Okay, good morning, everyone. I'm Brian Abrahams, Senior Biotech Analyst here at RBC Capital Markets. We're really pleased to have our next presenting company, PTC Therapeutics, represented by three of the members of their management team: their CEO, Matt Klein; their CFO, Pierre Gravier; and their Chief Commercial Officer, Kylie O'Keefe. So, Matt, Pierre, Kylie, thank you guys so much for joining us.
Thank you, Brian. Great to be here.
All right, a lot to cover. Maybe we start with Huntington's disease, because I know we're going to see some data coming up from your small molecule, splice modulator, 518. Maybe just setting the stage, what aspects of the data to date do you find most encouraging in 518's potential to ultimately demonstrate clinical benefits for patients in Huntington's?
Thank you for the question, Brian. We're incredibly excited about the potential of PTC518. As we've talked about, it comes from our splicing platform. First therapy that came from that splicing platform was Evrisdi, which was obviously quite successful in its development for the treatment of SMA. It also provided us an important blueprint on how to design and develop an oral small molecule splicing agent for a whole brain disease, like Huntington's disease. So a lot of those learnings went into the early development of PTC518, including the importance of selectivity and specificity, having a molecule that not only gets across the blood-brain barrier but is in efflux and has blood-brain biodistribution, which is incredibly important, again, for a disease like Huntington's disease where you have impact on the whole brain.
So as we move through the clinical development program, there were several important questions that we needed to answer. First and foremost was getting proof of splicing activity, mechanism of action, which we uniquely can do with an oral molecule by checking the blood cells. This is something that you can't do with an ASO that's intrathecally administered or within locally delivered gene therapy to the brain. By looking at blood cells, which we know have the same genetic machinery as brain cells, we're able to really understand what the PKPD relationship is with PTC518 and get that important proof of splicing mechanism of action. We got that in phase I. We also clearly saw that in the 12-week data from the PIVOT-HD study where we showed dose-dependent lowering of peripheral mutant Huntingtin protein in the range that we want to see, which is roughly 30%-50%.
We've said all along that the target of this program is to lower Huntingtin protein in the brain 30%-50%, and that's because there's a number of preclinical studies as well as epidemiological studies that confirm that by lowering Huntingtin protein in that range, you can have a significant impact on disease progression. So checkbox one, we know that the drug works the way it's supposed to work by looking at its activity in blood cells. The second important aspect was to ensure that we're getting the CNS exposure necessary to allow for that same effect on the genetic machinery in brain cells.
Importantly, we got that proof in both the healthy volunteer phase I study as well as the 12-week PIVOT-HD data, which told us that we're having not only exposure in the brain, but we're getting greater exposure in the CNS than we are in the periphery. That's really important because that tells us with the levels of lowering of Huntington protein we saw peripherally in the phase II study at 5 mg and 10 mg, given the higher exposure in the brain, we may very well be at those, the exposure necessary to get that 30%-50% lowering at these dose levels. And then the third important take-home point from the 12-week data was safety. Incredibly important.
There's been a lot of discussion about peripheral neuropathy and NfL spikes with Huntington-lowering therapies because of the experience with other therapies that are actually quite different from PTC518. They lack the specificity and selectivity that we know is so important. And so it was incredibly encouraging, not surprising, but encouraging, to see that we had no evidence of NfL spikes, no reports of peripheral neuropathy, and very favorable safety and tolerability profile in 12 weeks. Now we're going to move into being able to share 12-month data on those initial subjects on whom we shared 12-week data. And now we're going to look for continued safety and tolerability, of course, very important as we move into 12 months.
Then also begin to understand, are we seeing any signals of effect on biomarkers, CNS biomarkers or clinical scores, that could tell us that at the dose levels we're at, 5 mg and 10 mg, which we believe to be the right dose levels, that we can start to see movement on metrics of the disease that can suggest that in the long run we're going to have that important disease-modifying effect and meet the significant need for Huntington's disease patients. So we'll be sharing data on CSF Huntingtin protein levels, NfL levels, brain volumes, and then on some key clinical scores such as Total Motor Score, which is a particularly relevant score given the stage of disease of the subjects enrolled in PIVOT-HD, those being stage two patients on whom we're going to report data. We'll also have data on Total Functional Capacity as well as Composite UHDRS scores.
