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

Good day, and thank you for standing by. Welcome to the AADC CHMP Positive Opinion Update Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Head of Investor Relations. Please go ahead.

Good morning, and thank you for joining us on the call today. Today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements. During this call, we will be showing a short video which all participants can view by logging into the webcast of the call. The video can also be viewed under the Events and then Presentations and Videos in the Investors section of our website, should you not be able to access the webcast. Today on the call with me is our Chief Executive Officer, Stuart Peltz. So let me now hand the call over to Stuart. Stu?

Thanks, Kylie, and thank you very much for joining the call of this morning. I founded PTC over 24 years ago with the goal of using pioneering science to develop transformative therapies for diseases of high unmet medical need. Over the years, we've talked about the 5 products that we're commercializing or receiving royalties for. These products include Translarna and Evrysdi, which were discovered at PTC, utilizing our nonsense suppression splicing platform. Today, I'm excited to talk about our next therapy, Upstaza, which we recently received a positive opinion from the European Medicines Agency, Committee for Medicinal Products for Human Use, or CHMP. With the positive opinion for Upstaza, the research and development team at PTC are delivering our third pioneering and transformative therapy for patients, a gene therapy for aromatic L-amino acid decarboxylase deficiency or AADC deficiency. AADC deficiency is a rare, highly morbid and fatal disorder. Following ratification of the CHMP opinion by the European Commission, Upstaza will be the first marketed gene therapy that is directly administered into the brain, the first gene therapy approved in a major market in several years, the third gene therapy that is on the market now and only the fourth in vivo gene therapy ever approved. It is important for the biotech community to have gene therapy products achieve approvals from regulatory authorities. And this important milestone for PTC will help us build our gene therapy franchise and grow our revenue base. Before talking about Upstaza commercial launch, I want to acknowledge the incredible work of our PTC team whose passion, grit, determination and patient-focused efforts brought us to this important point. It was a true team effort. We all know that gene therapy is a nascent technology in terms of its use of the therapy for patients. And while there are many companies working on potential new therapies, the regulatory path for gene therapy is rapidly evolving, particularly for manufacturing. I'm so proud of how our team was able to manage through the EMA process and to learn and become adept in gene therapy and its manufacturing, allowing us to be one of the few companies to be able to receive a positive CHMP opinion for gene therapy. On today's call, we'll first review background on AADC deficiency disorder and the Upstaza treatment results, and then we'll discuss details of our planned launch, including identifying patients, building centers of excellence and taking our next steps for commercialization. Let's start with some background on AADC deficiency. AADC deficiency is a rare inborn error of neurotransmitter biosynthesis, resulting from mutations in the dopa decarboxylase gene, or DDC, encoded for the AADC enzyme. The lack of the AADC enzyme leads to a severe deficiency of dopamine production. Without dopamine, patients are unable to gain motor function or achieve motor developmental milestones. Essentially, this means that babies with AADC deficiency can lack the ability to move. They're developmentally growth arrested. They can't do what the normal babies do, such as lift their head, feed by mouth, sit up, roll over, crawl, stand and walk. That usually occurs in childhood and results from failure to thrive as well as from infection. Upstaza, which is our new gene therapy's brand name and was formerly known as PTC-AADC, will be the first gene therapy approved that targets the underlying cause of AADC deficiency. Upstaza replaces the entire human AADC gene. Therefore, it's able to address dopamine deficiency regardless of the disease-causing gene mutation. Our gene therapy product uses the AAV2 serotype capsid to deliver the human DDC cDNA to produce a functioning enzyme so that dopamine production can occur. Another pioneering aspect of Upstaza is its method of administration. Upstaza is infused directly into the putamen of the brain using neurosurgical technique called stereotactic surgery that is used in a number of pediatric and adult neurological disorders. This surgery has shown to be safe, is well accepted by neurosurgeons and is a minimally invasive surgical approach that allows us to provide precise, safe delivery of the gene therapy. The CHMP positive opinion is exciting and groundbreaking as this will be the first approved therapy directly administered into the brain. There are multiple reasons why we chose to focus on gene therapies that are directly injected into a tissue. Direct delivery has advantage of being able to administer a much lower gene therapy dose. Our target dose for AADC deficiency is 1.8x10 to 11 vector gene copies. As a reference, this is 1,000 to 10,000x lower than systemically administered gene therapies. Furthermore, since the AADC gene therapy is directly administered into brain tissue, the significant risk of gene therapy administered systemically aren't relevant. Importantly, the