 1:1. I wanted to revisit because the human seems a little bit higher. When we look at the ratio, actually it's much higher. So that means you may have a higher -- whatever we saw the level of in a mouse knocking down in brain, but you may -- in human, would that correct to say that in human, we actually may see higher knocking down in the brain because you actually have a higher ratio in the brain? And then a related question is, I know it's open-ended, and nobody really know the answer, giving Roche failed trial. Despite impressive knockdown data and many open questions on toxicity or wild-type knocking down and also the real level of knocking down in the putamen. So there are many levels of open question, but certainly, one question will be wild type knocking down, how much negative contribution to that? So taking that into consideration, like what will be your thinking regarding when you look at the blood knocking down level and thinking about the CSF level?

Yes. No. So in some ways, this is actually really quite good where we -- obviously, it's efficiently being able to pass the blood brain barrier and efficiently be able to get substantial levels within the brain. And so, I think the advantage we have is we have able to measure not only the reduction in the blood, but we'll be looking at the biomarkers and looking at reduction both for the biomarkers that includes the HTT levels that you see in the CSF. And then, I think we'll take advantage of the titratability of 518 to be able to monitor those results into biomarkers that allow us to make decisions of how we're doing in terms of reducing dose and what dose levels -- dose level decisions. So -- and then, you have the advantage really nicely that we can actually think about the titratability of PTC518, right? That's the beauty of an oral small molecule. So we can really utilize the biomarker data and harness that to make the key decisions in terms of moving forward. So I think it really places us in a very good position.

Okay. My last question is regarding the Phase II study design. Is dose level 1 and 2 15 and 30 milligram?

So Matt, do you want to go through, I think?

Yes, Gena. So we have not -- obviously, here shared the specific dose levels. But clearly, the fact we now have all the inputs for the dose, right? And obviously, we're going to -- as we are developing the dose levels, we've taken into consideration plasma exposure, CSF exposure, ratio of the 2 relative -- what we're seeing in terms of dose mRNA and protein lowering in the blood, what that would mean for the brain. So all the factors you raised, of course, are ones we're taking into consideration as we establish dose 1 and dose 2, which we'll share as we get closer to starting. But we have all the inputs. And as Stu said, we regard the differential exposure of CSF and plasma is actually an advantage. We'll obviously take that into consideration and then knowing that we're going to be looking at the data and have the ability to titrate higher or lower as needed as we begin to harvest data looking at both HTT reduction in blood as well as some of the biomarkers. So we feel like we're in a very strong position now that we have all of these data and achieved everything we needed to achieve in Phase I to have those inputs to help us generate that dose 1 and dose 2 as we move forward.

Okay. Actually, I just had a thought regarding because your human plasma CSF correlation is in the healthy volunteers. Just wondering, would that be anything different in the actual Huntington patient?

Yes. We'll be -- we don't anticipate that they will be. But obviously, that's one of the things that we'll be doing is monitoring that. And I guess to your other point in terms of when you actually talked about the Roche data and the level, I think it's very hard to utilize much of the data that came from that study because of -- as I think we've talked about in the past, we think it's really a consequence of an inflammatory response. So it's hard to actually be able to talk much about that.

Our next question comes from Raju Prasad with William Blair.

I had a question on the 12-week time point for the Phase II. Is that primarily just for the biomarker data? I mean, do you expect to see clinical differentiation on some of the measures there? And then I have a follow-up on just what types of data you're looking at to determine if you need to look at the alternative dose in the Phase II study? Is it going to be clinical measures, biomarkers? Or is it primarily just mRNA and protein reduction below the 50%?

Yes. So I'll start and then I'll ask Matt. The key of the trial really is to look in -- based on the data that we have from the Phase I trial that we then want to make sure that what we see in healthy volunteers is the same that we see in Huntington's patients. And so then, obviously, from there, we'll review the results from the first 12 weeks from the Phase II study and look at them in relationship to the arm. So Matt, you want to go through a little bit more details of what the objectives are?

Yes, certainly. So Raju, we'll be -- so obviously, we don't expect to have a lot of clinical outcome data moving into 12-week placebo-controlled trial. That would be unexpected. Obviously, the earlier, the shorter phase will be more focused on biomarker, but of course, we have the open-label extension, which I think will put us in a position over time to be able to dive in the relationship between PTC518 treatment, biomarker movement and then ultimately impact on some of the clinical scales that we're going to use in the trial. As we talked about, we really worked hard to enrich this population with patients that are early enough in disease that would show modification and also -- and then using that PIN score enrichment strategy are likely to progress over time. So we'll be in a position to look at the impact on clinical scores over the open label extension and be able to compare them with what's been really well documented in the natural history databases. And in terms of the second part of your question, in terms of what will be the inputs to help inform a dose modification or dose -- they did the third dosing arm. Obviously, we'll look at the totality. Obviously, we'll look at, as Gena had asked, does the relationship between plasma and CFX exposure that we saw in healthy volunteers hold up in HTT patients. Are we seeing the lowering [indiscernible] in protein consistent with the healthy volunteers that we saw. And then also, obviously, looking at some of that early biomarker data to help us understand where do we want to go, in fact, to a higher dose or are we seeing enough reduction that we also want to even explore lower dose that was needed. But again, I think we're in a really good position here with all the data we have already and the design of the Phase II trial to be able to really leverage the advantages of this molecule.

