Unidentified Analyst: Hi, this is James on for Paul. Thanks for taking our question. Just one more on the lecanemab subcu and specifically in treatment-naive patients. Just wondering if you’re confident that you have enough data from a regulatory perspective here, if you’ve aligned with regulators, you and Eisai aligned with regulators and specifically, if you have enough safety data in that treatment-naive patient population? Any color there would be great. Thanks.
Priya Singhal: So yes, overall, this has been a topic that we’ve discussed Eisai and Biogen have discussed with the FDA. And just to step back, the design was to add a sub-study, a subcutaneous sub-study in the Phase III CLARITY study open-label extension, and the cohort that was treatment naive from lecanemab was about 72 patients. And then there was a whole cohort of 322 additional patients that provided safety and tolerability. So this was — the 72 patients is the premise for the PK/PD and bioequivalents. But there’s a larger subset of data that speaks to the safety data. So yes, discussions are ongoing, but overall, these have been discussed with regulators prior to starting them. Thank you.
Chuck Triano: Thanks, Priya. Next question, please.
Operator: We’ll go next to Phil Nadeau with TD Cowen.
Phil Nadeau: Good morning. Question on SKYCLARYS following last night’s approval in the EU. Chris highlighted the importance of the U.S. markets. Could you discuss the expected cadence and trajectory of SKYCLARYS’ launch outside the U.S. and Europe, in particular, when will be available in the major territories? And would you expect the uptake in those major territories to be as fast as it has been here in the United States? Thanks.
Chris Viehbacher: So there’s two aspects, I guess, to the launch. One is the early access programs and the other is the former launch. So for example, we’ll be able to launch now in Germany with this approval. So we will — this will be a formal launch. We still have an early access program and any patients on that will now convert to commercial patients. remembering that actually, the patients in early access programs in Europe are expected to be revenue generating for the most part. We have another program that’s up and running in France. And we are negotiating the establishment of early access programs in two other European countries, and there are some early access programs under discussion in countries outside of the EU.
And the early access program is important because as we all know, in Europe, getting pricing and reimbursement can take some time. So it’s a little hard to predict just because we have to understand the cadence of these early access programs. So I would expect that it’s not going to be quite as fast as it was in the U.S. That said, there is some suggestion that there are some patients, the warehousing effect could well be in Europe, but as I said and as a general matter, just because of the time to get reimbursement all increase in the fact that we are not going to be able to have early access programs in all countries that, that will be a slower uptake than in the U.S. That said, there’s also probably more patients actually per capita. Remember, this is a disease that is related to European descent.
And so the incidence of Friedreich’’s ataxia is slightly higher in Europe than it’s in U.S. The next big market opportunity to be Latin America, and we are submitting in Brazil and perhaps, Priya, you can give us an update on the regulatory time lines there.
Priya Singhal: Yes. I can comment on the fact that really, we are trying to expedite our regulatory filings in Latin America, Brazil, Argentina. We haven’t yet communicated the time lines, but our teams are working very expeditiously, meeting with regulators to really define the pathways that could provide earliest access to patients.
Chris Viehbacher: We estimate, it’s hard to get the numbers precisely, but we do estimate there’s around 2,000 to 4,000 patients in Latin America. So — and when we look at the experience of SPINRAZA, we are expecting particularly Latin America to contribute substantially to our revenue outlook as well. As you know, there are very few patients in Asia just because of the genetics. So we don’t intend to be filing or launching in Asia.
Chuck Triano: Great, thank you. Next question, please.
Operator: We’ll go next to Michael Yee with Jefferies.
Michael Yee: Thanks. We had a question on SKYCLARYS. Can you may be shed some more light on the dynamics of 800 patients to 1,000? And then the trajectory as we go forward into 2024, I know you mentioned there’s about 4,000 patients, but how many of those are actually identified. Do you expect growth to moderate just from an expectation standpoint? Talk a little bit about the complexities in 2024 that you commented about. Thank you.
Chris Viehbacher: Yes. Thanks, Michael. Certainly, the growth is going to moderate. Remember, this was — when this product was in hands of Reata, they had approval. I think it was back in the first quarter. I think it was February, if I remember accurately. And — but they were not able to commercially launch because of a manufacturing specification issue. So — and that did not get cleared until July. So in other words, the market and physicians knew the product would be coming to the market that it was approved, and they were just waiting for product availability. So I think the warehousing effect was even greater than what you would normally see for any rare disease drug. Now we’re back into the process of finding the patients.
