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Good morning. My name is Katie and I will be your conference operator today. At this time, I would like to welcome everyone to the Biogen Fourth Quarter and Full-Year 2023 Earnings Call and Business Update. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. [Operator Instructions] Today's conference is being recorded. Thank you. I would now like to turn the conference over to Mr. Chuck Triano, Head of Investor Relations. Mr. Triano, you may begin your conference.

Thank you, Katie. Good morning and welcome to Biogen's fourth quarter and full-year 2023 earnings call. Before we begin, I'll remind you that the earnings release and related financial tables including our GAAP financial measures and a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today are located in the Investors section of biogen.com. Our GAAP financials are provided in tables 1 and 2, and table 4 includes a reconciliation of our GAAP to non-GAAP financial results. We believe non-GAAP financial results better represent the ongoing economics of our business and reflect how we manage the business internally. We have also posted the slides on our website that will be used during this call. I would like to point out also that we will be making forward-looking statements, which are based on our expectations. These statements are subject to certain risks and uncertainties and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail. On today's call, I'm joined by our President and Chief Executive Officer, Chris Viehbacher; Dr. Priya Singhal, Head of Development; and our CFO, Mike McDonnell. Chris, Priya, and Mike will each make some opening comments and then we'll move to the Q&A session. To allow us to get through as many questions as possible, we ask that you limit yourself to one question. With that, I’ll now turn the call over to Chris.

Thank you, Chuck. Good morning, everybody. A year ago, I had the -- an opportunity of presenting Biogen's quarterly results for the first time. At that time, we expressed the objective of returning Biogen to sustainable growth. And I think in the intervening year we've made substantial progress and today it is a great amount of pride and pleasure that we can announce earnings guidance, which Mike will go into in greater detail, which says that we will -- we are expecting to see positive earnings per share growth. And as I have said on a number of occasions, once we can get Biogen growing, we really see it Biogen becoming a growth company for the foreseeable future. We have very little, if we have in fact no exposure to Inflation Reduction Act with our current portfolio. We don't have any new patent expiries really coming in anytime soon other than those that are already known. And I think we've undertaken a number of other measures that really reposition Biogen for growth. Now if I just review some of those things, the first is -- was really to refocus the company on growth drivers, in particular our new product launches. Biogen had four new product launches from approvals from the FDA last year. That's the second highest of anyone in our industry. And you know that required quite an awful lot of cultural change. The multiple sclerosis franchise has been the stalwart of our company for since its inception 45-years ago. Our people are passionate about the physicians to treat multiple sclerosis and the patients who have multiple sclerosis. And we are still a market leader in this space. However, that is a franchise that is facing increasing competition and we have to embrace new therapeutic categories and new businesses. And so we have really had a major shift in resources and focus, particularly towards LEQEMBI,

