Everyone, I'm Brian Heppelman, one of the senior biotech analysts at RBC Capital Markets. We're really pleased to have our next company, PTC, represented by their CEO, Matt Klein, and their CFO, Pierre Gravier. Thanks, Matt and Pierre. Really appreciate it.
Thank you, Brian.
I know there's a lot to talk about. I wanted to start on Huntington's because that was the latest update that you gave, and then move to PKU because that's what's coming pretty soon. Maybe we can get to PTC and the rest of the pipeline and commercial products as well. It's been a few weeks since the top-line data for PTC518. Can you talk about some of the overall findings in the last cut of the study and anything new in the last few weeks in your analyses that you've uncovered or that have changed the way you view the data at all? Any kind of KOL reactions as well that you're hearing?
Yeah, absolutely. As we said at the time and as we continue to have discussions with our partner Novartis, we're very pleased with the results of the phase II study.
I think when you think big picture about the objectives of a phase II study, really any phase II study, but particularly one for a complex neurodegenerative disease like Huntington's disease, to be able to come out of the study hitting your primary endpoint, demonstrating target engagement, being able to show an appropriate PK/PD response, data supporting that the drug is getting where it's supposed to go in terms of having the CNS exposure necessary for effect, demonstrating safety tolerability, demonstrating early findings of clinical effect, and finally, making important learnings about future development, including specifically supporting the hypothesis that the stage two patients are likely a much better clinical trial population in whom we can capture benefit in the short term.
When you put all that together, we ticked all the important boxes for a phase II study and really provided a solid foundation for moving forward now into stage three. In addition, we continue to believe that we collected data that can further the discussions on accelerated approval, recalling that we went into the study having discussed with the FDA the potential for HTT lowering to be a likely to predict benefit surrogate endpoint. We confirmed the ability to lower cellular huntingtin protein. We continued to show, as we did in the initial data set, early signs of effect on cUHDRS and some of its subscales at 12 months.
At 24 months, we're able to show dose-dependent NfL lowering, which is particularly important given NfL's understood value in demonstrating neuroprotection when you can lower it, especially when the natural history is that it increases, as well as benefit against well-matched natural history control at 24 months. That continues to be our view. As we look at the data, we're working with Novartis now to continue to look at any additional learnings we can make ahead of the next steps, which we believe should be in the phase II meeting with the agency where we talk about plans for an efficacy trial and discuss how the current data could support potentially an accelerated approval application. If that can't, what additional data can we harvest as the open label study goes on? In terms of KOL and community response, it's been overwhelmingly positive.
I think those in the community who understand the disease and have worked on Huntington's disease drug development have stated that the data set strongly supports that we have a safe and effective Huntington lowering agent. Others, such as Ed Wilde, who I think was fairly public on LinkedIn with his feelings and who is probably an expert in HD biomarkers, has talked about the value of seeing that NfL lowering. I think everyone also has been saying this stage two, stage three thing is really important in terms of trial design.
Certainly, their belief is that a HTT lowering agent could ultimately have benefit for a full spectrum of Huntington's disease patients, not just stage two and stage three, but of course, in that very large population of earlier stage, stage zero or stage one patients in whom targeting the underlying cause of disease would be so, so valuable in delaying disease progression.
Where are you with regards to a potential filing plan? I know a lot is going to depend on this end of phase II meeting and on kind of looking at the data more closely. What are the key biomarkers that you would propose as potentially supporting an accelerated approval? How should we be thinking about the potential for a shortened regulatory path? Should we think about the existing data set in and of itself as being likely to support an accelerated approval? Should we think about it as maybe a data set which, in conjunction with some elements of a phase III or perhaps interim phase III biomarker safety efficacy data, that could sort of together support an accelerated approval? I know it's kind of a moving target, but you had goals sort of going into this and you had some thoughts.
Where does this new data cut sort of steer you into your base case regulatory plan?
Yeah. I would say these data did nothing to change what we thought going in. We said all along that we were going to have discussions with the FDA in December with two objectives. One, to begin the conversation on the potential for Huntington lowering, cellular lowering to be a surrogate marker that could support potential accelerated approval, and understand what the FDA would want to see in addition to Huntington lowering. What we heard from the agency was they would like to see additional data that shows something else moving other than just Huntington protein that they could associate with Huntington lowering.
The other part of the conversation was about beginning to discuss what an efficacy trial would look like, given that in Huntington's disease, there's no precedent for disease-modifying therapy because we believed all along, and by the way, our partnership with Novartis didn't change this, that these things would move in parallel, that we would want to get an efficacy study up and running and see to what extent we could use the PTC data to support accelerated approval. Now we're on the other side of data. As I mentioned, we ticked all the boxes in terms of the things we need to understand to begin to formulate the efficacy trial plan.
