Welcome to the BioMarin conference call to discuss the positive CHMP opinion in Europe for Roctavian. Hosting the conference call today from BioMarin is Traci McCarty, Head of Investor Relations. Please go ahead, Traci.
Thank you, Ross, and thank you all for joining us today to discuss the positive CHMP opinion for Roctavian. On the call from BioMarin's management team are J.J. Bienaimé, Chairman and CEO, Jeff Ajer, Executive Vice President, Chief Commercial Officer, Hank Fuchs, President, Worldwide Research and Development, and Greg Guyer, Executive Vice President, Chief Technical Officer. To remind you, this non-confidential presentation contains forward-looking statements about Roctavian and the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding a positive approval decision from the European Commission for Roctavian in the third quarter of this year, the number of adults in BioMarin territories affected by severe hemophilia A who will have access to Roctavian, our ability to satisfy product label and post-marketing commitments, and BioMarin's commercial launch of Roctavian in Europe, the Middle East, and Africa. These forward-looking statements are predictions and involve risks and uncertainties.
Actual results may differ materially from these statements, depending on the outcome of the European Commission's review of the CHMP opinion and those risks and uncertainties detailed in the press release we issued today, as well as BioMarin's filings with the SEC, such as 10-Q, 10-K, and 8-K reports. Now, I'd like to turn the call over to BioMarin's Chairman and CEO, J.J. Bienaimé.
Thank you, Traci. Good morning, and thank you all for joining us on today's call. Earlier today, we shared the news of the positive opinion from the European Medicines Agency Committee for Medicinal Products for Human Use, or CHMP, regarding Roctavian, which positions Roctavian to be the first gene therapy product in Europe for the treatment of adults with severe hemophilia A. We expect the European Commission to adopt a positive approval decision based on today's CHMP opinion, which we anticipate in the third quarter. Approval from the European Commission will unlock Roctavian access to thousands of people with severe hemophilia A in Europe and many Middle East and African countries.
Additionally, a European approval is the first step to facilitating access to named patient sales market in the Middle East. Before we discuss Roctavian specifically on commercial launch details, I want to acknowledge the journey that has led to this extraordinary accomplishment. For over three decades, scientists and researchers have been gradually cracking the code on gene therapy. We hope we chose to pursue the development of this nascent transformative therapeutic platform for the benefit of people with severe hemophilia A, developing a targeted therapy that addresses the underlying genetic cause of rare disease that is something our R&D organization has successfully done many times before. Gene therapy development and manufacturing are extremely complex.
With Roctavian for severe hemophilia A, our goal is to deliver the factor VIII gene via a one-time intravenous infusion so recipients can generate enough natural clotting factor to prevent spontaneous bleeding into joints, muscles, and soft tissues for a period of years. For the majority of people in our studies accustomed to the burden of strict adherence to chronic treatment that must be frequently administered, the impact of Roctavian has been profound, and we are thrilled that eligible people with severe hemophilia A in Europe will soon have access to the same transformational treatment options. This explains why, based on recent marketing research, healthcare professionals we surveyed estimated that Roctavian could capture approximately 35% of eligible patients, which is in line with our projections. I know there will be a lot of questions about pricing.
We will communicate the final price after the final EMA approval, anticipated in late August. Jeff will talk about our intent to provide outcome-based agreement to all payers in Europe and the U.S. in the future. We have now demonstrated six years of bleeding control for most patients after treatment with Roctavian, which would be a key variable in determining Roctavian's price, considering the high cost of treating hemophilia A patients around the world today. We anticipated Roctavian price to be lower in Europe than in the U.S., but not substantially lower. Considering the size of the severe hemophilia A market and our anticipated price, Roctavian European sales should be a very significant driver of BioMarin revenues growth in the next few years.
What I am also particularly gratified by today is the passion and persistence demonstrated across BioMarin over the last seven years to bring Roctavian to patients, which is a mission that kept us focused even when the outcome seemed uncertain. To those who have participated in our clinical studies in the name of science, of innovation, and future generations, we wanna thank you for your courage and inspiration. To the many other companies in our industry that are working towards improving health outcomes for humanity, we share in today's accomplishment because it advances the scientific frontier for all of us. While BioMarin is known as a pioneering innovator with seven novel products available in over 75 countries around the world, today's achievement is a high watermark for our organization.