Thank you, Chris. As we previously discussed, we have focused on reviewing and prioritizing our development pipeline with a keen eye towards maximizing probability of success and increasing potential return on investment, as Chris noted. The intention was always to focus our pipeline to better represent a risk-reward balance, and one that we believe could help Biogen reach the goal of achieving sustainable growth. While this effort resulted in a number of program discontinuations last year, specifically in areas we perceived significant regulatory development or commercialization challenges. We also highlighted areas where we had deep expertise and promising pipeline programs and therefore warranted an invest-to-win approach. One such area is Alzheimer's disease where we have an industry-leading pipeline, and we do expect to continue investing in order to expand our leadership. This starts first with building upon our opportunity with LEQEMBI. Our first priority is to continue working with Eisai to help ensure that LEQEMBI is available globally to patients suffering from early Alzheimer's disease. With approvals now obtained in the U.S., Japan and China, and filings currently under review in 14 additional markets, we believe we are well on our way to achieving this goal. Second is creating additional treatment options for patients. The data presented at CTAD last year on LEQEMBI suggests that there is continued benefit associated with treatment out to 24-months, and that treatment earlier in the disease course had a greater effect on clinical outcome. For this reason, we are working with Eisai to submit a filing for maintenance dosing with IV LEQEMBI or every four-week treatment, as well as evaluating LEQEMBI administration in preclinical AD, as Chris mentioned, in the AHEAD 3-45 trial, which is before the onset of symptoms. Eisai also aims to submit a filing for subcutaneous version of LEQEMBI by the end of March. Beyond LEQEMBI, Biogen is also advancing pipeline programs targeting tau. We believe tau represents the next frontier in Alzheimer's therapeutics, and we are working to support the development of diagnostic tests and pathways. Our ASO targeting tau, BIIB080, represents a new mechanism for targeting tau distinct from prior antibody attempt. In the Phase 1b study, we saw a convergence of target engagement, reduction in tau pathology in the brain, and improvement in exploratory measures of clinical outcome. We are very encouraged by these results and are currently evaluating BIIB080 in the Phase 2 CELIA study. We also have BIIB113 of Phase 1 small molecule aiming to reduce the aggregation of tau. Importantly, Jane and the research organization is also focused on the future of Alzheimer's treatments and is pursuing a multimodality approach to evaluate a number of other potential targets implicated in Alzheimer's disease biology. Looking beyond Alzheimer's disease, Biogen has an opportunity to expand our growing rare disease portfolio. We see rare disease expertise as a core competency at Biogen. I will now address BIIB121 in Angelman's syndrome. Angelman's syndrome is a rare genetic neurodevelopmental disorder that occurs in approximately one in 15,000 live births worldwide. It is diagnosed in early childhood and is characterized by symptoms such as severe developmental delays, speech impairment, problems with movement and balance, and may involve seizures. While there is no specific treatment approved, individuals with Angelman's syndrome will generally have a near-normal life expectancy. However, they will generally require continuous care and are unable to live independently. Normally, the paternal allele of the UBE3A gene is silenced in neurons, leading to expression of only the maternal allele. In Angelman's syndrome, the maternal allele is either absent or inactivated through genetic mutation, leading to loss of UBE3A gene expression and impairment of synaptic connections and brain network activity. This can be visualized by an increase in low -- slow brainwaves or called delta waves. BIIB121 aims to remove the silencing of the paternal allele in order to restore expression of the UBE3A gene. While the HALOS 1 study is designed as an open-label, multiple ascending dose study across age groups and dose levels to assess safety and tolerability, importantly, the study also utilizes clinical measures that we can use to assess therapeutic potential. This includes objective EEG assessment, as well as clinical assessments evaluating multiple domains of Angelman's syndrome, like cognitive function and gross and fine motor skills. The HALOS Study has completed enrollment for the multiple ascending dose portion of the study, and last year, Ionis presented some encouraging early interim results. Overall, safety and tolerability support continued dosing in the long-term extension with no concerning safety trends having been observed to-date. The EEG data was suggestive of early trends to a reduction of slow delta wave activity as compared to baseline. And clinician-assessed clinical endpoints show a majority of participants demonstrating some level of improvement in overall functioning. Overall, we are encouraged by these early trends and look forward to sharing a more comprehensive topline study readout expected midyear. Following our review of those results, Biogen will be in a position to make its decision whether to opt in to conduct a pivotal study. Moving to lupus, this is another area with significant unmet medical need. We currently have two Phase 3 assets in Systemic Lupus Erythematosus or SLE. First is dapirolizumab pegol, being developed in collaboration with UCB, where we expect a topline readout of the Phase 3 study midyear this year. If positive, we expect to conduct a second Phase 3 study. The second is litifilimab, our anti-BDCA2 antibody developed in-house at Biogen. We currently have two Phase 3 studies of litifilimab in SLE ongoing. These studies are enrolling and utilize a 52-week primary endpoint. Litifilimab also has the potential to be a first-in-class biologic in Cutaneous Lupus Erythematosus or CLE, a skin-based autoimmune disease that can be associated with severe scarring and dyspigmentation and can be distinct from SLE. As I've previously discussed, we have focused on reviewing our pipeline to identify and prioritize the areas where we believe we have both sufficient expertise and confidence in the science to deliver meaningful new treatments for patients. While this initial review is complete, this process remains dynamic, and we are committed to holding ourselves accountable to efficiently seeking out scientific insights and continuing to build the pipeline with what we believe is the right risk-reward balance. While we look forward to four important near-term readouts this year, we continue to focus on identifying additional near-term opportunities, as well as continued expansion beyond neuroscience. Through collaboration with Jane and research organization, as well as Adam Keeney, our Head of Corporate Development, we are taking a holistic look across a spectrum of opportunities with both a research and development focus to identify strategic assets that we believe can contribute to Biogen's growth story now and in the long-term. With that, I would now like to pass the call over to Mike.

Thank you, Priya. Good morning, everyone. I'm going to provide some highlights and color regarding our financial performance for the fourth quarter of 2023, and I'll follow that with some detail on our 2024 financial guidance assumptions. Please note that all the financial comparisons that you will hear are versus the fourth quarter of 2022. Total revenue for the fourth quarter of 2023 was $2.4 billion. That's a decrease of 6% at actual currency and 5% at constant currency. Non-GAAP diluted earnings per share in the fourth quarter was $2.95, and that includes a $0.35 negative impact from the recently disclosed closeout costs related to ADUHELM. For the full-year of 2023, total revenue of $9.8 billion represents a decline of 3% at actual currency and 1% at constant currency, and that's consistent with our most recent guidance of a low single-digit decline. Full-year 2023 non-GAAP diluted EPS was $14.72, and that's also consistent with our most recent guidance range of $14.50 to $15. Total MS product revenue was $1.2 billion in the fourth quarter. That's a decrease of 8% at actual currency and 6% at constant currency, and that decline is broadly attributable to competition among the impacts from generic TECFIDERA. I'd like to now provide just a couple of quick updates to the MS business during the fourth quarter. First, for TECFIDERA, in Europe, in December, the European Commission revoked the centralized marketing authorization for generic versions of TECFIDERA, and in reaching this decision, the European Commission affirmed that Biogen is entitled to marketing protection for TECFIDERA until February of 2025, which makes TECFIDERA the only dimethyl fumarate treatment for MS that may be lawfully placed on the market for sale in the EU until that date. Also, a TYSABRI biosimilar is now launched in a small number of countries in Europe. We expect that biosimilars will continue to launch in the first-half of 2024 in other European geographies, as well as in the U.S. Biogen has patents related to TYSABRI, and we will continue to seek to enforce our IP. And although VUMERITY grew modestly in 2023, we are seeing continued effects from pricing pressure and an overall contraction of the oral segment of the market in the U.S., which we expect to continue to see in 2024. Now an update on our rare disease portfolio, which includes SPINRA

