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

Good afternoon, everyone. My name is Gena Wang. I'm SMID-cap Biotech analyst at the Barclays. It is -- welcome to our 27th Annual Global Healthcare Conference. It is my great pleasure to introduce our next presenting company, PTC Therapeutics. On the stage with me, we have Matthew Klein, Chief Executive Officer. We also have up here Gravier, Chief Financial Officer. So maybe before I dive into the specific questions, I know we have tons of questions, we have tons of programs we can discuss, maybe a very brief overview about PTCT for those who are less familiar with the company.

Absolutely. Thank you very much, Gena. It's great to be here. PTC is a global biotech company. We discover, develop and commercialize innovative therapies for diseases of high unmet need. We're coming off a tremendous 2024 with a number of important accomplishments including continued successful commercial execution with total revenue of $807 million. We submitted 4 approval applications to the FDA, all of which were accepted for review, setting us up for the potential for 4 commercial launches in the U.S. within 12 months. And we solidified our balance sheet now with over $2 billion pro forma, giving us sufficient cash to get to cash flow breakeven and beyond as well as allow us to continue to grow the company, succeed in our launches and conduct strategic business development to complement our R&D and commercial portfolio. So exciting '24, setting us up for a number of value-creating catalysts in '25.

Thank you. I wanted to make a comment, the Huntington program so far, I think we haven't seen any one can surpass that deal term. It's so favorable to PTCT. Really congratulations on that deal. And then I know this is one of very important pipeline asset, and that's why maybe Novartis are willing to pay so much money for the programs. So with the midyear update, I wanted to maybe give a little bit layout exactly -- I know you've mentioned in the past about 150 patients. Maybe lay out exactly where you will be presenting the data and what should we expect?

Yes, absolutely. And first, thank you. It was a tremendous deal that I think speaks to the tremendous potential and value of the program already. And not only did we have a significant upfront, but we're well positioned to enjoy a significant amount of the upside with the 40% profit share in the U.S. So really a win-win for us in many ways. The data readout coming in Q2 is going to be the 12-month readout from the Phase II PIVOT-HD study and will include about 100 to 110 additional subjects who cross the 12-month time point, bringing the total number of subjects who are at 12 months to about 140, as you said, 140 to 150. This study was designed to inform pharmacodynamic activity, so evidence of target engagement in terms of lowering of Huntington protein in the blood and the CSF as well as demonstrate safety and tolerability of the drug and additional markers, including clinical scales that can help confirm that not only is the drug doing what it's supposed to do, getting where it's supposed to go in the brain, but also starting to show early signs of clinical benefit that in the long term could represent significant efficacy. So we'll be sharing at the 12 months an update on Huntington protein lowering in the blood, Huntington protein lowering in the CSF, safety and tolerability, data from clinical scores such as the cUHDRS total motor score and others as well as other biomarkers of disease, including NfL.

So I did a quick calculation. If we -- and you did mention in the past, like it will be evenly split between Stage II and Stage III and each will be 3 arms. So when we calculate roughly, each arm is about 25 patients.

Close enough. Yes, that's exactly right. So the Stage II patients and Stage III, randomized evenly between placebo, 5 milligrams and 10 milligrams.

10 milligram, yes. So now when we look at the last update, I know each arm is about 10 patients, and you did show dose response and the -- certainly in the blood lowering and then also the magnitude like a 43% in the CSF. And then -- and you do see the longer follow-up, you do see the further improvement in terms of protein lowering.

Yes.

And then should we -- and then of course, you do -- you also did share a lot of the functional measurement, right? Some has a more clear trend, some a little bit noisy because given a small number of patients. So now we have, say, more than doubling of each arm of the patient, like should we expect the similar trend largely persist with this more comprehensive data update?

