Okay. All right. Good day, everybody. My name is Ash Fermal. I cover SPTC Biotech and SPTC Pharma. And with us, we have PTC Therapeutics, Matt Klein, who is the CEO, and Pierre Gravier, who is the CFO. Guys, thank you for joining us.
Thank you, Ash. Great to be here.
Exciting time in the story with the launch, with Sephience. Maybe if you can give a little bit of a high-level overview of the company, where the story has been focused on, and then we can take it from there.
Yeah, absolutely. PTC is a global biopharmaceutical company focused in rare disease. We discover, develop, and commercialize rare disease therapies. Our commercial portfolio includes six products that we market ourselves worldwide. We also have a robust R&D pipeline, including our small molecule splicing platform, which is the source of Evrysdi for SMA, which was the first-ever small molecule splicing drug, also for Votoplam for Huntington's disease. This is really a well-differentiated, validated, powerful platform. We just completed the third quarter, read out our third quarter earnings, very strong performance with $211 million of revenue, including contributions from Sephience, our PKU drug, which I'm sure we'll be talking about, which really got out of the gate quick and very strong. We also continue to be in a very strong financial position with about $1.7 billion on the balance sheet.
I think we're here at a time where we're launching a product that's gonna be really, provide us a foundation for future growth. We're in a strong cash position and a lot of exciting things coming out of our research platforms.
Great. Awesome. Yeah, exciting time in terms of the launch, as well. Yeah, I think with Sephience in PKU, just if you can kind of characterize, like, what was the prep that you had going into the market and, as you've seen some of the early signs, like, where is the source of patients coming from? Is it switches, naive? Like, what type of thing?
Yeah, I think just framing the opportunity first, I think this is a pretty unique rare disease launch opportunity. PKU is about 17,000 patients in the United States, and there's newborn screening, so they're all identified. While there've been two previous approved therapies, by and large, the vast majority of patients aren't served by those therapies, whether it's due to questions about efficacy or about safety and tolerability. We were able to bring Sephience, which is a small molecule, oral small molecule, once-a-day drug, very strong efficacy profile that's highly differentiated, very strong favorable safety and tolerability profile, into the space.
You basically have a space that has a lot of the pillars for commercial success already there, with centers of excellence identified, a well-aggregated patient community, payers who understand the disease, understand that you could tie value to phenylalanine lowering, and then, and newborn screening, of course. Then we come in with a highly differentiated therapy, a commercial team that's very experienced in selling rare disease therapies, particularly in genericized and competitive markets. When you put all of that together, you get really what could be a very large opportunity for us. When we think about the patient segments, they've broadly been broken into patients on therapy, patients who've tried and failed therapies, and patients who are therapy naive.
We have talked a lot about how, based on the mechanism of action of Sephience and the clinical data we have, showing that we can have significant effect in lowering phenylalanine and allowing diet liberalization, even in the most severe patients, and the fact that we have a label that is inclusive of almost all ages in the U.S., it is one month and above. You know, we believe we can access all of these segments. What we have seen in the early days of the launch is really just that. We are getting patient start forms. We said in the first six weeks of the launch, we had over 500 patient start forms, over 300 patients on drug, $19.6 million of revenue globally. With patients, you know, we have patients as young getting start forms to patients as young as two months of age.
We have a 79-year-old adult who's on drug, patients who have classical PKU with real severe mutations, all of which are, you know, doing well on the drug. I think this is really supporting the potential for Sephience to be a drug for, you know, really be the standard of care for PKU with broad adoption across all age groups and all disease severities.
Great. I mean, was there any kind of early, you know, warehousing patients that physicians were doing, particularly at these centers of excellence? I mean, if they knew that the drug was going to become available.
Yeah, I wouldn't say traditional warehousing, you know, in a sense, you know, first of all, with newborn screening, the patients were all identified. There are 104 centers of excellence in the U.S., probably 80+ % of patients are tied to those centers. We didn't know that there were a number of centers that had waiting lists of patients really interested to get on the drug. You know, I'll also add, it wasn't like we had expanded access or an ongoing clinical trial where a lot of patients rolled out of it.
