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

All right. Good morning, and welcome to the 41st Annual JPMorgan Healthcare Conference. I'm Eric Joseph, senior biotech analyst with the firm. And let me just say how thrilled I am to be back here in person with you all to host this conference the best week of the year. I'm looking forward to what I expect to be an exciting slate of presentations and I expect also constructive discussions over the course of the week. Our first presenting company is PTC Therapeutics, and presenting on behalf of the company is Chief Operating Officer, Matt Klein. Before I hand it over, I just want to say -- sorry, I just want to note that we're going to be doing Q&A after the presentation in the room here. There will be mic runners. So just raise your hand if you have a question. You can also submit questions via the digital conference book, and I can work them in where appropriate. So with that, Matt, thank you.

Thanks, Eric. On behalf of PTC, I'm excited to share our many 2022 achievements and upcoming 2023 milestones. Before I begin, I refer you to our forward-looking statements and SEC filings for an explanation of risks and uncertainties. PTC was founded a quarter century ago, with the mission of using pioneering science to modulate gene and protein expression and deliver transformative therapies to patients with high unmet medical need. We have succeeded in this mission and built a global biopharmaceutical company that discovers, develops and commercializes innovative therapies for patients with rare disorders. Our core scientific expertise is in four areas: nonsense mutation, splicing, modulation of bioenergy and gene therapy. In fact, we have pioneered drug development in each of these fields. Translarna is the first ever nonsense suppression drug and was the first ever therapy approved for patients with Duchenne muscular dystrophy, Evrysdi from our splicing platform was the first-ever oral splicing modulating therapy and is now approved in over 90 countries for patients with spinal muscular atrophy, vatiquinone for our Bio-e platform, is the first compound to effectively target the enzyme 15-lipoxygenase, which is an important regulator of inflammation and oxidative stress pathways that underpin a number of diseases. And we pioneered the field of targeted gene therapy with Upstaza, the first ever approved therapy that's directly administered into the brain. Our strategy is to continue to discover, develop and commercialize innovative therapies identified both from our internal research activities as well as from our business development activities. Our goal is to reach a steady state at which we deliver a new therapy every 2 to 3 years and become an enduring forever company. We have built a strong commercial portfolio with five marketed products and a sixth product Evrysdi from what you receive collaboration and royalty revenue. To sustain this product portfolio, we have also built a robust R&D portfolio in therapeutic areas of neurology, metabolism and oncology including both small molecules and gene therapies. We have a number of ongoing clinical studies, including several registration-directed trials, and we have a rich research portfolio with over 20 programs at varying stages of preclinical development. I'll first provide an update on our commercial performance and then provides more discussion on our R&D activities. 2022 was another strong year of revenue growth for PTC. We have now over -- approximately $710 million in unaudited total revenue, including $507 million of unaudited DMD franchise and product revenue. This represents an over 30% growth in total revenue and 20% growth in DMD franchise revenue. This revenue growth is particularly impressive when one considers the strong FX headwinds we faced throughout 2022. As we look to 2023, we again expect strong double-digit total revenue growth, and we're providing total revenue guidance of $940 million to $1 billion, and DMD franchise net product revenue growth of to $545 million to $565 million. Let me take a moment to describe the products in our portfolio that are driving this year-over-year revenue growth. First is Translarna, the first ever approved therapy for Duchenne muscular dystrophy and still the only therapy that is approved for boys with nonsense mutation DMD. It's now distributed in over 50 countries around the world, and we're still having product growth, both from geographic expansion and new patients in existing geographies. Emflaza is the first and only corticosteroid therapy approved for all U.S. DMD patients and has demonstrated superior efficacy and a more favorable safety profile over prednisone. And we're still having growth in Emflaza from new patient starts, favorable access, high rates of compliance and appropriate weight-based dosing. Evrysdi discovered from our splicing platform is now approved in over 90 countries around the world for the treatment of spinal muscular atrophy and it's established market leadership in all major markets with continued growth expected. Upstaza, there's the first-ever gene therapy that is directly administered into the brain and it's the first EMA-approved disease-modifying treatment for AADC deficiency. And has really