Our next question comes from Brian Abrahams with RBC Capital Markets.

2 for me. In the prior data, you showed that the mRNA reductions persist robustly post-cessation of dosing. So I'm curious what you saw on protein post day 21, assuming that this was measured, just given the long half-life of the drug and the mRNA protein kinetic relationship. Did you see proteins start to revert back or it continued to decline? And then I had a follow-up.

Yes. So we -- in the -- I think the week after, it didn't decline. It didn't go back up all that much, but you wouldn't expect it to early on. So we thought that it would take some time, but what we did is we saw stable lowering of that, and we anticipate that over time, just like we've seen in animal models that [indiscernible] back up and it gets back to the normal level once the drug has gone from the system and that there's a change of the steady state level.

Got it. So to clarify, you continue to see that 40% protein knockdown for a little bit of time after dosing?

Yes. That's correct.

Got it. And then also on -- my second question is also on protein lowering. I'm curious -- I'm realizing that you really need to get out to 21 days to start to see the more robust effects, but you did start to see -- it looks like that 20% reductions at 14 days, what did it look like in the 14-day cohorts? Did you see a similar track in those first 2 cohorts? And was there any dose dependence between the 15 and 30 dose levels? Protein...

Right. So we only have -- no, we don't have both those levels, really, have one dose level for the HTT protein levels.

Okay. Got it. Okay. So you didn't look at protein in the 2 14-day cohorts because of the genetics?

Yes. Let me go back. I think the -- yes, I think what you're saying is that it would be around 20%. I think that's what we saw when we went back and looked at there as well.

Got it. Okay. And maybe one more quick one, if I could squeeze it in. Can you make any comments on the safety profile that you observed with this longer 21-day 30-milligram dose? And overall, kind of what more needs to be done in order to enable an IND?

Yes. Matt?

Yes. So Brian, we have all of the safety toxicology work done to support the 12-week placebo-controlled study. So from an IND standpoint, we have a need of the -- from the Phase I study, overall, well tolerated. The majority of adverse events that were observed were mild, and they were -- consisted mainly of nausea and GI symptoms as well as headache. So for the dose levels we'll be using in the Phase II study, we have a very strong support in both the non-human primate study and the Phase I study to support those.

And we have a question from Eric Joseph with JPMorgan.

Just curious to know if we can talk about where the field is in terms of using PET or radiotracers for characterizing Huntington's and HTT accumulation, I guess, kind of following the ADUHELM model with [indiscernible] is developing a PET trace of the Huntington, an avenue worth exploring? Or is that something being explored that might help secure an accelerated approval? Or would those observations largely be captured by the MRI volumetric resonance that you're planning to do in the Phase II.

Yes, good question. The PET markers, there are people now working on it. CHCI is doing -- [Technical Difficulty] of finding people to get something now. It's still in the phases -- in the exploratory phase, but we're hopeful for that. I think the other thing that we're interested for the exploration is the volumetric MRI, which may also be put for that as well. So -- and then there's a lot of information on that as well. So I think when I think about where we're at, I think we're in a stronger position because the origin of the disease is due to a single gene right? So that the reduction of this could lead to -- at the end of the day, being able to use it as a biomarker to demonstrate the effect. So I think at the end of the day, I think we're in a good position to be able to utilize the biomarkers and then have -- and see if anything else comes up afterwards from there as well.

And I'm showing no further questions in the queue. I'd like to turn the call back to Stuart Peltz for any closing remarks.

Okay. Well, thanks all for joining us. You could see, we're pretty excited about this. We're very pleased with the results from the Phase I trial for studying PTC518. And I think it showed not only that we're seeing lowering of the HTT RNA that went to the HTT protein, and that we'll certainly be capable of achieving the reduction of between 30% to 50% that we've always said. And also, I think what was important also for the community was to confirm that it passes the blood brain barrier that is not efflux. So I think we're in a really good position. So this really places us in a position where we have a highly selective tool that demonstrates reduction in HTT, passes the blood brain barrier and now in a position to be able to move it forward study and its effects in HTT patients. So we're excited about the potential of this therapy and the potential of being able to be sped up by accelerated approval. So with that, let me thank everyone for joining and hope to see you all soon.

This concludes today's conference call. Thank you for participating. You may now disconnect.