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

Ladies and gentlemen, thank you for standing by. And welcome to the Duchenne Community Update call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference to your speaker today, Dr. Stuart Peltz, Chief Executive Officer. Please go ahead, sir.

Okay. Well, thank you. Thanks for joining the call, and your interest, obviously, in the results. And we -- I just want to make a point that we all appreciate the partnership we have with the patient advocacy groups and the patients throughout the journey. And obviously, we've been on this journey together now for nearly 20 years. And I think what we're learning as a community is just what it takes to actually bring from an idea to a drug to patients, and you're helping also in getting there. And in terms of being part of the trials as well as the contributing to the natural history studies and as such. We know how important that is. So today, what I thought I'd do is provide you with an overview of the results from the Translarna study 45 and then also, we've had a number of questions that have been submitted by the patients groups that we'll spend time talking about as well. So I hope you all have the slides, we provided the slides to the patient advocacy groups, and they can be found on their websites as well as in our website -- and the PTC website in the investor section under events. So let me take you through the dystrophin study results. And just as a reminder, this was a biomarker study that was recommended by the FDA to support a potential accelerated approval that is specifically for the United States. So on the next slide are the forward-looking statement that I will be making some forward-looking statements. So I suggest that you look at our SEC filings of interest into that. Let's go to the third slide, which is on the study design. And as you might remember, we enrolled 20 Duchenne boys with nonsense mutations, age 2 to 7, with nonsense mutation Duchenne muscular dystrophy. These boys received baseline biopsies prior to the initiation of the treatment and a follow-up biopsy that was scheduled at 40 weeks following the start of treatment. However, as you know, that due to the COVID-related delays, what we found was that 8 of the 20 boys were unable to undergo biopsies at week-40 and had their second biopsies between week 62 and 70 weeks of treatment. The full-length dystrophin levels were measured using both an electrochemiluminescence assay as the primary endpoint and a immunohistochemistry assay as the secondary. So the electrochemiluminescence assay, I'll talk about as the ECL assay and the immunohistochemistry assay, I'll refer to as IHC assay. So in the next slide, study -- Slide 4 are the examples of the 2 methods that we utilize to assess the full-length dystrophin. The methods were selected so that we ensure that we can reliably measure a full-length dystrophin in a quantifiable way. So we have spoken previously about the ECL assay. So it's electric -- it's a capture, a very sensitive capture assay. That's proven to be quite sensitive and linear. And the IH -- immunohistochemistry, IHC assay is also quantitative incentive assay that not only quantifies the amount of the dystrophin, but also lets you look at the intracellular localization of the protein. And that both assays went through extensive validation and FDA review and both are sensitive at low levels of dystrophin production. So if you go to Slide 5, it's just really the summary of the patient population. And what we call is the ITT population, which is the full population, included 20 subjects enrolled in the study. However, 1 of the subject was evidently noncompliant and only took half of the study drug, while the second subject did not have an adequate biopsy samples to establish baseline levels. So therefore, we had really 18 subjects that were compliant with study drug and had valuable biopsy samples and are considered evaluable population. 10 of the 18 subjects had their second biopsy at week-40 and 8 had their second biopsy between week 62 and 70. So importantly, the patient characteristics, including age and steroid use were consistent across both the 40-week cohort as well as the longer-term treatment cohort. If you look at Slide 6, we've shown here the results of the dystrophin expression for the ITT population of 20 subjects, and then the -- really the evaluable population. So overall, in the ITT population, there was an increase in dystrophin expression from baseline on both ECL as the primary endpoint and IHC as the secondary endpoint, but they did not meet the p-value of 0.05. However, when looking at the 18 subjects in the evaluable cohort, we saw a greater increase in the dystrophin expression, and this increase did reach a nominal p-value of 0.04 in the analysis of the IHC assay. So importantly as well as over 80% of the evaluable subjects demonstrated an increase in dystrophin expression, signifying a consistent effect. If you then -- as I mentioned, if you go to Slide 7, 8 patients in the evaluable population had a longer treatment exposure ranging from 62 to 70 weeks. These subjects had markedly greater levels of dystrophin increase with an average of approximately 24% on the ECL assay. The results suggest that longer duration of treatment