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

Good afternoon and good evening, and thank you for joining us to discuss the late-breaker update on ROCTAVIAN gene therapy for hemophilia A as presented today at the World Federation of Hemophilia Virtual Summit by Professor John Pasi. Today's press release is available on the Investor page of our website as well as the slides being presented during this call. In keeping with the format of the World Federation of Hemophilia meeting, we are using Zoom conferencing technology today, so all participants, with the exception of the speakers, have been muted. Thank you for submitting your questions in advance of this call and for your patience as we embrace this new technology. Our host today is Dr. Hank Fuchs, BioMarin's President Worldwide Research and Development, who will introduce our guest speakers momentarily. To remind you, this nonconfidential presentation contains forward-looking statements about the development of BioMarin's the valoctocogene roxaparvovec program generally and the impact of the valoctocogene roxaparvovec gene therapy for treating patients with severe hemophilia A. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements and those factors detailed in BioMarin's filings with the SEC. Now I'd like to turn the call over to BioMarin's President and worldwide -- President of Worldwide R&D, Hank Fuchs.

Thank you, Traci, and thank you all for joining us today. I'm very pleased to welcome our Chief Investigator for the 201 study who reported today, Professor John Pasi, Professor of Hemostasis and Thrombosis at Barts and the London School of Medicine. And Dr. Steve Pipe, Larry A. Boxer Research Professor of Pediatrics and Communicable Disease and Professor of Pathology At the University of Michigan, my alma mater, and also one of our principal investigators. Thank you, Professors Pasi and Pipe, for joining us today. The format of today's call will include a review of the ROCTAVIAN late breaker data presented earlier by Professor Pasi, followed by a fireside chat on the discussion of results. And then time depending, we'll take your questions. As Traci indicated, we have a log of all your questions, and so I'll try to run through those for us together. Every year around this time, we endeavor to provide an update on the ROCTAVIAN Phase II data and each year, I reflect on what's been achieved. And before we start thinking about what years 5 and 6 and 10 might look like, it's important to understand the magnitude of what's been shared today. All participants in our study are producing their own Factor VIII since receiving ROCTAVIAN. In Factor VIII, they are individually expressing the result of the treatment for ROCTAVIAN has essentially created a new phenotype for people with severe hemophilia that are lacking -- that are phenotypically behaving as if they did not have hemophilia or had mild hemophilia. The people now free from prophylactic therapy and who have achieved the level of hemostatic efficacy resulting in 4 years of bleed control and counting, is a really impressive result. I'm inspired every day by the commitment of our colleagues, our investigators in the community, and I want to extend our thanks to everyone who has contributed to the program. I hope you'll have an opportunity to enjoy Drs. Pipe and Pasi as much as I do because they're going to share their experiences in both in the science of the field and in the clinical trials and just the -- being clinicians in the area. There are even some awesome and inspiring comments that you're going to hear momentarily. And so with that, I'd like to turn it over to Professor Pasi to briefly review what was presented earlier today at the WFH Virtual Summit. John?

