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

Ladies and gentlemen, thank you for standing by, and welcome to the PTC Therapeutics call to review Part 2 of SUNFISH Clinical Trial Data at the SMA EU Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Head of Investor Relations, Alex Kane. Thank you. Please go ahead, sir.

Thank you, and hello, everybody. Welcome to the PTC Therapeutics conference call to review the SUNFISH Part 2 clinical trial data that was presented earlier today at the SMA Europe Conference. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations, including statements regarding the advancement of our joint collaboration program with Roche and the SMA Foundation and any related potential regulatory submissions, regulatory approvals or commercial prospects. These statements are subject to risks and to uncertainties that may cause actual results to materially differ from these statements. A description of these risks can be found in our most recent 10-K on file with the SEC. These statements speak only as of today's date, and we undertake no duty to update or revise them. With that, let me pass the call over to our CEO, Stuart Peltz.

Good morning, everyone, and thank you for joining us on the call today. With me on the call is Marcio Souza, our Chief Operating Officer; and for Q&A is Emily Hill, our Chief Financial Officer. We're also pleased to have on the call Dr. Basil Darras, Associate Neurologist-in-Chief at Boston Children's Hospital and who holds the Joseph J. Volpe Chair in Neurology at Harvard Medical School, to provide additional perspective on the study results and on risdiplam's potential to treat SMA patients. Dr. Darras focuses on care of children with neuromuscular conditions. And he also directs the Spinal Muscular Atrophy Clinical Research Program at Boston Children's. The results of SUNFISH Part 2 confirm risdiplam's potential to be the most competitive global product for a broad range of SMA patients. This was the first clinical study encompassing SMA patients representative of the real-world population. This includes patients not studied previously in clinical trials, particularly older patients and those with more progressed disease as demonstrated by the number of patients with severe scoliosis and contractures. Risdiplam is the only SMA medication that has been studied in a broad population of Type 1, 2 and 3 SMA patients, reflective of what physicians see in practice. Along with our partners at Roche and the SMA Foundation, we are excited about risdiplam's potential to help patients of all ages and disease stage across infants, children, teenagers and adults. We look forward to sharing the SUNFISH Part 2 results with you today as well as the full result of the positive FIREFISH Part 2 study in the first half of this year. Furthermore, I'd like to remind you that we look forward to the risdiplam PDUFA date set for May 24. As announced last November and detailed earlier today, the pivotal SUNFISH Part 2 study demonstrated statistically significant and medically meaningful improvement for a large population of non-ambulant Type 2 and Type 3 SMA patients from 2 to 25 years of age. We're proud that risdiplam represents a potentially transformative treatment for the broader SMA patient population. I will now turn the call over to Marcio to review the results in further detail. Marcio?

Thanks, Stu. Earlier today, Dr. Mercuri presented the detailed results from the pivotal study at SMA Europe. The results of SUNFISH Part 2 demonstrated statistically significant on the primary end points and key secondary end points. As Stu mentioned, this validates the potential of risdiplam to be the most competitive therapy across the broadest population of SMA patients. As a reminder, SUNFISH is a 2-part, double-blind, placebo-controlled pivotal study in patients aged 2 to 25 years old with Type 2 or 3 SMA. SUNFISH Part 2 had a broad inclusion criteria, enrolling a total of 180 patients with a median age at screening of 9 years. As mentioned, the patient enrollment in SUNFISH Part 2 were largely older and further along in disease progression than in any other clinical trial focused on this population. To provide additional context, Part 2 excluded ambulatory Type 3 patients and included patients with severe scoliosis and contractures. Additionally, this study has the most generous inclusion criteria of Motor Function scores, including patients deliberately excluded from other clinical trials. When considering this patient population, the primary end point for SUNFISH Part 2 was changed from baseline in the Motor Function Measure scale, the MFM-32, after 12 months of treatment as compared to placebo. Risdiplam demonstrated a change of 1.55 points when compared to placebo, which was statistically significant with a p-value of 0.0156. As a reminder, we chose the MFM-32 as the primary end point because we determined that it is the best measure to capture clinical response in patients across such a broad spectrum of disease. Not surprisingly, the strongest response was observed in the youngest patient group, with 78% of patients 2 to 5 achieving an increase greater or equal to 3 points in the MFM-32 versus 53% for patients in the placebo group. In the oldest patient population, 18 to 25 years of age, who are characterized by a more established disease, stabilization after 1 year of treatment was the main goal, which was achieved. 57% of risdiplam patients met the threshold as compared to 38% for patients on placebo. Statistically significant results were also demonstrated in key secondary end points. Revised Upper Limb Model, the RULM, mean change from baseline was significantly greater in patients receiving risdiplam when compared to placebo, with a difference of 1.59 points and a p-value of 0.0028. The RULM is critically important to further characterize the effects of therapy in a non-ambulatory patient population. Patients and caregivers also reported improvements in independence as measured by the SMA Independence Scale, a new measure that capture highly relevant day-to-day activities as like drinking and eating, getting dressed, the overall hygiene, amongst many other items. For the Hammersmith, there was a numerical difference in favor of risdiplam, which did not reach statistical significance at 12 months. There were no treatment-related safety findings leading to study withdrawal in SUNFISH Part 2. This is consistent with all risdiplam studies to date and encompasses more than 400 patients exposed to risdiplam. Importantly, no retinal findings were observed in risdiplam-treated patients to date. The adverse events profile in SUNFISH Part 2 was similar to placebo, and the most common adverse event were upper respiratory tract infection, nasopharyngitis, Pyrexia, headache, diarrhea and cough. On top of today's presentation on SUNFISH Part 2, I also wanted to highlight the announcement earlier this year about the positive FIREFISH Part 2 results, which reached statistical significance. As a reminder, FIREFISH Part 2 was a study in SMA Type 1 patients. The data from this trial are expected to be presented at the American Academy of Neurology Annual Meeting, which will be held in Toronto in April. I will now ask Dr. Darras to provide us with his view on the data presented today and on the prospects for risdiplam on treating SMA patients. Dr. Darras?