So in addition to those 12-month data, which we think will be important in being able to give us those first signals of important CNS effects, we'll also have additional 12-week data on the majority of the remainder of stage two patients as well as some of the stage three patients enrolled in the study.
That's on track for mid-year?
That's on track for Q2. So between now and June 30th.
How should we think about the translatability of 12-week, peripheral blood MHTT knockdown versus CNS knockdown over 12 months? I know you've talked about maybe having seen some hints of that already at 12 weeks, but I know there's a lag period and the brain and the blood are not exactly the same in terms of how you might expect things to play out. So what would your expectation be for the time duration of pull-through? And I guess how much variability is there in these assays? I know these are very minute amounts. And so I guess I'm sort of wondering if we should be most focused on this CSF MHTT knockdown, or if really by a year in we should be thinking more about some of these clinical parameters as being better gauges of activity?
All really good questions. I think in an ideal world, we'd be in a position where we could directly sample brain cells. That would tell us we could measure with the same accuracy and precision reductions in Huntingtin protein that we're able to do in blood cells. We can't do that. But importantly, what we do know is that cellular machinery is cellular machinery. And we know from our preclinical work and just based on first principles that the ability to exert the effect, on the genetic machinery to induce splicing, lower mutant Huntingtin protein levels, works the same in peripheral blood cells as it works in neurons. And that's really important. So that tells us that if we're getting drug to the neurons, getting CNS exposure, we can fully expect to see the same levels of reduction. They'll be exposure-related.
So if we're getting greater exposure in the brain, we'd expect to have greater lowering at the same dose level that we're seeing in the blood. That we know. How that specifically manifests itself in terms of Huntingtin protein in the CSF, which is a little bit different because CNS CSF doesn't have cells. It's a reflection of something going on in the brain. It's hard to know exactly what that time course is to get to equilibration. Nonetheless, I think we'd all agree that if we can demonstrate some level of Huntingtin lowering CSF Huntingtin protein level that gets us close to that, close to what we're seeing peripherally. That's a really good sign. That's a sign that things are working exactly as we expect they would based on the fact that we know the drug works and we know that it's getting to the brain.
You raise a point about assay variability and sensitivity. It's, you know, one of the challenges with these assays. Are they difficult? We also know that the levels of Huntingtin protein in the CSF of Huntingtin's disease patients, particularly those at stage two, are quite low. They could be down at picomolar levels, which gets you into challenges of detection. But all that is to say that if through all of that noise we can see a signal, that's even more compelling, right? In terms of the clinical data, yes, clearly in the long run, where our goal is to treat the clinical disease of Huntington's. So what matters most is being able to see an effect on clinical measures. We know that the disease doesn't move relatively slowly, so that at 12 months there's only so much change that you could possibly register.
So again, I think at the 12-month time point, with the number of subjects on whom we're reporting data, which is approximately 30. Being able to see some signals or some trends on even one or two of these would be really compelling. I think not seeing them doesn't mean that we don't have a drug effect. It just means it's going to take more time. But if we do see them early, along with some biomarker signal, that obviously, very much as you outlined, you know, this morning, that would be very compelling and give us a lot of confidence that we've got a really, really potentially transformative drug here.
Good. Maybe shifting gears to Translarna. So obviously CHMP had recommended the drug be withdrawn from the market, but, you the drug is still on the market. You posted one of your biggest quarters ever. So I think it seems like physicians and patients are at least kind of voting with their feet. What's the latest status? How much patient and physician advocacy is there to preserve Translarna's role in the EMA market? And have you guys heard anything or any hints coming out of that April meeting that the European Commission held about Translarna at this point?