Okay. Thank you very much, Hank. And I believe many of you may well have heard my late-breaker session complete with its technical hiccups earlier, so I hope, this time, we don't get it. So I'm going to just go through some of the slides that I presented earlier. So many of you already know about this program, clearly, that this is an AAV5 containing, a human Factor VIII gene as the expression cassette, where this Factor VIII gene has been modified by having the B-domain deleted with an SQ linker inserted. It's a sequence that has been codon-optimized to maximize expression. We use a truncated human liver-specific promoter. And obviously, this is all within the inverted terminal repeats of the AAV5, which this cassette is squeezed into. So if we could go on to -- am I controlling the slides there? Great. Thank you. So this also is the slide that many of you will have seen before. And as I'm sure you know, we're going to focus today on the 13 patients in the 6E13 cohort and the 4E13 cohort. The first 2 patients in the dose-escalation study did not generate measurable, reproducible levels of Factor VIII. And so that's why we got to focus on these higher 2 cohorts because they have demonstrated measurable levels. The baseline characteristics is given on the right. Important point to mention is that most of these patients, all but one in fact, were on prophylaxis prior to going into the program. And equally importantly, only 2 out of them have no bleeds prior to going into the program. We can see there that in the 6E13 cohort, their ABR was 16 prior to going in, and the 4E13 was 8. And in on-demand patients, they had ABR of about 25. So really, that's quite significant bleeding before they're going into the program. And so that's worth bearing in mind when we look at these next slides. And if we look at the next slide, now we look at all the treated bleeds. And we've presented data like this before, but obviously, the important thing here now is that we're into 4 years for 6E13 and 3 years for 4E13. And we can see the sustained and significant reduction in treated bleeds that has run consistently through over the follow-up period. And that's more than 90%, 93% to 95% reduction in bleeding rates within ABR that is really significantly low. And if we look at the number of participants who are bleed-free in 6E13, we see it's 6 out of the 7 with no spontaneous bleeds. And in the 4E13, we see 5 out of 6 with no spontaneous bleeds, but we had 2 patients who did have a bleed in year 3. What's really important, though, is all 13 of these subjects remain off prophylaxis. And if we go to the next slide, we will see how much treatment they've actually had to receive over this follow-up period. So on the left of each of these panels, you will see the treatments in the year prior to going into gene therapy, so the numbers roughly equating to all those alternate VIII gene therapy. And the key thing is that you see a 96% reduction in the amount of treatment that has been used. And in year 4, we see some treatment being used and in year 3 as well in the 4E13 cohort. But some of these include treatments for things such as surgeries, biopsies that were undertaken or cover for minor procedures, such as dental work or joint injections. So going on to the next slide. Here, we see the classic picture that we show of the assay levels over time. So green is 6E13 running out, as you can see, to 4 years. Gold is 4E13 running out to 3 years. Please note, as I mentioned earlier, this is the chromogenic assay that we've presented on this slide. Obviously, the 1 stage assay comes out with results that are about 1.7x higher on average. Here, we've got the chromogenic data, and we've used the lower of the 2 assays to be conservative about what we're presenting. And I think here, you can see that there is sort of durability that is going out to 4 years with perhaps a slow decline visible. And looking at the next slide, which is the low S curve. So this is a scattergram of all the results for all the patients that were taken in the study. Goal here being 6E13 dark gray, straight black being 4E13, and you can see that the smooth curves show pretty flat responses in years 3 to 4 and 2 to 3 in the 2 relevant cohorts. So I think this is really encouraging for the future going forward in terms of the data that we've got. Now the next slide, I think, gives us considerably more detail as where we are with these patients in the study. So we've got 3 panels here: on the left, annualized Factor VIII usage; on the right, annualized treated bleeds; and there in the middle, the current Factor VIII ranges. So let's look at the annualized treatment usage on the left-hand panel. To the left of the line dividing, we see the treatment received in the year preceding and in the right-hand panel, the amount of treatment received per individual averaged over the 5 -- sorry, 4- and 3-year periods. And you can see that many patients have not received any treatments at all. Some have received the odd treatment. And as I mentioned, that would be to cover things like dental work, injections and so on. There are 2 patients that do stand out, #6 and #13, who've received more treatment on average. These are the 2 lowest responding patients in the program, who have had some spontaneous bleeds in the study. And also they both actually had knee replacements along with patient #7 as well. If we look on the right at the annualized bleeds, again, we see significant bleeding before gene therapy and then lots of 0s afterwards. And we see just some low numbers of 0.2, 0.3, 0.6, aside the 2 patients I just mentioned, 6 and 13. If we think about the actual bleeding problems that we've seen in the last year, they've been restricted to the 2 lowest numbers, #6 and #13, again, all in target joints pretty much. #13 is now having target joint replaced, and so we're expecting to see far fewer, if any, bleeds in the forthcoming year. Patient #10 is the one that has had 2 bleeds in the last year, but both of these are traumatic. One, when he jumped off a bridge onto a small boat in a river and sustained an injury to his ankle and another when he was playing football and twisted his ankle. So these are both traumatic bleeds. And as we said earlier, the only patients that had spontaneous bleeds into target joints were 6 and 13. And what we can see in the middle is what their levels are. And what we can also see is that patients with apparently quite low-ish levels, as you might determine, have got remarkably low bleeding rates and remarkable low need for treatment, which is really encouraging. And again, bodes well for where we're going. And I'm sure we'll be talking about this as we go through. The last but one slide coming up is -- yes, sorry. Missed this one out, forgot about this. This is the quality of life. Dark blue is the 6E13 who showed an improvement in quality of life at year 1, recently maintained through to year 4. And the 4E13 show consistent quality of life. They came in at a higher level and as you will remember, had a lower bleeding rate to go in initially. Moving on to the next slide, which is what I thought was next. Really, this is just a summary of the safety and tolerability profile. And really, the program looks very favorable in terms of safety. The only issue is we've seen transient infusion reactions in a couple of patients and the ALT responses, which we talked about previously, none of which have had any long-term sequelae nor have there been any long-term sequelae with corticosteroid use, which was employed to manage the ALT elevations that we had in the first year. And in fact, there have been no need for steroids after that first year. Importantly, following patients of 3 and 4 years, there's been no emergence of any new delayed adverse drug reactions. I mean there have been no treatment-related SAEs in the past year, though the SAEs that we've had have been unrelated to valrox. Obviously, everybody's continuing in the program, no thrombotic events, which is clearly important. But what's really important is long-term follow-up now. There have been no patients that have developed any inhibitors. So in summary, what we've got is really good data out to up to 4 years. All the participants remain off prophylaxis. Cumulative mean ABRs are less than 1 for both dose cohorts, and the only spontaneous bleeds that we've seen are those in target damaged joints in the 2 lowest responders. And what we're seeing here, it seems hemostatic efficacy maintained at all Factor VIII levels that we're seeing through the program from the lowest patients to the highest ones, all doing very well and not bleeding and not requiring treatment. There is a shallow decline, which is commensurate with what we've seen previously, and we are continuing with all the reduced treatment burden, to reduce bleeding to see improvements, maintaining quality of life. It's fair to say, I think, that the safety profile of BMN 270 remains very favorable and entirely consistent with the previous data that we've got. And I think that we've established a very important transformative therapy from a single treatment now through to 4 years, which really is a paradigm shift in how you manage hemophilia and bodes extremely well for what we might see in the Phase III 301 program. So I think -- is that my last slide apart from, of course, I must say thank you to absolutely everybody who's been involved in this, the patients, the TIs, the research teams in the centers. But of course, BioMarin's huge program that sits behind this data, which is something that we just simply can't do without. And so it's a huge thank you from us as the investigators and the treaters to BioMarin for making this happen. So I'm going to hand back, I think, at that point. I think, Hank, you're on mute.