direct administration of the gene therapy also assures that the drug reaches its desired anatomical target. In this case -- in the case of Upstaza, the target is the putamen, which is the major site for both AADC enzyme and dopamine neuron activity in the brain. Finally, the putamen consists of nondividing cells, so injecting the viral vector to these target cells allows them to persist as episome in the nuclei and to be stably maintained in these nondividing cells. The maintenance of dopamine production has been demonstrated in our clinical studies, and durability of the clinical benefit as shown to occur for as long as 10 years following gene therapy administration. AADC deficiency was only recently identified as a disorder. With the first case described in 1990, we believe that the global prevalence is estimated at 5,000 patients, and our work on patient identification has shown that patients have been identified in all major regions. As there were no disease-modifying treatment for AADC deficient patients, there hasn't been a strong emphasis on diagnosis. In fact, AADC deficient patients are commonly misdiagnosed as cerebral palsy or epilepsy patients. As part of our program to identify AADC deficient patients, we have initiated more than 100 programs in over 200 countries. These screening programs have focused on high-risk population in cerebral palsy and epilepsy centers. In addition, key activities are ongoing, including disease education programs to drive testing, disease-specific webinars and virtual congress symposia. All of these activities have collectively contributed to accelerating new patient finding. These efforts have been successful. And to date, we have identified over 300 AADC patients in countries where access and reimbursement to gene therapy products are available, including in the European Union. Of course, patient finding does not end with an approval. In fact, we expect patient finding will likely continue to accelerate, which is what typically occurs once approved therapy is available. As more and more physicians begin testing and treating patients and more families actively seek treatment, we anticipate that this will drive increased AADC patient numbers and Upstaza penetration. This is the common path for most ultra-orphan drug launches, where we have found that there are commonly more patients that have rare disorders than either the prevalence suggests or the number of patients found through patient finding efforts. Due to all the patient finding efforts, we're in a good position for launching Upstaza and will have a steady flow of patients throughout 2022 and beyond. In addition to our patient finding efforts, we also needed to identify and develop physicians with neurosurgical expertise to deliver the drug dose to putamen. As part of our launch prep efforts, we've identified a number of vendors of excellence in key European countries. These sites have been qualified as a requisite experienced medical staff and the facilities for safe conduct of these procedures and are ready to treat patients in the European Union. Most of these centers of excellence are also being prepared to treat AADC deficiency patients via early access program. Several centers have already surgically administered Upstaza gene therapy to AADC patients. The Upstaza positive opinion was based on 3 clinical studies conducted in Taiwan as well as from results from compassionate use treatment in Europe. Evidence of clinical benefit has been demonstrated across all AADC patients, including the acquisition of motor milestones, improvement in neuromuscular function, reduction in life-threatening infections, improvement in cognitive function, increase in weight gain as well as improvement in other disease symptoms. Importantly, these clinical benefits have been demonstrated to be durable with clinical improvements measured up to 10 years after treatment. The durable result is particularly important considering that this is a single administration gene therapy. Most children treated in the clinical studies were incapable of spontaneous movement, they could not lift their heads, crawl, sit up and speak. The treatment benefits recorded in these patients represent a true departure from the natural history of disease. Absent gene therapy treatment, children with AADC deficiency will not gain motor milestones and are likely to die in childhood. The results achieved with Upstaza truly demonstrate the promise of gene therapy. So I'd like now to show a video of 3 patients pre and post treatment. So you've not accessed the webcast video yet, please do so. So the picture is worth a thousand words, then these videos tell a remarkable story of benefits of Upstaza, as they capture the condition of 3 children before and after treatment with Upstaza. As you watch the video, focus on first the baseline characteristics of the AADC patient. No spontaneous movement, no interaction with others, feeding tube dependent and display no characteristics of a healthy child. Post treatment, you notice the children seem to be awaken. They're more alert, more spontaneous, purposeful in movement, show fine growth and motor skills and the interactions observed between the family members as well as others are being interactive. Over time, they gain the ability to stand, walk, run, climb, very much like a healthy child. Can you start the video, please? So you could see here is the child, the AADC untreated, pretty much not responding. And then a year after, you can see what a remarkable difference. He's wearing a hat, his parents put that on, but he's able to move, interact. Here, you see him standing. Two years after