demonstrated how gene therapy can deliver transformative results to patients. And Tegsedi and Waylivra are two therapies for rare metabolic disorders that we commercialize in Latin America where we have particular geographic expertise in commercialization and commercial infrastructure. Both therapies are made available now through early access programs, and we're currently working with CONITEC to simplify and broaden access in Brazil for both therapies. The approval of Upstaza was one of the highlights of PTC's 2022, and we've talked a lot about the pioneering aspects of the development program. But there's many pioneering aspects to the launch of the first-ever neurosurgical administered therapy. In addition to our successful and ongoing disease awareness and patient finding efforts, we've also worked hard to identify and train centers of excellence to ensure that Upstaza can be delivered safely and efficiently. Our initial launch efforts focused on early access programs in France, commercial access in Germany and cross-border treatments. We expect rapid growth in 2023, not only in France and Germany, but in other countries in Europe, and the U.K., where we have achieved marketing authorization. And then we expect additional growth worldwide as additional marketing authorizations occur. We're incredibly proud of our commercial team efforts in driving year-over-year growth. From $539 million in 2021 to what we're projecting to be between $940 million and $1 billion in potential future revenues in 2023. But growth doesn't stop there. We have a number of products in clinical development from which we expect to drive future revenue growth in 2024 and beyond. I'll now spend some time discussing our progress in our development programs. 2022 was a year of strong R&D execution with a number of important clinical and regulatory achievements, including the initiation of our PIVOT-HD study of PTC518 in patients with Huntington's disease, which is now enrolling in a number of countries in Europe the U.K., Australia and shortly in Canada. We completed the placebo-controlled portion of Study 041 of Translarna and demonstrated for the first time in an ITT population significant benefit on the key functional endpoints in Duchenne muscular dystrophy trials. These data, along with the data from our long-term STRIDE registry, demonstrating long-term benefit in patients with DMD supported the filing of a Type II variation in Europe to convert our conditional marketing authorization to standard market authorization. And we believe this data also position us to discuss with the FDA pathways for submission of an NDA. And we plan on meeting with the agency shortly to have those discussions. We also completed enrollment in our MIT-E study of vatiquinone in patients with mitochondrial disease associated seizures. And of course, as I mentioned, we had the approval of Upstaza in the EU and the U.K. As we look to 2023, we again plan for substantial pipeline progress. We have readouts expected from four ongoing clinical trials in the first half of the year, three of these trials being registration-directed studies. And we plan to continue enrollment in two additional registration-directed studies, our SunriseLMS study of unesbulin in patients with leiomyosarcoma and our CardinALS trial of utreloxastat in patients with ALS. Let me now provide some detail on the trials from which we expect readouts in the first half of the year. First is the APHENITY study, our Phase III study of sepiapterin for patients with PKU. Phenylketonuria is a metabolic condition caused by mutations in the phenylalanine hydroxylase enzyme that lead to elevated levels of phenylalanine and neurological sequelae, including cognitive disruption and seizures. There's approximately 58,000 patients worldwide with PKU. And despite there being two approved therapies, the majority of patients are still not served by these therapies, and there remains a large unmet medical need. People often ask us, how large is the opportunity for sepiapterin in PKU? Let me provide some data. As we said, there are about 58,000 patients worldwide with PKU. About 70% of them have tried Kuvan, but 30%, including classical PKU patients. Those are those with the most severe forms of PKU remain therapy-naive. Of the 70% who try Kuvan, only approximately 30% respond to therapy. And of those that respond, only 40% are well controlled. So in essence, less than 10% of patients are well controlled on Kuvan, and this represents a significant potential opportunity for sepiapterin. In addition to the large unmet medical need and market opportunity, there are a number of other factors that make the commercial opportunity, particularly unique for PTC. Newborn screening is in place, it centers around the world, they're well-known metabolic centers of excellence, most of which PTC is already actively engaging with. Disease pathology is well understood and documented, incredibly important for market access. And there's a connected and coordinated patient advocacy community. Essentially, all the pillars for commercial success are well established. So why do we believe that sepiapterin can meet this large unmet medical need? Well, it comes down to bioavailability and potency. Kuvan is a