Thank you, John. Good tip there, press the button. Thank you also for the acknowledgment of BioMarin's contribution to the hemophilia community. Our teams are so fired up about this collaboration and what we can do for patients. It's impossible to capture. And in fact, it's kind of my -- the first question I wanted to pivot to bring Steven to the conversation and start thinking about this a little bit differently. We spend so much time thinking about numbers. But now you're all gathering more and more clinical experience with what happens to patients. So I wonder if you could talk for a few minutes or so about for each of you, what's tangible to a patient, to their family, to their caregivers about having received gene therapy. Move away from numbers and talk about the life of your patients. Steve, you want to start?

Yes. I think this is really important. Things shift very quickly post gene therapy and the conversations I have in the clinic encounter. I'll tell you about one of my young guys. I mean I asked him how he's doing when he comes in, and he just says I'm living life. And that, I think, is really telling. We don't talk about numbers anymore. He doesn't care. What he knows is he doesn't bleed anymore. He's doing all the things he wants to do. One guy can think of -- he really had to be diligent to manage his prophylaxis before gene therapy, every other day infusions. So think about going through college, looking for work. What possibilities are there opening up to him? Can he go away to look for a job in another state, et cetera? And post-gene therapy, he just has everything opened up for him. He just sees that he has potential to do whatever he wants to in life. So I really enjoyed the clinic encounters now, just seeing the transformation. He honestly does not think about his hemophilia anymore. And I think that's just an amazing intangible outcome that there's no number that John can show from the program that I think really can base that. Even these quality of life measures we have, I don't think really drills down to what's meaningful for the patients. I think we need to get these patient stories out there and allow them to share how they've been feeling.

John, anything you want to add to that?

No, I think Steve's absolutely right. I mean it's been transformational for patients and the burden that it lifts from their shoulders. It's not just the infusions every other day. It's not having to think about their hemophilia. It is being able to lead their life to go out and do whatever they want without having to think, to be able to go on holiday without having to pack concentrate and have to get letters from centers, just that freedom. I think people under treaters by -- historically, have hugely underestimated the burden of hemophilia. And I think it's this type of treatment, which has opened my eyes how much people carry and how much this has transformed things. I mean you use words like game changer, transformational. They do sort of underestimate how much it impacts people's lives, and it's amazing to see. It really is amazing to see it and they wander in and so on. And even, as I say, the guy -- we've got from the guy with the low results and he's doing amazingly. He's so happy. He's not bleeding. He's not on prophylaxis. He's had his joint replaced. He's gone off. He's got married. He's very happy with life.

I'm going to advise that John's sharing the examples of the guy who jumped off the bridge onto his boat. And I mean I have young guys who are challenging their clotting systems on a regular basis with their sporting activities and white boats leading to bumps and bruises and road rash. And honestly, I think I would come out worse than some of them have with some of these injuries. And actually, I think once they see that they can do well with these kinds of activities, it really emboldens them. And you just see that it's just opening up their life to them.

Yes. Absolutely. I mean one of our patients described how he felt. He said I feel like Superman now. And I think it's just all the aches and pains melt away, and they just feel that they can do things that they couldn't used to do. And I think jumping off the bridge is just tantamount to somebody -- you can say this is a bad thing, but I think it's a good thing. They've forgotten about their hemophilia. Maybe we do need to talk to people to remember it hasn't necessarily been completely sorted. But that is actually a really telling thing about burden lifting. And happily being able to lead your life, and as they go off and do mad things now, I mean, nice mad things, not completely mad things.

Things they're supposed to be doing as young people. So...

Oh, yes. I mean, suddenly, they think they can run a half marathon and do the triathlon and so on. And think I thought I can actually do it.

So with that enthusiasm in our background, when we talk about transformative therapy, these are the kinds of things that demonstrate efficacy and benefit in a relatively small number of patients, which is where we are. And you had a lot of the questions that were being asked about, have to do with questions that take years to develop answers to. So how do you talk to patients about their interest in gene therapy now? How do you manage their expectations? And what role, if any, does a Factor VIII level -- Steve, you touched on it, but maybe just be concrete about that. What role does Factor VIII level trajectory play in patient decisions? Maybe, John would want to go first?