Yeah. So so what do we know? We know exactly what you said, that there was an opinion provided by CHMP at the end of January to withdraw therapy from the market. Therapy we knew is safe, we knew is effective, and we knew that patients and physicians believed it. Nonetheless, the CHMP made their decision, and we've talked a lot about that. The European Commission, which typically adopts the CHMP opinion, given that they charge the CHMP with doing the appropriate scientific and technical evaluation of a drug, didn't do that. Instead, they decided to pause the procedure, not withdraw the therapy, and to meet in person to discuss the case the week of April 22nd. We know that there has been a tremendous outpouring of support from Translarna, from the patient and physician community throughout Europe.
One could assume that the response of the EC or the lack of action of the EC to withdraw the drug is likely in response to having a tremendous outpouring of physician experts and patients who want a drug that's safe and effective and don't have an alternative therapy. We have not received any updates from that meeting. As you alluded to, it continues to be business as usual for us. Again, we're in a position where the physicians want to continue to prescribe Translarna. They believe in the drug. The patients want the drug. And we're happy to be in a situation that we are going to continue to provide the drug. So as much as we want clarity, certainly if particularly if it's favorable, we're going to continue to make the drug available.
And I think for us, you know, this is all upside. This is all.
Have they given you any timeline for potential communication?
We have not heard anything. And I think, truthfully, you know, the other question we get a lot as well is, are there any precedent for this? And we say we're really in the realm of the unprecedented. I think first, the withdrawal of a therapy in Europe, for therapy that's safe, is unprecedented. The only precedent we're aware of, the European Commission not adopting an opinion, is Glybera in 2012, and they basically sent that back to the CHMP and through an additional procedure that took several months. In the end, a positive opinion was issued by CHMP. But again, it's very hard to even say, should there be any read-through to this?
We're in the realm of the unprecedented, and we're going to focus on making sure that all the kids in Europe get drugged, and we'll continue to build the business home.
Can you remind us the breakdown of sales internationally between Europe or EMA or EU, and the rest of the world for Translarna and what you've seen on the ground since the CHMP recommendations, both in terms of countries in the EU, which may have been affected, as well as countries, I guess, from a commercial and regulatory standpoint, outside of the EU, how they've responded to some of these developments?
Yeah, absolutely. So as we've said in the past, from a total Translarna revenue point of view, around 45% of that is a contribution from Europe, and the remainder is obviously contribution from outside of Europe. And we've talked a lot about our strategy over the last couple of years has been not only about deeper penetration in existing markets, you know, starting off where we were in Europe, but also particularly around geographic expansion. And I think that shift over time has been growth in these newer markets because we have a much stronger growth rate. Thinking about sort of the response across the board, as Matt said, it's been unanimous. I think we've seen support both from payers, physicians, and patients continue while the product is still on the market. And I think you saw that play out.
And as you said, a very, very strong performance in the first quarter. And the teams have been working hard as we say business as usual to ensure that business as usual is occurring in reality. Okay. And I think from that perspective as well, even as we look at markets outside of Europe, you know, since our quarter call, we've seen the order come through from Brazil with regards to Translarna, the group purchase order, which we expected in the first half. And so that's continuing to show that we're able to execute upon business as usual activities. And you'll hear more about that at the second quarter earnings.
Okay. And then for Translarna in the U.S., you've signaled that there may be some FDA amenability to reviewing the file. Can you maybe talk about additional data sets that are going to be included in this NDA filing? And I guess what gives you the most confidence that the FDA may have, I guess, a favorable view here? And is there anything that one can glean from the CDER's recent review of another DMD drug, Duvyzat?
Yeah, absolutely. So we wanted to be sure in our discussions with the FDA that they believed that we had a file that was not only reviewable, but potentially approvable. You know, I think we're all aware of the history of Translarna in the United States, and we certainly made it explicitly clear to Dr. Buracchio in the neurology division. We if there's any question of an RTF here, let us know where we won't move forward. And we had the assurance that any questions they had would be a matter of review. So that was incredibly encouraging, and that's why we are moving forward with the submission.
