BioMarin Pharmaceutical Inc. (BMRN) Earnings Call Transcript & Summary

All right. Welcome, everyone, to the 2021 JPMorgan U.S. All Stars Conference. My name is Cory Kasimov. I'm a senior biotech analyst here at JPMorgan. And it's my pleasure to be hosting our next session with BioMarin. As you can see here to represent the company are CEO, J.J. Bienaimé; and CFO, Brian Mueller. I thank you both very much for being here with us today. Before I turn things over to J.J. for a brief intro, just let me remind everybody that you can participate in our discussion here by asking a question either by clicking the blue Ask a Question button on your portal or, alternatively, you can send me an e-mail as well, and I'll work it into the conversation. So with that, J.J., let me hand things over to you for a quick intro.

Yes. Thank you, Cory. So we appreciate the opportunity to speak with you today. We see that with nearly 3 quarters of 2021 behind us, we feel good about what's being accomplished so far this year. Our latest product approval was just 4 weeks ago with VOXZOGO in Europe with achondroplasia. Regarding ROCTAVIAN gene therapy for severe hemophilia A, we submitted the marketing applications to European authorities with a 1-year data from all 134 subjects in our pivotal study back in June. Midyear, we reported strong financial results through the first half of the year, resulted in improving full year 2021 guidance. So back to VOXZOGO for the treatment of children with achondroplasia. We announced 4 years ago that we had been granted approval in Europe for children ages 2 and up, which is a broader label than what we anticipated and a testament to the good safety profile of VOXZOGO and the serious unmet need in this pediatric condition. So this approval unlocks eligibility for treatment for roughly 11,000 children in Europe, the Middle East and Africa for treatment with VOXZOGO, which is the first therapeutic option, and which is approved in this indication. Our European commercial team is in launch mode. I would say for the remainder of 2021, we expect France, Germany and Italy to be the drivers of VOXZOGO revenues with France and Italy coming in online this month through named patient sales, the so-called ATU program in France. We anticipate treating our first patients in France next week based on some prescriptions that have been written already by several hospitals in France under this early-access program, following -- followed by commercial sales in Germany starting October 1, so hopefully pretty soon. In the U.S., the November 20 PDUFA action date is on track. VOXZOGO represents well over $1 billion opportunity within our global footprint, and our commercial team is eagerly preparing for the launch of this significant new opportunity in the U.S. and Europe and other parts of the world. So turning to news 2 weeks ago regarding BMN 307, which is our investigational gene therapy for PKU. The product was placed on clinical hold by the FDA based on interim safety findings from a preclinical non-GLP pharmacology study in immunodeficient mice, DKO mice, double knockout mice. We do not believe that these preclinical findings with BMN 307 are suggestive of a significant risk to humans. We are being prudent and investigating the results thoroughly. The preclinical findings were specific to BMN 307, and we do not believe this suggests a risk to our other gene therapy programs. We are working with FDA and other health authorities that we will communicate next steps when available, so we will keep you posted as we learn more. I mentioned ROCTAVIAN, and with the validation of our marketing authorization application in Europe, we anticipate a CHMP opinion in the first half of next year because we were granted accelerated assessment review based on the unmet medical need despite the availability of therapies in hemophilia A. So we are very encouraged to be on the path towards potential approval next year in Europe, given the breadth of clinical evidence, demonstrating dramatic reductions in bleeding rates, Factor VIII utilizations and Factor VIII infusion following treatment with ROCTAVIAN. In the U.S., we continue to expect to resubmit the Biologics License Application for ROCTAVIAN in the second quarter of next year, assuming supportive 2-year data, which we'll have at the very beginning -- at the end of this year, very beginning of next year, followed by an expected 6-month review procedure. So we have many more next-generation programs advancing through the early stages of pipeline that we'll plan to share with you at R&D Day at the end of November. So lots more to talk about beyond the strong base business and beyond ROCTAVIAN and VOXZOGO. And that is -- so that's a brief overview of where things are today. So I will turn the call back to you, Cory, for questions.