Thank you for your support as we have persevered through our global clinical development program and regulatory procedures, as well as investing in our world-class gene therapy manufacturing facilities in preparation for this day. Next, Hank will describe the conclusions of the regulatory process in Europe. Greg will outline product supply readiness from our state-of-the-art manufacturing facility. Jeff will describe launch plans, the reimbursement outlook, and the market opportunity. I would now like to turn the call over to Hank to provide the regulatory update. Hank?
Thank you, J.J., and good morning, everyone. I would like also to extend our gratitude to the families, investigators, and European health authorities who have all contributed to the significant achievement on behalf of the hemophilia community, and a special shout-out to leaders at BioMarin, specifically Jim, Elizabeth, Aurélie, Brad, and Tara, who worked pretty much nonstop for the last couple of weeks. For BioMarin, today's accomplishment further validates our underlying approach to development. By applying our proven scientific principles focused on the underlying genetics of the disease, we have been able to leverage our core capabilities to maximize value for patients and shareholders. The end goal always remains the same, putting forward medicines that profoundly improve patients' lives. The path to success is often not entirely straight, and in Roctavian, this has been no exception.
However, the many things we've learned in our journey to this positive opinion have resulted in an even stronger package of information for patients. We will take this broader, harder, and lessons from this experience forward with us as we continue to fulfill BioMarin's mission of transforming lives. Turning now to some label highlights. Roctavian's indicated for the treatment of severe hemophilia A in adult patients without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 AAV5. The recommended dose of Roctavian is [ 6x10^13] vector genomes per kilogram, administered intravenous infusion from vials that contain [2x10^13] vector genomes per milliliter. I know there was a little bit of confusion about that, but there's a dosage strength in the vial, and then there's the dose administered to the patient. The dose administered to the patient has always been [6x10^13].
Prior to the administration of Roctavian, recipients will provide baseline measurements of liver health. After infusion, monitoring will be conducted for the purpose of detecting potential increases in alanine transaminase, or ALT, levels to determine if corticosteroids are needed, as well as to monitor factor VIII activity levels. After receiving Roctavian, ALT and factor VIII levels will be monitored more frequently during the first six months post-treatment, and then on a less frequent basis over the following 18 months. We believe this is an acceptable monitoring framework for people who have likely lived with a burdensome healthcare routine, especially considering the potential health outcomes possible after treatment with Roctavian.
As for corticosteroid administration in the real world, the expected course of corticosteroids will be administered on an on-demand basis should ALT levels rise above the upper limit of normal or one and a half times baseline, consistent with the protocol outlined in our phase III trial. As expected, given the novelty of Roctavian, the CHMP has adopted a positive opinion recommending a conditional marketing authorization or a CMA. Conditional marketing authorization is an approval pathway that recognizes that benefit to public health of the immediate availability outweighs the uncertainties inherent to the fact that the science is still new, as is the case with any gene therapy, and that the fact that additional data are still going to benefit our understanding.
If the conditional marketing authorization is granted by the European Commission, BioMarin expects that the results from our ongoing studies will be used to satisfy additional data requests specified in the CHMP opinion. On other safety measures that may be of interest and items that may be of interest, given the revolutionary premise of gene therapy for the treatment of severe hemophilia A, health authorities are interested in integration considerations due to the potential risk of cancer for patients.
Excuse me, operator?
Yeah, it looks like Henry, his line disconnected, so we'll wait a moment till he calls back in.
Okay.
Traci, maybe we move to Greg and Jeff, and we'll come back to Hank.
Yeah. I'll send Hank a text. Please, Greg, go ahead. Thank you.
Okay. We'll be glad to. Good morning, everybody. It's Greg Guyer. I'm pleased to share that we've been preparing for this great news for some time now. Our state-of-the-art gene therapy facility that J.J. referenced was originally inspected and GMP certified by European health authorities two years ago. Also just last month, HPRA once again came and reinspected the facility, and that inspection was also successful. We're ready to go. We have ample supply of Roctavian ready for labeling and shipping as soon as we get the final approved labeling and artwork. Once we have successfully labeled and packaged our finished product at our strategic European distribution center, it'll be ready to ship to treatment centers for use by patients.
With an approved dose of 6x10^13 vector genomes per kg, administered as a single IV infusion, we have currently released inventory of Roctavian to meet all launch demand, and also are in the process of supplementing that supply as the commercial launch rolls out across the EMA region.