Thank you, Marcio, and thank you to PTC for inviting me to participate in today's call to discuss these important study results for patients living with SMA Type 2 or Type 3. As a physician, I'm excited to see the results that Dr. Mercuri highlighted earlier. The ambitious trial design for SUNFISH Part 2 was driven in part by the voice of the SMA community to ensure that an often-overlooked group of patients was appropriately represented in clinical trials, with the goal of bringing a therapy to those patients in the broader SMA patient population. Today's data validate that decision with a statistically significant change from baseline in the primary end point, demonstrating clinically meaningful results. Additionally, significantly more patients with risdiplam demonstrated improvement or stabilization in total MFM-32 as compared to placebo after 1 year. The age-related effect was notable and consistent with SMA disease progression, with the younger patients showing clear improvement, while other patients demonstrated disease stabilization, in some cases, improvement as well. In older patients, functional improvement can be difficult, so it is very important to show stabilization, and risdiplam achieved that in this study, highlighting the impact that a systemic drug could have in this group of patients. In terms of where an oral therapy such as risdiplam may fit into the treatment paradigm moving forward, I'm enthusiastic about its potential to treat patients broadly across Type 1, 2 and 3 SMA. For any medication to treat SMA patients, disease modification is paramount. Additionally, there are other important benefits to keep in mind. Having the option of an oral therapy that patients can take at home is a real advantage. Intrathecal injection is a burden for patients and the health care system. A distinct advantage of a small molecule therapy such as risdiplam is the expected ability to access a brainstem and central nervous system, with potential to benefit a patient's motor function and swallowing and breathing ability. Having a clinical trial that actually reflects real-life experience for SMA patients has been a long-standing need for the SMA community, including doctors and families. I'm very excited that this trial, despite being quite ambitious, has been able to achieve such a positive result in that context.

Thank you, Dr. Darras. Before we turn to Q&A, I want to take a moment to put these results in perspective. SUNFISH Part 2 demonstrated the safety and efficacy of risdiplam in Type 2 and 3 SMA patients. Data from this trial is particularly meaningful given that it encompasses the most severe patient population studied, patients who have been previously ignored in SMA clinical trials. One example is patients who are non-ambulatory as well as patients with scoliosis, including those with the most severe form. Another example is older patients, a large percentage of whom have contractures which limit their mobility and their ability to perform particular assessments measured in certain motor function scales. Importantly, even in the youngest population, our trials have the broadest inclusion criteria, without limitation to their baseline MFM-32 or Hammersmith scores. We're proud to have conducted a study representative of the real-world SMA population, which provided the opportunity for underserved patients to participate in a clinical trial and move these patients closer to potentially having a treatment option. Our mission at PTC is to bring therapies to patients with high unmet medical need. The real heroes in this journey are the patients, their families, doctors, physical therapists and other health care professionals who supported this trial and made it a reality. We look forward to having risdiplam available to all SMA patients in the near future. With that, operator, we'll now open the call for questions. Let me remind you that with the conference ongoing, our speakers, Marcio and Dr. Darras, are in France and therefore, I'll ask Marcio to moderate the Q&A.