There was also a number of analyses they asked us to provide ahead of giving us that signal that they would review, particularly sensitivity analyses that demonstrated the robustness of the findings in Study 041 in the ITT population across all the key endpoints. All of those analyses continue to support that we have a significant treatment effect across walk in walk distance, North Star, Timed Function Tests, time to 10% worsening. So all of the key clinical endpoints. The other part of this was, do we have the confirmatory evidence? And we were able to clearly demonstrate that in STRIDE we have important evidence of long-term benefit, in terms of delaying time and loss of ambulation, loss of pulmonary function.
So a lot of the discussions with the agency were around having a package that had the requisite persuasive evidence from Study 041, along with the confirmatory evidence from STRIDE. So the fact that we were able to address the concerns in the pre-submission discussions at the FDA raised were very encouraging and gives us a lot of confidence. You referenced the recent CDER action approval of Duvyzat. Reading through that review, I think that gives us even more confidence, quite frankly, because a lot of the issues raised by the reviewers on the negative side, and their concerns in that evaluation, were things that they had asked us about already. They were the same analyses they wanted us to perform to show them that we had robust evidence in Study 041.
So when we see the scrutiny that they applied to a therapy, and quite frankly, the scrutiny that didn't help the approval, and we know that we have stronger evidence on those additional analyses, that gives us a lot of confidence. And also on STRIDE, I think if you look at the review of the natural history data and the natural history comparative data, in that NDA and in the FDA's review, they raised a lot of concerns about the inability to have a matched comparison. When they did a matched comparison, they lost too many subjects. It was an unmatched comparison. And notwithstanding those concerns, they still said they see these data as confirmatory. We have propensity matched data on over 280 patients and an incredibly robust. We had a pre-specified analysis plan. So all their concerns they raised and approved that drug, we actually can address.
So that's why, in reading that, that gives us even more confidence that when we see the way that the CDER reviewers are thinking about persuasive evidence and confirmatory evidence, we clearly believe we can check all those boxes.
Moving on to PKU. How are you preparing for the launch? And maybe actually, can you give us a little bit of the latest color on the filing timelines? There may be some of the additional elements that you're working through on the tox side, where things stand.
Yeah, absolutely. So, first starting on the regulatory side, we submitted the MAA to Europe in March. We share that information. We expect that will get validated and the review to begin this month. Just based on the European timelines, we have all the components of the U.S. package otherwise ready. We're waiting to complete the 26-week transgenic mouse study, which we shared will be completed in June, and then we'll look to make the submission shortly thereafter. And then we're also readying submissions, as we talked about, for Brazil and Japan as we look forward to this being our first true global launch.
Can you maybe elaborate on your launch preparation? What are some of the key accounts and centers that you guys are targeting? How much sales force expansion? How much investment will this should we think about this entailing?
Yeah, so absolutely. From a, maybe starting with the back end of your question first, Brian. From a Salesforce expansion point of view, none. We have the infrastructure in place. We've talked a lot about the way that we've built our commercial infrastructure globally with the purpose of executing on today's business, but also being ready for tomorrow's. And tomorrow is here. And so that's incredibly exciting for the commercial teams. So from a launch preparation point of view, I think there's a number of key areas the team's focused on. You touched on call points. I think one of the things that's really exciting for the team is, you know, whether it's pediatric neurology or pediatric metabolic specialists, they're very close in the pediatric hospitals outside of the U.S.
There is some overlap between some of the KOLs that we see from a DMDs point of view as well as a PKU point of view. So, you know, we know patients are identified in the vast majority of markets around the world through newborn screening. So we're not needing to go and do patient identification. The treatment centers of excellence are well known. We've talked about them being geneticists as the primary prescribers in the U.S., pediatric metabolic specialists outside of the U.S., dieticians playing an incredibly important role as we think through, obviously the Phe-restricted diet and how to liberalize that in the face of a substantial Phe reduction. And then also we've talked about the fact there's well-documented, well-understood disease pathology and pathophysiology, which helps from a market access preparation point of view.