The technical operations team has anxiously awaited this day and are 100% ready to rock and roll. I want to extend my thanks to the entire Roctavian team for their contributions to this accomplishment. I also want to personally thank Robert Baffi, my predecessor here at BioMarin, for whom this day would not have been possible without his brilliant leadership in the gene therapy CMC field. Once we have a clearer sense of product uptake from our our commercial colleagues in the market beyond launch, the manufacturing team will manage additional production, inventory, supply and shipping to the EMEA region accordingly. With the largest and most sophisticated gene therapy plant in the world, we are ecstatic to begin supporting our European launch over the coming months and also ensure supply long term.
With that, I'd like to turn the call over to Jeff to discuss launch plans. Jeff?
Thank you, Greg. On behalf of the commercial organization at BioMarin, we also want to thank the hemophilia community, clinical study participants and others who made today's positive CHMP opinion possible. With the EC decision on the horizon in the coming couple of months, we kick off launch plans and preparation for commercial sales later in this year. Our sales teams are in place and enthusiastic about bringing the world's first gene therapy product to market for severe hemophilia A. Our market research and stakeholder interactions give us confidence that Roctavian will be an important treatment choice for many adults with hemophilia A across the EMEA region. With an EMEA market of approximately 20,000 adults with severe hemophilia A, the launch cascade will begin with Germany and mirror our European launch of VOXZOGO in many respects.
As Greg described, we have ample Roctavian supply ready for labeling and shipping, and we expect pricing and reimbursement market by market to follow a European decision later in the summer. We expect the German price to be listed approximately one month after the EC decision, so stay tuned for more particular information when available. As we have said previously, we've been in discussions with health authorities and health insurance organizations in the first market in Germany. Our discussions have resulted in a framework for outcomes-based payment models. We are excited to be in the process of finalizing these agreements over the coming weeks, which we expect will facilitate commercial treatment with Roctavian. In France, we expect to submit for early access for Roctavian following an official EC approval. We've been very pleased with the growing body of market research illuminating both awareness and interest in treating with Roctavian.
Based on recent market research, healthcare professionals surveyed estimated that Roctavian could capture approximately 35% of eligible patients in line with our projections. We're pleased to report also that approximately 80% of healthcare professional respondents expect to treat at least one patient with Roctavian within 12 months of approval. That's a very positive response going into a launch. Additionally, insights from clinical experts indicate a large degree of confidence in the treatment opportunities Roctavian can offer beyond current treatment options. We've been frequently asked for an anticipated early adopter profile, so some important considerations on this point. We know that those who experience suboptimal bleed control with existing therapies have a keen interest in new treatment options, including potentially Roctavian gene therapy.
More broadly, we know the chronic treatment burden of prophylactic treatment is a major motivator for some to consider treatment with a one-time infusion of Roctavian, including patients who are doing well on prophy. Importantly, positive quality of life data shared at the World Federation of Hemophilia meeting in May showed that even patients with zero bleeds can experience clinically meaningful improvement in quality of life after taking Roctavian. The commercial organization is excited to get started on the European launch this year, and we look forward to sharing metrics of uptake cadence once we are further along. Thank you for your attention, and we will see if Hank has rejoined the call to finish his remarks, followed by question and answer.
Thank you so much, Jeff. Thank you so much, Jeff, and I apologize everybody for the bonus interruptus. I wanted to mention other safety items that may be of interest given the revolutionary premise of gene therapy for the treatment of severe hemophilia A. Health authorities are interested in integration considerations due to the potential risk for cancer patients. While there is no evidence that Roctavian or any AAV containing gene vector causes tumorigenesis in humans, we appreciate the EMA's decision to provide clear language concerning integration on the label. We are also pleased that no box warning will be required. Further, as agreed with CHMP, we will ensure that patients fully understand the benefits and risks of Roctavian treatment, what is known and what remains uncertain about long-term effects related to both safety and efficacy prior to receiving therapy.
Additionally, as part of our commitment to substantiate long-term efficacy and safety of this gene therapy, patients are expected to be enrolled in a registry designed to follow patients for 15 years, as agreed with EMA and in line with EMA guidance. In summary, and I think I speak for the whole team here, we are very proud of our team's efforts and perseverance to get this positive CHMP across the finish line. The transformational impact of Roctavian demonstrating a benefit in annualized bleeding rate and factor use
Unmatched by any available therapy today is an important breakthrough for patients. Getting to this stage with Roctavian has been a humbling and sometimes unpredictable journey, but it has validated our belief in great science and patient-focused outcomes. What a great day for the hemophilia community and for BioMarin and for our shareholders. Thank you for your support, and I will now turn it back to the operator for questions.