I have to say the Friedreich’’s Ataxia Research Alliance, otherwise known as FARA, is an extraordinarily effective patient association and we’re working with them to help identify patients. There is a requirement really to diagnose a patient accurately a genetic test. But this genetic test is not sold readily available. And so we’re having to look and make sure that the supplier of that test can make the tests readily available. And then we’re also doing the contracting really to make sure that as patients have start forms that they can quickly get on drug. So we’ll be back to, I think, a regular growth cadence on SKYCLARYS in the U.S. I don’t think we’re necessarily going to get another 20% this year. but we’re growing every month. And certainly, SKYCLARYS is contributing significantly to our return to growth in 2024.
Chuck Triano: Great. Thank you, Chris. Let’s move to our next question, please.
Operator: We’ll go next to Colin Bristow with UBS.
Colin Bristow: Hey, good morning. Thanks for taking the questions. I just wanted to clarify something in your slides that says that the subcu that we can be filing is now first-half of ‘24. But in your commentary, it sounds like it’s still 24, so if you could just clarify that? And just talk to specifically what FDA is waiting to see, I think it was a 12-month data last time we spoke. What is it within that? And then maybe just as a follow-on, you had three, four, five study, what is the timing or thresholds for any interim analysis there? A – Priya Singhal I can get started. So overall, I think with the subcutaneous, just to be very clear, Eisai has communicated as recently as their earnings a few days ago that we aim to file by Q1 2024, which is end of the first quarter this year.
And just shifting gears to AHEAD 3-45, this is really a platform — a set of platform trials with different amyloid levels for defining preclinical Alzheimer’s disease. So at a very high level, A45 is preclinical Alzheimer’s disease with an enrollment target of 1,000 patients, and patients need to have an amyloid level of 40 centiloids or more. There’s three phases of dosing with different doses, which is titration, induction and maintenance. And in this particular trial, the outcome is a PAC 5, which is a preclinical composite for Alzheimer’s disease, where it’s sensitive to patients who are still in the preclinical phase. The A3 trial is — has a target enrollment of about 400 million and the preclinical amyloid cutoff is between 20 and 40 centiloids.
And then again, it’s got a different holding schedule of titration and then maintenance. Now the primary endpoint for the A3 trial is really a biomarker endpoint. We haven’t really communicated exact time lines. These are very large trials. I think the Eisai and Biogen are very pleased with how they are being enrolled. And I think we’ll communicate more. There is an opportunity to do an interim analysis and Eisai has spoken to this, but we haven’t communicated a time line yet.
Chuck Triano: And Colin, just a quick note on slide 28, right. The docs that does show Q1, right? We wording says expected mid-year, if there’s something sort of in the middle of the year. So I get the confusion because it says half one, half two, but the dots are kind of at the end of the quarter there. So if you were looking at — see if there was a disconnect, there’s not it is. They have said in the end of March is what we’re looking at here. So Priya…
Priya Singhal: I think there was the latter part of the question. I’ll just wrap it up that with regards to FDA, I think I mentioned previously, there have been a lot of discussions. Eisai has recently mentioned the scheduling of more meeting another meeting. And so that strategy will be finalized. Looking at the 6-month data, we are very encouraged with what we saw. We believe that the highest threshold, really, the biggest hurdle was to meet bioequivalence, which we believe we’ve met. So we’ll continue to wait for more data. But we are very encouraged with what we’ve seen so far.
Chuck Triano: All right. Thank you, Priya. Let’s go to our next questioner.
Operator: We’ll go next to Chris Raymond with Piper Sandler.
Chris Raymond: Hey, thanks. I wanted to maybe circle back on the Angelman program, and I wanted to understand a little bit better previous commentary around the program. Can you maybe clarify the calculus that goes into deciding to participate in future development. And obviously, there’s a competitive approach with Ultragenyx’s program. Curious how you’re thinking about approvable endpoints? That’s obviously been a big question mark. And how you think this product, if successful, would sort of compare and any sort of commentary there in terms of the competitive set? Thanks.
Priya Singhal: Sure, sure. So overall, just to step back, this is a program that Ionis, our partner, is operationalizing and the way the contractual agreements are written, we have the option of opting in to take the data that we see midyear and decide whether we would like to do a pivotal program — a pivotal study. So that’s how it’s set up. And then to step back, I described it briefly in my opening remarks that this is a Phase Ib trial. So this is a Phase I trial that’s being conducted in patients. It has a multiple ascending dose component for three months, followed by a long-term extension. So we will get data. This is across different age groups and different doses. So we’ll get a composite of data. And importantly, we’ll be looking or trends on EEG, which we know these patients suffer from the delta waves as I spoke to, the slowing.