resulted in greater biological effect, which is consistent with the long-term Translarna treatment benefit we previously reported from our clinical studies in our real-world STRIDE registry. If you look at Slide 8, that's the CK level. We also collected a CK level, the number of relevant clinical outcomes of exploratory analyses. So first, let me start with CK, and consistent with the increase in the level of dystrophin, we also saw a marked reduction of approximately 20% in the creatine kinase level, which is an objective measure of muscle damage. And then as a reminder, dystrophin acts as a shock absorber during muscle contraction and would be expected to protect against muscle damage and, therefore, reduce CK levels. So once again, we observed the longer treatment with Translarna that was associated with the greater magnitude of biological effect. If you look at Slide 9, which are the clinical endpoints, let me take you through some of the clinical outcomes. So as you can see, there was a positive trend with an improvement over baseline on every endpoint. Once again, we observed that longer treatment with Translarna was also associated with greater magnitude of clinical effect. You can see both on the time function test as well as the NSAA. So if you look at Slide 10, that really shows that the overall Translarna treatment resulted in increased full-length dystrophin expression on both the ECL and IHC assays, and while the increase did not reach a p-value of 0.05 in the ITT population, it did reach a p-value of 0.04 in the evaluable population in the IHC assay. In addition, there was a consistent treatment effect across the population, with over 80% of the patients demonstrating increased dystrophin expression. So importantly, longer-term treatment with Translarna was associated with the greater increase in dystrophin expression, which is consistent with previous results. Lastly, Translarna treatment resulted in a marked reduction in CK levels, again, consistent with dystrophin production as well as an improvement in all clinical measures. So as shown on Slide 11, when looking at the top line results from Study 045, it confirms the biological effects of Translarna treatment and adds to the existing totality of clinical and real-world evidence demonstrating Translarna's clinical benefit. And this includes data from our placebo-controlled trial, which demonstrate consistent improvement across multiple clinical endpoints and our STRIDE registry which provides crucial real-world evidence of the long-term benefit of Translarna in key aspects of disease such as preservation of ambulation and pulmonary function. So if you look at Slide 12, which is the clinical trial data, the results here are for key trial endpoints, demonstrate that the totality of the data shows a consistent treatment effect for Translarna across multiple clinical endpoints in a number of slides -- in a number of studies as well as the meta-analysis. If you look at Slide 13, the other point that I really want to emphasize and I'm going to make is related to our real-world evidence. Our STRIDE registry provides real-world evidence of long-term treatment benefit of Translarna. Long-term meaningful effects that cannot be -- practically be captured in the clinical trial. Specifically, we can study critical disease aspects like loss of ambulation and loss of pulmonary function and long-term functional benefit. So the STRIDE registry is the first and largest real-world study of nonsense mutation in DMD patients. And this registry includes over 250 patients followed for 5 years in a real world setting. So if you look at the STRIDE data on Slide 14, the result are quite dramatic. The results demonstrate Translarna treatment preserves ambulation by 3.5 years and physical function and pulmonary function. All factors that lead to mortality in these patients. These results have been key to the annual renewal of the marketing authorization in the EU. So I think these results are really quite strong and actually show things, what patients, I think, really care about and their families, is preservation of ambulation and actually keeping pulmonary functions strong. So when you think about the regulatory path, and what we think is that when you conclude and looking at all the data, the totality of the Translarna results demonstrates the biological activity and increasing full-length dystrophin production and that the meaningful clinical benefit across multiple endpoints in several placebo-controlled trials and real-world evidence from STRIDE registry of long-term clinical benefit on key aspects of the disease progression. So these results are quite clear. And then our goal is and what we plan to do is to discuss the 45 dystrophin results and the totality of the existing clinical and real-world data with the FDA to determine if there's a potential accelerated approval path. But alternatively and Study 041, we'll also have a readout on the fully enrolled Study 041, which is a placebo-controlled trial in the third quarter of 2022. And based on the positive outcome, we'll be able to submit the NDA at that time. So that we've shown you 2 potential paths for approval on, an accelerated path and the normal path that comes out a little bit later. So let me stop there and entertain some questions.