We believe we have further data showing associations between Huntington lowering and clinical effect, namely dose dependency, which we believe in these small populations supports the fact that if you, for example, lower Huntington protein twice as much, you have a greater clinical response, which is an association. Now the NfL data. We then say, okay, the next step is to go and have conversations with the agency, one, to understand what the efficacy trial looks like. Let's get that going. I think this is a place where the partnership with Novartis is particularly valuable given their study startup team is probably the size of about a third of PTC. They can get a trial going super fast and get this done. Ask the question, does the current data set support a filing?
If the answer is not quite yet, to your question, Brian, it's we're going to turn the corner over in 12 months on an additional 100 patients at 24 months. We have a source in the open label extension PTC study to continually harvest data that could, if it's not now, could in the short term support an accelerated approval package while that long-term study is ongoing. We see many shots on goal, many different opportunities at different times to continue to augment that data set if needed.
Got it. I know you haven't had the end of phase II with the FDA yet, but in your other engagement with the agency, I guess, have you had engagement with the agency at all on this program since the new administration has been in place? Do you have any views as to whether this administration, this new leadership, might be more amenable? I know we've talked about mechanistic plausibility or less amenable to a package that you might be able to present to them.
Yeah. We have not had any discussions on this particular program, as we will talk about. We've had interactions, of course, on our NDAs, all of which are going quite well. I'll say for the Huntington's disease program, we are in CDER, so the leadership changes have not been as, let's just say, significant right now as they've been in CBER. We continue to believe that there'll be an openness at FDA, as there have been for years, particularly in the neurology division, of leveraging the accelerated approval pathway for these complex, slow-moving neurodegenerative disorders that take very large long trials to establish efficacy. I think that there's been an overwhelming voice from Congress about wanting FDA to leverage the ACT for ALS, which talked about FDA trying to accelerate therapies for ALS and other neurodegenerative diseases like Huntington's disease.
There have been a number of public statements regarding the desire for acceleration for having the openness for HDS for other therapies. Certainly, as you pointed out, Brian, there have been words from leadership to suggest that they want to be a little bit more pragmatic in terms of mechanism and supporting data, which I think we are sitting squarely in, having an incredibly rational mechanism for something of unquestionable relevance to the disease, the protein that causes the disease.
Right. When do you think you'll have a better sense as to what the path forward could be? Just can you walk us through kind of the potential timelines for the end of phase II meeting? How soon after that do you think you may have a definitive sense on the go-forward path?
We're right now working with Novartis. They'll take the lead on subsequent regulatory and clinical activities. We have a joint development committee that will work very closely on the details of that meeting. We're still going through the trial data. We expect that we'll have some KOL meetings just to get input because we view the next interaction as, again, addressing both work streams, right? Getting the efficacy trial going and accelerated approval. We'll want to get as many views on forming that as possible. I don't have a timeline for you today other than to say I think both companies are keen on moving as quickly as possible.
Got it. Maybe we can shift gears to Sebastian and the PKU market. Maybe just bigger picture, how has that dialogue with the agency been going? Obviously, I know you can't give a blow-by-blow on what exactly has been said during the review process, but I guess maybe you can characterize the discussions more broadly and kind of your level of confidence. Are there any sort of key debate points to consider, whether it's label or indication or anything like that?
We've had very productive discussions with the agency. We've recently completed the late cycle meeting on time, on schedule, and we've gone through labeling discussions. We've gone through discussions on carton and crate on patient information leaflet. We believe the only remaining item at this point is just alignment on the post-marketing commitment. I think that's a very good place to be a little more than two months ahead of the PDUFA date. In our late cycle meeting, it was communicated that there's every expectation that we're going to be on time with the decision, which these days, I think, is a very important reassurance given the concerns about workload and impact on the FDA. We're quite optimistic given the fact that it appears we're through all of the review questions.
Having gone through labeling discussions and such puts us in a position where we see this as something that should come on time. In the event that it could come early, which we're not guiding to, our team is ready to launch. Everything's in place and we're ready to go and excited to get this drug to patients as quickly as possible.
Yeah. Where are you with regards to the launch? I guess what kind of work are you doing needs to be done to kind of build out the commercial infrastructure to be able to leverage some of your pre-existing Salesforce and infrastructure? What are some of the strategies you implement in kind of the pre-launch and launch stages?
We're fully built. We're in place and we're ready to go. We've been working on this. We had the existing infrastructure in the U.S. that we've been able to redeploy for PKU. We've supplemented that with additional case managers. That's our PTC Cares team. That's incredibly important in really shepherding patients and physicians through the prescription process, whether it's reminding patients about getting prescription renewals or helping physicians with prior auths or reauths and all the things, medical documentation, anything that could be needed. That team's in place. We augmented our medical team a bit to include dietitians and nutritionists because we understand that nutritionists are important in driving prescribing decisions and centers of excellence. In terms of just tactics, we've mapped the specialty centers, the 103 PKU centers in the U.S. We've mapped them.