gene therapy, you could see here, he's now walking. You can see he's moving, gaining strength. Here's 4 years after gene therapy, he becomes harder to keep up with. He's almost able to run. Here's 5 years after gene therapy. He is running. His mom can't keep up with them anymore. I couldn't keep up with him. Now he's going up steps. Pretty remarkable. Here's the second child. You can see again without treatment flaccid baby, no real interaction, unable to move. Here's 9 months after gene therapy. You could see a far more interactive. You could see, he's looks happy. Can interact with the environment. Tries to get the ball. You could see better hand motion, can do feeding. His eye-hand coordination. Here's the third, just look, you could see, again, a flaccid floppy baby. Has feeding tube, needs respiration. Now here's 7 months after gene therapy. Remarkable achievement, able to stand, capable of moving. You could see eating. [indiscernible] it's really pretty -- look at this, the child being a normal healthy kid, able to go upstairs, kick a ball, goes to open the doors, turns on the light. Really amazing, what is occurring. He can read as well. Good. So I think as -- I think you've just seen of these videos truly capture the transformative effects of Upstaza. We've not been able to view those videos, and I encourage you to watch them so you can fully appreciate the remarkable journey that these patients and families have taken. So let's talk a bit about the label. We're proud to have achieved the label that reflects a wide range of AADC patients who will benefit from Upstaza. The Upstaza indication will be for the treatment of all patients with AADC deficiency aged 18 months and older who have evidence of severe disease symptoms. Based on the clinical results, Upstaza has the potential to benefit patients of all ages suffer from AADC deficiency. In addition, the European approval allows us to expand to many countries outside of Europe. Based on our commercialization efforts for Translarna, we also plan to treat AADC patients in many other regions through the early access or named patient program. We can also have cross-border health patients from non-European families who travel to centers in Europe to obtain Upstaza gene therapy treatment. We believe that Upstaza gene therapy clinical data package that we have accumulated over the last decade is very robust and demonstrates that Upstaza is a transformative therapy. As we'll prepare for commercial launch, we'll be working to identify a commercial price that appropriately reflects the value of Upstaza. The Upstaza value will reflect that Upstaza is transformative to patients, has demonstrated durable treatment effect, reported in clinical trials with over 10 years of follow-up, has shown that dopamine as a biomarker has been produced over the 5-year clinical trial, that Upstaza addresses the high unmet medical need of the AADC deficient patients, that there is no standard of care for these patients and that the disease is highly morbid and fatal. Furthermore, we'll also take into account the small ultra-orphan AADC patient population with a small budget impact from this onetime treatment. For reference, we point out that the recently approved gene therapy for MLD called Libmeldy was recently priced in the range of $3.5 million. The patient population for MLD is 2x to 3x larger than that estimated for AADC deficient patients. All of these points will be taken into consideration and will be providing more detail on pricing for Upstaza after the European Commission ratification. Let me briefly touch on next steps for Upstaza. With the positive CHMP opinion, we anticipate adoption of the opinion by the European Commission within 72 days. We've begun pricing and reimbursement discussions in the launch countries. In addition, patients in countries like France that have early access programs are already scheduled for treatment with Upstaza. These programs allow us to initiate paid commercial therapy prior to completion of pricing negotiations. While the EU will be the first approval for Upstaza, we plan to have additional approvals around the globe. As we mentioned in our Q1 earnings call, we are planning to submit Upstaza for approval to the FDA in the third quarter of this year as well as regulatory submissions in other countries where gene therapy treatments are likely to be reimbursed. Our goal is to treat the prevalent AADC-deficient population as fast as possible. We anticipate that the Upstaza opportunity will exceed $1 billion over the life cycle of the treatment. We have included anticipated revenue from Upstaza as part of our revenue guidance of $700 million to $750 million for this year. We anticipate that the revenue for 2022 will fall between $20 million to $40 million. As we progress with additional regulatory submissions and expected approvals outside the EU and where they're required for commercialization, this will also accelerate revenues of Upstaza. In summary, I'm incredibly proud of our team's effort. This marks the first positive CHMP opinion of the first gene therapy that is being directly administered to a specific region of the brain and only the third gene therapy that is being commercialized. This is a tremendous accomplishment. We're on the verge of delivering this pioneering and transformative therapy for patients with AADC deficiency. We believe that the innovative gene therapy approach is groundbreaking and defines a new and important breakthrough that can lead to safer method to utilize gene therapies to treat diseases. With that, I'll now turn the call over to the operator for questions-and-answers. Operator?

