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

Good morning, and welcome to the 39th Annual JPMorgan Healthcare Conference. I'm Eric Joseph, senior biotech analyst at the firm. I want to thank everyone for logging in and joining us this week. Our first presenting company this morning is PTC Therapeutics. It is my pleasure to welcome and introduce Stuart Peltz to tell us a little bit about the company. A quick formatting note. There is a Q&A session after Stu's presentation. [Operator Instructions] With that, Stu, let me pass it over to you for the presentation.

Yes. Thanks, Eric. Thanks, everyone. Welcome. Thanks for coming today. As shown on Slide 2 in our presentation, we'll be making some forward-looking statements, so I want to refer you to our SEC filings. So as on Slide 3, I'm going to tell you today about how we're translating science to transform lives. And if you go to Slide 4, I think this slide summarizes the strides that we made last year to continue to build our company. We made significant progress in moving our pipeline forward to bring new therapies to patients on all fronts from research and development for commercial. In 2020, we initiated 6 clinical trials, including 2 registrational trials of PTC743 and our healthy volunteer trial with PTC518 for our Huntington program. The analysis from the dystrophin study will be completed this year. I won't focus on this today as we held a deep dive for everyone just last December. The AADC deficiency gene therapy MAA has been submitted, and we expect a decision in the first half of this year. The BLA is also anticipated to be submitted again in the first half of 2020. The DMD franchise continues to be successful with expanding patient usage and a year-over-year growth. It's also very exciting to see the Evrysdi's strong commercial launch after its approval. Roche has projected that Evrysdi will become the treatment of choice for SMA patients in 2021. And we're proud to have a strong and sustained capital structure with over $1 billion in cash. So on Slide 5 shows you our pipeline, and over the past 21 years, we've built a diversified and innovative pipeline. We are recognizing unique challenges in drug development, which is why it's important to have a robust pipeline, so that you have greater opportunities to be successful. We at PTC have built multiple innovative discovery platforms that has allowed us to have a strong and diverse pipeline across all stages of discovery, development and commercialization. We're proud that our research engine drives the development of products in our pipeline, including 2 innovative approved therapies, Translarna and Evrysdi. I believe that the key element, the secret sauce, is that PTC brings an innovation mentality to all our platforms and therapies. Underneath the platforms and programs is a drive to have a sustainable innovation engine that creates value for all our stakeholders. So as shown on Slide 6 that since I've shared a unique science-driven approach to discovering new drugs, I'd like to focus on the therapies in our portfolio that made significant progress in the clinic in 2020 and our near-term value drivers. So let's begin with the Bio-e platform. So as shown on Slide 8, the Bio-e platform focuses on diseases of oxidative stress by targeting enzymes called oxidoreductases, which are a large family of enzymes that perform important electron transfer reactions. Using this platform, we can target a large number of diseases characterized by high levels of oxidative stress. The first oxidate reductive enzyme we're targeting is 15-lipoxygenase or 15-LO, which is known to be a key regulator of the inflammation and oxidative stress pathway that is the underpinning of a number of disease states, in particular, in the CNS. So on Slide 9, so -- really to answer the questions how do these compounds work, they directly target the 15-LO enzyme inhibitor's activity, which shuts down the potent feed forward inflammation and oxidative stress response cycle, resulting in decreased cellular stress and increased cellular viability and CNS function. So we've initiated 2 registration-directed trials with 15-LO inhibitor, vatiquinone, also known as PTC743, one in mitochondrial epilepsy and one in Friedreich ataxia. So on Slide 10, let me start with the MIT-E registrational trial of vatiquinone for mitochondrial epilepsy. It's our first pivotal trial with vatiquinone. So first, let me provide you with some background to this disorder. This is shown on Slide 11. Mitochondrial epilepsy is the highly morbid condition of refractory seizures in patients with adherent mitochondrial disease. While mitochondrial diseases can affect every organ in the body, they most severely affect the brain. These diseases are typically diagnosed in the first year or 2 of