Right.
We had our long open label extension study from our phase three, which had about 10 patients still in it. This was really about, yes, a lot of interest, broad interest, across the full spectrum of the patient population. We have had basically participation of almost all the centers of excellence. Three quarters of them have submitted more than one start form. What we are seeing again is just very broad uptake and broad interest in the drug.
Got it. Yeah, I think, and then just, like having launched in August, just the month-over-month, like, have you seen that type of a trend that, yeah, early, early, you know, the drug becoming available and then sort of more, reaching at a stable state, September? I don't know if you've commented about October.
Yeah, what we said, what we shared at earnings last week was that clearly strong, strong start, over 500 patient start forms in the U.S., and that we were seeing continued momentum in October. You know, we expect that momentum to continue. Of course, it's still early days in the launch. We've got Thanksgiving, Christmas holidays and such. What we're seeing so far is really consistent momentum and, again, a great deal of enthusiasm. We're hearing from a lot of physicians, many of whom tried the drug for their first patients where they're more severe patients. Seeing these more severe patients respond, we're now hearing things like, "I'm not gonna try all my patients on the drug," which is really what, you know, is great to hear.
Yeah.
Because if you think about this opportunity with 17,000 patients, the key really is to have a wide funnel, and to have prescribers thinking about trying all of their patients on the drug. You know, that's how this can become, you know, really a very big opportunity.
Yeah, we've heard from some KOLs, you know, that they had hosted calls previously that they want to try it on all of the patients. I think, like, as you're seeing the focus from the physicians, like right now with the 500 that you mentioned, how many physicians is that coming from? How does that expand over time?
Yes. What's interesting is, so we've, so a couple things. One is one of the data dynamics in this launch is we're getting prescriptions from physicians, also from nurse practitioners. We spent a lot of time before the launch getting to understand the centers. Part of the mapping of the centers of excellence is understanding who are the touch points within the clinics for patients and also who are the prescribing decision-makers in the clinics and who writes the prescriptions. In PKU, certainly you have physicians, but you also have nurse practitioners that do a lot of the day-to-day care.
In fact, as I said, the majority of our start forms have come from nurse practitioners, and also dietitians who play a very important role for the PKU patients because in the absence of a therapy, the mainstay of care is a modified diet that is a low-protein diet and that requires a lot of interaction and management from dietitians. It may very well be that patients, it is the case that many patients do not have, you know, are not in touch with the doctor who is prescribing something for them, but their point of contact is the dietitian. Having been able to map all that out and build relationships with all of those key folks has really helped the launch. We are seeing, as I mentioned, you know, PSFs from, you know, across all the centers of excellence.
Yeah.
Some prescribing more, but all that gives us the confidence that we can have a sustained momentum.
Great. And, is there any dynamic from, like, when you're converting the patient from Kuvan versus, like, naive that, in terms of, like, the physician, monitoring and the level of involvement that they need to, you know, take care of?
Yeah, I think we, we've heard a lot and we fully expect patients who are on Kuvan, the branded or generic, to switch over to Sephience. And that's just a data-driven decision. We have a head-to-head study, the results of which we shared recently. It was a crossover study. So individuals with PKU got both Sephience and BH4 or Kuvan generic. We showed that we had a 70% greater reduction in phenylalanine in these patients. That's in addition to data from our phase three trial where we had, again, significant reduction, additional reduction in phenylalanine for those who came into the trial on Kuvan branded or generic.
If you basically are on a once-a-day oral therapy and you could switch to another once-a-day oral therapy that has an equivalent safety and tolerability profile, but much greater efficacy in terms of lowering phenylalanine and less likely allowing greater diet liberalization, that becomes a very easy switch.
Right.
We expected early in the launch to see a number of these switches. We are seeing some, but what we're also seeing is a desire by physicians and nurse practitioners to prioritize those who aren't on a therapy, which makes sense.
Mm-hmm.