We've talked about early engagement with payers and understanding what it takes to ensure that we're establishing a strong pricing corridor and favorable reimbursement. And then last but not least, engaging with the patient advocacy community. And truly across the board, we've talked about the pool from the market being both from a physician and from a patient and patient advocacy point of view. And we're talking broad segments. You know, we obviously had segments identified early on about where we think we can penetrate. But we've seen it truly across the board, even in those that are well controlled on Kuvan, because physicians are saying, if we can get an extra 100 micromolar per liter Phe reduction, then we can really make a difference with diet. And ultimately, as we've talked about, both from a patient and a physician point of view, that's the Holy Grail.
What are you hearing from the payers on that front?
So obviously, I think it slightly differs when we look at the different geographies. So I think in the U.S., it's less of a focus just by the nature of the fact that U.S. payers don't fund medical foods and formulas. So it becomes less of a focus. Ex-U.S., it's obviously a focus because payers are paying for medical foods and formulas, and they want to know if I'm also paying for a therapy, how do I reduce my costs? How is the patient able to liberalize their diet? And so we knew this going into sort of preparations, and that's why inclusion of Phe tolerance data in the long-term extension study was a must for us. Yeah. And we've been incredibly excited by that data. And as that data continues to mature, it just continues to get better. And so from that perspective, we're excited.
One of the questions we get frequently is some of the intrigue around the effects sepiapterin showed in the classical patients, which you wouldn't necessarily expect to see in a BH4 for a BH4 drug rate. So I know there's only a small handful of patients, but I guess how different of a label would you expect? Or would you be hoping for relative to Kuvan?
Yeah, I think so. I first of all, let me just say that we expect the label to be broad. Full age range, full disease severity. We have the data to support that on both the age and the severity side. I think there's been some misunderstandings around classical and classical patients. I I think, first of all, I think people assume that all classical patients have no functional enzyme. That's not true. It's a very, very small number that are homozygous null and have no functional enzyme. So you're left with patients who do have some functional enzyme and having a drug like sepiapterin that's bioavailable and potent, and by the way, has two mechanism distinct mechanism of actions. One is as a precursor for BH4, which acts which is responsible for the cofactor activity similar to other BH4 therapies.
But the other is as a chaperone, the ability to stabilize the morphology of the phenylalanine hydroxylase enzyme, which when in combination with provision of the cofactor allows for a more optimal effect on enzyme function. So I think it's that dual mechanism of action in part that's allowing us to see in the APHINITY study a mean reduction of 69% in the classical PKU patients. Which is pretty impressive. And then when you consider that we had those patients, while it was a small number in the active arm, we had a slightly larger number in the placebo arm, which told you that those placebo patients had a greater than 30% reduction as well. And then as we move into the extension study, we're seeing the effect on diet liberalization and Phe tolerance in these severe classical patients.
So I think these data are, let's just say, dispelling a lot of myths about the ability of our therapy to treat classical PKU patients. And the market pull that that Kylie described is not only amongst patients who are traditionally served by existing therapies, but by classical patients who we see on social media say they want to enjoy hamburgers also. So it's incredibly exciting.
Good.
No, I was just going to add. I think where we see the clinical data coming into play is not from a regulatory point of view, as Matt said, because we expect a broad label. It's from a physician uptake and payer point of view, convincing them that we have the true breadth and ability to treat the full patient population.
I know we only have less than a minute left, but maybe, Pierre, for you, just wondering how you're thinking about your latest thoughts on capital allocation, potential path to sustained profitability, and sort of balancing investments in R&D and some of these launches with capital preservation as well.
Yeah, absolutely. I mean, last year it was very important for us to obviously, you know, reduce OpEx, which we've achieved. You saw Q1 a 32% reduction already. And I have a very strong balance sheet, right? Which is, you know, I think we closed at $885 million. So that's going to, you know we'll keep on looking at our capital allocation going forward to make sure our OpEx are aligned with top line. But as Kylie mentioned, we are fully ready to go. I mean, the day PKU is approved. There's no additional investment. The sales force is ready and will be ready to go, you know, globally and very strong.
Good. There's so much more I'd love to cover, but unfortunately we're out of time. So, Matt, Kylie, Pierre, thank you guys so much.
Thank you, Brian.