life. They're rapidly progressive, highly morbid, and usually fatal in childhood. About 40% to 50% of all patients with mitochondrial disease have associated epilepsy, which are refractory to additional antiepileptic medications. This equates to a global prevalence of approximately 20,000 patients. There are no approved disease-modifying treatment for these patients. Vatiquinone targets the energetic and oxidative stress regulatory pathways that underpin seizures in these patients. As shown on Slide 12, vatiquinone has extensive safety and exposure history, having been evaluated in over 500 patients with duration of exposure up to 10 years. Previous results of vatiquinone demonstrated a positive effect on seizures and seizure-related morbidity across multiple mitochondrial epilepsy disease subtypes. The results showed reduction in seizure frequency, disruption of refractory status epilepticus, decrease in seizure-related hospitalizations, decrease in disease-related mortality. On Slide 13 shows the results. The results give us confidence that vatiquinone has the potential to show clinically differentiated improvement for mitochondrial epilepsy patients. We have initiated a randomized placebo-controlled study with a 28-day running to establish baseline seizure frequency. The trial will enroll 60 patients, and patients will be treated for 24 weeks. The primary end point is the change in frequency of observed motor seizures from baseline. The results are expected in the third quarter of 2022. So let me now switch to discuss the MOVE-FA, the registrational trial of vatiquinone for Friedreich's ataxia. This is our second registrational trial with vatiquinone. An overview is on Slide 15. Friedreich ataxia or FA is a rare, inherited, progressive neuromuscular disease that mainly affects the central nervous system as well as the heart. Onset of the disease occurs in childhood with a global prevalence of approximately 25,000 patients. There are no approved disease-modifying therapies. Vatiquinone can be an important drug for FA patients since oxidative stress-mediated cell death plays a key role in the pathology of FA patients. Results are -- for vatiquinone are shown on Slide 16. In a Phase II trial, vatiquinone treatment resulted in a significant improvement in disease severity compared to a matched natural history cohort. The result shows that the natural history data demonstrated an overall worsening of neurological function over 24 months. However, vatiquinone treatment was associated with an overall improvement in function over this time. These results support the -- that vatiquinone can deliver a meaningful effect in Friedreich ataxia patients. So the trial designs on Slide 17 is the registrational -- it's a randomized placebo-controlled study that will enroll approximately 120 patients. Patients will be treated for 72 weeks. The primary end point is the change from baseline using the modified FA rating scaler, mFARS. Along with the primary end point, the key secondary end point is the change in baseline of these activities of daily living, the FA-ADL scale. The trial has begun enrolling, and we expect -- near-term results are expected in 2023. Now let me transition and talk to you about our plans for PTC923, which we're really excited about because it's a potentially approved therapy for PKU patients. So in 2021, we'll start a registrational study of evaluating PTC923 for treating PKU called the APHENITY. So the overview of the -- is on Slide 20. PKU is a serious metabolic condition caused by mutations in phenylalanine hydroxylase, resulting in hyperphenylalaninemia. High levels of phenylalanine are toxic to the brain and are associated with cognitive dysfunction, memory loss and can lead to psychiatric problems. It's clinically diagnosed at birth through newborn screening for elevated phenylalanine levels. Onset is progressive and correlated to blood phenylalanine levels. The global prevalence is around 58,000 patients. As shown on Slide 21, the majority of PKU patients are not well addressed by current therapies, and there are still high unmet medical need. As I mentioned, PKU patients are diagnosed at birth through newborn screening and are often started on a phenylalanine-restricted diet. Approximately 30% of patients -- of patient treatment are naive, while the remaining 70% of patients are treated with Kuvan. Most PKU patients either don't respond or are poorly controlled on Kuvan, with approximately 60% of the Kuvan-treated patients initially failing. Of the 40% of patients that initially respond to Kuvan, approximately 60% of those patients subsequently fail or are poorly controlled. So as shown on Slide 22, this highlights that only a small number of PKU patients are well controlled by Kuvan. Therefore, there is a large opportunity for PTC923 