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

Good morning. I'd like to welcome you all once again to the Citi's 18th Annual Biopharma Conference, and we're pleased to have with us in this session, the team from PTC Therapeutics. I would recommend anyone to go to the Citi website to look at any disclosures. But with that, I guess it's been a pretty busy year from PTC from both the corporate and from a therapeutic perspective. So if you could start and dive in, talk about the history of PTC, what the overall mission of the company is? And what types of changes have occurred?

Sure. David, thank you. So Matt Klein, CEO of PTC. And as you said, it's been a very exciting year for us. PTC celebrated its 25th anniversary in 2023. We were founded in 1998 with the mission of using innovative science to develop transformative therapies for patients with high unmet medical need. We've succeeded in that mission, and we've built a global biopharmaceutical company that discovers, develops and commercializes transformative therapies for patients with rare disorders. As we moved into this year, we had ambitious plans, including projected revenue of $940 million to $1 billion as well as readouts from several important clinical trials. As we celebrated our 25th anniversary, our Founder, CEO, Stu Peltz, elected to retire. And I proudly assume the helm as CEO of PTC, after serving as the Chief Operating Officer. We then moved into a busy Q2 where we read out data from several important clinical trials, including the successful Phase III AFFINITY trial of our drug sepiapterin for the treatment of PKU, an incredibly robust data set positions us strongly to now move forward with an NDA submission we're saying later this year, and this represents another potential $1 billion market opportunity, more than $1 billion market opportunity on top of our already solid commercial revenue base of $940 million to $1 billion. We also had important data readouts from our PIVOT-HD Huntington disease trial, which is a study of PTC518, which is a small molecule splicing agent that reduces the levels of mutant Huntington protein in the brain. Our 12-week data showed that we were not only having the desired pharmacodynamic effect, but we were doing so safely, which is very important given the experience of others in the Huntington low in the space. We also had important readouts from our Friedreich ataxia trial with vatiquinone that we look forward to having a discussion with the FDA later this year. I've got a potential path to approval based on those data. So across from corporate changes to continued strong year-over-year revenue growth, the potential to bring new products on the market in the near future with themselves very large revenue opportunity makes this quite an exciting time for the company.

Thank you for that. With respect to the pipeline, there's been a shift in the last year also towards focusing on certain types of candidates versus other candidates and discontinuing certain areas. Could you tell us more about that strategic decision?

Absolutely. So as we celebrated our 25th anniversary and started turning cards over on clinical trials, including our PKU trial as well as in light of our very strong revenue base, we believe as a company we're at the time where we needed to really focus down, focus our investments on products and programs that had, one, potential for high return on investment; and two, sits squarely within our strategy of delivering important therapies to patients with rare disorders. . We made the decision in the spring to discontinue a number of our preclinical gene therapy programs that while we believe they could hold promise for patients were not progressing quite frankly, at the pace that we thought warranted continued investment as well as the continued uncertain commercial landscape for these products once we -- if we were to succeed in getting them through a very long and very expensive development program. Quite frankly, we're in a situation with a number of innovative scientific platforms in the small molecule space, the ability to not only discover those therapies but develop them as well as commercialize them globally. We have a more than robust R&D portfolio to support the company's continued future growth and really wanted to take this opportunity to focus our activities down on to small molecules which we are [ infill ] and capable of continuing to deliver.

Got it. Now PKU, you announced data for 923, 2 sets of data actually in the last couple of months. And I guess, could you tell us #1 about the market as a whole, how it has evolved from the beginning and how you see 923 ultimately fitting in?