Yes. We can -- we certainly would expect to continue to see similar magnitude of Huntington protein lowering. We expect that to be consistent. And we do expect to see the continued trends of clinical benefit as well. Now it may look a little different for the Stage II and Stage III patients because as the disease progresses, the clinical scales that are most relevant, the clinical scales on which we can record an effect on disease progression are known to be a little bit different between Stage II and Stage III. So we will, of course, look for that early evidence of clinical effect with the understanding that it might look a little different for the Stage III patients than the Stage II patients. So when we share the data, we expect to be showing not only the patients together, but also, if necessary, breaking it out by Stage II and Stage III, so we can clearly understand if there is a different pattern of benefit.

So I know you will not be able to comment on the actual data, but in terms of pattern difference, what kind of a functional measurement you think it could be different between Stage II and Stage III?

Yes. So it's well known that one of the endpoints that's particularly sensitive to change at Stage II is the total motor scale. And not surprisingly, when we look at the data from last June's readout, which included all Stage II patients, we saw a very clear dose-dependent pattern of clinical effect on TMS. So that's one where we may see a similar effect on Stage III, we may not. Something like the cUHDRS, which has different subscales relevant to both Stage II and III may be a very good measure for looking at the whole population together because, again, given the structure of the cUHDRS having many parts to it, it's able to assay clinical effect across a broader spectrum of disease severity.

So what about the other functional measurements? Any major differences between the 2 classes?

There shouldn't be. I would say with the exception of -- well, total functional capacity is interesting because total functional capacity is -- changes on the TFC signifies the transition from Stage II to Stage III. The definition of a Stage II patient in Huntington's disease is a TFC of 13, which is normal. And someone has said to cross into Stage III when -- that you start seeing a lowering to 12 or 11. So we'll be looking at the TFC, though I think it's also important for Stage II patients because we could be looking at a transition from a 13 to a 12 as being informative of progression as well. So that's a to-be-determined one.

Okay. Very good. And then you likely will share either a separate or group.

Whichever is most informative. And I realize I didn't answer your earlier question about where we're going to be sharing the data. It will be similar as we always do, which would be a press release and a call. It's not going to be at any meeting.

Okay. Good. And do you see all these data real time?

No. In fact, we are -- we remain blinded. We were blinded for the first data readout. We're blinded to treatment assignment, and we don't do any interim looks at the data. I don't believe in doing blinded data reviews because when you look at data that are blinded, they always seem to look the way you want them to look, that's why you do blinded study. So we just -- we focus on executing the study to the highest quality possible. We lock the database, do the data cleaning and then we'll analyze the data and understand them.

Okay. Does any clinical team in your company see the data, blinded data?

No, no, we do the same. It's the same way through.

So the same -- the whole company...

Yes. We don't...

Do not see any data?

Yes.

Okay. Good. And then unblinding and then do the analysis, like how long would that take?

It depends. There's a lot of analysis that has to be done because remember, we have a lot of biomarker data to analyze. We tend to run -- we try to run the biomarker data in -- as, let's just say, infrequently as possible. So a given subject, what you want to do is run their baseline 3 months, 9 months, 12 months altogether because that decreases the variability in the assay. So there's going to be a lot of biomarker analyses that are going to have to be done. That just simply takes time. And so that will dictate -- I can't give you an exact estimate, but that will dictate where we are in terms of being able to read out the trial. I can comment that we have completed last patient last visit for the 12-month time point. So now we're in that data cleaning time frame now.

Okay. Because we are almost at the end of 1Q, so you only have few more months.

Yes. Right.

Okay. Good. Maybe the neurofilament as a biomarker, how important that is?