All right. Perfect. That's helpful. I think we're going to probably touch on everything you just brought up. So let's start with VOXZOGO following the recent approval in Europe. This is, obviously, all very new and fresh right now, but can you describe the early progress you're making there with the initial launches, you kind of alluded to it, but maybe even more so the reaction you're getting from the medical community in Europe to date?

Yes. I mean so again -- so we expect to say French, Germany, Italy will be the early drivers, revenues with VOXZOGO in Europe this year. Again, the first patients would likely be treated in France next week under the ATU program. In Germany, we do expect a [ prices ] deal on October 1, which will allow us to start commercial therapy in Germany on October 1. We expect the German price to be consistent with the French ATU price, which is around $300,000. And in Italy, we have the potential for named patient sales approval under what's called the 326 protocol, which will allow our patients to begin commercial therapy as early as the end of this month or early next month. So the second wave of EUMEA launches will begin in early next year and then cascade from there, and we can talk more about it if you want some more specifics.

And your interactions with the medical community.

Yes. So I mean so far -- I mean, yes, so sorry. So I mean, obviously, there is a lot of excitement about the products. I say they, I think, like already 5 French hospitals that are prepared planning to or have ordered some drug. The community, based on our -- the feedback from our commercial operations here in Europe is the achondroplasia community is very excited. To give you administration of the pie of demand and the unmet need here, again, there is no approved therapy for achondroplasia. So what patients have been doing so far is some of them -- and actually 75% or so of them, I mean, in some parts of Europe are doing -- have been doing limb-extension surgery. So that gives you an idea of the unmet need here and the desire of these patients to get taller. So limb-extension surgery is painful, dangerous and expensive. So the patients get their -- the bones of their legs broken. And then they're putting on a rack so that there is space between the fracture, and the new bone grows in between the fracture. And so they have to stay in bed for several weeks or months. And I would say again, over 70%, 75% of them do that right now. So that's a testament to the fact that there is a desire of these patients to get additional growth and there is a huge unmet medical need. So again, it's very early in the launch, so we don't have that much feedback and specifics. But based on the [ feedback ] that we're hearing from French hospitals and some of our German colleagues, we believe that it will be a successful launch.

Yes. VOXZOGO seems like a much better alternative than having your legs broken. So...

And to the rack, yes.

So as we think about the gating factors to launch, obviously, reimbursement is a big part of it in Europe. How do we think about the time lines there and how that sort of coincides with your expectations for the early trajectory of the product?

Yes. So Brian, do you want to go over that? You're pretty familiar with that.

Yes, of course. Yes. Thanks, Cory. So yes, so first the -- what's unique about this launch for BioMarin is that this is the first time that we've had a major product approval and launch in Europe before the U.S. So you've probably heard us talk about the different dynamics between a U.S. launch and a European launch with the U.S. because it's essentially a single large market that you access with the FDA approval. And because of the pricing and market access, it tends to be the earlier and faster launch. And again, in our past, it's usually been first. In Europe, while the European approval allows us to access a much larger patient population, we've said that we estimate about 11,000 patients in our EMEA region, which is Europe, Middle East and North Africa. And by the way, the European approval also enables registration and access in many other global markets as well. U.S., China and Japan are exceptions where there's a very separate and discrete, unique registration process. But across the rest of the globe, the European approval can also enable named patient sales or facilitate a local registration. So we're also working on the global launch. But back to Europe. It's a country-by-country pricing and reimbursement negotiation. Certain countries are earlier because of early access programs or some of the pricing mechanisms J.J. touched on, France, Italy, Germany. And so the way you can envision the launch over the course of 2022 is those country-by-country negotiations taking place in a prioritized fashion based on market size and the ability to access those markets.

Okay. And Brian, just when you think about just the initial wave in France, Germany Italy, does the impact of this make you rethink 2021 guidance at all or just too soon?