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

This is Eileen on for Alethia. And congratulations on the data. So my first question is for the doctor. Can you just discuss how clinically meaningful is the 1.55 point change on the motor scale in Type 2 and 3 patients and maybe in the context of different age groups? And then secondly, can you just discuss how you view this data versus SPINRAZA?

We're waiting for the doctors to connect back in from France. So...

Yes, they disconnected. So can you repeat...

Can you hear me now?

Yes. Yes.

Can you repeat your question?

Okay. Okay. Yes. Sure. So my question -- my first question is for the doctor. Can you discuss how clinically meaningful is this 1.55 change on the motor scale? And then maybe just discuss it in a context maybe of different age groups. And then my second question is can you discuss how you think about these data versus SPINRAZA?

Great. Okay. So until -- they got disconnected. So while -- until they come on, I'll just give you, in a sense, what we heard from doctor -- from what Dr. Darras said. He said that he thought these were clinically meaningful results. And that I think one of the points that he made, which I think is important, is the broad patient population of the patients in the sense that they're more real world-like patients that the SMA -- of the SMA population, and hence, you're really getting a real view of what would work in that broad population. And that would mean, when you think about that, where a high percentage of the patients had scoliosis, about 2/3 of them, about 1/3 of them had severe scoliosis, there was a large degree of contractures, and so the real world of what happens with these patient populations. And so we thought that what you're seeing within that organization -- within that group, that you're seeing clinically meaningful benefits. And that obviously, and as we said, as you break up, if you look at the younger patients, it's not surprising that you're seeing the larger number of around 3, and that as we said, stabilization, at least in 1 year, is important. And we're seeing that within these trials. So I think from that point, I think what he would have said is that it's clinically meaningful, that the age group -- are they there? That they're -- yes, okay.

Hi, Stuart, it's -- yes, so it's Marcio and Dr. Darras here. We are back, and my apologies for the line dropping. So I'm going to pass for Dr. Darras, too. If I understand the question correctly, it's the clinical meaningfulness of the change we've seen on the MFM-32. So Dr. Darras?

Yes. I think it is important. It is a positive result in a population of patients between 2 and 25 years of age with a somewhat unusual cohort for an SMA clinical trial. And as Stu said, if I heard well, was that many of these patients have contractures. Many of them, like 1/3, had severe scoliosis. About almost 40% of the patients were older than 12 years of age, which means they have advanced disease, established disease. And most importantly, almost 41% had a baseline Hammersmith score expanded less than 10. And other trials in the past have used a score less than 10 as an exclusion criterion for enrollment in the trial -- in the trials. That means that the baseline Hammersmith score for SUNFISH was much lower than in other trials. And in a scale that was chosen correctly, the MFM-32, to assess efficacy in this population -- like population of patients, it did show efficacy. And you can ask me what difference that makes if you have only a 1-point improvement. Well, that's the difference between a patient being able to roll over by himself or herself at night versus needing help from a parent or a caregiver. So these changes, these improvements, even if they are small, they are clinically meaningful, and they mean a lot to the families, particularly in terms of care.

If I understand correctly as well, Dr. Darras, the other part of the question was in relation to other treatment options, how would you see this fit and how would it compare amongst the population.

Well, again, the age range is quite different here. We're going up to the age of 25 years, which means that, in practice, it could be used in patients who are adults. And despite the efficacy, getting a spinal tap once every 4 months is not an easy thing to do, and the truth is it's not just a spinal tap, but also the fact that these patients, they have to be sedated, they have to be anesthetized multiple times. Sometimes, they have to be exposed to radiation. And so some of these families and patients with SMA, older patients with SMA, would like to receive something like this because it's easier to administer, taken by mouth. So it does seem to fit an unmet need in adults, who so far have been somewhat reluctant to receive a treatment. And so it would be an easy way for them to receive a treatment that's going to increase the production of full-length SMN protein in their motoneurons and other cells in the body systemically.

Thank you, Dr. Darras. Stu, any final word?

Well, I think there was also one question, probably Dr. Darras should comment on, which was -- and this is a question I think we often get, is people always want to try and compare the results of one clinical trial to the other. And there's -- and I think, as you alluded to earlier in this piece, is why you can't do that. But maybe it's worth elaborating that a little bit.