[Operator Instructions] Our first question comes from Kristen Kluska with Cantor Fitzgerald.

Congrats on the positive opinion. And those were some incredibly powerful videos that you played for us this morning. So I wanted to ask how you expect an approval, coupled with the field doing more work across rare diseases, including some that have overlapping symptoms with AADC deficiency could lead to a greater prevalence closer to this 5,000 that you believe are out there? And then what do you believe is the annual incidence rate? And then lastly, what is the latest on different diagnosis initiatives, including through biomarkers? So for example, [ SAW ] study identifying 3-OMD and 5-HTP, for example.

Yes. So as we said, we said we think that the prevalence is around 5,000 patients. But we think -- clearly, this is -- more work needs to be done with it for that as well as a consequence of it's really -- when you think about it, it was -- it's a relatively new disease that was diagnosed or identified in 1990. And there was no treatment so that there wasn't necessarily a reason to define the -- what -- that they were AADC patients and that they were misdiagnosed. There's not -- and so therefore, very few were diagnosed as a consequence of that. But now with this treatment, there's now a real reason to. So I think we're going to get a much better handle on what we think the numbers are. So I think that's going to be helping and we'll be able to find better what the numbers are as time goes on. In terms of the testing, yes, you're right that OMD and others that -- we use an array of looking for things like those spots in terms of looking because you'd see increased levels as a consequence of heavy mutations in the DDC gene, that is one of the tests that we have as well, as well as genotyping as in looking directly at the DDC gene to look for mutations as well. And you have to put this together in line with trying to -- when you think about cerebral palsy or epilepsy to think about symptoms that a patient has that may push it towards AADC, like the ocular, the gyration that's observed in these patients in order to give physicians such clues to be testing. But I think along this with really pushing testing, which is what we've done. And as we've said, we've spent a whole lot of time figuring out what's the best way to find patients. What we've done is we've utilized the global -- our global footprint with different countries tried different approaches and then shared what were the best approaches as well. So -- and then we learned what seems to work in terms of identifying those patients. So while we continue to find them and use them as well. Then what was the final question that you had?

Yes. The third part was just the incidence rate.

Yes. Kylie, do you want to talk a little bit about the incidence rate?

Yes, I think -- yes, absolutely. Thanks, Stu. I think as we sort of have been working through, there's a number of different incidence birth rates that are represented in literature, and we've obviously been working closely with physicians and understanding that in more detail. I think there's a fairly wide range when it comes to incidence rates. I think that can range from 1 in 42,000, all the way up to 1 in 200,000-plus. And I think what we're seeing and what's giving us confidence in the 1 in 42,000 is we're continuing to find patients in all countries and all regions as we've said. So we'll continue to focus on working through what -- more details around those incidence rates, but it ranges from 1 in 42,000 up to 1 in 200,000-plus.

Yes. And both of those, as you might think in terms of that, that makes you think there could be more patients than we anticipate, but we'll have to follow that as we continue to find patients.

Our next question comes from Raju Prasad with William Blair.

Stu, you mentioned the $20 million to $40 million in guidance, can you just give us some benchmarks on what went into that number, particularly kind of pricing and reimbursement considerations?

Yes. So I think what I wanted to do is -- I think what we'll probably use as a metrics for discussing where at is the revenues over time. And so we'll be -- as I said, I think we'll be finalizing our pricing and be reporting that at the -- after the European Commission ratification. But I just -- what we wanted to give you some estimation of where we think we'll -- if you think about it, not only do we have the CHMP opinion, you wait up to 72 days to get the European Commission ratification, then you have to do some work to get it so that you get the first patient officially treated on the commercial scale. So that you can imagine that being somewhere in the third quarter. So -- and then there could be some expanded access as well. So we think that the price point benchmark are when you think what's already out there and that when you think -- I gave you possibilities like Libmeldy, this is only right now a consideration, and we haven't finalized it yet. But I think the importance here is I hope I've given you a little of why we think the fact that this transformative therapy, every patient responded to it. Biomarker was demonstrated. A really robust clinical package with over 10 years of both clinical data and follow-up that -- and the remarkable achievements of these patients as well as the fact that it probably will be the smallest patient population for gene therapy. All makes it so that it would be a high-value product. So we -- so that's why we think we're looking at the benchmarks that we talked about. We think access uptake that there'll be fast commercial uptake in countries like Germany quickly, plus an expanded access program like in France, and perhaps even other countries as well around -- it's not just Europe, it could be around the globe for those who will do it so earlier. And so I think there's also cross-border patients that can come into Europe as well. So we think it's going to be a robust startup.

Great. And then this is more of a broad question. Obviously, some of the other gene therapies that have been approved and launched in the EU have maybe tried a reimbursement, annuity type model pay-as-you-go to show durability. I mean what are your thoughts on that type of model, just given kind of the mix results that we've seen?

Yes. I think a lot of things go into what you have to do. It's hard to tell you what will happen. We believe the -- we're in a different situation in a way that we have a value proposition with already 10 years of durable data, a disease where there's no standard of care, right? I think 1 of the problems earlier was the standard of care, that there are other things you can have. So I think that the fact that the pack is just like I elucidated before, it's so strong, it's so transformative, it's so durable, has biomarker data, that and a small patient population. It's pretty easy to talk about the value that this product brings to the patients.