If you would like to ask a question, please press star one on your telephone keypad now, and you will be placed in the queue in the order received. Please be prepared to ask your question when prompted. Once again, if you would like to ask a question, please press star one on your phone now. Our first question comes from Chris Raymond from Piper Sandler. Please go ahead, Chris.
Oh, hey, thanks for taking the question. Maybe two, if that's okay. I just wanted to maybe first drill down on some of the market research stats that Jeff provided. I think I heard you say that you found that 35% of adult hemophilia A patients would be eligible and that 80% of doctors are planning to prescribe the drug within 12 months to at least one patient. First of all, is that right? And secondly, is that specific to the EU or is that maybe a global number? I got a second question.
Hi, Chris. Maybe I'll take that one. The question about the 35% of patients is specific to the EU and the 80% also is. However, the 80% also is consistent with what we've seen in the United States.
Great. Okay, thanks.
I think I'm interpreting that right.
Yep. Then maybe for Hank, you know, congrats, obviously a long and arduous process here. Now, if you're willing to talk about the situation with FDA, but is there any update with respect to your communication with the agency that you can provide?
Hi, Chris. Thanks, and congrats. No updates. I mean, we gave an update fairly recently on a fairly extensive communication we had received from the agency in response to getting ready to submit the Biologics License Application, which, by the way, was an enormous increase in the amount of communication that we had previously experienced. We think that that part of the process is already going better.
I think the main news of the day is the EMA's action, which, you know, in spite of all the sort of clouds and the ups and downs of, you know, combined with the pandemic and CBER being overloaded or whatnot, really reflects on the abundance of the data on the benefit to patients and on the public health need that would be served by making the product available even while unknowns are still existing. I think it's the power of that data at the end of the day, which is gonna really inform the agency's actions on the BLA.
Great. Thank you.
Our next question comes from Matthew Harrison from Morgan Stanley. Please go ahead, Matthew.
Great. Good morning. Thanks for taking the questions. I guess two from me as well. One, just functionally, can you maybe talk a little bit more in detail about how some of these value-based agreements are going to work? And also maybe just clarify how they will be recorded from a P&L basis, and then I have a follow-up.
Maybe Jeff, you start, and then Brian can pick up on the revenue recognition.
Okay, perfect. Thanks, Matt. I've talked about this a little bit before. We think that a key to capturing the full value of Roctavian with payers is to take some risks off the table for the payers. The payers are concerned about initial response. We've seen in the clinical trial experience that the initial response rate is very, very high. We can take that off the table. They're concerned about durability relative to, you know, what we would consider a price that could be tied back to a multiple of years of costs of prophylactic therapy.
If we can take both of those risks off the table for payers, in an outcomes-based agreement, then that allows us to capture full value of Roctavian with those payers. We've essentially constructed outcomes-based agreements that very simply attempt to do both. You could imagine in rough terms that, with European payers, we would agree if there was a patient that did not respond, we'd be happy to refund the entire cost of treating with Roctavian. Remember, the experience from the clinical trial would indicate that that's gonna be a very, very small percentage of patients treated.
We could construct an agreement, and we're working on it, that if we agreed to a durability that was expected to last X many years, if the durability for a particular patient only lasted, let's say, 85% of that, then we could refund back at a later date the 15% of the value that the payer did not capture. As J.J. Pointed out, we now have not only robust two-year data from the phase III study, but six-year data at the 6x10^13 labeled dose from the initial study that would indicate we should be expecting a very durable response from patients. We think that we can do all this pretty simply and at a relatively modest cost against capturing full value for Roctavian.
If Brian's on the call, I'll ask him to step in and talk about revenue recognition.
Jeff, actually Brian is not on the call at this time.
I'll cover it. Based on discussion with accounting firms and current accounting regulations, we expect to recognize the estimated liability in our net revenues at the time of sale. We'll book the whole sales up front, recognize the liability up front through a reserve. Because of the high success rates demonstrated clinically with Roctavian so far that lasted , at least five-six years, we expect this expense to fit our normal gross to net revenue range.
Okay, perfect. Thank you for that. Jeff, just my quick follow-up is, would you expect these agreements to take the normal timeline that we've seen for other agreements in Europe? Or is it possible that these will take longer to get into place? Thank you.
Thanks, Matt. In our first markets, we're already working to facilitate getting these agreements very specifically in Germany in place right following an EC decision. We would like this to be facilitative of getting the reimbursement approval, if not an additional delay. We would be doing this. Germany is kind of a unique situation where we have the free pricing period. For other markets, we would be looking to use these outcome-based agreements as a facilitator to get the overall reimbursement deal done market by market.