cofactor therapy. The idea is that by giving BH4, the cofactor for the phenylalanine hydroxylase enzyme that's dysfunctional in PKU patients, enzyme function can be increased. And phenylalanine levels lowered. But here's the problem. Synthetic BH4 whether Kuvan or Kuvan generics is rapidly oxidizing the gut to BH2, and this BH2, the majority of which is cleared by the kidneys. Then the remaining BH2 does not easily get into the cell. In other words, there's a significant problem with bioavailability. In contrast, sepiapterin is rapidly absorbed and actively transported across the cell membrane and gets into the cell where it's converted [ inside ] to BH4 and can exert its beneficial effects on the phenylalanine hydroxylase enzyme. In addition, sepiapterin itself has some chaperone function, which can further augment phenylalanine hydroxylase activity. So sepiapterin is both more potent and bioavailable in terms of cofactor therapy. The benefits of sepiapterin were well demonstrated in the head-to-head Phase II trial versus Kuvan, and now we're conducting the Phase III APHENITY global registration trial of PKU patients, both adult and pediatric. To enrich the randomized population, the study includes a run-in phase during which patients are treated with sepiapterin for a period of 14 days, and we asked a simple question, do patients respond to sepiapterin. If they do, they are then randomized to receive sepiapterin or placebo for 6 weeks. And if not, they're not randomized. The primary endpoint of the study is a reduction of blood phenylalanine levels and the primary analysis population is those patients who have a greater than 30% reduction in phenylalanine levels during the run-in phase. Due to our desire to enroll additional patients and the time lines required for washout, screening and bioanalysis to occur of patient blood samples, we now expect results from the placebo-controlled portion of APHENITY in the first quarter of this year. However, I'm very excited to share the promising preliminary data from Part 1 of the APHENITY study. As a reminder, Part 1 is an open-label run-in phase to identify subjects who are going to be randomized. And the patients who have a greater than 30% reduction of phenylalanine will make up the primary analysis population. So I'm going to share with you data the first 64 subjects who had a greater than 30% reduction in phenylalanine levels during that run-in phase. Overall, we had a mean reduction of 65% in phenylalanine, 65%, which is not only recognized as being significant, but would be recognized as being clinically meaningful. By comparison, in the pivotal Kuvan study, the mean reduction in phenylalanine levels was 29%. Now I want to share data from the subset of 10 patients who are classical PKU patients. Those are the patients with the most severe form of PKU who are not served by Kuvan. As a reminder, we have a cap of 20% enrollment, total enrollment of classical PKU patients. Here are the results. We observed a mean reduction of 57% in the classical PKU patients. And again, by comparison, this is a group of patients who are not served by Kuvan. In fact, in our Phase II study, there was zero change in phenylalanine level. So this 57% demonstrates that we can provide a benefit to the most severe patients. Taken together, these data substantiate the concept that a more bioavailable and potent cofactor therapy can deliver meaningful and clinically differentiated benefits to the full spectrum of PKU patients. We now look forward, of course, to the placebo-controlled data coming later in Q1. Let me now move on to the MIT-E registration-directed study of vatiquinone in patients with mitochondrial disease associated seizures. Mitochondral disease-associated seizures refers to symptom of refractory seizures which are highly morbid and very common in patients with mitochondrial disease. There's approximately 20,000 patients worldwide with mitochondrial disease associated seizures and there's currently no approved therapy. Vatiquinone works by targeting 15-lipoxygenase, an enzyme that's a regulator of the inflammation and oxidative stress that underlies the seizure pathology in mitochondrial disease patients. Our MIT-E study is a global registration-directed study of vatiquinone that begins with a run-in phase during which all patients are observed and they're for 28 days, and we record their number of observable motor seizures. Patients have been randomized to receive vatiquinone or placebo for 24 weeks, and the primary endpoint of the study is the change from baseline in frequency of observable motor seizures with secondary endpoints capturing other aspects disease morbidity. Study enrollment is completed. In fact, the study was over enrolled, and we expect data from this study in the first quarter of 2023. Moving to our MOVE-FA trial of vatiquinone patients with Friedreich's ataxia, which is another registration-directed trial. Friedreich ataxia is a rare inherited genetic disease causing neuromuscular and neurological defects in patients, and it results from mitochondrial function. In addition to the neurologic aspects of the disease, there's also other organ involvement, including cardiac dysfunction, which could be life shortening in patients with