Yes. So I think inevitably, when you're talking to patients, they've seen all the data or we talked about it. And they look at what's the average, the median or the mean and so on. But I tend to talk to people about what's the minimum they can expect. And the minimum they can expect is something that is pretty transformational because if you get -- what we're talking about is getting people off prophylaxis, reducing their burden, transforming their lives. And that's what's important. We don't need to fixate on numbers because it's a much bigger thing than a number. So it's coming off prophylaxis that is going to be the big thing, not bleeding when you do come off prophylaxis, changing your life. You can't put a number on that. So the discussion with people is not about, well, after a year, the average result is so and so and 50% of patients are above this and 50% below. It's not that. It's this is what you can expect about your life, how it's going to impact your life. So everything now, I think, is moving to lifestyle change, lifestyle benefit. And the fixation on numbers is arguably a bit artificial.

Steve, thoughts? How do you talk to patients now?

Yes. The other thing I try to explain to patients as well is that there's this tendency to extrapolate from our clinical experience in hemophilia across a broad range of factor levels, from very low sub-5% up through 15%, 25%, up into the non-hemophilic range. And the trouble with doing that is everything we know about hemophilia in those ranges of factor levels is driven by a mutant molecule. There's some sort of a mutation that has led to that level in that patient. And there's very few patients who are even in the mild range that don't have something wrong with that Factor VIII molecule. And now what we're delivering is a fully functional copy. There's no mutations. Sure, it's a truncated copy, but this is a fully functional Factor VIII molecule. And it's entirely possible. And I think sitting with the clinical experience that John showed a few slides ago, that there will be continued protection from bleeding to levels that we're not used to seeing with mutant molecules, if you like, in the context of hemophilia. So I try to encourage patients that you have a chance here with a therapy that clearly could push you into the normal range. But there's also a chance that you might actually have a much lower level. But I think the numbers here aren't really telling. It's what's going to mean for you. How is it going to change your life? And I think John's absolutely hit it. I think with great confidence, I can tell people that this is going to transform your lives regardless of where you settle out.

Great. So then that kind of bridges to a sort of a last fireside topic I wanted to raise for you all, which is understand your view of the competitive context of what's going on here. And so the way -- I thought of a way of asking this, but may or may not work. But hopefully, the discussion will be a good discussion. So the way I phrased it was if you were advising a potential competitor interested in hemophilia, what advice would you give based on this data? You could look at that as, what should I be doing next or what should I worry about. But I wondered, Steve, maybe you want to start and then, John? How do you think about the competitive landscape now?

Yes. I mean, if you go back over the legacy of attempts with gene therapy for hemophilia, you're talking about a blip of expression then that was completely lost. This is what we've now overcome with these new platform therapies. And so to have sustained expression here now over multiple years, I think, is the achievement that we were all looking for. I don't think we wanted a therapy where we were just going to have a transient expression and then lose everything. So the time frame here from a competitive landscape is, if you're going to bring another gene therapy to the forefront here, you've got to be able to deliver the safety and efficacy over what's been already demonstrated here for ROCTAVIAN.

John, you're always on the front edge of these bleeding edge things.

I think I agree with Steve. I think basically, any competitor has got to hit 4 years, and then you can start thinking about it. They've got to be at the same point with the same issues. And what we've -- as Steve said, this is not a flash in the pan. This is long-term data with long-term change. And so competitive programs have got to be able to get to 4 years before you can start to really start to think about what differences there are. At the end of the day, irrespective of the levels, let's look at how the patients are behaving. They're not bleeding. There's a 96% of reduction in their treatment requirement. And they're all off prophylaxis. Those are 3 quite significant milestones that you've got to be able to equal before you can start to think about competitiveness, I think.

Okay. Very helpful. So with that, what I'm going to do now -- Traci had pulsed out to our colleagues and gotten a lot of questions. We have vastly many more questions than we can possibly address. So what I'm going to do today is we're going to focus today's discussion on the data and not particularly commercial or pricing subject. We'll be happy to address those on our next quarterly conference call. What I'll do is I'll transmit the questions as substantially as I've read them and then open up to Steve and John. So Salveen Richter from Goldman Sachs, our first questioner, kind of builds on what we were just talking about: can you describe the profile of patients to which you expect to first administer ROCTAVIAN when and if it's commercially available? What percent of your treated patient base is there interest in trying to estimate? Steve or John, you want to take a crack at that?

Yes. Okay. I mean this is a really common question that I get asked by all sorts of people and payers as well. I think the first patients who are going to be interested in gene therapy, are those that have been looking at it for years. And as we often talk about it, it's a bit like buying an iPhone. There are some people that are really keen on it and will queue up outside the store to get it in the first day. The reality of it, if you take a step back and say who will gene therapy benefit, I think, firstly, gene therapy could benefit anybody who's eligible for this program, whether you're younger or older, whatever you do because it lifts that burden, it changes your life. So I think it's always hard to say who is the first type of patients. It's easier to say who wouldn't benefit from it. I think that's -- I think everybody would got -- has got some benefits. And what percentage of patients, in fact, that will represent? Well, I think that first I say that about 40% of our patients are really interested in hearing about gene therapy. And about 25% who would want to talk about it in considerable detail. So first off, we're talking about 1 in 4 of our patients is very interested.