We've got a list of questions that have come in from the community, from families from advocacy groups. And so I will start with the first one. You mentioned accelerated approval. Can you expand upon that and talk about what that means and what the differences are with accelerated approval versus the normal approval process?

Sure. So when you think about accelerated approval versus the normal approval process, it's -- the goal of accelerated approval is to bring therapies to patients that are likely to benefit them. And when you -- and therefore, you can use something they call surrogate markers, which are reasonably likely to predict clinical benefit. We're -- and so that -- those are the differences so that you can use something that could predict clinical benefit, then you usually then have a -- or you do have an obligation as a consequence of getting an accelerated approval, which is that you confirm that result with a clinical study that shows clinical approval. So the difference between the 2 is 1 uses -- can use clinical endpoints or surrogate markers that could be reasonably predictive of clinical outcomes versus clinical outcome measures that can reasonably predict -- that can reasonably predict benefits to the patient. So we're in a very unusual situation here where I think probably the community knows well, the accelerated approvals from Sarepta were based on dystrophin. That was an unusual approval, and everyone can remember of that process, but it's a precedent now. Because -- and it's really sort of the difficulty of using dystrophin as a surrogate marker and reasonably predicting clinical benefit. But the FDA actually had done that for Sarepta, and therefore, a precedent was set. And so one of the goals is trying to use dystrophin as a biomarker. And so if one way we could try and speed bringing the drug to patients in the United States, which I think is actually critically important since really, were distributed now to patients in over 50 countries that we want to bring it to patients in the United States. And that we already have patients who've been on our clinical trials are still getting it. And we want to bring it to others as well. And so we're in this position where we have clinical results, we recently now just redid the dystrophin measurements. And I think, while imperfect, I think the totality of the data shows that dystrophin is being made. We've given a potential to hang the hat on the 0.04 IHC with the p-value of 0.04. But we then also have, which is, I think, unusual within the DMD market is clinical data that shows -- in virtually every endpoint that we measured from the 2 placebo-controlled trials, the results always favor Translarna versus placebo. So we have that data set. And then we have also the data set from the real-world registry, which I think was pretty -- when you think about what a clinical trial is supposed to do is have outcome measures that predict long term consequences to the patients. And if you think about Duchenne muscular dystrophy, some of the key milestones are, loss of ambulation, reduction in pulmonary function. But those are difficult to measure in a clinical trial because they take a substantial amount of time to watch that. And clinical trials don't run for 5 years necessarily to see those outcomes. But we've done a registry study, which can use in a sense those hard outcomes like loss of ambulation, like stabilization of -- or loss of pulmonary function. And the results that we showed you today clearly demonstrate when compared to a matched natural history and those match actually quite well that patients actually walked at least 3.5 years longer. And you can look at the pulmonary function, and we've looked at FVC less than 60%, which is in terms of ventilation. And the same results, you can see it in the publication in less than 1 liter. The results aren't really quite dramatic that the patients on Translarna did quite well. So we're in this unusual position where we're talking about dystrophin levels, which aren't necessarily accurate predictors of clinical benefit where we have trials that demonstrate substantial clinical benefit that patients ultimately should want, which is preservation of pulmonary function and ability to walk longer. So we think the combination of having both dystrophin, which is a regulatory event of the dystrophin production with the hard clinical data that we have that actually is the -- probably 1 of the best data sets in Duchenne muscular dystrophy showing an improvement. That we think that this is important enough to take forward where they can hang their hat for an accelerated approval, knowing that they will also have results from Study 041. But really, where the trial will be completed in the third quarter of 2022. So we think this is an important thing to move ahead and talk to the FDA about. I should also point out that from the patient's perspective, that to 2020, that this is step 1 is the potential for the approval earlier with the data we've just had versus the -- that's just one backstep, and you have the 1 stop, but we also have the backstop of the Study 041 that will be completed in 2020 -- near the end of 2022.