FA. In patients with Friedreich ataxia, vatiquinone again, targets an enzyme 15-lipoxygenase which is a key regulator of the inflammation and oxidative stress pathways that have been demonstrated to be key to Friedreich ataxia pathology. It's approximately 25,000 patients worldwide with Friedreich ataxia, and there still are no approved therapies for this disease. Our MOVE-FA study is a global registration-directed trial of that includes a 72-week placebo controlled portion to which patients are randomized 1-to-1 to receive either vatiquinone a placebo for 72 weeks. The primary endpoint in the study is the change in the disease-validated mFARS rating scale with a key secondary endpoint, including the Friedreich ataxia activities of daily living scale. Enrollment in this study has also been completed, and the study was also over enrolled, and we're expecting data in the second quarter of 2023. And Finally, I'd like to discuss our PIVOT-HD study of PTC518 in patients with Huntington's disease that's actively enrolling study sites around the world. Huntington's disease is a neurodegenerative disease that is highly morbid and life shortening. Huntington's disease, though, is unique among neurodegenerative disorders in that we understand the underlying cause. Huntington's disease results from mutations in the Huntington gene, which produces a mutant huntingtin protein that's toxic to cells. This mutant protein leads to cell injury, cell death and eventually neurodegeneration. PTC518 from our splicing protein leverages splicing targets in the huntingtin pre-mRNA to decrease the production of the mutant huntingtin protein. In other words, we're able to treat this disease at its source, the causative mutant huntingtin protein. The PTC518 program follows on the heels of the successful development of Evrysdi, which was discovered at PTC and as the first ever splicing agent approved. And we learned a lot of lessons from successful development of a CNS splicing therapy, including the importance of selectivity, specificity, broad bio distribution to every region of the brain, and this obviously is particularly important in the disease like Huntington's disease, which is a whole brain disease. The PIVOT-HD study is our global Phase II trial of PTC518 in Huntington's disease patients. This study is a 12-month placebo controlled trial that includes two parts. Part 1 is 12 weeks in duration and focuses on pharmacology and pharmacodynamic effect of PTC518 and also examines biodistribution of PTC518. The second part of the study is nine months in duration, also placebo-controlled, where we focus on blood-based CSF-based and radiographic biomarkers of disease. The study initially includes two dose levels, 5 milligrams and 10 milligrams with the ability to include a third dose level of 20 milligrams leveraging the titrability of the molecule. The decision to initiate the 20-milligram cohort will be based on the pharmacology and pharmacodynamic in our distribution data from the first 12 weeks of the 5- and 10-milligram dosing cohorts. We expect results from the first two cohorts in the first half of 2023. When we initiated the Phase II PIVOT-HD trial, we focused a lot on what we call the Goldilocks population. Now given the mechanism of action of PTC518, targeting the underlying cause of Huntington's disease, we believe that it can deliver benefit to the full spectrum of Huntington's disease patients, including juvenile HD patients. However, given the course -- limited time course of a clinical trial, we wanted to ensure to enroll a population in whom we thought we could best capture treatment effect over the course of 12 months. We availed ourselves of the robust natural history databases and developed a set of inclusion criteria that we thought positioned us best to capture that treatment benefit. While a lot has changed in the Huntington's disease clinical trial landscape since we initiated PIVOT-HD. And therefore, we've made the decision to now include patients who are early stage 3 those that have a TFC or total functional capacity score of 11 or 12. We'll be initiating additional 5- and 10-milligram cohorts for these early stage 3 patients and as I mentioned, still expect data from the Stage 2, 5 and 10-milligram cohorts in the first half of 2023. In conclusion, as PTC celebrates its 25th anniversary, we're incredibly proud of how our pioneering efforts have delivered transformative therapies to so many patients with rare diseases around the world. As we look to 2023 and the start of our next quarter century, we're again preparing for a potentially transformative year. 2023, we again expect to have strong year-over-year revenue growth with potential revenues of $940 million to $1 billion. We also have a number of potential transformational development milestones in 2023 with the readouts of several trials, including three registration-directed trials and the submission of the Upstaza BLA in the first half of 2023 and the initiation and continuation of additional registration trials through which we once again seek to use our pioneering science to deliver transformative therapies to patients with high unmet medical need. Thank you very much, and I invite our team on stage for the question-and-answer.

