So that’s another dynamic that could just draw the disconnect that you mentioned. And then perhaps to the first point, there’s some unique aspects right now with the supply constraint. We are managing through the supply constraint by managing orders at the specific market and SKU level and that’s going to throw the trends off a little bit. You might recall back in Q4 where we reported revenues over our guidance, not because we overperformed on patient additions, but because some additional supply became available, and so we shipped it into the market. So we’ll ask you to stay tuned. We’re trying to provide the right metrics in terms of patients and ask you to follow revenues to watch those trends. It’s a great question, but it is dynamic. And just give me a thumbs up, so we’re covered.
And that there was a gene therapy question, whether the divestiture is an option.
Alexander Hardy: Yes. Thanks for the question on ROCTAVIAN divestment. As I mentioned before, our focus right now is making sure that we really establish what the ROCTAVIAN opportunity is, and we really focused our strategy around that. I talked already about the possible outcomes of our assessment. And one of them could be that we remove it from the portfolio and divest, that is not our focus right now. We are not engaging with people around the divestment of ROCTAVIAN. Our focus is really on establishing on the opportunity right now. But should we remove it from the portfolio, we will absolutely look at the options around divesting it.
Operator: We’ll go next to Jessica Fye at JPMorgan.
Jessica Fye: Hey, guys. Good afternoon. On the pipeline, can you talk a little more about the long-acting CNP product you’re prioritizing? What’s the half-life there and the dosing frequency you’re contemplating? And then just a quick one on BMN 293, the gene therapy for hypertrophic cardiomyopathy. Is that one staying or going, I don’t know if I caught it in the list? Thank you.
Henry Fuchs: I guess, long-acting, we have every reason to believe that the dosing interval there could be as long as weekly. But obviously, that’s going to be informed by early human clinical trials to actually measure what that dosing frequency is going to be. On 293, that’s a program we want to gather a little bit more information. We recently learned that there is a population of patients with C3 deficiency in hypertrophic cardiomyopathy, who are very severely affected with really poor outcomes as measured, for example, by short time to left ventricular assist devices or mortality. And we are actively working with investigators to understand better how findable those patients are and how interested and motivated those patients are.
And finally, whether there’s a regulatory pathway to a faster approval by virtue of the severity of their condition. As we learned, the more significant the medical, the unmet need is, the more motivation there can be for the uptake of these novel disruptive types of therapy. So that’s the additional information we’re gathering and we’ll keep you informed as to decisions that we make about further advancement of 293.
Jessica Fye: Thank you.
Operator: We’ll go next to Joseph Schwartz at Leerink Partners.
Joseph Schwartz: Great. Thanks very much. I was wondering, can we infer anything from the amount of savings that you expect to realize as a result of the strategic portfolio assessment of R&D programs, which you announced today about the amount of operating expense savings, which might be realized as a result of the remainder of the strategic and operating assessment, which is ongoing. Can you give us any insight into the relative degree of operating expense savings, which might remain to be realized relative to what you announced today, even if it’s just a general order of magnitude?
Brian Mueller: Yeah. Thanks a lot, Joe. It’s a really good question. Given we talked today about the financial impact of what was a discrete clear eye view on the portfolio. The financial repercussions and the net reduced R&D were a consequence of that portfolio review, not the purpose. And that — from there, I would not make an inference on what the future potential savings are for two reasons. This was a review, top to bottom of the current portfolio. And again, a consequence but also the strategic review and the remaining optimization of the business is work in process. So we’ll have to put that latter part in the category of stay tuned for Investor Day to hear both the strategy, both top level business strategy, operational excellent strategy, long-term guidance. And we’ll get color on all the line items, how we’ll plan to be more efficient on cost. But the heart of your question, I would not make that influence today.
Joseph Schwartz: Okay. Thank you.
Operator: Our next question comes from Gena Wang at Barclays.
Gena Wang: Thank you for taking my questions. I have one regarding ROCTAVIAN revenue of $0.8 million in the quarter. We also, together with, I believe, many investors did due diligence regarding exactly how many patients got treated in the first quarter. So based on our due diligence, we understand that Germany actually there’s no patient got treated and as some investors they are due diligent believe there a few patients got treated in the U.S. So the question here is $0.8 million. Can you remind us where that revenue is from? And also at what point the timing for you to recognize revenue as well as pay for performance, the warrant at what point you booked this? My understanding previously was gross to net, but I just want to make sure.
Jeffrey Ajer: Hi, Gena. Jeff here. Yes. We are aware and have heard of some survey or due diligence work by yourself and others, but without knowing the methodology and so forth of the survey results we can’t really speak to them specifically. We can speak to our revenues. So in the press release, it was noted that first patient was treated in Italy, and the revenue that you see in Q1 is tied to that first patient in Italy. Revenue recognition varies a little bit by market. But essentially, Gena, we can tell when product is shipped to patients, we’re scoring revenue right around that treatment of patients. And so if your question is, is it likely that there’s been a bunch of patients treated, and we’re not seeing that in our prepared remarks or revenue. I think the answer is no. And maybe Brian could make some further remarks about revenue recognition.