Steve?

Yes. I think that estimate for interest is probably similar to what we're seeing. And then on top of that, of course, the eligibility will trim those numbers down somewhat. So I think I'm going to be practical. I look at my population of patients and suspect that maybe it's about 10% or so of patients that are going to meet all the eligibility criteria, also have the interest out of the gate. But as far as who that patient profile is, I can tell you, across all my gene therapy programs, I've dosed as young as 18 years old, and my oldest was 68 years old. There's benefits across the entire age group. You start talking about some of our older gentlemen even with legacy joint disease, for them to be able to be liberated from prophylaxis, I think, is a huge achievement. And then for the youngest guys to have a chance to just not have to think about hemophilia for however long that's going to last, I don't know what to tell an 18 year old. I don't think there's any therapy that I could think of right now that I could promise 60, 70 years of treatments. I don't think I have to promise that. What I can promise him, he can have a long window here where he's not going to have to think about his hemophilia. And I think that gets people excited.

Yes. And sometimes, these sort of things are really telling. One of our older patients needed to have his cataract done, and there was no fuss about that we have normally put in place with other cataracts. They're low bleeding operations. He basically waltzed in, had it done, and waltzed out, much like any normal patient. And he was gobsmacked, frankly, that could happen to him. So that's interesting. That's really nice to see.

All right. The next question comes from Robyn Karnauskas at SunTrust for both of you. And I'm going to bring into the conversation this question once. This question can be asked 450,000 different ways. I've gotten 440,000 versions of the same question. So we do it once. Here we go. What are your thoughts on the decrease in factor activity levels between years 3 and 4? And how much of a concern is patient-to-patient variability, particularly based on the Factor VIII activity levels they've seen with the data from the pivotal trial?

Well, maybe I'll start with patient variability. We -- anybody who's worked with Factor VIII knew we were going to see broad variability amongst patients. You're expressing at a steady state out of the cell. And whatever the natural clearances of Factor VIII for that patient is going to determine the steady state level. If we infuse Factor VIII in patients, we see a fourfold variation in half-life and therefore, a four-fold range of what you would expect to achieve in a steady-state level from gene therapy. And that's not taking into account any of the nuances of the transduction and the intracellular mechanisms of expression, et cetera. So the fact that there's variability across the hem A program, I think it is a given. We would have expected that. So that's not so much related to the treatment. It's the profile of patients. We're always going to have this big spreads, some who are going to be at the upper ranges and some who are going to be at the lower ranges. The drop over time that has been observed, I think what I remain encouraged of is there doesn't appear to be any impact on the clinically meaningful or patient important outcome measures for these patients. They're not bleeding. They're not needing additional factor. They're still feeling great about their transformed lives. And I think it's a mistake to try to extrapolate a trajectory from these curves because that doesn't represent what we're seeing in the clinical expression in these patients.

John, anything to add?

Well, not really. I think Steve's covered it fantastically and pretty much mirrored what I would say and feel as well. Variability is inevitable. We see variability across all gene therapy programs, and there's lots to understand why. And as we see variability with standard Factor VIII. And I think that, again, the year 3, 4, it's a shallow change but what has been maintained is the transformation of patients' lives, which is actually what matters.

Okay. I'm going to -- I'm going to give you guys a 1-minute break and I'm going to take a question from Matthew Harrison from Morgan Stanley. It looks like you only had 6 patients in the data set versus 7 last year. What happened to the seventh patient? Can you comment how the factor levels could be impacted if you added that patient back in? Would that imply a dramatically different slope? The patient #7, good catch, Matthew, there was a COVID-related delay. We've done the analysis in a lot of different ways. This particular analysis just happened to drop the patient out. If you do observation carry forward or don't even replace the data just treated as 0. Instead of it being 24/16, it's like 21/15. So it has essentially negligible impact on calculated slopes. And I think one of the important things that I just picked up from Steve and John's comments are sloped to what end. We don't know where that end point is, and for the reasons that Steve just articulated, that number could be lower with a normally functioning, normally regulated Factor VIII expressed compared to mutated Factor VIII genes. So it's going to take observations to directly correlate changing Factor VIII levels. Another point that John made also about the trajectory that we're talking about is the population trajectory, the people -- the population trajectory is driven by the high people there that have -- if you look at the scatter plot that John showed, it's the high people that are moving down the most. So those low guys are hanging in there. And it's conceivably possible that we'll be entirely flat when we go forward. That was my question. So now I'm going to go back to you guys. Chris Raymond from Piper talked -- wants you to talk about how defensible you think this therapy is in the context of other Factor VIII gene therapies? For example, if Pfizer were to show a good curve tomorrow or any other gene therapy, Factor VIII curves, how do you react to that? I think we covered this a little bit, but I just want to zero in on Chris' question. If they show good data tomorrow, how do we think about that?

Well, we can compare it to what we saw previously. I mean, at the end of the day, what we're saying is we need to be in the same place at the same time in 4 years. Other than that, we are speculating.