Great. Thanks, Stu for that explanation. And the second question was also around the accelerated path and what that would look like, but drill down a little bit on the time lines? And how long accelerated approval versus normal approval might take?

Yes. So we are just working on getting ready to discuss with the FDA and then a lot will depend on how rapidly they can review the results that we have. And that's probably what we would be adding to our NDA would be, obviously, the results from Study 45, but also the results from the long-term registry study as well. They already probably have seen previously the other results. So it would be really how long that would take for them to look at the new data set as well as reviewed what we had previously. So until we -- to say how long it would take will depend a lot on how they deem, how long it will take for them to review that, which we'd probably be able to give a better answer once we talk to them. So that will -- at the conclusion of our discussions with the FDA, we'd be able to give you a better view of the time line. But at the end of the day, the way to think about this probably is to give at least a year earlier of people being able to obtain Translarna.

Great. The third question was based around that FDA discussion and communication process. And they asked specifically was the FDA involved early on in the build-out of this trial and during or after the trial has the results been shared, do they have any thoughts that you can share as of yet?

So a couple of things. Yes, the first of all, when we talk to the FDA, we talked to the FDA about what tools -- what assays we would use in terms of measuring Duchenne muscular dystrophy. And it was interesting, at first, we thought of the western blot, we actually talked about that. They actually told us, yes, we have used this before, but it's not our favorite necessarily assay. And if there are other assays, we would welcome you using them. And then we talked about -- we've used -- we've developed for our other studies this ECL assay that is really quite sensitive. And they actually knew about this type of assay. No, it's a good assay. You need a certain amount of instrumentation that not everybody has, but we have had. And so we spent a fair amount of time with them validating and having them review the assay IHC, and they really liked it a lot, which is why we ultimately chose that as well. And they also -- and now that you can -- you might remember some of the people who've been on drugs for probably now more than a decade in the early trials, the Study 041 trial where we did immunohistochemistry quantitative or semiquantitative measurements that it's moved a bit. And so they want -- what we wanted to do is that assay as well. So we also validated the IHC as well as the ECL assay. And so we spent a fair amount of time making sure that they understood the validation and review and approved it. So there was quite a bit of discussion about that with the FDA prior to the trial. And then we've obviously had an agreement with them on that as well. And so we've had that. And then the question also was, did we share the results? We always -- we obviously submitted the results. We always like to get the results to the FDA even prior to us talking public about that. So we did that. We haven't had conversations with them yet. But the data was submitted to them, and we're now getting ready for that. So when you think -- so we don't know that -- we haven't had any discussion. So I can't really opine on how they feel about it right now.

Okay. Now in regards to the time lines and the next steps, you discussed third quarter of 2022 for another trial result. Are there more trials in the works or planned for Translarna? Or are we planning on meeting with the FDA first to have further discussions?