That is why we're seeing some of the more severe patients get tried first. It is great to hear that those individuals are getting significant benefit from Sephience. We expect to continue to see contributions from those therapy naive or tried and failed patients, but we also fully expect to continue to see patients who are on Kuvan branded or generic to switch because, again, you are swapping one once-a-day oral therapy for another and getting a whole lot more efficacy.
Great. Great. Okay. Can you maybe talk a little bit about, like, the access? How's that developing? I think you said, you said that, like, in terms of the patient start form versus the, like, how many patients were on therapy, there's a little bit of a lag, I'm assuming. Just any kind of medical exception process that they're going through while the coverage is being determined?
Yeah, it's going very well. We've said that from start form to drug, in many cases, we're getting that done in less than two weeks. On average, it's been two to four weeks. What mostly, prescribers are being asked to have a prior auth, but it's prior auth to the label. We're not seeing step-throughs from Kuvan or Kuvan generic.
Mm-hmm.
and we've also had policies now from a couple of payers, including, very large, one very large payer that's basically no step edit, prior auth to the label, and criteria for renewal being basically either a pro, a diet response, phenylalanine response, or medical benefits. Really what we're seeing play out is what we expected based on our, the extensive discussions we had with payers prior to and in the early days of the launch, which is they appreciate the differentiated qualities of Sephience.
Yeah.
In, we were also able to provide them head-to-head data, which is really nice to say, "Look, with this clear superiority to the other oral therapy that's been in the market and that's now genericized," and also be able to show them based on mechanism of action, we have benefit in patients who have mutations, what were called non-BH4 responsive mutations that never thought would be responsive to Kuvan. So when you have those data in front of you, it becomes very clear that there may not need be a need for a step.
Great. Okay. And then, just on, like, the U.S. versus Europe dynamic, so, like, what have you seen from the, from the launch, XUS, and how do you expect that to shape up?
Yeah, so we were in a, at least for rare disease launches, in a kind of unique situation that we launched in the U.S. and Germany almost simultaneously.
Yeah.
We launched in Germany on July 15th when the price was listed in Lauer Tax. We're in that six-month free pricing period. We've talked about how PTC has always emphasized maintaining a rigid, narrow pricing corridor, particularly in these early days of launch. Of course, with the more macro discussion of MFN, we wanted to be sure to have pricing parity where possible so that the German price and the U.S. price are on par. We expect to bring Japan on soon. We expect approval there by the end of the year and launch there in the first quarter where traditionally the PKU therapies have been at a premium in Japan to the US. We do not see any issues with the pricing corridor there.
Back specifically to the dynamic in Germany, that's where we did set up a compassionate use program prior to launch because in Germany, the law says when you launch, if you're in that compassionate use program, you automatically switch to commercial therapy. We had about 30 or so patients in that compassionate use program. That got us a small number of patients who right away got onto drug. Importantly, it also allowed us to get the drug in the hands of the major centers in Germany.
While they did not put all of their patients in the compassionate use program, they got used to prescribing the drug and got to see the benefits early on so that when we did launch, we are seeing a lot of uptake, both in the larger centers of excellence in Germany as well as in some of the smaller centers. We had $19.6 million of revenue in the first and the third quarter that we read out, $14.2 million of that came from the U.S. The remainder was from Germany. We are seeing some nice contributions from Germany.
will continue to see contributions not only from Germany but from other countries in Europe where they have early access programs or named patient programs, which will allow us to get patients on drug, paid drug, while we go through the sometimes more lengthy pricing and reimbursement discussions in a number of those countries. That includes in Southern Europe, Eastern Europe as well. We are starting to see named patient requests from Middle East to North Africa as well as Latin America. While we are getting approvals in certain countries and getting pricing reimbursement there, we are also getting patients on drug through named patient mechanisms that again allow us to maintain that rigid pricing corridor.
Great. I guess I'm in, you know, early launch success. That's great to see. Yeah, anything I'm curious to understand, like, is there any good analog that you would suggest or, I don't know if you've talked about setting either any mid-near-term or long-term goal.