to be a treatment for the large population of PKU patients. So as shown on Slide 23, we talk about a Phase II trial that was a head-to-head responder study that was performed. Of the 12 patients that responded to cofactor therapy, PTC923 demonstrated a significantly greater reduction of phenylalanine levels in the blood when compared to Kuvan that was statistically significant. The results demonstrated that 60 mg/kg per day of PTC923 was the most effective dose and demonstrated a twofold greater reduction of phenylalanine level in blood relative to Kuvan. Importantly, the results also show that 50% more patients responded to PTC923 as compared to Kuvan. So Slide 24 shows our proposal of the trial. It's the APHENITY trial, it's evaluating the reduction of blood phenylalanine in subjects who are suffering with PKU. The registrational trial is a randomized, placebo-controlled study of PTC923 versus placebo. Patients are treated for 42 days. The primary endpoint is the reduction of phenylalanine levels in blood. The trial is expected to begin mid this year, with data expected year-end 2022. Okay. Slide 25. Let me switch gears now and start discussing our splicing platform. Over the last 2 decades, we've been the pioneer in developing a splicing platform to identify selective and small molecules to modulate splicing. The success of these efforts can be seen with recently approved drug, Evrysdi, demonstrates that the small molecules can be identified that are both selective and specific. So as shown on Slide 26, our next most advanced splicing molecule is PTC518 for the treatment of Huntington disease. So the overview is on Slide 27. Huntington's disease is a progressive genetic brain disorder that usually has adult onset. It is a rare inherited triplet repeat disease that causes progressive brain cell death, leading to degeneration of nerve cells in the brain. HD has a broad impact on a person's functional abilities and usually result in movement disorder and also causes cognitive loss. Disease onset is usually in a person's late 30s or 40s, with a global prevalence of around 135,000 patients. There are no therapies to treat the underlying cause of the disease. We're very excited about PTC518, which is an orally bioavailable molecule that is very effective in crossing the blood-brain barrier, distributes to all tissues in the body and brain and is highly selective. We believe that analogous to Evrysdi for SMA, PTC518 has the potential to be the best-in-class treatment for Huntington's disease patients. So as shown in Slide 28, and as I've said, HD is caused by CAG repeat expansion, leading to HTT protein aggregation that becomes toxic to the brain and leads to deep brain necrosis. HD is a whole brain disease, and this is shown here with brain MRI images that clearly demonstrate that in an HD patient, there is extensive neuronal loss in virtually all parts of the brain when compared to the healthy brain. We believe that a successful drug for this disease needs to achieve broad tissue distribution in all parts of the brain. The molecule should have little to no efflux, so that it remains within the brain. As shown on Slide 29, the way PTC518 works, it does so by reducing HTT levels, and it's quite remarkable how the mechanism is. In the absence of the molecule, the transcript is spliced normally, leading to production of the toxic HTT protein. As shown on Slide 30, though, PTC518 works by modulating the splicing within the HTT RNA to induce a region within an intron, called the pseudoexon, to become part of the HTT transcript. This pseudoexon contains a premature stop codon. In the presence of PTC518, the stop codon pseudoexon is included into the HTT mRNA, making the transcript unstable, and the stop codon prevents the production of the HTT protein. Thus, the level of HTT protein are reduced. I think it's ironic that we get to leverage our knowledge of stop codon biology from the development of Translarna and small molecule splicing from the development of Evrysdi to develop this unique and novel approach to treat Huntington's disease. Now let's look at the effect of PTC518 in an HTT animal model. This is shown on Slide 31. The results show that in preclinical studies, the compound demonstrates a dose-dependent reduction in the HTT protein in the brain of the BACHD mice. The HTT reduction is clearly titratable based on drug levels that the level of HTT lowering can be tightly controlled. As shown on Slide 32, furthermore, the compound can reach deep brain structures uniformly, including the striatum, cortex and cerebellum, and reduce HTT RNA and protein levels in all of these studies. This is critically important as Huntington's disease is a whole brain disease. In addition, our compound achieves broad tissue distribution throughout the body as