Thank you.
Our next question comes from Cory Kasimov from JPMorgan. Please go ahead, Cory.
Hey, good morning, guys, and congratulations on this development. I guess two for me as well. Re cognizing EMEA as a sizable opportunity long term, how should we think about the rollout there, kind of the earlier days? And what can you learn or take from prior gene therapy launches in the region? And then my second question is, of the 20,000 patients that you estimate are in the overall region, do you have a sense of how many are in Germany, given that that'll be the first country you're moving into? Thank you.
Jeff.
Hi, Cory. Happy to take this one and, at least for the start. I think the rollout across the EMEA region, we've got a really great model on that, and that is VOXZOGO. What we've experienced so far is that, our first and substantial market uptake was experienced in Germany. I would expect the same thing to happen with Roctavian. Right following Germany, we were able to get patients treated under an early access program in France. Now, the early access programs in France have changed a little bit, so they're probably a little bit more restrictive than our historical experience. I would expect France to be coming right behind Germany.
I would expect that there would be smaller named patient sales opportunities that are popping up individually small in smaller markets and in Middle East markets, for example, individually small, but collectively adding up to be material. I think we can learn a lot. I expect that we will learn a lot from the VOXZOGO experience that we'll read through to Roctavian. In terms of other gene therapy treatment experience, there have been a number of approvals in Europe, and not all of them have gone well. I would say we've watched with interest, not only with interest but with a resolve to try to have different outcomes than some of the ones that haven't been very positive.
Of course, there's been Zolgensma that was very positive and so we would seek obviously to have Roctavian look more like that launch than some others. I think fortunately, Cory , we've got a team that's been launching products multiple products and for the most part very successfully. You know, we know how these systems work. We've got people on the ground in place. We've got relationships. We've been able to leverage that to do the early pre-launch work. I'm pretty confident at this point.
We also have a very exciting cost offset situation, which some other gene therapies haven't had. Jeff, you wanna say one more thing? Did you cover, h ow many of the 20,000+ patients are in Germany?
Sorry. Yes, we know the patient population in Germany. I don't think we've disclosed that to this point. Give me a moment. I'll be happy to track that down.
Maybe we can move to the next question, you can come back to that later.
Yep.
Yep.
Okay. Thanks a lot, guys.
Our next question comes from Gena Wang from Barclays. Please go ahead.
Thank you for taking my questions. Also add my congrats on the approval. Maybe I have also two questions. One is regarding, again, the EU pricing. You talk quite a lot about outcome-based. I just wanted to make sure, and I remember, J.J., you mentioned in the past, in Europe, like you'll be thinking about lump sum, upfront payment, and the pricing could be in the 70% of the U.S. range. Would that still hold? Would that be true, mainly based on the Germany and the France discussion?
That's currently our plan. I think these are metrics that are in the ballpark. Yes. We are obviously, you know, way back, a few years ago, we thought that payers in Europe and U.S. would be interested in pay over time. They are not interested in that. They are not organized for that. They work on an annual budget, but they are very interested in outcome-based agreements, because, there is no real risk for them if we tell them that, if the patients, a few patients that, will not respond or will stop responding after a few years, will be at no cost to them, there is no risk for them.
As far as we explained, we're gonna book the sales, and we'll charge the payers upfront for the whole price, and we'll take a reserve for the anticipated cost of treating patients that don't respond after a while. Jeff, do you want to add anything to this?
No, I think that's right, J.J. Maybe just to circle back, sorry for being slow on the uptake with Cory's question. Close to 10% of that EMEA market opportunity is going to be found in Germany.
Okay. Follow-up question from me is, you mentioned that the gross margin will be largely in line with current. When I take a look, it's roughly in the 75%-77%. Would that also apply for Roctavian? You know, does that cover both cost of goods sold and also the reserve?
I think the gross margin will be higher than 75%. It will be in the mid to high 80s%.
Okay, fantastic. Quickly, one question regarding the ALT monitoring. How frequent monitoring you need to do for the first six months?
Thanks, Gena. I think that's the kind of thing that gets delineated with specificity in the SMPC, which will be available when the EC authorizes the marketing application. What I would characterize it as is to say that it's more frequent early after vector administration, and then at the six-month mark, it declines pretty substantially. This monitoring doesn't necessarily require visits to the healthcare provider. If we can arrange for patients to have home health services, for example, do blood draws, that can be made to be very convenient. This has been a subject of discussion that we had with the EMA to ensure that that didn't get in the way of the benefit of therapy.