Yeah.
On, ultimately what is the potential here?
Yeah, look, it's still early days, so it's hard for us to provide overall guidance. I think the way we've always thought about this opportunity is very much in line with what you'd expect from a highly differentiated rare disease therapy, right? You have 17,000 patients and a differentiated rare disease therapy can often get their peak penetration rates in the 40%-50% range. I think that's something we think about as a potential for Sephience. Obviously, we're still in early days. We will be able to give much more exact guidance and ideas as we get further into the launch.
I think we're just excited in these early days to have seen the broad uptake, the message from physicians about a desire to treat all their patients, try all their patients on the drug because those are the things we believe are important to have in place if we're going to try to have that very wide penetration into the large accessible market.
Great. Moving on to just, you know, like, other topics. I mean, we've seen some of the updates from a regulatory standpoint for the NDF, vatiquinone. You had, like, the priority review acceptance in February, but then got a CRL. I know that there is a lot going on with the FDA, and, you know, just, we can talk about it in, in, like, more specific. Just, based on your current interactions with the agency, where do you think the review process is?
For just in general or?
For vatiquinone.
Okay. So we got the CRL and all.
Yeah.
That was a pretty clear decision. I think we felt, you know, going into that review, we knew the main question would be whether they would provide approval based on upright stability, which was a specific subscale of the disease rating scale. We had pre-specified the whole disease rating scale, the modified Friedreich's Ataxia Rating Scale, as the primary endpoint. What was learned while we were doing the trial is that different subscales have different relevance based on the age and stage of the patients. For the specific pediatric and young adult patients enrolled in our phase three study, it was determined while we were doing the study that the upright stability subscale was the most relevant.
Of course, when we read out the trial, we had highly statistically significant effects on the upright stability scale, which was the most relevant, but again, had pre-specified the entire scale. The question for the review was, would the FDA be willing to approve the drug, show the flexibility, based on the fact that we had significant effect on the only part of the scale that mattered, and that there's a significant unmet need for children and adolescents with Friedreich's ataxia? The only approved therapy is for 16 and above. With the CRL and the fact that the CRL, which is public, was very clear, it was a statistically driven decision that we could not establish substantial evidence of effectiveness because the pre-specified primary endpoint did not hit. We will take advantage of the opportunity to meet with FDA.
We said that meeting will occur in the fourth quarter. You know, that'll be in a meeting where we'll talk about potential paths to resubmission, whether there's a more accelerated pathway available just given the unmet need. Is it a clinical trial? If so, what does that clinical trial need to look like? For us, it'll be a matter of making the decision, you know, if it's a trial, what does that trial cost? What do we think the market opportunity is? What is the probability of success? Make a data-driven decision about the next steps.
Got it. Yeah. I mean, I guess, have you talked about, in terms of, in the range of scenarios that can play out, are there some roads that you do not want to go down the path or is that,
Look, I think there's basically, you know, a couple of paths here. You know, for us, we understand, the FDA has very much wanted to try to be flexible for rare diseases where there's unmet need. I think, you know, the reason you have these meetings after CRL is just to hear directly from them what are their concerns and in a productive discussion, figure out how best could you meet those concerns and whether the only route is through a clinical trial or there's other routes. Those are the kinds of things we'll discuss.
Yeah. I think there's a lot of, you know, just focus from the investors' community on these external data cohort-based, you know, regulatory pathways. I mean, we've talked about this before just with what has happened with some of these other companies as well. It seems that there is some positive, you know, it's not that FDA is shut for business from that aspect. If you can talk about, like, how your application or data or approach is different from some of the ones that we, you know, generally, like, Stout, Biohaven, Cure.
Yeah. I mean.
Briefly.
We can certainly talk.
Briefly.
We can certainly talk.
It's a good dinner talk.