Yes. We're asked quite often to compare studies, including gene therapy patients and all that. And it is difficult because most of the studies, particularly the SUNFISH Part 2 study, is unique because as discussed earlier, it represents a real-life cohort of patients, the patients that we see in the clinic all the time. They are -- many of them have severe scoliosis. Many of them have back contractures. A large number of them had scoliosis surgery, or they're going to have surgery in the future. They had hip surgery. And they need to be treated. And in this particular study is -- the criteria were designed in a way that were going to reflect what we see in clinical practice on a daily basis. In this -- in having a positive result in this diverse population of patients, with all these difficulties that have been exclusionary criteria in other studies, I think is very, very encouraging, not just for the families in the SMA community, but also for us physicians, if we are able to offer a treatment in these group of patients that seems to be effective.

And our next question comes from Martin Auster of Crédit Suisse.

And congrats on the trial's success. I was wondering if you could -- a couple of things. One, if you could elaborate on the placebo response in the -- on the MFM scale in the age 2 to 5 cohort. That was really surprising to us to see such a high response rate in that population. And then secondly, I guess for Dr. Darras, when you're thinking about treating a new patient, given the considerable administrative advantages of risdiplam, what are the scenarios where you would still elect to start SPINRAZA once risdiplam becomes available? And then secondly, do you think there's enough data now that would make you confident to switch a patient who's currently on SPINRAZA and doing okay or stable? And if not, what additional data would you like to see to get more comfortable about switching SPINRAZA patients over to risdiplam when it becomes available?

Hey, Martin, thank you so much for your questions. So I will start on the placebo behavior on this study. And then I'm going to ask Dr. Darras to comment as well. We actually don't believe it's that unusual, right, once we consider the entire patient population, the fact that this was a multinational center. But very importantly as well, we just like being here, it's in the conference the last few days in a lot of talks about the need to really control these studies externally, in this case, with a placebo because these patients do behave differently when you're talking about larger cohorts. The data is similar to the natural history that's been published in terms of this population, while it's wider and bigger in terms of the size of the cohort, so you end up having a little bit, in terms of the point estimate, a difference, but not necessarily the overall behavior. But maybe Dr. Darras wanted to comment a little bit more since you have such a large cohort of patients.

Sure. It is well known for many years there were other history studies that were conducted by Susan Iannaccone and other colleagues that showed that under the age of 5 or 6 years, patients can improve without any treatment. So that was -- has been known for many years. And it was really the PNCR network, another history study that was conducted by a group between 2005 and 2009, that actually confirmed this finding. And it's really very -- it's known that patients under the age of 5 can improve. This is why you see some -- there's a significant number of patients in the placebo group that seem to have improvement in that age range. As far as the question about what will make me prescribe risdiplam versus SPINRAZA, I have to say that our responsibility as physicians is to present the information in an objective way to the families. We have to describe what's known. And if there is a clinical trial that's being conducted, like let's say like the SUNFISH Part 2, my obligation as a physician is to actually explain the significance of the results, how it was conducted, the fact that we're talking about a diverse cohort of patients who were treated and all that and then present information about the other interventions. And the family will make that decision. I mean there are cases where we try to help the family make a decision. It could happen if you have a situation where it's difficult to do, let's say, a spinal tap and there are too many difficulties and use of radiation and difficulty with anesthesia and all that. I would make that recommendation directly to the family. But the truth is in a clinical practice, at least in the United States or where I practice, we give the information to the families and ask them to make that decision. But it has to be presented in a very objective way.

Maybe just to quickly follow up on when you make that -- have that discussion with -- yes, when you have that discussion with families, how would you anticipate with the availability of risdiplam as you're maybe talking with the new family or an existing family with the child on SPINRAZA, how would you think about -- what was your expectation for what the appeal of this drug is to the family then?

I think that once the results become publicized even before approval, we're going to have a lot of questions in the clinic if a family is asking about risdiplam and whether it could be an option for the children who are getting spinal taps once every 4 months. I think there would be a lot of interest, given that in pediatric practice, I have noticed over the years that the parents tend to try to avoid anything that's burdensome or difficult for the children, painful, has an effect, even a psychological effect. And this is the reality in pediatric practice, so I feel that there will be a lot of interest. And so we'll be there trying -- responding to their questions and all that and ask them to make a decision.

And our next question comes from Vincent Chen of Bernstein.