Absolutely. So from a market as a whole, David, there's around 58,000 patients globally with PKU. And we've talked a lot about sort of how that breakdown of patients occurs. So roughly 30% of PKU patients remain therapy-naive despite 2 therapies being available. And within that therapy naive population includes classical PKU patients. So those that have baseline phenylalanine levels of 1,200 micromole per liter or greater. And have traditionally been very difficult to treat patients. And so hence, remain therapy-naive. 70% of those patients have tried Kuvan and have failed. And then there's 30% roughly speaking, that have a response to Kuvan, but 60% are poorly controlled over time. And there's a number of reasons why they're poorly controlled and come off drug, whether it be in ability to liberalize the diet or compliance or a number of other factors that come into play. So from that perspective, that's the marketplace as it stands today. So where do we think sepiapterin can fit into that? I think we see it fitting across all PKU patient segments. And the reason for that is a number of different factors. So first and foremost, we've shown very strong data in classical PKU patients, which historically have not had therapies amenable to them. And so from that perspective, it's a vast opportunity across a number of different geographies. And obviously, in addition to that, we've had a very broad response rate. 66% of patients have responded to sepiapterin. So an ability to also target some of those therapy-naive patients. In addition to that, obviously, those that have failed Kuvan, as I just said, the response rate will help drive them to try sepiapterin. And then in addition to that, the sheer fee reduction levels, so the 63% we saw across the broad population and then the 69% fee reduction that we saw across classical PKU patients. And lastly, and I think this is probably one of the most important differentiating factors is the fee tolerance data that we're collecting. And the importance of that is because both from a physician, a payer and a patient point of view, while fee reduction is extremely important and is tied to cognitive benefit, there's also fee tolerance in the ability to liberalize your diet. And that is equally as important across all the different segments. And that's important because patients have a fee restricted diet from birth, and this is a huge burden to their life. And so any therapy that allows them to liberalize their diet is absolutely essential. And so that's another key important factor as to why it's going to drive uptake in the marketplace.

If you're to look side-by-side, sepiapterin with Kuvan and Palynziq. What type of fee reductions do they lead to in their respective populations? What specifically are the challenges that are associated with Palynziq on one end and Kuvan on the other end.

Yes, absolutely. So maybe let's start with classical PKU because I think that's a little easier one to do. So in Kuvan, it's, I would say, minimally responsive, not responsive at all. So that's why many of those classical PKU patients are therapy naive, whereas we showed a 69% feet reduction in those patients. So minimally responsive to 69%. It's a dramatic difference. While classical PKU patients do see fee reduction in -- do see fee reduction. In many cases, they have to step through Kuvan. So it's for those that remain ineffective on therapies that are standard of care, which is Kuvan, and have fee baseline levels that are more than 600. That often what payers put in place. So getting access to Palynziq is challenging as well as it's only for adults. So those patients that are classical PKU that are younger than 16 don't have the ability to access Palynziq. In the broader patient population, Kuvan has a 29% fee reduction. That's out of their label. Obviously, it's not a head-to-head study, these numbers that I'm providing. But for our study, it was a 63% fee reduction. And that's what we're seeing for the AFFINITY trial. And as I said, in addition to that, I think one of the things that Kuvan does like is that fee tolerance data, which is so important. So it's not just a fee reduction in the AFFINITY study comparing to what was seen in the Kuvan Phase III study, but it's also the fact that we're able to say, okay, now you see those -- that fee reduction coming down, and we talked a little bit about this during the top line results. the percentage of patients that came within target phe levels. And that's so important because from there, once they come within target phe levels, that's when the dietitian is able to help alongside the pediatric geneticist or metabolic specialists, slowly prescribe an increased fee intake. And in many cases, we've seen it above the IDA.

Given the differences in the trials how do the physicians ultimately compare Kuvan and sepiapterin?

I would say -- I think it's -- a lot of what Kylie said, is taken as well understood, right, that the vast majority of classical PKU patients don't derive benefit from Kuvan. And therefore, there's not even a choice or a decision to take. And while they certainly can look across studies, we can also look within our own studies. For example, in the AFFINITY trial, we had 25 patients who came in, who were on Kuvan, where we were able to demonstrate that once we switched them over to sepiapterin, we had a [ 40% ] greater reduction in phenylalanine levels. So that gets you closer to with inpatient an apples-to-apples comparison, which is a very important data point for physicians to see that the same patients once they switch therapy, get much greater benefit. In fact, we've had KOLs and professional [indiscernible] error PKU commercial deep dive we held over the summer, made it very clear when she saw those data, she said now every one of my patients, even the ones who may be getting some benefit from Kuvan should be switched over to sepiapterin.

In the trials, there, as most trials in PKU, there's a diet control as part of the process. And when people go to real world, diet is obviously naturally less controlled. What type of differences could there be between real-world use of these drugs and the clinical trial use of the drugs and how that might affect the long-term efficacy.

I don't really see a difference there. I think the reality is that most patients are on potentially some sort of diet modification and the goal of therapy is to get them off modified diet. So when you see what we're seeing with the fee tolerance data, it tells you that even if diets are liberalized, patients are getting efficacy. They're maintaining their phe levels within control, which I think is incredibly important.

And as far as patient compliance to therapy once -- how was that for Kuvan? Was it -- do you expect it would be easier for sepiapterin?