So I think there's 2 ways to think about neurofilament in Huntington's disease. It's become incredibly important as a safety marker. A number of the other HD therapies have shown NfL spikes either early on or over the course of treatment, which, of course, is not good because that signifies neuronal injury. And we have not seen any treatment-related NfL spikes with PTC518, which is a testament to its safety and tolerability. Now on the other hand, there's the potential of NFL as a biomarker of efficacy. It's understood that in neurodegenerative disorders, neuroinflammatory disorders, neurofilament light chain will increase over time. So if you can slow that increase, that's thought to be a marker of efficacy. Now in Huntington's disease, it's much more of a longer-term biomarker. The reason for that is, one, it's a more indolent disease, slow-moving disease versus something like ALS, where you have rapid progression and therefore, marked changes in NfL over a short period of time. And over the shorter period of time, such as 12 months, it's understood that there could be intra-patient sort of variability. And in fact, if you look at the spaghetti plots that we've shared previously on the NfL levels, you can see within an individual patient, there's not that there's spikes, but there's slight ups and downs, which in the short term makes it hard to detect a reliable signal of efficacy. We'll nonetheless look at NfL and are open to the possibility that we could see an early effect there. But I think in Huntington's disease, things like NfL and brain volume, it's really hard to get a meaningful effect in a short period of time because things are just moving so slowly.

With the data update, will these 2 also be presented?

The data update will look very much like what we presented in June in terms of the type of endpoints.

And the FDA communication, like what kind of data do you think that will satisfy their comments on, I forgot the exact...

Associations.

Yes, associations between the Huntington protein lowering and the function.

So we met with the FDA in December. And the purpose of that meeting was to align with the agency on the potential for Huntington protein lowering to serve as a surrogate endpoint that could support accelerated approval. Our argument was based on the fact that Huntington's disease is a monogenic disorder caused by a toxic mutant protein. And there is substantial literature showing that if you can lower Huntington protein 20% to 50%, you can impact disease progression. And so with that in mind, we wanted to ensure that the agency was aligned with our thinking, and they said they were aligned scientifically of the rationale for Huntington protein to be a surrogate endpoint, but not surprisingly asked with the large data readout coming, can we show in that readout some associations between changes in Huntington protein and clinical changes. Why? Because the definition of a surrogate endpoint is something that is likely to predict clinical benefit. And so they asked to see in this data set, can we see some things -- while it's early, can we still see some suggestions that over the longer treatment time, this lowering of Huntington protein can translate to clinical benefit. They were not prescriptive in terms of what they wanted to see which I think is -- tells us that we need to look at the data and understand how we can best make an argument. I think things like what we showed in June, dose-dependent lowering tells you that -- or dose-dependent changes on the clinical scales tells you that if you can lower someone's Huntington protein more, you are likely to have a greater clinical effect. To me, that is an association between Huntington lowering clinical effect. So I think that's one example of the type of data we could present to the agency.

So do you think that -- I totally agree with you. The minimum one, you have to show dose response in terms of Huntington protein lowering, right, and then ideally both in the blood and the CSF. So do you think the agency also will be looking for the correlation? I know they use the word association, but would they also wanted to see the dose response in terms of a functional measurement. And which are the -- I'm pretty sure you will share all the functional measurement and which one you think most importantly likely would they care about like say, in the future, if you do the confirmatory study, that could be the primary endpoint.

Yes. I think it's hard to know what they'd prefer to see. I do think the dose-dependent changes in the clinical endpoints would be important. Some of this will also be driven by what the data look like. The biomarker data are clustered around the median or clustered around the mean, then dose-dependent changes are going to tell you a lot on the clinical measures. If we see more variety and more of a spread on the biomarker data, that would then allow you to look at, say, a subject that had really much higher than average lowering, did they have much better score. So that's going to be a little bit of the nature of the data are going to help inform how best to show those associations. But I think we'll look at a number of the different scales. And again, I think what was so compelling about the readout in June is that on 2 of the more meaningful endpoints, TMS and cUHDRS, we saw that dose-dependent effect.

So for the 2Q update, let's say, 3 scenarios, maybe even more than 3, some gray area. So one is a very clear association. Like what would you define as a clear data that you think FDA will be happy or have an accelerated approval path there?