The overwhelming conclusion of the consideration was that the substantial benefits outweighed, not just the long-term uncertainties, but also the immediate burden of monitoring, if you will. A relatively small impact overall for the patients given their journey with severe hemophilia to this point. A pill and a blood test is not much of a burden.
Thank you very much.
Our next question comes from Salveen Richter from Goldman Sachs. Please go ahead.
Hi. Thanks for taking our question and congratulations. This is Tommy on for Salveen. Our question was about the additional data to support a standard authorization. Understanding that it's a little too early to know for sure, is there a sort of desired duration of follow-up or how does the study on prophylactic steroids also factor into this? Thank you.
Yeah. The post-approval measures specify conclusion of two studies that are already fully enrolled. Obviously, the main pivotal study trial participants have now experienced 2+ years and counting. That study is designed to be a five-year study with a subsequent rollover. The specific reporting obligation is at the five-year time point, but every year we'll be looking at the data as part of the conditional authorization. Ultimately, the decision to convert to full approval will be a data-driven decision, not so much a time-driven decision. The other study referenced is the so-called prophylactic steroid study, which again is fully enrolled and has a planned study duration, but again, can be evaluated on an interval basis to determine if the information is sufficient to warrant further inclusion in the label.
I think the EMA is interested in both of those aspects, for the former, having observed, and EMA commented this in their press release, that the durability of effect has been substantiated in up to two years following a single infusion, and it's been reported in over 100 patients in the main study and up to five years in a few patients in a supportive trial. I think they would be interested in bolstering that as we expect that the durability and on the go-forward basis will be important and revealing. In regard to steroids, I think the general consensus has been that essentially less is more in the prophylactic steroid study that's ongoing is a much simpler approach to using corticosteroids to manage any potential vector-related inflammation of the liver.
I think those two things were of particularly high interest 'cause on some level they could make the product better understood. Even, you know, depending on how the data turns out, could actually make the product look even better or more attractive as a therapeutic option. That's a big stay tuned.
Our next question comes from Paul Matteis from Stifel. Please go ahead, Paul.
Hi, this is James in for Paul. Thanks for taking our question and maybe just a quick follow-up one on the prophylactic study as it relates to the FDA. You know, with the BLA submission delayed until September now, do you intend to include or, you know, have any thoughts about including a cut of the data from the prophylactic study in that BLA submission? And I guess, do you expect the FDA to want to see that data, whether that's, you know, a part of that initial BLA or later on when the full study reads out in 2023? I guess the key question is what's the risk there that the FDA wants that data and it causes some sort of delay in the regulatory process. Thanks so much.
Well, the agencies are always interested in the most recent and available data, and as we commented when we talked about the agency's request for additional information to be provided prior to the submission, that request essentially meant that the action date for that submission would be after the three-year data from the main trial are available and after the one-year data from the prophylactic steroid trial would be available. I expect that they'll look at it before the product would be available, not to say that they have said, "Hey, this is a really integral part of the program," but rather because it's known to be available. I don't think either of those elements are particularly risky one way or the other. The prophylactic steroid study, as I mentioned, has the virtue and the upside of it can only get better.
Given what we've observed and albeit a smaller number of patients, namely the seven patients that are out six years, the six patients who are out five years, all of whom remain free of continuous prophylactic therapy, and the 17 patients who have gone already three years who are doing quite well, our expectation is that the three-year bleeding control will be consistent with what we've seen so far. On that basis, I wouldn't think of any of the interim data updates that could be available as potentially dispositive to the submission overall, unless something very unexpected happened.
Our next question comes from Phil Nadeau from TD Cowen. Please go ahead, Phil.
Morning. Let us add our congratulations on the recommendation. A couple from us on Germany in light of the fact that investors are likely to use the launch there to evaluate the prospects. To follow up on [audio distortion]'s question, do you know how many centers there are in Germany and kind of how many salespeople you have on the ground promoting? Second, what launch metrics will you be able to provide early in the launch? Could you provide patient numbers and centers that have prescribed? Then maybe last question, of those 65% of patients in the EU who are not eligible, can you remind us as to why? What percent have AAV5 antibodies versus inhibitors versus something else that disqualifies them? Thanks.