Steve, anything to add?

No, not really. I mean we're talking about handfuls of patients here, right? Phase III studies are really going to tell the tale. They're going to give us the breadth of the variability across patients. And it's going to build on the durability that's been shown from the Phase I/II. So I think you can only compare the apples to apples here. And so you're just going to be limited to a dozen patients or less.

Next question comes from Cory Kasimov from JPMorgan on a topic that we've touched on, but I think it gives us an opportunity to think about the question a little bit more, too. Can you describe the impact you believe that valrox has on a lifestyle of severe hemophilia patients and because you talked about jumping off boats and playing sports, it seems they're likely living a much more normal life. But I want to add a little spice to this question because I was struck by John's comment. I don't think we as hemophilia clinicians fully appreciated the burden. We're seeing patient after day -- patients after patients in there. Then you just sort of get acclimated to, that's where you are. So maybe talk about the transformation for your own selves and how that pertains to the transformation of patients.

Yes. I mean you have to remember that most of the people coming into these programs have had decades of caregiving by their well-meaning moms and dads trying to protect them, cautions during their adolescence years. They probably learned as they got older, if they had legacy joint disease, oh, I can't do that or I can't go on that hike or I can't do that climb because I know that's going to manifest with a bleed afterwards despite my best intention. This is what they all came into these programs with. And so when they start pushing the envelope, they're trying to retest what their bodies can do. And I don't discourage them in that regard. I think they need to find out, do they have new limitations?

Yes. I think it's really -- it's one of the great benefits of gene therapy, is to give people an opportunity to spread their wings and find out what they can do. And I'd say, I certainly feel that, for years, I underestimated the burden. I first saw it with EHLs when people would go down from alternate day treatment with Factor VIII to twice a week and often say, really, does that make that much difference, it's one injection less a fortnight almost type of thing and then say it's a huge difference. And so going from twice a week or 3 times a week to nothing, I mean that's just amazing.

Great. Now Geoff Meacham from Bank of America wants to ask how does this update your -- how does this update affect your thinking about a potential lower dose option? I mean can you envision a world where people just say, I'm going to -- I know the prescribed dose is 6, but I'm going to give 4?

Well, we're going to see which way -- how things play out in the long term, but I'm very much somebody who sticks to the data. When you start fiddling with doses and changing things, you can't guarantee where you're going to end up necessarily. So -- and we've seen that in hemophilia with some of the EHLs that things get changed as you think you might be able to get away with it and you end up with a completely different picture. I wouldn't do that.

Steve?

You got to stick with the data, and there has to be a rationale why you would want the lower dose. Is there something that you're trying to avoid with the higher dose? I think you're going to have a huge database to share with us in another year or 2 from the Phase III program at the 6E13 and I think that's going to really help guide us going forward even after, hopefully, an approval for this product. Later, we're going to get all that additional data that I think will really help guide the clinicians going forward.

And I would add something we've talked about in different context. I mean, in the one-and-done context, you have to be exceptionally careful about that because you don't have a -- it's not like you can go back and give the other 2 E13 a couple of weeks if you didn't like the outcome. Okay. Michelle Gilson from Canaccord has a question that you're going to love, John. You zeroed in on this as well. So the question is there was one patient 7 on the slide that appear to have a higher Factor VIII activity than patient 6 in the last update, 156 weeks, 11 versus 4 [per] deciliter who now appears to have dropped the lower limit of quantification. Is there anything unique about this patient, his factor activities, his lifestyle? Also appears his low factor activity did not translate to bleeding. How do you interpret all that?

Okay. So basically, you do get some variation in Factor VIII levels, and this guy, by chance, came in to have his [ 208 ] week sample, and it came in below the lower limit of quantitation. We got him back a couple of days later, and it was actually much higher. And he runs along a significantly higher level than that. And you do see some variation. He isn't actually long-term running at that level. So it was just a one-off fluke for that individual day. You do see variation in these patients for some days. I mean we see variations in us, we shouldn't -- we could argue that we wouldn't necessarily expect to see it. But as Steve said, there are so many other things that control Factor VIII that could change from day-to-day. That you will get some variation. But he isn't actually long-term running at that level.

So he didn't come into the clinic and go, "Hey, Professor Pasi, my Factor VIII level plunged. I'm breaking through bleeding left and right here. What happened?"

No, he didn't. What happened, we saw the results and said do you want to come back and get you redone. We think -- we don't think it's right. He said, okay. So he came back and we redid. He said, yes, it wasn't right.

And phenotypically, how is the patient -- how was the patient clinically?

Well, he was fine. It made absolutely no difference at all. He works in a cinema, a cinema manager, and he was too busy with some major blockbuster over the time. So he just went on with his life.

All right. Phil Nadeau from Cowen has a question. How rapidly do you think ROCTAVIAN will be adopted? Who are the most appropriate patients? And how does this thing get started in terms of going first? I think we talked about this a little bit, but maybe a little bit more. Like who has been expressing interest? Maybe, John, you want to start.