Yes. It's great for the approval to happen consistent with our expectations, and we'll look forward to November 20 PDUFA. But we were expecting this so while there will be some sales, as J.J. mentioned, we're planning to treat our first patient. Last week I saw a picture of a box on the loading deck yesterday ready to -- of VOXZOGO ready to go out to patients. So while we will have some sales, it's so early. It's not going to be a material contributor to revenues this year. So we plan on talking about VOXZOGO revenues and guidance more for 2022 when we give guidance in February.

Because, again, this is quite therapy, and the patients in '21, they just started right now or are to start, they're going to do a few months treatment. So that's why the impact of the launch is going to be relatively financially limited this year but sure we will be -- first it will be next year, that's when we see the impact and especially considering hopefully then the U.S. also will be onboard by then. So to give you a feel of the U.S., back to your questions in the interest from the doctor. There was another -- there was a call last week, I think, with some key opinion leaders in the field of achondroplasia in the U.S., and one of them was Dr. Wilcox, who we know very well. And he said some of his U.S. patients are asking him if there are ways he can get them a drug from Europe so they could be treated in the U.S. So [indiscernible].

Yes. So J.J., you alluded in your opening comments, the label here is pretty broad or broader than expected is the EMA did this for patients greater than 2 years of age. Do you hear any signs of pushback from whether it's regarding access or physician comfort in prescribing to the younger age group because they weren't really...

Yes. It's still early for us to -- we need concrete feedback on that, but I'd very much -- I think clinicians and, obviously, the regulators understand the importance of treating those patients early because, again, I mean the fact that the EMA gave us approval for patients for 2 to 5 years old is a testament to their understanding of the importance of treating the patients early because we had -- as of today or as of when we filed, or when they approved it, we have limited efficacy data in patients under 5 years of age because that -- we enrolled the last patients in our 0- to 5-year-old study in March of this year. So we're going to have the 1-year data in Q2 of next year, and that's where we're going to have, hopefully, KOL efficacy in those patients. But the regulators in Europe, they understand that the growth velocity is much -- is highest in the first 5 years of life. Your growth velocity, any of us here is maximum at birth, then it goes down actually until the age 11, 12 or so when -- right before puberty when you get a growth spur again, and then it stops. But since the growth velocity is the highest in the first 5 years of age, the potential loss of growth because of the achondroplastic disease is the maximum during the first 5 years of age. So although we didn't have any KOL efficacy data under 5, they understood that it was still fundamental to give access to these patients early. And if the regulators understand that I can assure you that the clinicians in Europe and the rest of the world will understand that, too. And you can talk to any KOL in the field. They will tell you that, consequently, since we have demonstrated safe use in those patients, we don't -- really don't anticipate any pushback in that patient population of given we anticipate a lot of interest in it.

Okay.

Yes.

And you said the ongoing age-stratified trial in the sub-5 years olds, that data is Q2 next year, you said?

Yes. Early Q2 next year. I mean we have the top line, yes.

Right. Okay. And it might be a difficult question to answer right now, but are you expecting a similarly broad label from the FDA to include the 2- to 5-year-old?

I would say our base case assumes no. Actually even in Europe, we're not anticipating the 2 to 5. We're hoping for it, but we're not anticipating based on the limited data we have so far. We were pleasantly surprised. I would say U.S. regulators are more data-driven than the Europeans. Europeans are -- I mean, of course, they look at the data, but they're also pragmatic. And so, again, as said they understood the value of treating the patients early even if we have limited data. So based on the overall attitude, I mean FDA's approach to this, I would be surprised if we had under 5 in U.S., but -- so we're not counting on it right now. But still, there are plenty of patients to treat over 5. And I would say there are also -- and we're going to get the data in Q2 next year. Maybe we'll file and -- maybe by the end of next year, and then we'll get these patients on the label in U.S. down the road. So that's not a huge problem. And we're not going to promote the drug under 5, but it's likely that some U.S. docs will prescribe the drug for patients under 5 even before we have the label.

Right. Okay. So sticking on this regulatory theme and again, recognizing there's only so much you can stay at this stage. How would you broadly characterize feedback you're getting from the FDA on the review? And maybe where is your confidence level ahead of that November PDUFA?