Great. Maybe just one last one for me. On the -- for the BLA package, is what the CHMP put the positive opinion on what's been submitted to the FDA? Or has the FDA requested additional data to be submitted for the BLA filing expected in the near term?

No. You might have remembered the reason Europe was first over the FDA was in part a consequence that we needed to do that while the cannula was been -- that we use and ClearPoint has been approved in Europe. It wasn't for gene therapy in the U.S., and that's why we have had to do some work. And that's why the EMA moved faster than the FDA. But that being said, obviously, getting ready for the MAA for submission really, I think, helped strengthen our package. And as we said, we plan to file by the third quarter of 2022. That's our goal.

Our next question comes from Hannah Adeoye with JPMorgan.

This is Hannah on for Eric. And congrats on the positive opinion. Just a few questions from us. So first, the decision speaks to a pretty broad label indication. I'm just wondering how you're thinking about just that distribution of addressable patients by age? And as you anticipate that any cover descriptions might come on the part of health care authorities based on anticipated benefit depending on the age of patients appear? And then I have a follow-up on that.

Sure. Matt, do you want to talk a little bit about this?

Yes, sure. Hannah, thanks for the question. So first, we were pleasantly surprised by the broadness of the label. I think it really reflects the CHMP's desire as well as the physicians' who participate in the scientific advisory group to make this therapy available to as many patients who might benefit as possible. Since we're in the realm of gene replacement therapy, really any patient who has a defect in the AADC gene leading to decreased dopamine production and decreased motor function, clearly will benefit by having a functioning gene that can increase dopamine production and therefore, restore motor benefits just as we saw in the videos that Stu shared on his presentation. Therefore, we believe that with this label, we can seek to provide therapy to those older than some of the patients who are in the studies as well as perhaps those who are not as severe as those in the studies. So it really opens up whole new opportunities as we pursue patient finding and patient identification. I think what's very clear is that given, again, the simple stuff that the defective gene leads to decreased dopamine and decreased motor function and that replacing that gene will lead to restoration dopamine levels and benefit, as just demonstrated in our trial, makes it very clear that there is a benefit to be had by all patients with AADC deficiency and those that are covered in the brand label.

Okay. That makes sense. And then you mentioned earlier that you expect some non-EU countries might reference the CEO approval decision. Just wondering maybe you get more specific on what those countries are and maybe what would enable approval on commercialization of agent territories such as South Korea and Japan?

Such as what? Regulatory in Japan...

Such as South Korea and Japan.

Yes. I think there's countries that -- we're talking about hypothetical except for France was clearly has expanded access. Clearly, there are patients there that are ready to do. We have them already scheduled as part of that in a sense the commercial expanded access program. But we've done it around the globe in terms of -- we'll have to work with and see like in Latin America and Brazil, where we've seen them. We've done it in other countries as well. So there's been a fair number of commercial paid is real -- U.K. So I think North -- Middle East, North Africa are good examples and references for named patient programs as well. On the regulatory bodies, obviously, we'll be working the U.S. and you're absolutely right, Japan as well as -- we also think that, as Kylie alluded to, there's a prevalence probably is a bit higher in Asian countries as a bit of a founder effect there. So there's certainly in the Asian markets as well, Taiwan, China and other Asian markets as well. So we're currently assessing those regulatory pathways as well.

Okay. And maybe just one last one. Just thinking about the SMA parallel or SMA treatment landscape. Can you just talk maybe about whether there's much of a role to be played by patient support advocacy programs in order to help you get these patients under the drug and have access to therapy?

Patient supported -- patient advocacy is that what you're saying?

Yes. If it could help in anyway with providing access.

Yes. There's -- so in a way, I think patient advocacy, patient support has always played a major role in what we do. I mean -- and that's always been true in rare diseases as well. We try to work -- and in this case, as a consequence of most when you think about it, most of the AADC patients are probably are misdiagnosed in other groups that we're not only going to try and utilize and work with the small number of AADC patient advocacy groups, but also work with other CP -- where CP is found and epilepsy as well. So we have to go a little bit broader in order to get the advocacy support and help for that, and that's what we're doing. We -- in terms of ensuring patient again, caregiver support, we do a lot of work also presurgery during the post surgery, during -- and post surgery to make sure and working along with the treatment centers of excellence that everything goes smoothly and well, help organize the whole process. So there's a lot that goes into it. And it's an interesting from a commercial point of view where you have the commonalities of not only in gene therapy, but also having to make sure that you have the neurosurgery go as well as long as using the device with the ClearPoint cannula and MRI. So there's all that works ahead of time that makes us a pretty interesting commercial launch experience.