Yes. So we've got a lot of patients who've seen the data and increasingly encouraging to say, 4 out of 10 wants to talk about it. 25% wants to talk about it in a lot more detail after they've heard more. I think the idea that you can be off prophy, not bleeding is really appealing to people. And the patients that are really interested in it come from all age groups that we've talked about. So I think it is a treatment because it's once and done, that patients need to be engaged in and need to want to do it. This is not something we're going to be going around saying you definitely need to have gene therapy because there's so many unknowns attached to gene therapy in general that it is a joint decision that you work through. So I think that's the sort of patients that we'll be talking about first. The cop-out for me always is that we won't be the first probably to use it commercially because we're the NHS. And we don't spend money on anything. But I -- yes, well, yes, exactly 50p a day. Well, that's a bit pricey. But we will have lots of people knocking at the door, saying can we sit down and talk about this? And that is without a doubt.

Steve, anything to add?

No, I think that's exactly what it's going to be like. I mean we've been maybe more proactive than some centers perhaps because we've been talking about this. I mean I have regular interactions with patients getting seminars and things like that, talking about these therapies. And so they know that it's coming. And we've also had some regional impact. And I've had many referrals from across our state from my colleagues of patients interested in gene therapy. So I mean postclinical trial phase, I'm sure they'll be able to pursue this through their own centers if they follow all the checklist to get up and running. So -- but I think the shared decision-making is really a key part of what we do at the hemophilia treatment centers all the time. Every time there's been a new wave of therapy, this is what we've gone through. We did this with extended half-life. We did this with HEMLIBRA, and now we're going to do it with gene therapy. And I'm sometimes surprised that the decisions patients made, people who I thought wouldn't be interested are, and others who I thought would be a great candidate, they said, "You know what, for these reasons, I'm very happy with what I'm doing right now." So that's what we're there for, to make sure they have the right data and that we can help guide them as best we can.

Marty Auster from Crédit Suisse asks, based on this presentation, there are 2 patients who had Factor VIII expression levels lower than 5%. How do you think about the criteria for recommending when to recommence prophylactic therapy? Is that a numbers thing? What is that?

It's definitely not a numbers thing. It's a how-you-function thing. You can't -- we're different here because we've got a normal nonmutant protein that is -- so we need to look at how the patients are functioning, how they're behaving in terms of bleeding phenotypically. So I think it's going to be a clinical decision. It's just not going to be a numbers game.

Steve, anything to add?

The only thing is that we may have some experience with patients who have legacy joint issues, maybe a target joint, and they may have experienced that if their Factor level drops below a certain threshold, they consistently have spontaneous bleeding. I guess we need to retest that post-gene therapy to see if that level still holds up. And if that's the case, we may have to talk about some other options because, if all their other joints are not bleeding and just this legacy disease joint, maybe there's other options that are open there to get that joint taken care of, and maybe that's the end of their bleeding.

Yes, absolutely. I mean, arthroplasty, if possible, give them a new joint, it will stop the bleeding. It's not all about Factor VIII in that situation.

Well, so in that regard then, especially John, because you've been on top of some of these patients for the longest, are you seeing anybody that's getting close to resuming? Have you started to have the conversation? I mean...

No. No, we haven't. I mean it's a very simple short answer. We've got one of the patients at the lowest end. And as I say, he's very happy. He's not bleeding. His level's pretty stable. He's off prophy. We have not had that discussion nor have we needed to even consider it.

That was a question, by the way, from Liana Moussatos from Wedbush. Sorry Steve, you were going to...

No. That was it.

Okay. Ellie Merle from Cantor Fitzgerald, what do you think hypothetically would be the clinical relevant implications of a Factor VIII level of a chromogenic Factor VIII level in the normal range versus in the 15% to 25% range if these lower levels below normal seem to be largely eliminating need for prophylactic therapy and eliminating bleeds?

Yes. It's an interesting question. I'm actually giving a talk tomorrow about managing expectations in patients with hemophilia considering gene therapy, and this is actually one of the points that I've put on one of the slides because these 2 patients, if you've got a normal level or if you've got 15% to 25%, you're not going to notice any difference day to day. They're not on treatment. They're not bleeding. And they've got no sort of major issues at all. The only difference would be if a person of 15% to 25% had to have major significant surgery or had a significant injury, so which could happen to all of us, and it's completely random. Other than that, these guys are going to look incredibly the same.

Steve, anything to add?

I think this becomes more of a problem for me as a treater than for the patient. If I've got a patient who's running 35%, 40% on the chromogenic, but on his one-stage, he's 65%, the question's going to come up, let's say, he needs surgery. The surgeons are going to ask me, do we have to give them factor before the procedure. And I won't know off-hand until I have a much broader experience in caring for these patients longitudinally, and it could be very individualized. But we have the luxury of being able to do that. We have these connections with these families. We're following them over a very long periods of time. So I'll learn that on an individual basis. But to pick a number and say this patient always has to have an infusion now because they're at this level by chromogenic or they're at this level by one-stage. I don't know how we can say that. We need to relearn all these clinical correlates according to the assays we have available to us in the post-gene therapy world. And it's going to be interesting to see what happens.