We understand the KOLs, their prescribing habits, understand their patient populations, the number of patients. We understand that physicians across the board are interested in prescribing suppliers for all of their patients in each segment, but we understand different centers have different sort of first segments to address or low-hanging fruits. We are trying to understand their practices and such. We have had very productive engagement with the PKU community, which is very closely in the community, understanding the needs of the community, who particular social media influencers are, and how we can sort of work through those channels to increase awareness and spread the word and the excitement and continue to generate the market pull. We have had very productive payer discussions where we now understand that the payers tie value to phenylalanine level.
Very, very important because of our strong data showing our ability to lower phenylalanine across the board in all stages of disease, including classical PKU patients and also superior effects.
Are they more focused on Phe level or dietary liberalization?
In the U.S., Phe level, understanding that lower Phe equates with neurological benefits, neurodevelopment benefits in children, and the recent ACMG guidelines, which clearly demonstrate that lower Phe is better. We have the Phe tolerance data as well. That's particularly important in ex-US, particularly in countries where the system pays for medical foods and formulas. Our discussions, as we've said, have supported that we could charge a premium to Kuvan and get coverage, which is very important. The other thing is just the experience of this team. The Emflaza team has worked in a competitive and genericized environment. I would say one where thinking about things like step edits and such are much more challenging in having to step through prednisone and DMD, where it may take six or eight months to show benefit, whereas in PKU, it's a couple of weeks and a blast.
This is a sort of a battle-proofing team that's incredibly excited, incredibly ready to go. The enthusiasm from the patient community has also been incredibly overwhelming. They appreciate the diet liberalization, the stories on social media about being able to have regular meals, and kids can go to birthday parties and eat with the other kids. All of these things speaking to the number of benefits that surveillance can provide.
Okay. What do you think are the market segments where we're going to see the most initial uptake? Should we be thinking about a certain proportion of patients with PKU who are just on the sidelines? Either they had poor or inadequate response from prior Kuvan, or they just never tried it for some reason, or patients who are maybe on Kuvan could do a little bit better. I guess, how do you expect sort of the layers of uptake to?
Yeah. The short answer is we've heard that physicians want to try patients from every one of those segments. Obviously, they're not going to try them all right away from all segments. We've heard different things. We've heard some say that they are going to consider switches from sapropterin to Kuvan, either generic or branded, because here you have a population that's in the clinic on a once-a-day drug, and they know they can switch them to another once-a-day drug. Our data continue to show that on average, we're having 50%-70% greater lowering in phenylalanine, and that allows for greater dialyzation. Others say the classical PKU patients who may have never been tried on sapropterin because it wasn't believed that they would have a benefit, these folks don't have a therapy. We'd like to get them a therapy right away.
I think what's been very helpful as well is some of the data we've been able to show that we're having a significant effect in non-BH4 responsive mutations, which that's the mutations that a lot of these classical patients have. One question we get a lot of is, "Hey, have you looked at the mutations in your study? Can you tell us whether or not you're able to affect these mutations?" We say, "Yeah, we've done a number of studies, both in vitro as well as the fact that over 70% of the patients in APHENITY had mutations that would be considered classical or non-BH4 responsive mutations." Of course, the response to those patients was overwhelmingly favorable.
That's really driven a lot of enthusiasm to raise those sort of classical or therapy naive patients to maybe the first segment that a number of physicians want to trial. The important thing is what we're hearing time and time again is an openness for physicians to try all of their patients on Sepiapterin at some point.
It sounds like payers are amenable. You're hearing a lot of enthusiasm from the practitioners, and it sounds like things are going well on the regulatory front. If we assume that this does get approved later in the year, are there any gating factors to initial uptake that we should be thinking about, that maybe there's a very large opportunity down the line, but we shouldn't be expecting an inflection in the first few months because of X, Y, and Z? Kind of walk us through how to think about the pace of launch and the gating factors.
Yeah. I don't know that there's any specific gating factors other than just the approval. The PDUFA date is on July 29 and we will be in line and ready to launch right after that. It is just a matter of working with the centers, getting prescriptions written, getting any authorizations that have to occur. We think that all can occur fairly quickly. I think, as always, you're dealing with 100 or so centers, right? Throughput at the center is going to always be the limiting thing. There are only so many patients who can get seen in any given time. We see that as probably the limiting factor in the first, let's just say, six months of launch.