I think patient compliance is very closely linked to diet liberalization. I think if patients are, I think what drives patients to be less compliant with therapy is when they're not able to have an impact on that troublesome and burdensome fee restricted diet. So I think at least what we've seen in our clinical studies is where they're able to liberalize that diet compliance is not a concern. And so when we are able to sort of get to the real world, I expect it to be very, very consistent.

On the classical side, how much success there, how easy is it to get to diet liberalization?

Yes. So I think from a classical PKU patient, how easy is it? It obviously depends of the patient coming into those target phe levels. And obviously, with the 69% fee reduction, we do see some of those patients come into that target of fee level of less than 360 micromolar per liter. If we look at the U.S. guidelines as an example. And then if they are able to increase their fee intake and still maintain those phe levels, then that's a win from a fee tolerance point of view. And we have seen a mix of both mild and moderate PKU patients as well as classical PKU patients be able to do that. So while their baseline phe levels start higher, obviously, with such substantial fee reduction is still able to come within those target phe levels.

Got it. I guess let's move over to vatiquinone. There were 2 readouts this year. Could you tell us about those readouts? I guess we'll emphasize more FA because -- that you're continuing. Tell us about what the drug does and what you've seen thus far?

Yes, absolutely. So vatiquinone is our small molecule that targets an enzyme known as 15-lipoxygenase, which is a very important regulator of inflammation oxalate stress pathways that underlie a number of CNS disorders. In fact, that target of 15-lipoxygenase in the target pathway of paraptosis is emerging more and more as a really key target for a number of disorders, including Friedreich ataxia. . And so we had trial readouts from our MOVE-FA phase study, particularly on Friedreich ataxia, as well as our [indiscernible] study, which was a study in children with refractory seizure secondary mitochondrial disease. In the MOVE-FA trial, which was a 72-week placebo-controlled trial that included principally pediatric and adolescent patients with FA, that did include some adults. We were able to demonstrate an important statistically significant benefit on a key subscale of the disease rating scale known as upright stability. This upright stability scale has been shown to be predictive of long-term loss of ambulation. It's also the one component of the disease rating scale, the MFAR scale that is known to be moving in children. That is the one that changes over time in children and adolescents with disease. So to be able to register such a significant benefit on the one subscale that's most relevant to children and adolescents and predictive of such a key morbid transition point in the disease of loss of ambulation was an incredibly important finding. We also had significant findings on the bulbar scale, which is another subscale of the MFRS as well as a significant benefit on fatigue, which has been called out by patients as their #1 most burdensome symptom and their #1 symptom that they would like to have addressed by a therapy. So where we sit now, given, one, the extensive experience with vatiquinone in children and the strong safety record it has, the fact that there are no good therapy still for pediatric and adolescent patients with Friedreich ataxia, given that the approved therapies, [ SKYCLARYS ] in the U.S. is for 16 and over. And the fact that we were able to register a meaningful effect on the endpoint that matters most to children and is reflective of the time to loss of ambulation of the most morbid transition point to disease loss of ambulation. We believe we're in a position to have a discussion with the FDA about the potential for an accelerated approval based on that intermediate clinical endpoint. So we look forward to having that meeting with the agency in the fourth quarter of this year to see if we -- the data we have could support an NDA.

So I guess based on the prior experience for drugs in front of the FDA for FA, how open-minded do you think they'll be about this approach?

Well, I think 2 things. One is, I think the approval of SKYCLARYS and there -- what was in the public statement and the report, I think, shows an openness by the agency to try to get drugs to patients who desperately need them. I think they definitely showed flexibility in what they're -- including flexibility in the previously stated standards for approval for a therapy for Friedreich ataxia, which included a statistically significant benefit on the primary endpoint of MFAR as well as on a key secondary endpoint, which was not in the SKYCLARYS package. So I think that's evidence that they're willing to be flexible in this context of an unmet medical need, which obviously for children remains in FA. And the second, in terms of an accelerated approval path, I think we've seen quite clearly the openness of FDA to utilize that pathway, particularly for therapies that are able to show benefit on things that might matter in longer, more progressive diseases as a mechanism to get drugs to patients who need them.

Do you see any other areas that you might look at vatiquinone?

I think right now, we're focused on the FA program and moving things -- moving forward in FA. Obviously, we have a discovery platform that looks at different mechanisms related to what vatiquinone is targeting that could be beneficial in a number of CNS disorders.

So can you tell us about 518 Huntington's?