Our next question comes from Joe Thome with Cowen and Company.

Congratulations on the opinion. Just a quick question on the age group, identified in the label. That's great to see the broad inclusion. I guess, in a patient that could potentially identified under 18 months, I guess is there any potential mechanism to drive that number down? Is there any intention by the group to drive that number down? Obviously, with the videos, you can see a great improvement in after that time. But do you think you could see an even greater improvement if you were able to identify patients before 18 months and deliver the therapy?

Yes. No, I think that's a great question. And obviously, we like to go as young as possible. There is sort of the age, it's more of a surgical issue in terms of that, and we'll have to skull development, right? And so that's the point. But I think it's something -- Matt, you want to talk a little bit about this?

Yes, Joe, as Stu alluded to, there's a balance. Obviously, we've seen patients of all ages demonstrate significant benefit from the therapy. What we see in the younger patients is they tend to achieve motor milestones a little bit sooner. So obviously, there'd be a desire to try to treat patients sooner and save them years of high morbidity and mortality risk. It's got to be balanced on the other side with safety of the surgery. The 18 months is really a time point where the children's skull has enough development to support the neurosurgical procedure. Without going into too many details, there basically is a need to put a fixation device on the skull, which requires some screws and other hardware that may not be feasible in younger patients. Now of course, 18 months is, I don't want to say an arbitrary, but it's certainly a level at which we can be sure that the skull has reached maximal development. That's not to say that younger patients may achieve early enough skull development that they could have the procedure done earlier, and that's obviously something we'll look at with the goal of, of course, getting to the therapy -- getting to the therapy to children as early as possible, but as safely as possible.

Yes. And we'll probably be working with [indiscernible] as well on that.

Great. That makes a lot of sense. And maybe one more quick one. Just in terms of the U.S. approval, we've seen the FDA sometimes like see some patients treated in the U.S. given that the package is predominantly to having these patients and the open label in the EU. Has the agency in the U.S. requested additional surgeries in the U.S. outside of, obviously, those 3 that you've performed? Or do you have any desire to do sort of an open access program in the U.S. to generate additional patient procedures in the U.S.?

Yes. Good question. And in a way, as part of the testing of the cannula, right, which was subject -- because the FDA, we haven't used -- it has not been used in gene therapy before. We had opened an IND, and we have 5 centers open where patients have been treated with it using the ClearPoint of that. So we've already done some of that. Matt, do you want to add a little bit more?

Yes, absolutely. So Joe, we have those treatment experiences. And as we said, we'll be meeting with the agency to align on the package. But in addition to getting experience with the devices as you said, this has the added benefit, of course, of also getting these expert centers ready ultimately for launch. So it's really both getting us experience with the cannual in U.S. cases and also that important step in center readiness, which we know is going to be key to the launch, much as we've done in Europe in terms of identification of centers of excellence for both surgery and pediatric neurology.

Yes. Great. Obviously, we do like [indiscernible] as well prior to them moving forward. So there's a lot of effort that goes into making sure everyone is ready.

Our next question comes from Robyn Karnauskas with Truist Securities.

Great. And congratulations on the CHMP approval. Maybe just talk a little bit about the limitations of the stereotactic surgery from a hospital and a patient perspective, like what are -- are you staggering them with the hospitals? And what -- how do patients from the parents that you're interacting with feel about that type of surgery? And apart of that, you also mentioned the studies from a patient. So are you staggering them? Is this really more of an identification -- expect identification to be steady? And then I have a follow-up.

Okay. Great. Yes. No, I would -- I mean, I think what we've seen is that there's such a high unmet medical need. And as you could see from those films, the changes, the transformational effects of the drug, I think make this a highly desirable outcome in order to have the -- I don't know if there's a lot of hold back in terms of the surgery. I think really, if you can -- that I think this is an important treatment where you can have true effects to that. And then in terms of the initiation, no, I would argue, obviously, in the practice in doing it prior to commercialization, there were more one-offs. I mean what we'll have is a line of patients over time where patients are getting treated. And so I think there's a lot of new things, there how many can each site work on at any given time? How many can they do a month? And so those are, I think, are all things that I think become part of the commercial launch process that I think we learned over time. And I think also, as centers get more in depth at this and the efficiency of doing this will increase as well. So I think it's not a matter of limitation, it's a matter of -- this is a new thing where we're getting patients ready. We're getting both the neurologists and neurosurgery to interact, get through the process. So that, you know what I mean, that is more of that. I don't think there's any limitation in terms of getting. Matt, do you want to add anything else in terms of the surgical approach?