We know that a number of centers have been maintaining waiting lists of patients that they want to try, patients reaching out saying, "I want to get on the drug as soon as possible." We have an opt-in program where both physicians and patients and families can allow us to proactively reach out to them and help navigate these first steps of launch. We are confident that we can get a pretty rapid uptake. Though, again, throughput, as always, is a limiting factor, but we are enthusiastic about having a pretty robust launch.
How many patients can these centers see in a quarter or in a month?
I can't give you an exact number. It's going to vary center by center. We have centers that have, we have some that have told us they have 200- 300 patients on a waiting list. I think it's unrealistic to think that a center is going to see 300 patients in a month or two months. I think for us, the important thing is starting to see over the course of the six to nine months that we're getting those patients in and the patient numbers are rapidly increasing. That's what we'll look out for. After approval and at launch, we'll give some projections and kind of share how we are guiding this and what our dashboard looks like so everyone has a way to follow this in the way that we're thinking about it.
Right now, the focus is squarely on making sure we're ready and we are and drumming up as much pent-up demand as we can. That's being driven by both the patient's own interest and our ability to continue to increase disease awareness and spread the word about suppliers.
Okay. I know we only have a couple of minutes left. I want to touch on PTC518 and then maybe capital allocation. Just can you give us the latest on the PTC518 regulatory process and kind of how things are going on that front?
Absolutely. We shared at earnings that we had our mid-cycle meeting. The FDA shared that they do not expect to have an ad com. At this point, we are moving through the information requests across the board as one would expect at this point in review. Site inspections are ongoing as we speak, and everything seems to be moving forward quite well, and we are on target for the August 19 PDUFA.
Following the Novartis partnership, you have an even stronger balance sheet now. What's your level of interest in external business development? How are you thinking about allocation of capital? You have sort of this internal pipeline that's generated some promising products and candidates in the splice modulation, but you also have a history of kind of going outside the company to bring in assets that you find interesting. What do you think the landscape looks like now? What's your latest view on capital allocation, deploying the strong balance, $2 billion or so that you have now?
Yep. We're very pleased with the $2 billion plus we have, especially in this environment. We're in a luxury position to go through all our products without looking over our shoulder every day when the market goes down and there's a new executive order. We're going to be in, we have a lot on site on profitability with first cash flow breakeven profitability with PKU alone. We are talking about a billion-dollar-plus opportunity in the U.S. alone. As you mentioned, PTC has historically looked at business development, and some of the products were ingrown and some of the products were acquired. We will complement the line of sight we have with business development. There's a number of opportunities that are commercial, late-stage commercial, also development-stage assets, which we can show that we have a track record to get things to the finish line.
The exact timing on how we're going to look at that depends on over the summer how many products we're going to launch. If we're going to launch PKU in France and U.S. and FA, I think our commercial team is obviously capable of doing that, but that's probably enough. We look at products that are launching in the late 2026, early 2027 timeframes. That's how we're thinking about it, but we're actively looking at business development ideas as we speak.
What do you think of the opportunity set that's out there?
I think, look, there's a plethora of companies out there that they lost a lot of their market cap. They need to raise capital. Raising capital in this environment is very complex for them. Those are high-quality assets. As I mentioned, we're going to be very, very disciplined in the way we look at capital allocation. We do not have to do anything, right? Obviously, for the right opportunity, we will go after them. Obviously, we do not have to bet the farm either, right? That is how we're going to approach our capital allocation, which is, by the way, how we've been approaching it over the last couple of years. It is a very disciplined, targeted approach to make sure we maximize return to shareholders.
Maybe just in the last 30 seconds, you had a positive CHMP opinion for Sepiapterin for PKU in Europe, label included all ages and disease severities. I think there's been a little bit more skepticism, at least among the street, around what the European opportunity could look like, just because of generally higher budgetary scrutiny there and availability of generic. What's the right way to think about the Europe opportunity and sort of launch dynamics as compared to the U.S.?
We've said we think that the ex-US, Europe, and rest of the world would be about 50% of the market opportunity, and the bulk of that would be Europe and Japan. In Europe, we're going to be very mindful of launch sequence and maintaining a narrow price corridor with publicly published price, which is important for a number of reasons. We're thinking very strategically about trade-offs between pricing and market segments where necessary. We're going to start in Germany as there are 8,000 PKU patients in Germany. We have an early access program right now ongoing that will allow us, once the drug is approved and we publish the price and allow tax, to flip those patients right away to commercial, which is done by law.
This early access experience has also allowed us to get into the larger centers in Germany so that, again, we're well positioned to enjoy that six-month free pricing period. We're similarly looking outside of Germany to countries where we can leverage named patient and early access schemes ahead of formal pricing and reimbursement, again, where we can get premium value for the product.
Good. I know we're out of time. Matt, Pierre, thank you guys so much.
Thanks for having me.
Thanks, everyone.