Yes. So let me just -- a second, but let me just give some context. I think where we are with the program for the long term. Very importantly, we've already established safety and tolerability. We've shown that the drug is working the way it's supposed to work and going to where it's supposed to go. So we have derisked this program for Phase III. And I think the only scenario where that would be in doubt is if there was a strong negative safety signal, which we don't expect to see given the fact that there's a DSMB monitoring the study on an ongoing basis, and we have some idea there. And everything seems to point to the fact that the drug continues to be safe and well tolerated. So that's really, really good. So now what we're really talking about is the upside for an accelerated approval and what that would look like. And as you said, I think the upside would be seeing some of these dose-dependent associations like we saw in June. I think the upside would be seeing what we -- a data readout that looks a lot like the one from last June.

I see. So you think the last year data that should be sufficient?

I think that would give us a very strong basis of argument to the FDA to support [indiscernible].

So when you talk to the FDA in December, and did they say if you can repeat this data, you have a path forward?

Yes. Things haven't changed at the FDA so much that they would ever say that. But they try to -- because they, in general, don't like to tell you if this and that because it boxes you in. And quite frankly, it's good for us that they don't because that gives us the leeway to look at the data and be able to have a narrative that's compelling of how this shows an association that would support ultimate efficacy.

Okay. And is it fair to say 10 milligram will be the going-forward dose if we saw similar data sets?

That's something discussion now, both the PTC and Novartis teams are discussing that now as we think of the efficacy trial because, as I mentioned, we're all of the belief that we're moving forward with that efficacy trial. Great if that's going to be a confirmatory study in the context of accelerated approval. If we're not yet at the point that we could file for accelerated approval, that will be designed as the Phase III trial. So all that's moving forward now. And the thinking is we may move forward with both 5 and 10. The other thing we're thinking a lot about is not only the Stage II and Stage III patients, but the very, very large number, probably 3x the number of Stage II and Stage III patients that are earlier that may have no clinical symptoms at all that would absolutely benefit from a drug like PTC518 that can slow the onset of symptom presentation. And so as we start thinking about a strategy to go earlier and earlier, we may want to also have a lower dose available to understand what the effect could be in earlier-stage patients. So right now, I think both are very much in play. Of course, as you alluded to, the data readout will help confirm which of those doses we bring forward, but it will also help our thinking in terms of which we're going to be looking at over the longer term to access that very large number of patients who clearly would benefit from something that could slow disease onset.

So wouldn't that be likely would benefit from accelerated approval because functional data would take us forever, right?

There's no question that the strategy there will likely be a biomarker bridging strategy where if you think about it and you could show that a biomarker like Huntington lowering is associated with long-term benefit, then the extension earlier would really be about showing you're similarly lowering Huntington protein, which, of course, is something that we would be confident we'd be able to do.

Okay. Great. Okay. Now switch gears. You still have tons of other pipeline assets. We have a few more minutes. I wanted to ask about the vatiquinone in the Friedreich's ataxia. So I think I was informed that you guys will not have the 74 letter. So that's already FDA community with you guys already?

Well, we -- as you know, the vatiquinone Friedreich's ataxia program, we received acceptance of the filing with priority review, and that was notified in the day 60 letter. So they weren't obligated to issue a day 74 letter since they've already confirmed that the filing was accepted with priority review. So the next update we would have would be during the review cycle.

Okay. So the mid-cycle review basically.

Yes.

And then I've given my rough calculation, that should be April time frame.

Yes. We usually don't guide to mid-cycle because it's -- first, there's the internal FDA mid-cycle and then it may be a couple of weeks before we know about it. But let's just say, I trust your math is probably you could calculate on 6 months what the middle would look like.

Right. Okay. Good. And then -- so at what point when you don't hear from FDA, hey, you will not have -- they never talk about AdCom, that you know that, okay, you will not have AdCom.

Yes. Typically, so in the day 60 letter, what they communicated to us is they hadn't yet reached a decision about an AdCom. And what that suggests is they want to get a little bit further into the review before they make a decision about an AdCom or not. I think from our standpoint, we look forward to whatever they decide. I think clearly, if they had decided that an AdCom would be beneficial, we would certainly be in a very strong position to be able to have the appropriate people support the strong scientific rationale around efficacy. We know that this is a very vocal and thoughtful patient community, very educated patient community, who we know will be at the ready to help come and explain the unmet need, the unmet need for pediatric patients with FA and also share the experiences that the FA patients have had with this drug. So if the FDA wants it, we'll be ready. If they don't, we'll be ready to continue to work with them and work towards an approval.