shown -- and as shown on the bottom right, it's showing a near 1:1 ratio between blood and CNS concentrations. This is because the drug levels in the blood let you know what level is in the brain, so that you know the level of HTT lowering that is expected. The same approach was successfully used in the SMA program and was able to demonstrate proof-of-concept in its healthy volunteer study. So on Slide 33, PTC518 is currently in a single and multiple ascending dose Phase I trial in healthy volunteers. We will be measuring both HTT mRNA and protein levels in the brain, allowing us to quickly demonstrate proof-of-concept for PTC518. This will also allow us to know what dose to use, to have a drug exposure that causes the desired level of HTT lowering. We're very excited about this program and look forward to the results that are expected in the first half of 2021. So before I move on to our commercial portfolio, let me talk about our gene therapy platform. As shown on Slide 35, PTC has a differentiated targeted approach to gene therapy for rare monogenetic disorders, primarily in the CNS and retina. We focus on local administration to desired tissue, requiring a small amount of virus, which should result in lower systemic exposure in immunogenicity. We also target diseases with low cell turnover, which should lead to improved durability. We leverage stereotactic neurosurgery technologies to enable precise and accurate delivery. In using this approach, we have a pipeline of programs, with our lead program being AADC deficiency and now focus on our lead treatment. Slide 36, the overview. Aromatic L-amino acid decarboxylase deficiency, or AADC deficiency, is a rare, highly morbid and fatal childhood disease. Children with severe AADC deficiency never achieve motor development milestones. There are currently no approved disease-modifying therapies. However, gene therapy for this disorder has the potential to provide significant benefit for AADC-deficient patients. We believe PTC AADC gene therapy has the potential to become the standard of care for AADC deficiency. AADC deficiency has an estimated global prevalence of 5,000 patients. As shown on Slide 37, we think that PTC AADC is a transformative gene therapy that can produce meaningful changes in patients' lives with this disease. As you can see, this is a 2-year old patient who cannot lift his head, sit or walk. Just 1 year after receiving a onetime gene therapy, this child can sit up on his own without support and has motor control. Furthermore, and importantly, he's able to recognize and interact with his surroundings. And approximately 30 months following the treatment, the same patient is now able to walk. As shown on Slide 38, we're currently preparing for our first gene therapy launch for patients with AADC deficiency, which is expected to occur during the second half of 2021. As part of these efforts, identification and preparation of expert pediatric neurosurgical centers of excellence is underway throughout the U.S., EU and Latin America. Patient finding activities are also accelerating, with over 60 screening programs in over 20 countries to identify 300 patients by launch. As a reminder, our MAA has already been submitted in 2020, and the CHMP opinion is expected in the first half of 2021, and the BLA is also on track for the first half of this year. So Slide 39, let me transition to our commercial portfolio. We're excited about our year-over-year growth in our DMD franchise, despite the trials and tribulations of the pandemic. So as shown on Slide 40, first, let me touch upon our global infrastructure that underpins our commercial success at PTC. We have corporate headquarters and research laboratories in South Plainfield and Bridgewater in New Jersey. Our international headquarters are based in Dublin. We have medical and marketing teams based in Zug, Switzerland, and our Latin American headquarters is in São Paulo, Brazil. We're now a truly global company with a footprint in over 50 countries. PTC's offices are in 20 nations, and over approximately 1,000 employees are present to support the current and future growth of the PTC product portfolio. As I mentioned, we're proud of the continued growing global DMD franchise, Slide 41. And Slide 42, as a reminder, Translarna is for the treatment of nonsense mutation DMD ages 2 years and older. We had revenues of $192 million in 2020. Translarna is currently distributed in over 50 countries worldwide. And as we've discussed in the recent deep dive, the dystrophin data is expected in this quarter. Slide 43. As we move on to Emflaza, which is the first and only corticosteroid approved for all DMD patients ages 2 years and older, Emflaza saw revenues of $139 million in 2020, which is a 38% year-over-year growth. We continue to see results from