Yes. So we are now in pretty advanced discussions with the FDA since the PDUFA date is less than 2 months away. And I would say -- so we are in active labeling discussions, packaging discussions, potential post-marketing requirement discussion. So -- and I would say this division of the FDA is not as -- I mean it's more available and more communicative than the ROCTAVIAN -- the division taking care of ROCTAVIAN. So we're in pretty active discussion with them. So we are cautiously optimistic that we're going to get approval by the end of November. So stay tuned.

Okay. And then with regards to pricing, how tight of a band do you think you can maintain on a global basis? Should we think of U.S. assuming approval being the kind of a similar level to Europe on a gross level?

Yes. I mean actually, Brian, do you want to comment on that, too?

Yes. So, so far, we've announced the French ATU price in the European approval press release, and our goal, by the way, consistent with the rest of our product portfolio, would be to not only get similar pricing in the U.S. but maintain that pretty tight pricing corridor globally. As I mentioned, we've had that strategy in place for years with our base business. And again, that's different from a lot of the big pharma models, but we think is indicative of the value of BioMarin's therapies. So we do think that's a good price as an indicator. But just a reminder, that's fully compliant. There could be some -- a small percentage of noncompliance with the daily injectable therapy. And then that's also a gross price. So there'll be accounting gross-to-net adjustments as well.

Right. Okay. All right. So final question for now on VOXZOGO is what do you see as the biggest hurdles to adoption? Obviously, there's the reimbursement component as you launch in Europe. But as you think about just the product really anywhere in the world, what are the things you're going to have to convince prescribers and patients of to broadly adopt the product?

I mean, I think, again, the safety is pretty well established, the compliance. We now have patients that have been treated with VOXZOGO in our Phase II extension for close to 6 years. Compliance is like 95% plus once a day set for injection. So -- and I think the drug is effective. So the effect of the drug is not dramatic every year, but the cumulative effect could be dramatic because what we do is we just bring -- in the over 5, certainly, in our pivotal trial, we -- 5 year and in our Phase II trial, we bring patients back to close to a normal growth curve because they're significantly below every year, which actually is good because you don't want to overshoot because that's what's going to happen a little bit with growth hormone that you accelerate the growth for 9 months to a year, and then the effect disappears. Our efficacy data in the Phase II trial, where 5-years plus shown that the benefit of the direct achieved over many, many years, that there is -- we have animal data and human data, retroactive data that there is -- that VOXZOGO does not induce early closure of the growth plates, which would be a potential problem because you could accelerate the growth of the patients for a few years, and then the growth plates closed early, and then final adult height has not changed. So which is not the -- will not be as good a benefit as increasing final adult height. And then finally, we believe that actually treating the patients under 5, and we're going to have to demonstrate this in Q2 of next year, will have an even more dramatic effect on the growth of the patients because the AGV, the annual growth velocity, is so much higher -- is higher in the first 5 years of age. So we have reimbursement -- we had a lot of reimbursement discussions. We don't anticipate payers -- payer discussions. We don't anticipate a major issue there. Obviously, the European price is not going to -- in a year or so from now, will not be the current price. There will be a discount to it. But remember that there is no approved therapy today for achondroplasia. I mean patients undergo a lot of that limb-extension surgery, and I think insurance companies pay for it and that's expensive. And also, what's great about VOXZOGO is that it's only going to be used in the first maximum 18 years of life, so 15 to 18 years of life, because once the growth plates close, then there is no benefit to treatment anymore. However, the benefit of the treatment will be a lifetime benefit for these patients to grow close to the other foot of their treatment and [ benefits stays for a child ], and also, there is improvement in their overall morphology. And should -- and I think that's also kind of interesting. We tested an ad campaign with some health care professional taking care of achondroplasia patients for Europe. Actually probably going to use it also in the U.S. And there was a picture of a little girl in the campaign, and we show that to achondroplastic health care professional there. And they say, "Well, you should use real achondroplasia patients in your advertising." And we told them, "Well, that little girl has been on VOXZOGO." She's-- I think she's 8 or 9 years old now. She's been on VOXZOGO for 4 years. And they couldn't tell that she had achondroplasia. So that's kind of one picture says a thousand words. This is a real story.