Yes. Robyn, I would just add that this is funny saying minimally invasive brain surgeon, but it actually is in terms of the approach of that could be taken for delivering the drug without doing a major operation on the brain. I think that's very compelling that you can deliver such a transformative therapy with a less invasive surgery. And while this is a standard procedure done for a number of different pediatric and adult neuromodular disorders. It's a procedure done all the time. We're basically leveraging an existing safe and established technique to provide for the delivery of this transformation of therapy. Now of course, while it's an accepted technique, it's still typically done by specialized trained surgeons at specialized centers. And so that's why we talk about identifying these specialized centers of excellence, where we can be certain that there are the surgeons with this expertise as well as the supporting teams to provide all the necessary pre and postoperative care that's really important for these patients.

And quickly, Novartis made a lot of good headway with their SMA gene or newborn screening working with SMA advocates. And where are you at with newborn screening and -- towards doing that and getting that up and running in Europe?

Yes, that's -- I mean, I think that's something that we would -- that takes a fair bit of work. They've been working on this for years. I mean we just know how long it takes. We know people have been working on that for attrition. Just the result takes time to be able to do that. But we'll be working with groups to be able to move that forward.

Our next question comes from Brian Abrahams with RBC Capital Markets.

This is Steve on for Brian. Congrats on all the progress. Curious, can you share a bit more about the early access programs and an approximate number of patients who might be on these programs? And maybe a bit more about the reimbursement rate and process there since your prior to commercial pricing agreement?

Okay. Yes, thanks. So -- yes, so I think, obviously, the early access process is something we're working on. And you've got to remember that, obviously, we know that AADC deficiency is a rare, highly morbid and fatal disease. We think there's about 5,000 patients. We have 300 patients already. And while we're not sort of giving out specific country numbers of patients, I think we found enough patients and there's enough EAP that's going to keep, I think, the sites busy through 2022 and probably beyond. And as I said, we're already having patients reach out to the German centers and schedule for -- and they're scheduled for paid EAP as well. And so I think the -- obviously, we're moving ahead on this. There's a robust number that we have to get moving. But clearly, finding the patient doesn't end with the approval. And as I said, we always look -- we always find that there's going to be an acceleration that we've always seen that, especially once we have an approved therapy. So as we focus on -- and turning to focus on our commercial launch, as in the development of this drug, I think there's -- in a sense, a lot of pioneering work to do that I think is quite exciting, right? So it's not only the AADC that's exciting. But as I said, the genetically requiring the surgery, the device, the direct injection into the particular region of the brain. So what we need to do is always to continue to workout all aspects of this process and getting, so that it can be very rapid and efficient with the patients. And I think that's going to happen as it goes on and on. So we'll have a better idea of how we're going to do with the EAP as we talk to more countries and payers. And then I think it's also good to know when you think about the overall payer process, and I think you're probably aware of this, right? Well, the regulatory approval is a centralized process, the payer access for treatment is country by country, right? So you negotiate each country in their own timeline. It's not like it goes immediate. It's very different than the Europe -- than the U.S. So we use the EAP where we can, as we're talking through the payer process, that you can get those patients that are waiting to get them treatment. So we'll get more as we move on and as we get better, as we see how the payer discussions go. I hope that is helpful.

Yes, it was. And congrats, again.

Thanks a lot.

Our next question comes from Danielle Brill with Raymond James.

Congrats on the accomplishment. So I have a few. I guess, first, is that $20 million to $40 million forecast you provided already factored in the full year revenue guidance? And then I saw that the recommendation was -- for authorization was under exceptional circumstances. I'm curious of the practical implications of this designation are and how it's different from a full authorization? And then also curious how the severe phenotype is defined? Are there certain parameters and what proportion of the population is severe?

Yes, sure. Thank you for that, and thanks for the questions. Yes, so the revenue guidance is inculcated into -- includes the $20 million to $40 million what goes into that, right? So that's what we said the $20 million, $40 million. The exceptional circumstances is a full approval. It takes into consideration for rare disorders like this, that there are small patient populations and doing a placebo-controlled might not be capable of it as well as the whole notion of doing brain surgery on a kid and the placebo has been unlikely to do. So you're unlikely to get the same type of evidence that you might in the larger indication. But I think that really, obviously, you shouldn't be doing brain surgery on infants and children. But the pathway really ensures that diseases like this can achieve approval. And there's no further -- we're very happy to receive this designation, and there's no requirement for us to conduct any other placebo-controlled trials. This is a approval of a consequence of the CHMP opinion. And then what was your third question, again?