multiple publication that demonstrate Emflaza's clinical benefit over prednisone. As shown on Slide 44, on the graph, the DMD franchise continues to perform well. DMD franchise sales in 2020 was $331 million, with the annual revenue of Emflaza totaling $139 million and the annual revenue of Translarna totaling $192 million. This represents a compound annual growth rate of 58% since 2015. We expect this growth to continue in 2021, with geographic expansion for Translarna and new patients for both Emflaza and in Translarna. So let me talk a little bit about Evrysdi on Slide 45. We're very excited about the strong launch in the United States. And as you know, it has a strong efficacy and safety profile as well as the first at-home orally administered treatment for SMA patients. These attributes have contributed to its success thus far. The use of administration and access to home-delivered therapy is particularly important to patients during the pandemic. Evrysdi showed clinically meaningful and durable improvements in motor function and developmental milestones across a broad range of ages and functional abilities. Roche has previously shared that Evrysdi is currently being prescribed for approximately 30% of SMA type 1 patients, 40% of SMA type 2 patients and approximately 30% of type 3 SMA patients, showing usage in all SMA types within the patient community. They also shared that the treated SMA patients are approximately 1/3 treatment-naive, while 2/3 of the SMA patients are switching from Zolgensma and SPINRAZA. Roche has projected that Evrysdi will be, in the United States, the treatment of choice in 2020 for SMA patients. There have been additional also global approvals. Regulatory submissions are continuing, and we look forward to an additional global launches, with the CHMP opinion expected in the first half of 2021. Evrysdi is also under priority review in Japan. We have received $42.5 million in milestones in 2020 and have a potential additional $355 million in sales and regulatory milestones. In addition to the milestones, we received a blended average of approximately 15% tiered royalties. So Slide 46. From our multiple discovery platforms, we have a robust pipeline, so that we have a significant opportunity to transform patients' lives by bringing life-changing therapies to them over the next decade. We have the opportunity to treat over 500,000 patients across a number of disorders from both our commercial and pipeline therapies by 2030. Slide 47, where we have had a strong financial performance that will continue to support our future growth. The 2020 unaudited net product revenue was $333 million. I'm happy to report that we're in our strongest financial position, with over $1.1 billion on the balance sheet. Our base DMD business continues to grow from $291 million in 2019 to a preliminary net product revenue of $331 million in 2020. As shown on 48, our guidance for the Duchenne muscular dystrophy business is between $355 million and $375 million in 2021, and we expect OpEx for 2021 is in the range between $725 million and $755 million. As shown on Slide 49 -- shows our upcoming milestones, and while 2020 had a number of important milestones that were achieved, 2021 is also chock-full of value-driving milestones that will occur throughout the year. As you can see, this is going to be an exciting year that we anticipate will create substantial value for all our stakeholders in delivering on those milestones. So on Slide 50, I think we -- what I want to talk about is we constantly think about how to translate science to transform lives. We started out to deliberately build a sustainable company. It took 2 decades to go from a purely science-based to a commercial organization with an enduring innovation engine. And now we're a company with multiple products, a strong pipeline with many shots for future growth. We did this with proven groundbreaking science, building an enduring innovation engine with multiple scientific platforms and a strong commercial infrastructure. This has allowed us to provide access to patients throughout the world. These pillars are built upon a foundation of operational excellence. We have a strong cash balance in which we continue investing in our innovation engine with a laser focus on our mission to bring innovative products to patients and their families. The other foundation of our company is our culture. I think it's our secret sauce where we work to make every day count, to care for each other, our community and our patients. So as Slide 51 is our wrap up, where I started out today -- with today with PTC showing you that we continue to translate science to transform patients' lives, and we're very excited to continue to drive the value this year for all our stakeholders. Thank you for your attention.