Topic. Yeah. I mean, look, I think in both, I would say both in our Huntington's disease program with Votoplam, as well as our MOVE-FA phase three clinical trial, we have placebo-controlled data, right? I think that in neurological and neuromuscular disease, of course, for FDA, the most interpretable data for them is placebo-controlled data. They are very used to seeing that. They are always concerned in these types of diseases that there could be practice effect on endpoints, that there could be, you know, if it is a patient performance measurement, different things can contribute to the performance that is other than the drug. In their minds, the best way to eliminate confounding is to have randomized placebo-controlled data.
What we were able to do, certainly in MOVE-FA and again, with having placebo-controlled data in our Huntington's program, phase two Huntington's program with Votoplam, is to be able to say, "Okay, here is evidence of benefit relative to placebo." In the case of our FA program, we did use long-term open label extension data to confirm a longer-term benefit, in patients treated for three years with vatiquinone, and we were able to show a significant effect over time. Importantly, we were able to show there that the slowing of disease progression in the placebo-controlled trial was consistent with the rate, with the benefit of slowing of progression longer term, which I think connects the data in a nice way.
Look, it's always hard for open label data, for external control data to convince the agency that you have apples to apples comparison. You know, that's something we try to spend time making sure that we account for any potential source of confounding because we know that's what's going to be front of mind. I think being in a situation in the FA program and HD program to have placebo-controlled data in the Huntington's Disease program as well, to be able to have bio, pharmacodynamic measurements, and we have evidence of dose-dependent Huntington protein lowering in cells, those things are helpful to give them confidence that the drug is working from a biological standpoint the way it's supposed to work in order to have clinical benefit.
It's just helpful for them to understand, "Okay, if you have to first lower Huntington protein before you have clinical benefit to be able to tick the Huntington lowering box, I think it gives them more confidence that the clinical effects you're observing are indeed related directly to the drug and not some other external or confounding factor.
Yeah, and like we were discussing just before, it's a little bit difficult to, like, establish imaging data-driven evidence in this case.
Yeah. I think in, in Huntington's disease.
Yeah.
Yeah. I think, well, you know, I think part of one of the, in Huntington's disease, the imaging data change slowly over time. Also, something I think that was observed in the Alzheimer's trials was the concept of pseudoatrophy, that if you have a therapeutic effect in the brain and you're decreasing brain inflammation, you may in fact have a lowering of volume that's a reflection of a favorable therapeutic effect. I think in the long term, certainly a disease like Huntington's disease, which is characterized by loss of brain volume, I think brain imaging is helpful. In shorter one to two-year trials, I'm not sure that the techniques we have are reliable for ascertaining what could be very small and meaningful evidence of clinical effect.
Great. I wanted to talk about a couple of the other commercial programs, you know. Just, like the latest on Translarna dynamics. You have shown pretty reasonable sales despite several generics that have entered the market. Just curious, you know, like, do you think that this continues on the same trajectory or any potential changes on that?
Yeah. So this is from Emflaza in the U.S. with.
Yeah.
We have the six generic entrances into the market. We lost exclusivity in 2024, but yet we still are having pretty strong revenue performance. I, look, I think we're of the belief over time that should erode. The erosion dynamics in a rare disease market are different than larger drug markets, right? You have smaller populations. You don't have the price-volume trade-off that a generic could have in a larger market. There's not a motivation, a great motivation for generics to come in and significantly cut the price because they can't make it up in volume. I think that's part of the reason. The other thing is we've been, our patient services team, our company has been very well integrated in the Duchenne space for a long time. There is a great deal of brand loyalty that's there.
Our patient services team provides support to the families, not just in getting Emflaza, but a lot of the other issues that families navigating Duchenne face. I think there's a desire to stay on Emflaza because you want to continue to have the benefits of those patient services. I mean, we've even had boys, young men who've switched to generic and then came back to Emflaza, because for whatever reason they said they didn't feel the benefits as much on or tolerability issues that arose with the generic. I think there's many factors contributing to the stickiness. Clearly, we're getting to the point with six generics in the market that we will see some more erosion over time.