That's great. Okay. So in interest of time, let's switch over and talk about ROCTAVIAN next, but maybe let's segue into it by first touching on BMN 307 on the heels of the recent safety update you mentioned upfront. So I guess is there any additional color you can provide on the hold at this time or maybe any theories what might be causing the safety signal in mice?

Well, I mean, again, so we believe -- certainly, I believe the people who hold this -- I mean so the finding is specific to the mouse model that we've been using, which, again, was a double-knockout mouse. It was a mouse that had PKU and also a mouse that's 100%. It was ENU2 rat to mouse, and it was 100% immunodeficient, had no immune system whatsoever. And that study actually was not a study that we implemented because it was a request from any regulatory authorities or it was not even a toxicity study it was a study to look into the durable effect of PKU gene therapy here. So the clinical hold is specific to 307. All the gene therapy programs are ongoing. We have 2 other programs. As you know, ROCTAVIAN there are internal trials going on right now, and our BMN 331 study for hereditary angioedema [indiscernible] is going to start in the next couple of months in terms of enrolling the first patients. So this is still ongoing. It's also clear that from -- actually, when we reported this finding, it was at the end of the -- or day after or so of the AAV gene therapy advisory committee that we have reorganized 3 weeks ago or so. And one of the conclusion of that meeting from experts was that there is limited data on the trustability of any mouse toxicity to humans. So -- and that was -- the panel discussed on this before. We reported this because there have been already many reports in many studies in rodents of signs of findings of carcinogenicity of rodents, but it has never been observed in larger animals, whether it's actually dogs or nonhuman primates or humans. Over 3,000 patients over several decades now have been treated with AAV gene therapy. None of them has developed cancer that was attributable to gene therapy. And there was no signs of insertional mutagenesis on any of those patients that could be responsible for cancer. So these are the fact. So there's a lot of work underway to understand the cause of this finding. And so we are encouraged that those findings were specifically through [indiscernible] another interesting factor is that we actually have -- we have studied a gene construct that's very similar to ROCTAVIAN. It's the same vector, the same promoter, the same -- pretty much all -- what's important here is basically the same [indiscernible] and stuff. I think the Factor VIII gene into the vector construct -- the gene construct, we had the, I think, the [indiscernible] genes so that we could treat the mice without creating some problems to them. And so we treated the mice at [ 6e13 ] at that dose at 1 year. There was actually no sign of any carcinogenicity in those mice. So these are the facts. And there have been many clinical holds by the FDA in many indications and modalities, some of them in gene therapy, and most of them have been removed. It's too early to tell to give you a time line on if and when the hold can be removed. We've got to meet for the first time or talk to the FDA in October about this. And also, what's interesting, though, is that -- by the way, the finding was also on a dose is much higher. It was [ 2e14 ], which is much higher than the dose that we treat our patients so far. The highest dose we used was [ 6e13 ]. And we are -- with what's kind of ironic is that we are starting to see some clear signs of efficacy at [ 6e13 ] in PKU, which that is hopefully we will be going to be able to proceed in the future.

Okay. So given that you just said you're meeting with the FDA next month, I assume you don't know at this stage of how you get off the hold or what you need to do to [indiscernible] the oncogenesis isn't related to either 307 or the AAV vector.

Yes. No, we don't. But again, however, the hold is specific to 307, our program -- [ chief internal ] programs are moving forward.

And then you mentioned the FDA AdCom as well on AAVs. Anything else you learned other than the limited translatability from mice to humans from a safety standpoint? Anything you learned there that gives you comfort or maybe pause with regard to ROCTAVIAN specifically?