And congrats on the data. A couple of questions, one for the team and one for Dr. Darras. So first, for the team. I was wondering, is there any way you could provide us a little more color on what the HFMSE and the RULM scores would look like in the younger patients relative to the older patients? I see that you've got the blended data here, but I would be curious to see what it looks like for kind of the younger 2- to 5-year-old cohort versus the older ones. And then a question for Dr. Darras. I was wondering if you could talk a little bit about what you're hearing from patients and parents about the level of interest in switching off of SPINRAZA onto drugs like risdiplam or gene therapy now that, I guess, gene therapy -- or risdiplam will be potentially available, soon. And then finally, just to follow up quickly on the earlier one for Dr. Darras as well. So suppose that you had a patient of a fairly young age, fairly young Type 2 patient, someone who is 2 or 3 years old, and you give them the -- you describe the options, describe the trial data, and they were to say, "Doctor, what would you do if you were us?" How might you steer them?

So thanks, Vince. Let me start with your first question, right? So obviously, we're going to stick to what we presented today. It's being practiced, as you know, others know, to present the data first at a medical journal, at a medical conference, and we're going to continue to do that. We're excited, obviously, by the results we are showing. Maybe one point to help with the question without breaking down the cohorts, right? One of the reasons why we were excited to look into the MFM and the RULM as a complementary is because the RULM measure other things, including an indirect measure of strength for these patients that also has not been seen in previous trials in different compounds. So you end up having a more -- a broad and I would say, comprehensive effects of data when a clinical evaluation is being done. And stay tuned, we're going to be presenting this in another conference. Obviously, a manuscript is going to be written, with the full results as well. And as the data for FIREFISH is presented at AAN, I think the full package as well is going to be very clear for this drug and its place in the marketplace. And Dr. Darras for the other questions?

Yes. As far as the MFM-32 for the younger patients, this scale, as you know, was developed in France, and it has not been used a lot in the United States and also some of the European countries like Italy, U.K., Germany and so on. But if you read about it, it does seem that it avoids the floor effect of Hammersmith in younger patients. So -- and also, this is a scale we developed for patients between the age of 6 and 60 years, and there is also have a version called MFM-20, for patients between 2 and 6 years of age. And the -- so in various patients, if they started with that...

Dr. Darras, you cut out a bit. Maybe you could repeat yourself?

So I'm saying that when this trial was designed, it made a good decision to use the scale that were more suitable for this particular study, given it was enrolling patients between the age of 2 and 25 years. And it seems that they were proven correct. So there are -- this has been disputed in the SMA community over a number of years, which scale is better, and there appear to be advantages in using the MFM-32, particularly if you want to have older patients. So that's something that -- and this is what we know about the MFM-32. And the reality is that it was used and it showed efficacy. And there's no scale that's perfect. There's no -- every scale had its own problems. And the Hammersmith was used because a decision was made. It was thought to be an attractive scale many years ago, and it was used and it did show efficacy in some of the previous trials. But again, it's not the perfect scale. And I'm not saying that MFM-32 is perfect, but in this case, it seems that it's probably better when you try to study such a broad range of patients of different ages. So that's what I can say about MFM-32. As far as trying to guide a family in their decision-making when the patient is 2, 3 years old with SMA Type 2, again, I'm going to have to talk to the family and explain the results and what they mean. Safety is important. And so far, about 400 patients have been exposed to risdiplam, and there had not been any particular problems, so I have to inform the family about that. So it's not just efficacy, it's also the safety profile. And at the end, they're going to have to make that decision. It's hard for us to tell them exactly what to do, unless they're trying to do something that would be potentially dangerous, like having a patient who has high liver enzymes, if at the age of, let's say, 1 year, and they want to give gene therapy. In that case, this is not -- I would not prescribe gene therapy in a case like this.

Thanks, Dr. Darras. And Stu, I believe you wanted to add?

No, I just wanted to also, just to add a little bit on -- and there's even posters from one of the companies for SPINRAZA, where I think there's an explanation where -- why they chose less than 10 on the Hammersmith scale, is that they saw that it wasn't reflective to changes. And so that's why they actually have an exclusion criteria, and they had a poster on, in a sense, showing some of that data as well. So I think that's consistent with what Dr. Darras was saying.

And maybe to follow up quickly. Dr. Darras, what are you hearing from patients and parents so far about sort of interest in switching off SPINRAZA given the coming availability of, I guess, risdiplam and I guess, the availability of gene therapy?