Thanks for that presentation, Matt, very exciting there. Maybe just before we kick it off with questions, we'll introduce the rest of the team here. And?

Good morning, everybody. I'm Kylie O'Keefe, and I'm the Chief Commercial Officer of PTC.

I'm Emily Hill. I'm the Chief Financial Officer of PTC.

Good morning. I'm Eric Pauwels. I'm the Chief Business Officer of PTC.

I guess the first place to start off is really on the PKU update that you're providing today. I guess, the data that you're presenting so far is non-placebo -- oh sorry, just treated patients. How should we be thinking about the performance of patients on the placebo arm? And -- and really, the -- yes, maybe I'll leave it there and just really want to focus on when we see the fuller update. Is it really a placebo-adjusted number relative to Kuvan's performance that we should focus on?

Yes. Look, I think those data are incredibly exciting. First, it's important to note that there are many reasons we believe sepiapterin can meet this unmet medical need, and I talked to my presentation about bioavailability and potent is incredibly important because for cofactor therapy to work quite simply, it has to get to the cell in enough quantity to be able to exert its effect and once it's there, it exert a meaningful effect. We did our Phase II study where we compared sepiapterin head-to-head with Kuvan and demonstrated not only the 50% more patients responded to sepiapterin, but also in those patients that did respond to Kuvan, we had over 100% greater reduction in phenylalanine levels. So as we look to the data that we shared today, there's every reason to believe that they provide further verification that having a more potent to bioavailable cofactor deliver meaningful effect. The endpoint here is a blood test. So we don't have to worry about placebo effect or things that we would worry about in other patient assessments or patient-reported outcomes. It's very hard to -- for a patient or any in any way to change that phenylalanine level. So what you're seeing here is really what would go on in the real world when you initiate the therapy. And then so you have all comers with all different levels of severe disease and you're seeing 65% reduction in phenylalanine levels. And then the classical patients over 50% reduction, which has never been seen before. So quite frankly, we believe that these are a very good predictor of how the therapy will perform in the placebo segment because, again, it's the same endpoint. It's a blood test, and it's not given to placebo effect. And I think these data go a long way in demonstrating the potential meaningful effect that we can get with sepiapterin and how we can really become a standard of care and be a truly differentiated therapy to meet the unmet medical need.

So I guess with respect to the fuller data set that we could see later this quarter, how should we think about timing maybe also just the -- any difference in the baseline performance of the balance of 40 patients, I guess we would see an update on? And then also, with respect to sort of longer-term outcomes or fee performance? Is there -- I guess, do you -- should we expect to sort of phe production levels going beyond the initial Part 1 interval?

Yes, absolutely. So look, we're as excited as anyone to get the placebo-controlled data, and we look forward to be able to sharing them later in the quarter. These are data from the 64 of the 80 patients who will make up the primary analysis population. So I think we're expecting very much the data to look consistent with what we have now. Following this 6-week placebo-controlled portion, of course, all patients are enrolled at a long-term open label extension to build up our safety dossier and also be able to confirm that we're having a durable effect of sepiapterin treatment, and there'll also be an element in that open-label extension trial of phe tolerance, which is incredibly important because what that says is not only are you able to deliver a benefit to patients on a strict regimented diet, but that they can start to liberalize their diet, and still have acceptable phenylalanine levels.

Okay. So I guess, what is the complete package look like that you would then take to regulators for registration [indiscernible]?

Yes, absolutely. So the registration portion of the study is the placebo-controlled study. And so those 6-week data, along with the data we generate in terms of safety from the patients in the six weeks and the safety data we have available once we read out the placebo-controlled portion, we believe will be sufficient to support filing in the U.S. and the EU.