Not really. If anything, I think the panel was somewhat positive, we believe, I mean, in terms of hearing those issues and, I think, consensus that and so clear that there is any translatability of ours to rodent findings to humans or larger animals. Regarding liver tox, we -- I think there were some recommendations to do a liver scans for patients before giving them gene therapy. We've been doing that, and we're -- in our studies, we're planning on continuing to do it. And it's likely that will have to be done for commercial use and then probably do some liver scans on a regular basis with those patients. But -- and I listened to the whole first thing I didn't listen the second. The second year was more specific to other AAV vectors, 985, which is our vector because it was all about neurotoxicity observed with AAV9. And we have never observed neurotoxicity in our AAV5 trial so far, whether it's in animals or humans overall.

And then with regard to ROCTAVIAN's clinical profile, what's the latest market research or investigator feedback kind of saying? How has that evolved as you have more data on the product and everything else?

I would say it's getting better and better. I mean, Brian, do you want to cover that? Or do you want me to go ahead?

Yes. Sure. Thanks. That's exactly right. So while we're waiting for the second year of full Phase III data from the 134 patients to refile in the U.S., hopefully, second quarter of next year, and we're on file with Europe with a 1-year data. And then with the 2-year data becoming available early next year, they'll be able to see that data during our review. But when it comes to the marketplace, whether it be patients, patient advocacy groups and payers, while the ROCTAVIAN delay after the complete response letter was disappointing for BioMarin and our stakeholders and the patient community, it has allowed for additional time to -- for folks to get educated on gene therapy generally. And the size of the dataset only helps improve the confidence in ROCTAVIAN and the value and the impact it has on patients' lives. Just a reminder that when we filed initially for what was a rather aggressive, accelerated approval, we had these 7 patients in the Phase II study and then 16 patients that have reached just 6 months in the Phase III study. That's a pretty slim data package. So to have a full robust Phase III data set with 134 patients reaching that statistically significant end point of bleeding control and not using prophylactic factor, getting a fifth year of durability data from the Phase II study, as that data has emerged and has chance to be out there in the public domain for several months, we think it's going to aid the ROCTAVIAN launch in the long run.

Okay. So...

So the market -- yes, we've done market research -- sorry, we've done marketing research now since the 1-year Phase III data, and I would say the trends are -- in terms of willingness to prescribe, interest in the product, have been going up as compared to before the CRL, previous [indiscernible].

All right. So what do you think will be the key factors physicians will be looking at in the 2-year Phase III update? I mean what matters the most at this stage?

Yes. I mean I think they're going to want to see continuous bleeding control as we observed in 1 year, which was pretty dramatic, over 95% reduction in bleeding episodes, 95%-plus reduction in Factor VIII usage. And again, this reduction is not as compared to placebo. This was a trial comparing treatment with ROCTAVIAN to standard of care before patients we treated with ROCTAVIAN, which was prophylactic infusion of retargeting Factor VIII 2 to 3 times a week. So here, we've shown actually demonstrated superiority in terms of bleeding control at 1 year as compared to standard of care. So I think which is that I want to see continuous bleeding control at 2 years, I think it's likely to happen for 2 reasons why we actually have 5 years data now showing bleeding control based on the Phase II and also the fact that there was a subset of patients, 17 of them in the -- when we reported 1-year data there were 7 patients who already have 2 years -- of 2 years -- which we had 2 years before. And this patient also had major bleeding control. And [indiscernible] hope to see that ABR I think that's to be about similar to the first 17 patients and also that their Factor VIII levels at 2-year will be similar to the first 7 patients. And by the way, these first 17 patients at 2 years, their Factor VIII levels were between the high dose and the low dose of the Phase II trial where post of those showing continuous bleeding control at 5-year for the high dose and 4-year for the low dose where ABRs were under 1 or on 1 per year as compared to 14, 15 before treatment. So I think that's going to be the focus of the clinicians look at the data, and of course, any safety findings are personally important.

Okay. And then I'm sick of asking this question, but the comfort level of physicians with the durability of the product, I mean, I think investors make a lot between Factor VIII levels and bleeding control. But now that they're out 5 years in the high dose, 4 years in the low. Where is that comfort level at this point, would you say?