I think what's so exciting for the company is that, you know, we were really looking forward to the Sephience launch given the significant potential we believe it has. To be able to still get meaningful revenue from our legacy products like Emflaza, like Translarna, while we're ramping up the Sephience numbers is really a great place to be.
and then just on the, like, the Huntington's, just going back, so you have, like, a meeting scheduled with the FDA for the fourth quarter. yeah, just, like, trying to understand, like, what are the ultimately, what are you trying to get alignment on, with that?
Yeah. The program is partnered with Novartis. We announced that partnership last year. It was for $1 billion upfront, $1.9 billion in development and sales milestones, 40% profit share in the U.S., double-digit, tiered royalties ex U.S. Novartis will assume all phase three and future costs of the program. At this point, the program's over with Novartis. Yet we're still working closely through our joint development committees, and the companies are very well aligned. It's been a very productive and collegial partnership. This meeting with FDA has two objectives. The main objective is to align with FDA on the key design elements of the next efficacy trial, whether that efficacy trial is the confirmatory study in the context of accelerated approval or whether it's the registrational study if there's not accelerated approval.
There is a desire to obviously get that study going as soon as possible because it's going to be helpful in either context. We'll also discuss the potential for accelerated approval, but we have data coming, additional data coming in the spring. All trial participants will cross the 24-month time point, which will be a pretty important time point. We know that, and FDA knows that. This is not really a meeting where we're going to go and say, you know, can we file?
It's more of a meeting to say, you know, confirming the openness of the neurology division to accelerate approval, get some discussion on what they think will be helpful to see in a data set that could support accelerated approval, knowing that we'll turn the data card over, be able to do an analysis, and then come back and have the more specific discussion.
Great. Just a side comment for the audience in the room, if you have any questions that you want to submit, feel free to do that through the QR code, and I can bring it back here. Yeah, I guess, like, if we think about the next, like, 12- 18 months, maybe you can talk about just what are the key, what are the key milestones that you're looking for, obviously the Sephience launch and then some of the pipeline developments.
Yeah. I would say we've been, we've really been on a journey the past couple of years. I've been CEO for two and a half years, and Pierre with me has been our CFO for a little over two years. We've been very focused on transforming PTC and positioning us for future success. I think we're at the point in time now where we got to what we thought would be the key moment, which is the launch of Sephience, to be able to be there with a strong balance sheet, as I mentioned, with about $1.7 billion of cash, and, you know, having a foundational product that could be as successful as Sephience will be. We've really outlined a series of steps. Really, the next step for us is to get to cash flow breakeven and profitability.
Sephience we believe can get us there in the very near future. We've then established the next lily pad being getting to $2 billion top line, and then continue to grow the company from there. In the next 12- 18 months, the goals are, you know, execute on the Sephience launch, continue to make sure we're keeping that funnel wide, and we're driving revenue forward as strongly as possible, continue to bring things forward from our R&D platforms. We're hosting an R&D day on December 2nd. We're going to pull back the curtain on some of the things that we've been working on. Understandably, the attention on the company over the past year or so has really been on late-stage clinical, regulatory, commercial things, but we've been spending a lot of time bringing the same focus and discipline we've been bringing to later-stage programs.
To our research, particularly our splicing platform. As I mentioned, this is a really valuable platform that's already yielded Evrysdi, which is the, you know, largest SMA drug, the HD drug. We have the same team that brought those drugs forward, have been at this for over a decade, and we've been working on innovating the platform. We have a whole new set of preclinical programs that we'll, we look forward to sharing in the R&D day, as well as our inflammation and fibrosis program. We have two clinical stage programs that we'll be talking about. It is going to be driving those programs forward, continuing to work with Novartis on the HD program, whether that's accelerated approval or that's a standard development program. Of course, with our cash, we have the ability to do BD, to complement either the commercial or R&D portfolios.
You know, that's something we are very thoughtful about. We do not have to do anything, but we will continue to be very thoughtful and strategic about any business development we do participate in.
Great. With that, we can wrap it up. Thank you so much for your time.
Thank you very much.