Yes. So a couple of things. One is the next steps will be obviously talking to the FDA, putting together our package for the potential accelerated approval, get what their thoughts, time lines and next steps would be based on that. And then the Study 041 was initially set up as a commitment with the European agency, which we got buy-in from the FDA as this could be, depending on the results, sufficient for approval to -- for the FDA as well. And this is really, I think when you think about Study 041, you have to sort of go back and think we were the pioneers of Duchenne muscular dystrophy when we started here. In truth, there never was a drug approved for Duchenne muscular dystrophy before. And therefore, really the endpoints that from a regulatory point of view that were available to them, it really wasn't well-known nor was the natural histories well understood, and we understood that going into it, but there were physicians who are obviously very committed to the Duchenne community. And that we worked with them, the patient advocacy groups to really build out financial history for these trials. And as we did trials, we learned a lot from -- because when you think about a trial in Duchenne muscular dystrophy, especially while we're looking at the Duchenne muscular dystrophy and you think about nonsense mutation Duchenne muscular dystrophy. When you're not -- when you're the first, you don't have a path that anyone else has created for you. So you've got to create that path and you've got to move forward with really usually lack of really good natural history, lack of endpoints that the FDA would be interested in. Because the endpoints are those that tell a patient how they function or feel or replicates that and gives the outcomes or thought that it has consequence to the disease. And you got to -- and then you have to know the natural history of the patient. So you could pick the patients that you can measure a difference in treatment of as a consequence of the treatment versus what they would look like in the absence of treatment. So none of that was all unknown. We had to do all the, really a lot of the heavy lifting to try and figure it out. And in particular, some endpoints, well could be great, they don't change enough. They're not sensing enough to see it or the variability is to create. And then -- so we had to work out which ones could be done. And then you had to work out what are the best patients to show in a given time. For instance, like the 6-minute walk test. It turns out that if patients are above 400 meters in 6-minute walk test, they are unlikely to change for that year, dramatically as an average. But if -- or if they're under 300 meters, the patients under 300 meters, they may change too quickly become non-ambulatory. So you have to -- so we have to figure out what's the best patient population. And through Study 007 and Study 020, we really made a I believe, a significant contribution in the understanding of the natural history for the patient population that changed the most, but that don't necessarily go down ambulatory, what are the best endpoints that you can use with the minimum number of patients within the trial, right? Because some endpoints could be good, but there's so variable you need lots of patients in order to see this. So we had to work all through that out. We learned through 007 and 020, much about that. So we took all the learnings and education of what we had. And frankly, we also had the data from the BioMarin study as well as others, the Eli Lilly data, the placebo studies that they had that we can use all of that data then to figure out what's the best endpoints, what's the best patient population to be able to use to get the result, the best results in the time frame. And we elongated the time frame for Study 041. So now it's an 18-month study. So we put that all together that we think we're in a really good position now to demonstrate clinical benefit. And I think we're seeing within the community just how difficult that has been. And it takes real continuous grit and determination to keep figuring it out. So that we could move forward for the Duchenne community to find therapies that can help patients. So I think we're in a pretty good position for Study 041.

Great. Specific, we had a question about 041. And if you could expand upon a little bit what it is evaluating? You touched on a few points, but maybe some more specifics what that study looks like?