So far, we have families who have asked about it, and it does come up almost all the time in the clinic. But I think the families are waiting to see -- to hear results. I think that hearing about the results of SUNFISH Part 2 and also about JEWELFISH, I think that will trigger a lot of questions because they hear about these trials from the Cure SMA website, the Internet. So I think that we're going to hear more questions as time goes on, particularly as we're approaching the time with which approval may come from FDA. The -- we do have an interest in the JEWELFISH study, for who -- these are even more diverse patients from 6 months to 60 years. And there was a lot of interest there to the point we're actually looking to enroll those patients because we didn't have enough slots in the JEWELFISH study to enroll them.

Yes. And maybe to add, Dr. Darras and Vincent. So JEWELFISH is a good, I would say, surrogate for that from our perspective, right? You heard the expert's perspective from a company perspective. So JEWELFISH is officially fully enrolled. And I don't believe we mentioned that before, there were a number of gene therapy previously-treated patients, a high interest there. We're going to see the numbers soon once we present in a medical conference. There's a substantial number of SPINRAZA treated. So for all its worth at this point in time, as for a trial that is relatively small, in the low hundreds, we have like a substantial number of patients on both current treatments who had an interest to switch to -- if we can even call switch, but to start with the plan after having tried the other compounds.

And our next question comes Tazeen Ahmad of Bank of America.

Marcio, I just want to get back to the Hammersmith score. Relative to the other scales that you looked at in this study, how important is that, not just from a clinically meaningful standpoint for physicians in a real-world setting, but how is that important to FDA? And how is not meeting that particular scale in terms of significant importance or not important? If you could try to give us some color on that, I'd appreciate it. And then I have a follow-up.

So let me just make something clear, right? So the Hammersmith has its place out there. It is a scale that's being used -- it's relevant for highly functioning individuals, which was not the case on this trial, right? But if you were to be running a trial for highly functioning, we probably would have chosen that because that would be the appropriate scale. In terms of order of endpoints, maybe to start answering your question from a regulatory perspective. The first in an order of secondary was the 3-point increase for the MFM. The next one was the RULM. So you can see that it's not even high on the list of things that we prioritize to analyze once we were designing this trial, the statistical analysis plan. I can't speak on behalf of the FDA, but I can give you color on the conversations and on the discussions throughout the years with them. They've accepted part 1 for the application. Obviously, Roche will completely support the decision, submitted the summary of the trial, submitting information to them for context. But the approval, to our understanding of the conversations, it's not bearing on this trial. So that's more from a regulatory risk perspective that I'm talking. But from a context, they really wanted to see a chain of the primary endpoints in all the function of these patients. When you add on the top of the endpoints, right, the fact that by the first time, we're looking into an SMA activities of daily living scale that actually showed results that are meaningful for this patients. I would go in a little bit of limb here and say that they are totally okay with what we show. And they are definitely on board with the MFM as the primary endpoint, and that was very clear in our communications. So again, the final decision is the FDA's. And I'm not going to try to ever project their decision. But at this point in time, based on all the conversations we had with them, and Roche, there is no indication that this would be a, whatsoever, something they would pay attention to. Was it helpful?

Okay. And then maybe -- yes, that's helpful, Marcio. If I could jump ahead, and this might be theoretical. But as we look to commercialization of this drug, do you have market data as it relates to the U.S. market, especially on how difficult it is to get the currently approved therapies for SMA approved for use in older patients where efficacy may not be as meaningfully evident? And how do you think that will translate to reimbursement for risdiplam knowing, of course, that Roche will be in charge of that?

Yes. So Roche has been working with Bayer for a while, and they've been doing a really good job, I believe on talking about this. The fact that this population is broad and being studied. There are likewise indicators here and this definitely bodes very well with Bayer's side. I can't foresee a niche which obviously -- like if you think about the totality of the benefit package here, right, so being able to deliver a home that is not current. So when payers are looking into drugs, they're also looking to procedures. When you look into the current schedule for physicians on the reimbursement that they have for the current therapies or the procedure itself is extremely low. So it takes time in the clinic but not really has any benefits there for the hospital or for the [Audio Gap]. When you look into the total cost [indiscernible] in favor of risdiplam. The majority of the adults in the United States remain untreated, right? So we know their disease progress, but they're not treated. So all of that adds to the benefits here. So if I sum all everything -- and again, you know as well, Roche is in charge of this. But if I were to kind of bear a little bit on the previous experience, I would say, there is a lot here to be successful. And the other point is by being an oral, like plans know how to deal with this very well, like it's normally a simpler process for authorization, we expect a broad label. We expect the label to reflect the experience, so it should be a straightforward process.