Hi, Phil Nadeau. I'll jump on this and see how we do. With respect to German centers, I'm not gonna quote you exact numbers, but I'm gonna point to the way the hemophilia community in Europe and Germany in particular is approaching this, which is to say in a hub-and-spoke center of excellence model. This has actually been published in anticipation of having a gene therapy treatment available. The idea is that there would be a relatively small number of centers of excellence, drawing from, let's call it the largest hemophilia treatment centers or HTCs in Germany, which is the model there, like it is in many other markets, and smaller HTCs referring into those centers of excellence.
We think that's a really sensible model in that it creates a manageable number of treatment centers, at least initially, let's say, meaning the first year or two, that we would have to engage with and would allow those treatment centers to establish a critical mass of experience and expertise. As a result of that, we have a small number of sales reps on the ground in Germany that I won't quote specifically for competitive intelligence reasons, but they're on the ground. They've been profiling and making relationships and doing preparation for treatment already. That much on that one. In terms of launch metrics, of course, we always do provide launch metrics when we're going into a launch.
We have not addressed that on today's call. I believe that that's something that we would be circling back to in the next couple of months so that we could be prepared on earnings calls to give you launch metrics. Finally, you're exactly right. T here's, as we evaluate the patient opportunity in each market and collectively there's what we call an eligibility funnel that starts with an estimate of the number of total patients in a market with hemophilia A. There's various ways of getting those estimates. Then we estimate how many of those patients are adult patients versus adolescent and pediatric for eligibility.
We estimate the percent of those patients that have severe hemophilia that are on prophylactic that are AAV5 negative, and so on. That gets us to kind of our target number of patients. I'm not gonna quote those target number of patients because we expect that that's going to be variable over time, for a variety of reasons. I think the most relevant number I would suggest you home in on is that estimate of adult patients with severe hemophilia A. Thank you.
If I may, to further elaborate on the question. There is, to make it clear, there is an initial percentage of patients that will be eligible for therapy, b ased on, you know, Jeff went around, which is, it has to be adults, no inhibitors, no [AAV5] antibodies, all this. Now that we basically have close to approval in Europe, we already have initiated different studies, but we're gonna accelerate the program to now access all the segments of the population and to potentially emerge much larger patient opportunity here. We have studies going on now in patients with preexisting [AAV5] antibodies, patients with inhibitors. We're planning on doing studies in adolescents, doing studies potentially in patients with moderate hemophilia.
The market is gonna grow for many, many years, and we have a very substantial lifecycle management program, which we can talk about in the future to expand eligibility criteria for therapy with Roctavian over the years.
Our next question comes from Joseph Schwartz from SVB Securities. Please go ahead.
Thank you. Congratulations from us on this great achievement. Given that Roctavian is a different kind of treatment compared to your legacy products, we were wondering whether that introduces any special commercialization considerations as you roll it out with physicians and nurses who will have to monitor patients and manage steroids and liver health. I was wondering to what extent you've been interacting with these treatment centers in order to ensure that they'll get the adequate support to onboard patients. Do treatment centers feel like they're reimbursed adequately for any of this burden that they'll face? How does this situation differ in the EU versus U.S.? Thank you.
Hi, Joe. Maybe I'll take a first shot at those questions, which I think are highly relevant. You know, the first thing I would note is, hemophilia is a large existing and competitive market. So in preparation for this launch, starting a number of years ago, we worked to attract some of the best talent in commercial talent in the hemophilia business to BioMarin. You won't be surprised with the gene therapy prospect that we were a pretty positive draw for talent. So we've had talent on board for years, helping to develop our plans and also to leverage the relationships and the knowledge that these folks have. So we've been really fortunate on that front.
Let's talk about a one-time treatment versus a chronic, what could be lifetime treatment for many of our products. I think we've got a simpler situation when you talk about an event that needs to happen one time versus an event that needs to start and continue for many years over time. That's another distinguishing feature. You're right, there is a level of follow-up required. The follow-up required is not an extensively long period of time, and we're able to leverage the considerable experience that we have helping patients follow up with chronic treatment. Of course, you're right, we've been working, including with our medical colleagues and building off the experience from the clinical trial to prepare what I already described as a nicely concentrated set of target centers of excellence that will be doing this work.
I think you touched on pretty much everything. Good job.
Our next question comes from Tim Lugo from William Blair. Please go ahead, Tim.
Thanks for the question, and congratulations for today for this great outcome. I guess speaking of outcomes, for these outcome agreements with payers, can you drill down a bit on how response is going to be determined through a patient's journey post-infusion? Is this gonna be through expression levels, through bleeding episodes, infusions? Are there gonna be any patient-reported outcomes which will be tied to this response?