I think, again, it increases every year. Every time we demonstrate continuous bleeding control, and we thought we had 1 year, so we added 1 year in late May or June last year -- of this year. We're going to have 6 years of data. So by the way, by the time we launch in Europe and the U.S., even Europe, even if you get approval in Q2, by the time we launch, we're going to have 6 years of the high-dose data and 5 years of the low-dose data, which we will continue to demonstrate bleeding control. We'll see where the Factor VIII levels are. But I would say Factor VIII levels measured by the chromogenic assay might not -- nobody knows what is the relationship between Factor VIII levels or the level of Factor VIII almost, minimum levels that you need, the chromogenic assay to show bleeding control. It is also an interesting anecdote that one of our -- one of the key opinion leaders that we're working with told us that he had a patient in hemophilia B treated with gene therapy with Factor IX. That patient never really had any detectable or significantly detectable Factor IX levels for gene therapy -- for Factor IX after gene therapy. And that patient has not bleeding control and has not had a need to go back to the Factor IX injections for several years now. So there's a lot of stuff we don't know yet in terms of the relationship between continuous transgenic Factor VIII or Factor IX expressions and bleeding control. But as every year that goes by, we learn more about it. But I would say, I think where we stand today with the state-of-the-art and the value of dollars that's available is that it's always unlikely that ROCTAVIAN is going to be a lifetime cure. I think that's pretty clear now. However, it's -- we've shown 5 years of efficacy. It's likely to be significantly more than 5 years. It's going to be 7, 8, 10 years. Nobody knows that. But even if it were just 5 years, a lot of clinicians and patients are very excited by [indiscernible] 5 years free of the need for injection of any product to control their hemophilia and allow them to have a more normal lifestyle.

Okay. So in terms of the regulatory outlook for the product, can you kind of broadly speak to feedback you may have received from EMA at this point since you're under submitted? And on the U.S. front, has the FDA confirmed with you that it expects a 6-month review after the resubmission next year?

Yes. I mean so the -- indeed, so the FDA that's kind of standard once you resubmit after first cycle and we get into your second cycle of submission. It is generally a 6 [indiscernible]. So that's pretty well established. Regarding Europe, we haven't had our -- since we filed this summer, we haven't had a meeting yet with them, but I think that's coming up relatively soon. So we don't -- we cannot give you any feedback. We haven't heard anything good or anything bad yet, but we know they're actively reviewing the data.

Okay. And we talked about how the evolution of kind of feedback on the product from physicians, from patients. From a payer receptivity standpoint, I mean we did a lot of work here. It was pretty strong ahead of the original PDUFA. Has that changed at all with the delay? I mean you do have longer-term data now? Has that helped on that front? Or do you look at data from the...

Absolutely. Yes. Right before we got the complete response letter from the FDA last summer -- or summer of last year, some docs were ready. There were some patients lined up to be treated. Some private health insurance companies in the U.S. who were talking to us to come up with some contract teams, some potential outcome-based agreements, some -- they wanted to treat some of those patients because they understood the potential savings that you would be generating by using gene therapies. That has not changed. If anything, now we have longer durability data. We have now a Phase III KOL demonstrating pretty clearly that we are superior to standard of care at 1 year after treatment. Hopefully, likely will be the same at 2 years after treatment in at the end of the year or early next year. So the strength of our dossier is actually better and better. ICER, which just was introduced cost-effective analysis in the U.S., independently from the industry and from us, before we got the CRL in the summer of last year, they did an analysis demonstrating that -- and that was before we had the 1-year data. The product was cost effective and they invested $2.5 million. For treatment, they also analyze then documented actually the lifetime cost of treating a noninhibitor patient, which is what we're going after is north of $20 million that they also looked at when [indiscernible] launched they looked also the lifetime cost of inhibitor patients, which is over $90 million, 9-0, for a lifetime, but we're going to try to get to these patients later. So the burden of the disease is very high. The cost of treating these patients is very, very high. And that's why we believe that we can bring something to the party, improve the quality of life for the patients and reduce -- and reuse -- and generate savings from the health care system around the world. Actually, we already have -- because there we have treated close to 150 patients with ROCTAVIAN now. And those patients have been saving -- have been helping their health care systems to save a lot of money, especially what have been treated 5 years ago. They are free from recombinant Factor VIII injections. We're talking tens of millions of dollars here.