Brian Mueller: Yeah. I think you’ve got it right, Jeff. Thank you. Maybe just noting the nuance in Italy is that Italy happens to be a market where title transfer and revenue recognition occurs before the actual dosing of the patient, hence, the March revenue and the first week of April treatment. I’ll share that in other key markets like the U.S. and Germany, the revenue recognition and Title Transfer is much closer, if not at the point of infusion.
Operator: We’ll go next to Ellie Merle at UBS.
Ellie Merle: Hey, guys. Thanks for taking my question. Can you help us understand how you’re thinking about the relative size of the opportunities between ISS and genetic short stature pathways? And also as well as the level of clinical risk or clinical validation from the data that you’ve seen from these to-date between the two of these planned studies and just help us understand how you’re thinking about the biology and confidence in activity in ISS as well as the genetic for stature pathways.
Henry Fuchs: Maybe I’ll start on the R&D science piece, and then I’ll look for help from Alexander on the market sizing kinds of pieces. I can say a little bit about things like epidemiology. But from an R&D perspective, our confidence that CNP is going to work in conditions beyond hypochondroplasia is driven by genetics, and we’ve talked about where patients who had humans who have gain of function mutations in the CNP pathway or taller than their predicted final adult high would be in patients who have negative mutations are shorter. So these are human, if you will, proof of concepts about exposure. There are also individuals who are extremely toll to have gain-of-function mutations in NPR2 or who are — or in its receptor.
So a lot of biological data, but what’s new now is, we’re days away from Dr. Dauber presenting his first 12-month cohort of using VOXZOGO to treat patients with either pathway conditions, in his case, Noonan syndrome or with things that were formerly known as idiopathic short stature because that term got coined before sequencing helped us to understand that specific mutations could be accountable for what was formerly known as idiopathic short stature and had an opportunity as has the Food and Drug Administration to review those emerging data, which led them and us to conclude that there is a great prospect for benefit with vosoritide and the treatment of these relatively more common conditions. So you’ve heard me talk about idiopathic short stature in terms of the volume of people who are available.
It’s something like two standard deviations below average stature encompasses 2.5% of the basically the human population. So we’re talking about some is a fairly large potential indication. I don’t know if Alexander you want to add anything more about that.
Alexander Hardy: In terms of the size of these future indications. JPMorgan, we talked about how the indications beyond [indiscernible] so hypochondroplasia, ISS and Noonan’s, Turners, shocks in total, represent about 600,000 patients and compared to the global addressable population for achondroplasia of 21,000. We’re obviously going to be, and I just want to highlight this that we’re going to be going for a more severe patient population in, for example, idiopathic short stature editions. And you’ll see if you go on clinicaltrials.gov it’s actually posted today, you’ll see the design of our Phase II study in ISS. So we’ll share more at Investor Day about the TAMs for all the different indications. They represent significant multiyear growth potentials for VOXZOGO.
And it’s really exciting to see and being able to share today not just the R&D prioritization but the progress we’re making with VOXZOGO, not just the uptake, which is really exciting to see in achondroplasia globally with growth accelerating, but we’ve had really productive conversations with regulatory authorities. We have definite plans now solidified heard from the feedback from the FDA on ISS. We have clarity now of the duration of the study, endpoints comparator. We have a very clear path forward in multiple of these indications and an opportunity to bring VOXZOGO to so many more patients around the world.
Ellie Merle: Great.
Operator: We’ll go next to Paul Matteis at Stifel.
Paul Matteis: Thanks so much. I was curious what the management team’s current thinking is on the various competitors are in achondroplasia given that we’re going to get data from a couple this year. And as you think about potentially, and I don’t know if it’s exactly potentially giving margins guidance or commentary aspirations at the Investor Day, it feels like whether or not there is competition into achondroplasia is a key variable. So I would love your perspective on that. Thank you.
Alexander Hardy: Yeah. Thanks very much for the question. Paul, I really do appreciate it. Overall, we’re feeling very good about where we are in achondroplasia and now with the path forward in all these other indications starting to become really quite clear from us — for us. Demand and the feedback from families is excellent. We see really good assistance and adherence to VOXZOGO. And we’re really — every day that we’re on the market, clearly, we now have over 3,000 patients now on VOXZOGO. We’re really establishing a safety and efficacy profile that gives a lot of confidence to physicians to prescribe the product and also family members and parents, children now infants beginning treatment. I think from our perspective, we’ve done extensive market research, we really understand these disease states.