Okay. Great. Thanks, Stu, for that presentation and overview. Very helpful. As we move to the Q&A portion, perhaps, just to start out, I'll have you introduce other members from the leadership team on the webcast with us this morning, and then we'll move to Q&A.

Sure. So you can see Emily Hill is here with us. I think most of you know Emily, she's our CFO; as well as you've met Eric Pauwels, our Chief Business Officer; and Matt Klein, who's our Chief Development Officer.

Great. I thought we -- a good place to start would be with the Translarna and DMD franchise on the commercial side. With the guidance that you are -- for 2021 that you're describing this morning, maybe you can just kind of help us unpack the inputs there, sort of what you identify as the key growth drivers, be it from expanded patient population to geographic reach. And maybe I'll leave the question there to start.

Okay. Great. Thanks for that. Eric, why don't you start to take that one?

Yes. So we're very confident actually, and we're very pleased that we were able to achieve $331 million and an increase year-over-year. With Translarna and Emflaza together, we see continued strong growth in 2021. Translarna certainly is continuing to grow. We're very pleased that in the second half of last year, we've been able to continue to add new patients, grow not only with new patients, but also with the label changes that we had recently, that really stopped the physicians and payers from discontinuing treatment for nonambulatory. We've been able to really emphasize the importance of maintaining treatment of Translarna for those -- for these patients. We see growth coming next year not only from the main markets that we currently have, and we've continued to see new patient growth, particularly the second half that we had move into 2021. But we also are going to expand geographically, and we have a number of key countries where we're not only working to identify and treat new patients in Latin America, but also in Asia Pacific. And we'll be opening offices as well as looking for future registration opportunities in Japan. And one of our goals is, obviously, we -- last year, we achieved approval in Russia, and then we continue to grow in a number of the Central and Eastern European markets and the Middle East. So geographic expansion, along with the label changes, are really going to be very important catalysts of growth for Translarna next year.

Something I should have tied into that question is to what extent the demands might be -- or the expansion of Translarna might be impacted by any economic stresses as a result of the pandemic. And I guess, looking longer term, how should we be thinking about sort of the 3- to 5-year growth outlook for the franchise there globally?

So I think -- well, Eric, why don't you go ahead?

Yes. I think -- well, we see -- we've actually seen that the current base of the business hasn't been affected by the pandemic. And in fact, we've been able to really work very closely in an environment where we have, if you will, been driving a lot of communication and education with patient through digital media, just like we're doing now. We're able to actually reach patient advocacy groups. We're able to reach health care providers in this different manner here. So we anticipate that the education and communication to find new patients is going to go forward. But the base of patients on Translarna, we've been able to maintain very high levels of compliance and minimize dropouts. And as I mentioned, with the 2 label changes that we had, which have really improved, is reducing actually the age down to 2 years. We've been able to drive education about earlier awareness and diagnosis. And then importantly, there seem to be the sort of stop criteria around patients who are ambulatory and then went nonambulatory. So in fact, in the beginning of last year, we may have lost a few of those patients. Physicians and payers now have stopped that process, or at least are reconsidering. And those patients who are nonambulatory are generally very high-value patients because it's a weight-based drug. So we've seen these 2 trends very nicely carrying into 2021. In terms of growth, we continue to see that Emflaza and Translarna together are going to be really important catalysts for growth over the next 3 to 4, 5 years. And we continue to -- we believe we're going to continue to see double-digit growth.

Got it. You recently held a deep dive on the Translarna franchise where a fair amount related to Study 045, I think, have been have covered, so I don't want to go too deep there, but I would just sort of be interested to kind of have you contextualize it -- the -- how you're thinking about the commercial opportunity for Translarna in the U.S., whether it might narrow down time lines, when we might see those data from Study 045 and whether there are any sort of regulatory contingencies that might permit going ahead with an NDA filing should the data fall short of a statistically significant increase in dystrophin expression from baseline.