Sure. PTC518 is our small molecule being developed for patients with Huntington's disease. It comes from PTC's validated splicing platform. the first therapy out of that platform was a Evrysdi for the treatment of spinal muscular atrophy, which was discovered by PTC and is now commercialized by Roche and available in over 100 countries. That approval, that -- the whole development, discovery and development of Evrysdi really set up a playbook for how to successfully develop a small molecule splicing agent to treat a whole brain disease like SMA, like Huntington's disease. So leveraging those important learnings from the Evrysdi program, we developed PTC518, which has the many important attributes that a successful cell molecule splicing therapy should have, which is high degree of selectivity, high degree of specificity, ability to cross the blood brain barrier, not be e-flux so that it can broadly [ biodistribute ] it throughout the brain, which obviously is incredibly important for a whole brain disease like Huntington's disease. We were able to move PTC518 forward into the clinic and show in Phase I that it's doing what we want it to do, which is targeting the etiology of Huntington's disease, which is the production of a mutant Huntington protein in the brain. The production of this protein causes cell injury, ultimately cell death and neuro degeneration and what PTC518 does is it basically turns down the production of this disease-causing protein in Huntington protein. And so what we look to do in the clinical development program is established that we're able to achieve the lowering of Huntington RNA and protein in a dose-dependent fashion. We showed that in healthy volunteers as well as collected important safety and pharmacology data. And then we recently released data from the first 12 weeks of our PIVOT HD Phase II study of PTC518, which is a 12-month study that in 2 parts. Part 1 is 12 weeks in duration, that looks at important aspects of pharmacology and pharmacodynamic effect in Huntington's disease patients, as well as looks at brain biodistribution to ensure that we're getting the necessary exposures in the brain that we believe are necessary for delivering the ultimate therapeutic effect. Second 9 months of the study is focused in a biomarker approach to try to understand the biomarker, biochemical and radiographic marker benefits of Huntington lowering in the brain. And that will look at things like NFL levels in the brain and in the blood. We'll also look at radiographic changes on MRI as well as changes in mutant Huntington's protein in the CSF. In the 12-week data we shared, we were able to demonstrate that we are having the most dependent lowering of Huntington RNA and protein. We were able to demonstrate that were doing that safely. And also, we're able to demonstrate an early trend in NFL lowering in 12 weeks, which was surprising, but very important and meaningful and promising. The study was designed as to look at 2 dose levels of TC 518 initially, 5 milligrams and 10 milligrams. And of course, [indiscernible] on that we can contextualize the biomarker findings over time.

There's been a lot of companies that have targeted Huntington protein over the last few years. Could you run us through the challenges they have gone through and how you think the gene splicing approach could help to alleviate those issues?

Yes. I think I'll agree that the concept of Huntington lowering is a sound one. We're in a pretty unique situation in Huntington's disease as far as neurodegenerative disease goes because we understand the etiology. It's a monogenetic disorder, autosomal dominant that leads the production of this mutant protein that causes the disease. So that's an advantage certainly over other neurodegenerative disorders, where the etiology is less clear or it could be heterogeneous. Now we say we're in a position that we can actually target the etiology disease, which is incredibly promising, which is why there's so much interest in the Huntington lowering approach. There have been other attempts thus far. And I think several of the shortcomings of those are related to modality. For example, the Roche's tominersen trial, which was with an ASO that was intrathecally delivered that has limitations when you talk about trying to treat a whole brain disease because if you administer therapy intrathecally it will not get to the whole brain. So even if it has an effect in a limited part of the brain to which is exposed, that effect is going to be offset by the vast majority of the remainder of the brain tissue that continues to undergo neuro degeneration. Novartis had a program with a molecule called branaplam, which is also an oral splicing modulator. However, that molecule is a repurposed SMA agent, which tells you right away that it violates the cardinal rule of successful splicing molecules that is being selective and specific. Obviously, if it works on an SMA target, it's not selective and specific for Huntington disease. And not surprisingly, there were some issues with toxicity that led to the discontinuation of that program. So I think what we're seeing in the case of PTC 518. 2 things that are really important. One, the fact that it's an oral therapy that's titratable and that you can monitor peripherally if your blood sampling and get an idea of what your biodistribution looks like, what is the optimal target but also the fact that not only is an oral molecule, it's been developed in an optimal way to be safe, effective and biodistribute as needed.

I guess without actually taking biopsies, which is very difficult. How do you know if it's getting equally distributed throughout the brain?