There's a lot of learning here because there's a lot of new stuff coming out. It's not just the numbers. It's not just how the patient is behaving. There's a lot of other implications and theoretical stuff that we've got to get our heads around, as Steve said.

Well, so actually, Gena Wang from Barclays, her -- the next question actually follows this quite nicely for patients. She asked it very specifically, and maybe it'd be better to address it more generally. But for patients who have had Factor VIII use, can you elaborate on what condition level of endogenous Factor VIII and surgical procedure and how much Factor VIII is used and how many times and what happened after? I guess maybe more generally, like how the surgery has gone that you've seen.

So they've been fine. And what we found is that it's like operating on patients with mild hemophilia in the main. And we found that they probably needed less treatment generally. It's been very straightforward. We've managed them pretty much as we would any other patient with a factor level that's equivalent. And it -- there's really not a lot to say. It's not hard to do it. And does it seem particularly different? No, it seems a bit easier maybe, but that's completely anecdotal.

Steve?

Yes. I think single infusion precautionary to cover for a surgery until you've developed the longitudinal follow-up with the patient. I mean, that's just practicing good medicine in my opinion. We're all about protecting from bleeding because of the complications that can ensue. And so I think I would definitely in the early days until I really knew how our individual patient was behaving and how they handled other challenges, I'm probably going to err on the side of covering them maybe with a single dose of factor for those kinds of procedures.

Two more questions. Mohit Bansal from Citi asks we -- it's a little subject twist. We've used both on-demand steroids and prophylactic steroids. Check on us on loops. Do you have any personal preferences to offer?

I don't think we know at the moment. This is an open question, which is better. And we don't -- we spend a lot time thinking about this. So I can't give an answer to that.

Steve?

Yes. I don't think I could give an answer based on the Phase I/II data. I think the Phase III was structured in a reactive steroid modality. We're going to have a huge database to evaluate. And I guess I would just say, personally, at the end of the day, if the vast majority of individuals end up on steroid anyways, then I think it's at least reasonable to consider whether prophylactic steroids could be used in the post-authorization phase. Doesn't have to be necessarily driven exactly by the clinical trial experience. But I also want to be cautious that there are some patients who may want to avoid steroids. And so maybe we'll have that option, use both a reactive and a prophylactic approach. But I don't think we're going to know now just based on the Phase I/II data.

Yes, the -- I mean we've got 7 patients who essentially have prophylactic steroids, and 6 patients who are treated reactively in the Phase I. Now it's not enough to make a decision.

Yes. So final question. George Farmer from BMO asks, and we touched on this a little bit, but it's a good maybe last lap question. Would you prescribe valrox or some other gene therapy even if you knew that rescue medications like Factor VIII or HEMLIBRA would be required 5 or 6 years from now?

I think that's for an individual patient to be posed that question. And we do talk about what would happen because I have to be open with them. What if they had a really vigorous immune reaction and they did lose their expression despite our best attempt at management, what would be their options afterwards? And I'm really thankful, we've got fantastic options for treating patients. And so I think that is a part of the risk-benefit equation that each patient has to evaluate when we have that shared decision-making discussion.

Yes, absolutely. I mean, it is something that comes up when you're talking to patients about gene therapy, saying I don't know how long it will last. And so we do say well, what happens if it lasts 3 years or 4 years or 5 years. This is in the early days of the trial, and we had no idea where we were going, what the results would be, absolutely no idea. And the view of pretty much all the patients went through, admittedly, they're going through it as a trial rather than this commercial option was, well, if I get 3 or 4 years off or 2 years off, that's a wonderful holiday for me, and I will enjoy it and make the most of it. It is going to be about personal decision. And as we go through when it's commercialized, we'll have much greater data. But as we've just heard, and as Steve had said, this is a part of the discussion, and it's something that people will need to consider as individuals, what is their expectation.

I had a patient say to me once, if I'm only going to get a decade from gene therapy, let me be the one to decide what decade I choose. Am I going to choose that right out of the gate at 18 and cover all of my college and my early work years establishing my career or am I going to cover it when I'm at the back end of my work life when I want to enjoy my latter years, play with my grandkids, et cetera? Is that the decade that I want for coverage?

Or when they're having kids themselves.

Or when they're having kids themselves, exactly. Do I want to be able to keep bending over every day and pick up my little baby? So that's the wonderful thing about this platform. Let them choose. Let them decide what's going to fit their life and what's going to give them the outcome that they're looking for.

Sure. Of course, they have to do the hard work of figuring out if there's -- what's coming up later and when is that going to be and how do I handicap all that. Anyway, I could talk to you guys forever, and it's been a wonderful hour, and I'm sure that you guys are exhausted from answering questions about Factor VIII trajectories. So I think with that, that we're going to come to a conclusion on today's Zoom. Follow-up, John, thank you very much for your leadership and your inspiration and for your presentation. Steve, thank you very much for your leadership and your collaboration and your wisdom. And with that, everybody, I wish you all a very good day. Thanks.

Thank you.

Thanks so much.