Yes. Thanks for that question. Obviously, the -- as we've said, the dystrophin data is in the process of being analyzed now. We'll have the results -- I think that we should be able to report by the end of this month or so, and that -- or this quarter. And the goal here is to get -- is obviously on positive statistical data to rapidly move forward to put an NDA in so that we have accelerated approval that allows the patients in the U.S. to rapidly get that. In the absence of it, and depending on what the results look like, we can consider going to talk to the FDA and figure out a plan to see if we can move forward on an accelerated basis. Anyways, we have -- but that's a discussion that we have to have. I mean, we have -- obviously, we've refocused on getting clinical data, and we've done 2 pivotal trials, plus also a registry that, I think, the combination, when you look at all of that data and the long-term data and the 5-year registry, the power of that data demonstrating the ability to prevent loss of ambulation, allow kids to get up off of the ground, protect the pulmonary function of these children is pretty compelling data. So we're excited about that. We clearly want to get this therapy to patients in the U.S. as rapidly as possible. And of course, as a consequence of having Emflaza, we're clearly ready to do that quite nicely. But also then, we've -- our strategy also has been always to have the trial 041 as a backup plan that allows us -- and that's a large placebo-controlled trial that -- using all of our knowledge and what we've learned, I think we're in a pretty good position. So we have a strategy that, regardless of the results, we're ready on positive to move quite rapidly, depending on data to push. If that doesn't work, we're ready to get it on completion of the trial 041.

Got it. I think I would -- we'll pivot to a couple of questions on Huntington's disease. With the healthy volunteer Phase I study underway, perhaps you could just kind of elaborate on the type of -- a little bit further on the type of data that we might see later on in the first half of this year with respect to sort of patient numbers, and particularly with the -- there's a multiple ascending dose portion to the study. Can you just talk a little bit about sort of the treatment -- or yes, the time line treatments subjects will be -- will experience and sort of what criteria would determine the dose that might advance into Huntington's patients?

Sure. So maybe I'll start and then allow Matt to talk a little bit about the trial. But from a big picture point of view, what we -- what's nice about having -- as I said, what's nice about having an orally bioavailable small molecule is that -- and the fact that you can actually monitor the reduction of both HTT RNA in the blood and plasma is that -- and then based on the data showing that we get a good correlation of the amount of blood -- amount of drug in the blood as what you see in the brain, we utilize this by starting with -- in a single ascending dose. We get, obviously, an understanding of the PKU of the -- of PTC518. But we also, along with that exposure, we get the -- what's the consequence of lowering both the RNA and protein level, the Huntington protein level. And that's really important because it really sort of shows you -- it allows you to define, do you want 10%, 20%, 30%, 40%, 50% of patients of that -- of HTT protein that's lowered -- lowering. So you can define pretty precisely, based on the exposure, what the level will be. So we can use the clinical trials, both the single ascending dose and multiple dose trials, to really define that quite nicely, know the levels we're at. So Matt, do you want to go through the trial design a bit?

Yes. Absolutely. So in many ways, it's a standard Phase I approach, as Stu mentioned, with a number of cohorts in the SAD and then a number of cohorts in the MAD. That will provide the important safety and pharmacology data that one typically looks for any first-in-human healthy volunteer study, with the added benefit that we're going to be able to also measure the Huntington mRNA levels, which is going to give us that critical PK/PD relationship that Stu referred to, and this is analogous to what was done in the Evrysdi program -- development program, where we were able to use healthy volunteer data in Phase I to provide that critical validation of target engagement and splicing activity that then can guide the dose selection for the Phase II study. So the trial is underway. We've already moved through several of the SAD cohorts. The trial is progressing well. We'll move into the MAD portion soon and then be able to have the data readout in H1, as we've said.

Okay, okay. Great. We'll have to leave it there. We're roughly -- even went over a little bit. So many programs to talk through, not enough time. But I really appreciate your time, Stu and team, this morning. And thanks, everyone, for joining. Be well.

Thank you, Eric.

Thank you, Eric. That's great.

Thanks, Eric.