It's a great question. And obviously, we can't take biopsies in patients or we would ever think of that. But we can't -- we're able to do that in animal models. In animal models where we're able to understand the relationship between what we see in terms of exposure in the CSF as well as an exposure in all parts of the brain and seeing that uniform biodistribution, as well as being able to show that with that uniform biodistribution, we're getting a uniform lowering of the Huntington protein. What we learned is that the amount of Huntington protein lowering we obtained is exposure dependent. And so what we're able to do then in patients is through understanding peripheral exposure, central exposure through examining levels in the CSF, we can get confidence and also knowing the properties of the molecule that it's not [ influxed ], we can get confidence that we're getting it to the brain, it's staying in the CNS compartment broadly by distributing and then have the confidence that it's doing what it needs to do in terms of lowering Huntington protein levels throughout the brain because we know that, that is exposure dependent.

If you compare Huntington to SMA, SMA is a rapidly progressing disease. So it's a lot easier to measure clinical response in a short amount of time. Huntington is something that progresses over years and years and years. Towards that end, what is a pivotal trial ultimately have to look like to be able to demonstrate a benefit?

Yes, it's a great point, David. In fact, I think many folks in the SMA development space have said it's really having the SMA Type 1 patients who are the most aggressive form of the disease and unfortunately, rapidly lose pulmonary function and also don't achieve milestones. It's just -- you have an ability to register a meaningful clinical response in a short amount of time. Of course, Huntington's disease is on the other end of the spectrum, it's more similar to other neuro degenerative disorders which progress over a number of years, making it challenging in the context of a time of the clinical trial to record a clinically meaningful signal. I think a lot of our thinking as we put into play in the PTC518 development program. It's what informed the design of PIVOT HD, where we're taking in series, a number of important steps in the clinical development process to inform that we're on the path to having a successful therapy and for us ensuring that we have appropriate PK/PD that helps inform dose selection. And moving into the biomarker phase where we start to understand at those dose levels that we think are optimal are we registering a biomarker effect that is likely to ultimately predict clinical benefit. We're also in the process of this trial, looking at something else that's incredibly important in the study of neurodegenerative disorders, which is the optimal population for a study, patients with neurodegenerative disorders progress at different rates. If you're going to have a successful trial, you're certainly going to need to have patients who are at a stage of disease where they're progressing enough so you can register that you're altering progression, but they're not progressing so fast or so far advanced in the disease that they're really not amenable to a therapy or it's very difficult to register the benefit of a therapy that's targeting the disease all the way upstream. So what we did in designing the PIVOT HD study is work closely with a lot of the Huntington's disease experts and biostatisticians who worked with the longitudinal Huntington's disease databases like ENROLL-HD and TRACK-HD and say, can we identify a population that we think would be an optimal clinical trial population? Well, the short answer was yes. And we were able to take those attributes and turn them into the inclusion criteria for the PIVOT-HD study. So in the process of learning important details about the pharmacology and pharmacodynamic and biomarker effect of PTC518 in the PIVOT-HD trial, we're also going to learn very important information about what might be an optimal population that we would then move into a Phase III pivotal clinical study with the assurances that over the duration of that trial, we are well positioned to capture meaningful clinical effect.

Got it. And I guess on the progression in the U.S., I know the U.S. is on a hold because they wanted some preclinical relative to preclinical work. Could you tell us about what the situation is? I know the 12-week data that you recently produced to something that you would show them where -- what's the status in that area?

Yes, absolutely. So the preclinical data that we had that obviously enabled the study to be conducted at all the sites around the world. The FDA had placed us on a partial hold and wanting additional data to support the dosing and the duration that we plan to do in PIVOT-HD. As we've talked about, whether that was influenced by what they were seeing with some of the issues in some of the other Huntington lowering trials, we're not sure, but we made the decision, especially after talking with the agency and they said that additional data could take many forms. It could be clinical data. We said, okay, well, we're enrolling this trial around the world. We're going to necessarily collect safety data on probably the most relative species -- relevant species to humans, which is humans. And that we would collect those data and then bring them to the agency and have a discussion. So we -- obviously, at 12 weeks, we had 12-week data on all those patients that we shared in June. Several of them obviously have been treated for beyond 3 months. So we've taken all of those data, share them with the agency, and we're in discussions about a potential path forward in the U.S. The good news is we are able to fully enroll the study outside of the U.S., but obviously, we'd love to be able to be in a position that we can allow for patients in the U.S. to participate in the trial.