Right. Okay. So last thing on ROCTAVIAN. I mean when you think ahead to the launch both Europe and the U.S., given everything we've talked about, how do you -- how are you thinking about this now with regard to either a gradual launch? Or is there an initial bolus of some of the early adopters for a new technology like this? What are your expectations?

I mean it's going to be a gradual launch as usual because, again, the early adoptions are clearly not the majority by definition. So there's going to be -- I mean like we had 150 patients that wanted to be treated even before we had any data, the metrics that we see there. And -- but there are other -- there are lots of patients that have not been in clinical trials that would like to be sure the early adopters. So the key would be to make sure that those early adopters do have a good experience with the drug. Based on the clinical data so far, the majority of them should have. And then I think this is a pretty tight community. They have a lot of social media interactions. And I think if they have a good experience, the patients will be talking that have -- the trials already have been talking, I mean, they don't have free to do it as commercial patients. But this is how by word of mouth, the experience is going to be communicated to the entire hemophilia community. So it will be gradual, but -- and I mean penetrating the market is going to take many years. And also, we launched -- we're going to launch a specific if we get approved with a specific indication label is going to be through patients under patients over 18 years of age, severe hemophilia patients, patients that do not have inhibitors to Factor VIII, patients that don't have high levels of AB5 antibodies. So the target market initially is going to be about 25% to 30% of the overall market. But we have a life cycle management, detailed plan to actually implement some studies to go after younger patients, to go after patients with AB5 antibodies, we've got to go after even patients with inhibitors to Factor VIII, to go after moderate hemophilia patients, so to grow the market over many, many years.

Okay. So we're down to the last couple of minutes. Not a lot of time to get to the existing portfolio. But I guess just to throw one question, I'm interested if you're seeing any changes with PKU clinics just during the ongoing pandemic. Or is it still pretty challenged there?

It's still challenging, but Brian, you want to answer that one.

Yes, of course. Yes. Thanks, Cory. We're obviously still watching this very closely. We're just a week away from closing out Q3, and then we'll have our Q3 call here in just a few weeks. So we'll give a more detailed current-state update on Palynziq and PKU clinics. But it was just a few weeks ago when we gave our Q2 update, and at that time, we said that we were observing that still about 50% of U.S. PKU clinics were closed to in-person visits. And while about 85% of them were doing telemedicine, most Palynziq new patient starts occur in the clinic. There's a REMS associated with Palynziq. And while we do have a started home program that we initiated during COVID, it's in its early stages. So we'll continue to be optimistic that we'll reach prepandemic new patient start rates when things open up further. We did observe, just like much of society, a bit of an opening up back in June when we had those few weeks just before the Delta variant surge. So that was definitely a continued setback. But we'll definitely give you more details in just a few weeks.

Okay. So last question here, we're down to under a minute. With your R&D Day coming up, just curious, are you willing to guess and what product might start capturing everyone's attention much like ROCTAVIAN and VOXZOGO over the last few years?

Yes. Yes. I think, hopefully, our vision, the second-generation [indiscernible] vision muscular dystrophy, we're going to give you an update. It's pretty exciting. I mean we're going to have [indiscernible] gene therapy update. We're going to update our BMM265 for a subset of product disease, which could be extremely exciting, too; update on in vitro even data, animal data on gene therapy for hypertrophic cardiomyopathy. If this one works, it's going to be a huge market, our biggest gene therapy product ever. And then let's get the program we're going to talk about that we have not disclosed so far the new exposure, which is extremely exciting. So I would highly recommend you attend our virtual meeting.

All right. So we will end it with that teaser. J.J., Brian, thank you both very much for participating here today.

Thanks for having us.