The severe phenotype, if there are certain parameters to define that? And what proportion of the overall population are severe?

Yes, I think I'll start with that. I think you could see in the video, patients tend to be quite severe, lacking motor milestones and you expect that as a consequence of not making production. So we think virtually all of the patients will be considered and fall under the definition of these major milestones. And we're obviously pleasantly happy about the breadth of the label. And I think that even patients that made out of the study, I think it was agreed that these patients would benefit from the treatment. And I think that does translate to a higher number of additional patients that ultimately will get treated. Matt, do you have any thing you want to add to that?

I would just add a couple of things. I mean first, I think we are -- I think the EMA is incredibly thoughtful in having such a pathway as exceptional circumstances that accounts for the fact that there's going to be certain situations due to disease rarity or for ethical considerations. We're doing traditional double-blind placebo-controlled or sham-controlled trials as practical. So I think when you think about the context of this disease that as Stu said, really the inability to do a sham-controlled and surgical procedure in small children, this was the appropriate pathway and importantly, because there's no additional clinical trials needed to support the approval of the [indiscernible] it's in approval. Obviously, we'll submit long-term registry data is done with any type of approval. But this really reflects a pragmatic approach to allowing therapy to get through the rigorous regulatory processes when the disease are rate and don't necessarily conform to what would be needed for a trial of hypertension therapy or a diabetes therapy. So we really want to acknowledge the practicality of this pathway. In terms of severe phenotype, as Stu mentioned in the SMPC and in fact, in the EMA's own press release announcing their adoption of the opinion they refer to Section 5.1 in the SMPC, which really talks about the fact that severe phenotype represents not being able to do a significant motor milestone like standing or walking, which again is the vast majority, if not all the patients with AADC deficiency. You saw in the video, this is a severe disease, not being able to walk, not being able to stand. That's a severe impact of the disease and we believe that's all is intended to be included in the label.

And our next question comes from Judah Frommer with Credit Suisse.

Congrats as well on the progress. Just following up on kind of phenotypic severity here. It seems like -- and again, the literature is limited just given the limited patient population. But it seems like there are genetic variants that are tied to varying severity of phenotype and there are some mild patients out there. Obviously, they tend to be older. So just as far as the genetic screening goes at this point, is there an effort to kind of tie genotype to what may be more mild or severe disease going forward or is that still developing? And do you think patients might decide on surgery based on genotype at some point?

Yes, I think that's a good -- I think really, at this stage, the genotype, phenotype isn't really available yet. We will be having a registry where we'll be watching patients over a 10-year period, which will accumulate data like genotype and how they're doing. So I think at the end of the day, I think that requires a fair bit of data to be able to do that, and I think we'll be able to understand that over time as we find patients and follow that.

Okay. That's helpful. And then just in terms of other or competing programs, I think there may have been 1 academic center working on a gene therapy dose to the mid-brain, that maybe the only other thing kind of in clinic for AADC. Are you aware of how any other programs are going? Or does it seem with this positive opinion and likely approval that patients are really going to call us around your therapy?

It's our view, like -- this is the only program that we know of that's going through the rigorous actions of getting a regulatory approval, not only on the surgical technique actually, right? I mean part of why you do this is to ensure that you have high-quality material that's been approved and that there's -- will follow the normal pharmacovigilance. So I think the safety and efficacy has been tested and reviewed and scrutinized by regulatory authorities. The other thing I'd say that's important is I think we're injecting into the putamen, which is the key spot for dopamine activity. I think it's the safest of all the approaches to get in to be able to get gene therapy to the brain versus going more into deep. So I think the fact that the putamen is the key side of dopamine action, which you could easily access it through stereotactic surgery, I think compared to other potential sites that includes like the substantia nigra which is located deeper in the brain and has more potential safety risk. So I think all those come together to say, this is the -- having the drug that's been approved by a regulatory authorities really puts it in the top of the class.

And there are no other questions in the queue. I'd like to turn the call back to Mr. Stuart Peltz for closing remarks.

Yes. Well, thank you all for joining today. And it was to share the exciting news of the CHMP opinion for Upstaza and really updates to our ongoing commercial effort. I think this is an important milestone for both patients and for PTC. And we couldn't be prouder of this accomplishment. I think a clearly strong -- shows a strong demonstration of innovation that will continue to drive revenues for us. And as we approach the EC ratification and treating the first commercial patients, we look forward to sharing and continue to share updates to you as the launch progresses and see how we do with revenues. So thanks for joining today.

This concludes today's conference call. Thank you for participating. You may now disconnect.