What are the next steps? When should we, I guess, hear the next set of data?

So we've said that we expect to have the 12-month data, approximately 9 months after the 3-month data that we shared, so 9 months from June. And then we're enrolling the remainder of the Stage 2 patients, and then we opened up another cohort of slightly later-stage patients, again, part of this effort to test the hypothesis around that optimal patient population. And we've not given a time line yet for when we'll share those 3 months data, but we will as soon as we have a more precise estimate of timing.

Moving on to DMD, Clearly, one of the early areas for PTC. Can you tell us the products that have been growing pretty well. What's been driving that at this point, both Emflaza and Translarna.

Yes, absolutely. So maybe starting with Emflaza. I think there's 2 elements, which have been driving the growth within Emflaza. The first is the continued mounting evidence of benefit of Emflaza over prednisone. And that's both on an efficacy and a safety point of view, and there's been a number of key publications that have been produced over the last couple of years that have really helped establish that benefit. And that has driven both physician requests to switch and also patient request to switch. And that's been important for the number of new patient starts that we've been seeing. The second aspect, which has been driving the growth is really around, I guess, commercial excellence. And ensuring that we're delivering upon what is needed to ensure success. So what do I mean by that? Ensuring the broadest access possible, making sure that we have the broadest coverage of patient access. Ensuring that we have high compliance, ensuring that we have low treatment discontinuations and also ensuring that we have patients as quickly as possible, transitioning on to commercial drug, so helping to support that broad access.

One of the challenges I've had is trying to project revenues. They kind of can be very volatile. And I'll also say upfront, my revenue estimates haven't been very good, missed pretty substantially each quarter. Could you talk to us about that fluctuation from quarter-to-quarter. What drives it and how should we look at it going forward?

Yes, absolutely. So that's on the Translarna front. Obviously, Emflaza is pretty consistent. But on the Translarna front, I think there's 2 different parts of the business that we have. So we have the standard business, which obviously is through typical patient goes to the pharmacy gets the product, goes from the other side of our business that we see in a number of different regions is what we call government ordering. And so that you see in markets like Brazil, in Latin America, in Central and Eastern Europe and Middle East and North Africa and then the Commonwealth of Independent States. So a number of different markets that we have Translarna in. And what occurs there is once you find a number of patients, the government says, okay, there's 100 patients, we're going to order supply for 6 months for those patients. And obviously, I'm just giving you an example of numbers. But so what happens there is then they supply those patients for 6 months. And then once that supply is coming to an end, they say, okay, you now have 120 patients, we'll order it for 12 months. So there's inconsistency in the way that they go about it. And obviously, as we continue to identify new patients, the number of the size of the orders increases. And so we see that across a number of different markets in our business. And what this drives, David, is lumpiness. And that's why we don't give quarter-over-quarter revenue growth because it's very difficult for us to predict. And often, in some cases, we might even see an order in Q4, for example, which is partially delivered in Q4 and partially delivered in Q1. So you even see revenue across 2 years that occur for this government-based purchase orders. So what we've tried to do to help smooth that out in many ways is continue to geographically expand the business to make sure that we're trying to see a geographic split that allows us to have some smoothness in the way that we have our business. But because of the size of these orders, they do create that lumpiness. From a sort of revenue point of view, it is difficult to predict even for us, we obviously have forecasts that suggest when Ministry of Health orders will come in. but particularly in markets like Brazil as an example, where you see changes in the Ministry of Health. Sometimes orders come in earlier, sometimes they come in later. So it's very difficult to sort of predict that lumpiness that we see, which is why we focus on annual guidance because we're confident we'll be able to secure the order on an annualized basis.

When we look at the annual guidance, I assume that because you don't know exact timing of when these orders come in, there's some sort of probability weighting going in when you try to determine if you're going to make it into this year or into next year. To what extent does conservatism play? And because, for example, the current guidance does imply a downtick in the second half of the year. Is that -- should we view that as conservatism? Or should we view that as -- that's where we should expect things in the second half?

Yes. So I think just to touch on the guidance. So our guidance at the beginning part of the year was $545 million to $565 million for the DMD franchise. We adjusted the guidance at Q2 earnings to $545 million to $575 million. So as you said, we maintain the low end of the guidance, but we increased the top end. I think it's twofold, David. I think one is we didn't have as much insight or we didn't have as much clarity on the timing of orders in Q2 as we will in Q3. So we have an ability then to say if we have more insight that the orders will definitely come in 2023 that we can then take the guidance another step. But also, I think it's also around supply of what we see from those government purchase orders. So in other words, if an order happens in Q2, there's a chance it could happen again in Q4 or Q1. And so once we have further insight into that, we'll be able to provide further clarity at Q3. So I think it's a little bit of timing. And I wouldn't say conservatism, but I think it's important that we give you the most accurate forecast of our business. And obviously, that increases as time increases in the year.