So do you think that you have a better chance with AdCom or without AdCom?

I don't think it matters. I think we have a strong chance in both. I was merely saying that if we had an AdCom, we would certainly take advantage of it to continue to articulate the important value of this therapy, both in terms of efficacy, safety and meeting a very significant unmet need for pediatric patients with Friedreich's ataxia.

Maybe based on your prior experience, at what point you will start to discuss with the FDA about the label?

So I think we'd be a little bit further into the review. I think that sort of gets closer to late cycle time. Again, this is an accelerated -- this is an expedited or priority review. So it's relatively short from the acceptance of February to August, which is the PDUFA date. So I think we'd be getting closer to this summer time frame before we start discussing label. We would expect that we would have a full age spectrum of Friedreich's ataxia patients given that the NDA includes both safety and efficacy data in children and adults.

Okay. Good. We still have a few more minutes. I wanted to discuss about sepiapterin PKU. So maybe launch strategy and then also maybe the thoughts on the pricing and then also the patient population, where you think it would be the low-hanging fruit you can start?

Look, we're incredibly excited about the opportunity for sepiapterin. This is a pretty unique rare disease context. While there's 2 approved therapies, the vast majority of patients are not on therapy and would like to be on a safe, tolerated and effective therapy. So when you think about a population of approximately 17,000 patients in the United States, that's a very large number of patients who we believe we can provide sepiapterin to and make an important difference in their life. The data set we have continues to get stronger and stronger. We've already shown very high proportion of patients having a significant response to sepiapterin. We had 84% of patients in the trial reaching target guidelines. We shared on the Q4 earnings call that the latest Phe tolerance update shows that 97% of patients are liberalizing their diet, the Phe tolerance protocol. 2/3 of those are reaching the recommended daily allowance and beyond, all very important points. We're doing a little bit more work into some of the genotyping of patients who've been in the studies, and we have already previously shown that we're having an effect in patients who have what are known as non-BH4 responsive mutations. These are mutations that are often associated with classical BKU. And these are the types of mutations that a lot of the patients who are in the therapy-naive bucket have. So to be able to have the efficacy data we have in these patients supports that not only could we reach patients who are on existing therapies, patients who failed existing therapies, but reach that bucket of patients as well who are therapy naive. And it's when you start thinking about the ability to penetrate all key segments is why we believe we can achieve significant penetration in the market. Based on the data package, the discussions we've had with payers suggest that we can successfully price at a premium to Palynziq. And when you do that math, our guidance of $1 billion globally, but even likely $1 billion in the U.S. alone becomes very real. In terms of low-hanging fruit and segments, it varies center to center. We know there's a lot of the key centers in the U.S. that already have hundreds of patients on waiting list. This can include patients currently on BH4 because it's known that all patients who have been on BH4 have a greater response to sepiapterin as well as patients who are therapy naive, who desperately want to be on a safe, tolerated and effective therapy. So there's lots of sources of low-hanging fruit that may vary center to center.

Okay. I'll ask the last question to Pierre regarding the revenue guidance and how much assumption for the DME franchise versus sepiapterin?

Yes. So look, as we started the year, we provided a wide revenue guidance, $600 million to $800 million. There's very little Transplant Europe in that guidance. I think the delta is really Emflaza, for instance. There's definitely PKU numbers in there, although we believe in the strong launch in the $1 billion opportunity, this is second half, right, will be starting. So it's a few months. So it's not going to be meaningful this year. It's really in line revenues for the most part.

Should we consider like a real revenue contribution will start 4Q for sepiapterin?

Absolutely. There's revenue, of course.

Great. We are running a little bit over time, but we have lots of great discussions, and then we look forward to the 2Q data update.

Absolutely.

Thank you, guys. Thank you.

Thank you Gena.

Bye-bye.