Sure. Like we're -- it's actually a relatively large patient population of Duchenne muscular dystrophy. Patients are earlier to later with a broad range of patients. But the primary endpoint is in the specific patient population, and they have an inclusion criteria that included, they had to be greater than 300 meters in 6-minute walk distance, but get up off the ground in greater than 5 seconds. So -- or less than 5 seconds. So that we were able to get patients that are declining enough that you can see it within the 18 months, but not so far within the disease that they're likely to go non-ambulatory very quickly. And that was very important that although we'll have a broad population, the primary endpoint will only be for that population in which we can see the -- where they'll most likely be able -- be changing but not change so much that they rapidly going non-ambulatory. So we thought that was really important. And the other important point we did is we used the rate of change as an important endpoint rather than the -- just where you were at week-48. So we're going to week-72 instead of week-48, and also we're doing the slope. So that way you'll be -- because if you -- if we -- when we look back at the other studies, it was very -- like if we had used the slopes, so you look at the rate in which they decline. You get -- because -- so in other words, if a patient declines in 6-minute walk test within the first 300 meters, suppose they were 350 meters, and they declined in 3 months. That patient got the same recorded if they decline -- if they went on non-ambulatory at 12 months because it's the rate of decline that -- it was the way you decline accounted, not the time it took. If you took the slopes of those, however, they'd be very different, and we would have had a statistically significant result there. So we took all the learnings from what's the best patient population to look at. What's the best way to measure the endpoints. And so those were -- and then doing the -- in a way, in doing a longer study so that you can see the differences more likely as patients change. Because when you think about Duchenne muscular dystrophy as a disorder that what happens is patients are losing muscle. So it's not like you're going to rapidly see improvements, you're trying to slow or stop than decline, right? So that takes more time than you could see substantial improvement, right? That's much easier to measure. But you can't -- but that's probably not going to happen alone without actual muscle building and other things. It takes longer to see the difference between the treated and untreated patient population. You need to go a little bit longer, and therefore, the slopes would be more important. And therefore, to treat the endpoint, and reach those the endpoints like 6-minute walk test NSAA, we're measuring multiple endpoints as well, rates of loss of ambulation. And so we -- but the primary endpoint being the 6-minute walk test for that unique patient population. And -- but these are outcomes that -- it's interesting, these are outcomes that are likely to predict what patients ultimately wants to slow the loss of walking, to improve pulmonary and cardiac function. And we're quite aware that by slowing -- if you could preserve ambulation, upper arm strength, pulmonary function, all of them, you start here, if you -- people walk longer, that's indicative of them being able to use their hands longer. Their upper arm strength, which is indicative of cardiac and pulmonary functions. So they all go hand in. So the longer you improve on one, the elongated all the other things that patients care about. And -- but we don't necessarily have time always to measure in a clinical trial. So I think now we're in a position to do that. And what gives us confidence of that is when you look at the STRIDE registry, just how substantial the preservation of walking was in these patients and how substantial the preservation of pulmonary function was in these patients. That gives us -- I mean, in over 250 patients over 5 years, where you have the time to collect results on patients who went non-ambulatory or patients, measure their forced vital capacity, to measure pulmonary function over 5 years. That's where ultimately, the things you want -- we're in this unique position with we have the data now that shows the Translarna in looking at long term effects, improves the patient. Now we have to do it in the clinical settings from a regulatory perspective. And I think we're in a pretty good position now with the knowledge that we have to be able to move -- to be pretty confident of where we're at right now.

Thanks for summary on 041 and the totality of the data. We'll shift gears back to the dystrophin 045 for a minute here to the list of questions. And the next 1 on the list was about the FDA. If the FDA does not accept the data, will the studies end? And what will happen to the boys on Translarna that are having good results, not only on this? The next question kind of builds into this one, will the boys that have been on Translarna be able to remain on it, if the -- no matter the FDA's decision?

Right. So we've -- so I think that's a very good point and very important, is like, look, we're -- if you think about it, we've built 2 plans on bringing -- getting positive results of Translarna for FDA approval. Clearly, our goal is to bring it to the Duchenne patients and their families as fast as possible. And we came up with a plan for accelerated approval to bring it to them where we can hopefully submit the data, include the registry data, get it approved prior and if it's accelerating approval pathway, there's another study that's coming up. If that doesn't turn out positive for us and the FDA wants to wait till the other study is, well, that's the backstop that we have Study 041. That's ongoing. That's fully enrolled, that will be completed. So we -- this is the 1 thing they always worry about for accelerated approvals is that companies say they'll do trials, but they're not well along or started, and they never really get to them. And that's not the -- if you think about PTC overall, in a way, I was arguing, we're putting our money where our mouth is. We're doing the trial that's fully enrolled, so we'll get the results. So there's no issue what the FDA needs to worry that we won't bring results from Study 041 to them. We're going to have it. The -- we know the last patient in, so we know the data of the last patient out. So that should give everyone confidence that the results -- we believe that the results here demonstrate Translarna's benefit to patients. But we've also have a backup study that we're willing to say we believe and we'll prove our point, and we're waiting for this study. So you could be guaranteed that you'll get additional information. So the question in -- from our point of view is if and when. And the other point I want to make the point is, yes, we're going to continue giving Translarna to these boys. That's our commitment. The patient -- they've been on trial and been on it and see benefit, we want to make sure that they continue with it.