Got it. As far as going generic, how is that looking as far as Emflaza?

So from an Emflaza perspective, for Translarna, we have patent extensions through 2029. So we're in a good position there. From Emflaza, we have shared that loss of exclusivity is expected in 2024. We're obviously looking at extensions of what quarter that will be next year. But I think what's important is rare disease is a little bit unique. There's a lot more brand loyalty that you see in rare disease that you don't see in some of these larger specialty areas. And the reason for that is many of these patients, and this is no different in DMD or Medicaid patients. So their ability to afford medicines, their ability to require those patient support programs that are in place, the specialty pharmacy access, all of that is very important for them in their access to treatment. And so what that doesn't provide them is when they switch across to the generic, the margins that they're saving there don't make up for the access to medicine. And so you see that brand loyalty that you don't commonly see in cheaper medicines. But in addition to that, we've also put a number of programs in place around partnering with specialty pharmacies, really expanding the breadth and depth of our patient support programs to really meet the needs of all DMD patients that we're treating, partnering with payers, partnering with manufacturing to make sure that we can really protect the tail of our business. And so we're not expecting that traditional generic erosion that you see. And I think Kuvan is actually a really good example of that. They've been able to maintain a good proportion of their business many years post genericization, I think they're maintaining around 45%, 50% of their branded sales 3 years post genericization, and we expect a similar story.

What type of -- given those dynamics, what type of price erosion would you expect?

Yes, it's an interesting one, obviously. I'm not 100% sure, but I think what we've seen as a trend in the generic space and particularly in rare disease over the last couple of years as you used to see generic sort of entering the market at that 50% to 80% price discount. You don't see that commonly anymore. You often see them entering with a 20% to 30% price discount. And that's why those ancillary factors that are associated with the brand, that value gets eaten up very, very quickly, right? If you've only got a 20% price discount from a generic, the access to therapy that disappears, it's eaten up very quickly. So it's hard to say, but if I were to guess, I'd say somewhere between the 20% to 30% price discount for a generic.

Jumping over to Translarna again. United States. I know there's another meeting coming up. Tell us how this meeting might differ from the one, 4Q, last year.

Yes, absolutely. So obviously, Translarna has had a long history in the United States, and we believe that we are in a position now with incredible volume of data, data from 700 boys and pre placebo-controlled trials for rare or subtype of a rare disease that showed clear and consistent benefit. We also now have registry data from our STRIDE registry, real-world evidence, collect in over 300 boys for an average follow-up of 5.5 years that show we're delaying the time of loss of ambulation by 3.5 years, a lot of time in loss of pulmonary function by 1.8 years. So really meaningful findings that we're now able to bring forward that show that the treatment effect that's been recorded in the clinical trials is manifesting itself cumulatively over time in important and meaningful delays in these key [indiscernible] disease transition points like loss of ambulation and loss of pulmonary function. The discussion that was -- there was a written response only that came from the FDA in Q4 last year that focused really on the most recent placebo-controlled trial, Study 41. And they're providing feedback that they didn't think that, that study alone provided substantial evidence of effectiveness to support its suitability as a 1 study approval. Obviously, we were concerned that there was a large volume of data being overlooked. We've had a subsequent conversation with the agency about that. We agreed that we would set up a meeting come in, review the totality of evidence and the fact that there's many sources of evidence, whether it's 41 as a study showing benefit confirmatory evidence from the meta-analysis or from STRIDE or many different combinations that can support the fact that this is a therapy that's demonstrated a consistent meaningful benefit, it's safe and has evidence of long-term effect. So we look forward to those discussions with the agency and the potential of bringing this therapy to boys in the United States.

Evrysdi, we got 5 minutes left and leaving it towards the end. Can you talk us through us about recent dynamics. It's obviously done very, very well. Last quarter was a little more bumpy than usual. Could you talk to us about what's going over there?