Hi, Tim. Let me take that one on. For competitive reasons, I need to be not overly specific on this call, but a couple of things in addition to the response to Matt's questions. First is we wanna keep things as simple as possible. I already mentioned the key risks are initial response and durability over time. Clinical measures of response and durability. There, there's not that many for hemophilia and coming out of the gene therapy treatment experience in the clinical trial. So those measures would include bleeding, return to prophylaxis. Those would be the big measures that we would be seeking to leverage. Sorry, was there another aspect of that?
Just patient-reported outcomes, but because it sounds like, you know, patients even with zero bleeds are benefiting from therapy when you kind of dig into some of the PRO.
Probably. Yo u know, we're very interested in patient-reported outcomes. Probably that's not an element that's specific enough that we would want to include in outcomes-based agreements.
Yeah, if I may jump in here, I think the agreements are gonna be pretty simple in this respect. It's not gonna be based on factor levels or patient-reported outcome. It's gonna be based on whether these patients require supplemental therapy to control bleeding. It's only based on the extra costs that will result from such an event to the payers. We will guarantee that we will, pay those extra costs up to a certain amount of years. That's it, t here's no complex measurement. It's gonna be very simple.
The patients need supplemental therapy after treatment with Roctavian. That's it.
Great to hear. Congratulations.
Our next question comes from Joel Beatty from Baird. Please go ahead, Joel.
Hi. Congrats on the positive opinion. Maybe a follow-up question on those value-based agreements. Do they take into consideration that different, you know, even within the severe category, different patients may have different factor levels and use of other therapies at baseline that could affect the value of factor for patients within the severe category?
Hi, Joel. And J.J., thanks for jumping in on the last question, f eel free to do that here too. Let me start. As J.J. mentioned, what the agreements are going to be as simple as possible based on durability and no bleeding, no prophylaxis use over a pre-specified period of time. Roctavian will be sold as vials of product, so and those vials will carry a price. Depending on how many vials are consumed will determine the cost of therapy for an individual patient. We're not going to have something complicated based on that individual's baseline bleeding rates or that so...
Our next question comes from Luca Issi from RBC Capital Markets. Please go ahead.
Oh, great. Thanks so much for taking the question, and congrats on the positive CHMP here. Maybe two quick ones. One, did the EU regulators actually see your recent genomic analysis of the case of salivary gland cancer before making this decision? Maybe related to it, I think your data suggested only 2% of the sample collected was actually cancer cells. Wondering, how should we think about the limitations of your data as you make progress also with the FDA regulators here? Maybe circling back on Phil's question earlier on the SG&A impact, overall, how many additional sales reps of MSL or back-office people do you anticipate you will need to add to your current infrastructure, both in Europe and in the U.S., assuming approval in both geographies? Thanks so much.
On the integration question, the EMA really notes what had already been in the public domain, which is integration can be documented with AAVs that are relatively low frequency. The EMA also noted that we have data from human tissues obtained from patients treated with Roctavian, and there's nothing unexpected about the integration pattern. Given the relatively short follow-up of patients in clinical trials, did want to advise patients that the risk of integration could carry a potential risk of tumorigenesis and at the same time advised patients that no cancers have been detected in patients treated with
Roctavian or as we said, previously for that matter, any AAV gene therapy. I think that it's great because it's a kind of, a good caution for patients to make sure they understand before they make their treatment decision, which is why we talk about adopters, people who are willing to do the research to understand the product that they're about to take. But at the same time, it's only acknowledged as a potential risk, not something that's actually been observed. I don't think they, you know, obviously we'll have to get into it with the FDA, but in regards to things that haven't happened, cancer , it's very difficult for that to weigh into a benefit risk analysis. Meaning, if it's not actually a risk, it's not really a risk.
Relative to the SG&A question, if Brian were here, he would say, we get a lot of leverage out of the infrastructure of our commercial and medical business, one. Two, much of our Roctavian team is already in place and exists in the SG&A expenses. Three, as we get new approvals and go into new markets, we will expand that team, but only incrementally. Expect as you go forward to see only incremental additions to SG&A because of Roctavian.
At this time, there are no further questions. I would like to turn the call back to Mr. Bienaimé for closing remarks.
All right. Thank you all for joining us today, to mark this significant moment for people with severe hemophilia, for the field of gene therapy and the good work of the team at BioMarin. As pioneers in the field of transformative medicines, we are so pleased by this tremendous achievement. Thank you all for your support and we look forward to seeing you soon. Goodbye.
This now concludes today's conference call. Thank you for attending.