Yes, absolutely. So across the board, Evrysdi has shown incredible growth since launch, and that's not slowing down by any means. I think one of the things that I just talked about for Translarna, the lumpiness also flows across to Evrysdi. They have the similar markets that I just touched upon in regions that are affected by government ordering. So they will see that same lumpiness quarter-over-quarter, and you saw that Q1 over Q2 from a revenue point of view, and you saw that in similar markets to what we see for Translarna. But across the board, I think one of the things that's consistent is Evrysdi has continued to grow in the number of approvals globally. So there's now more than 100 markets that Evrysdi is approved in, and they've been focusing on ensuring that pricing and reimbursement is in a favorable position in each of these different countries. So obviously, in the U.S. being the first market to launch, you saw a quick penetration, a quick uptake across broad patient segments. So across all ages, across all types, memory disease prevalence. You saw it across therapy naive patients as well as those previously treated with SPINRAZA and Zolgensma. And then what you saw was a little bit of a lag with ex U.S. growth, and that was because of the need to negotiate pricing and reimbursement on a country-by-country basis post approval. But I think from a European standpoint, they've done a good job of doing that. We're in a very good position with uptake in Europe, still growth to come, but they've established pricing reimbursement in many of the major markets. They've talked a lot about France, Germany, and they've shared that they are the market leader in all major markets and are on track to be the global market leader for SMA in 2023. You also saw the growth in Japan, as an example, in the international markets and also in the rest of world markets. The other thing that's really important, you saw the label expansion with the sNDA approved for presymptomatic infants in the U.S. and Roche shared that they quickly saw an uptake in that patient population. And then they recently received the CHMP opinion and also EC ratification for that same label expansion, presymptomatic infants. And I do expect that to be another growth driver in Europe in the near term. So they just received EC ratification for that. So I'll expect to see that in Q3 and Q4.

Has SPINRAZA use been settling into a certain kind of niche relative to Evrysdi? Or do you expect that Evrysdi will continue to take share?

I do think Evrysdi will continue to take share. I think where Roche has talked about roughly around 1/3 of the patients coming from therapy-naive patients, I think that's still a large untapped potential. And I think you'll continue to see penetration into that space. But also in the 2/3 coming from previously treated with SPINRAZA and Zolgensma, I still think there's room to grow there. And I think that you'll continue to see Evrysdi penetrate and erode the space of SPINRAZA.

Upstaza, could you update us on that area?

Absolutely. So we've been continuing the rollout of Upstaza in Europe. And we've been focused on 3 main access pathways that have been really important for us as we continue to write the playbook of the first-ever approved gene therapy that's directly infused into the brain. So the first important pathway, of course, is early access programs. We talked very early on in the launch in the latter half of last year, around treating patients in France as an example through the EAP program. So that's the early access program there. We also shared in Q2 that we were able to treat a patient in Italy, and that's also through the Early Access 326 pathway. So that's an example of early access pathway that we think is important for getting these patients treated in advance of formal pricing and reimbursement, which, as I just talked about with Evrysdi, same story, it takes time. There's a lag between approval and reimbursement. The other important pathway is cross-border treatment, and this is particularly important for gene therapy. This is in the case where patients are identified in countries that don't yet have treatment centers of excellence established. And so they cross the border and the host country is able to reimburse and pay for their treatment in, say, for example, France or Germany, or Italy or wherever a treatment center of excellence is established. And so we shared earlier this year that we were able to treat our first cross-border patient. It was a patient from the Middle East being treated in Europe, and we expect to continue to treat more patients through those pathways in the latter half of this year and also next year into 2024. And then, of course, the third is probably the most traditional pathway, and that's commercial access. We shared that obviously, we treated patients in Germany early on, and that's through the initial and rapid uptake that you're able to get in Germany. But we're also continuing to move forward with pricing and reimbursement negotiations in other markets. We also shared that we had a positive recommendation from NICE for Upstaza, and so we will look to treat patients from the U.K. in the very near term. And then we've also had positive recommendation from [indiscernible] a rating point of view, and we're working forward in the final pricing and reimbursement. So these are just some examples of the forward momentum that we're making in each of the different countries in Europe. I will say, outside of Europe, we continue to identify patients. We continue to focus on additional registrations, and that's going to be a key growth driver for Upstaza in the future. We've talked about, obviously, a BLA submission for the FDA, and then there's a number of other markets that we're focusing on outside of Europe.

I'll sneak one more in here. What's the timing on BLA in the U.S.?

So we said that we were expecting to submit that in the third quarter of this year.

That's about 3 or 4 weeks. With that, thank you very much, and appreciate you coming. Thank you very much.

Thank you, David. Thanks for having us.