Thanks, Mike. So we have a number of milestones this year that we'll all be watching carefully. You've seen we have a scientific advisory group for LEQEMBI in the first quarter, and assuming a positive result for the CHMP, that should hopefully lead to an approval in -- by the European Commission in the first-half -- later in the first-half of this year. SKYCLARYS in the European Union, of course, we've just achieved, as we announced last night, and the European approval for QALSODY, there is an expected decision by the CHMP and the European Commission in the first half. We have regulatory submissions coming up, as you know, with the subcutaneous formulation for LEQEMBI and IV maintenance dosing also for LEQEMBI. And then, as Priya has noted, we have four data readouts expected sometime mid-year for four programs. As I said earlier, I think we are going to be spending an increasing amount of time focusing on our pipeline and building out that pipeline. So Chuck, I turn that back [Technical Difficulty] and see if there’s any questions.

Right. Thanks, Chris. Katie, could you please open polling for questions? Thank you.

Thank you. [Operator Instructions] Our first question comes from the line of Marc Goodman with Leerink Partners.

Yes. Good morning. Can you walk us through just the subcu and the maintenance approvals? Obviously, timelines, I guess, would be around the end of the year, but just talk about the impact into the market. Let's assume Lilly's on the market as well with a -- they're going to get approved soon. So how do you expect this to change the dynamics and the uptake? And just give us a sense of that, please. And then also, maybe you could just talk about the uptake in Japan that you expect? Thanks.

Yes. Thanks, Marc. Priya, you want to just start with kind of the timelines? And I can hit the commercial.

Sure. Thanks, Marc, for that question. So overall, we shared our six month data for the subcutaneous formulation at CTAD last year. We believe we've achieved the bioequivalence with the IV formulation. Eisai has communicated very recently about the FDA meeting that is on the book to finalize strategy for submission. And currently, the aim is still to file by end of March 2024 for the subcutaneous formulation. In addition, there is data on the potential and need for IV maintenance, and that is also being aimed to file by Q1 2024. So that's the plan currently. I'm going to turn it over to Chris for the dynamics and the commercial implications.

Yes, so Marc, I mean, the main benefit of subcutaneous is going to be convenience for patients. And as we talked about earlier, over time, we're looking at the AHEAD study where we could potentially one day get an indication for much earlier-stage patients. We're looking at maintenance where patients should continue on, if we get approved, to prevent the recurrence of plaque. So the time on drug is expected to expand as we do these studies, and having a subcutaneous formulation at any stage of this disease could be quite beneficial. In terms of the actual competitiveness with donanemab, I think there's going to be a number of points. We do know that physicians are highly sensitive to ARIA and safety, and we have a significantly better safety profile with LEQEMBI than donanemab. There's an interesting thing with donanemab study, which -- their study actually followed patients until there was a decrease in plaques. So where Clarity looked at an endpoint for everybody at the same time point after 18 months, there was a variable endpoint in terms of time on donanemab. And so the stopping criteria are not quite clear. And I think we need to see what those are if you need a PET scan, for instance, that could be quite onerous. Now we don't know whether that's going to be the case or not. But I think we're going to have a number of variables with which we can compete with donanemab. And subcutaneous at some point will be helpful. Obviously, if think it these guidance, looks like donanemab is an indicated is going to be on the market before the subcutaneous formulation is. So we're going to be focused on some of those non-subcutaneous factors and competition. And then once we see the label for Lily, once we see the label for the subcu then we'll develop our commercial strategy accordingly.

Do you want to comment on Japan?

Oh, Japan. Yes, I think we certainly have a -- Eisai is basically putting all of its field force, not just the ones for LEQEMBI behind this. And you've got a government managed healthcare system. So I think some of the complexity that we have in the United States with reimbursement and different actors could be simpler. We do expect that there will be some of the same constraints in terms of access to neurologists, the PET scans. They'll probably use a lot more of the CSF markers and PET scans in Japan, but I think we could potentially see a faster uptake in Japan than we saw even in the United States, just because of the current system. So we're just out there since January and we'll give an update, obviously, again at first quarter, but certainly from what we're hearing from our own people from the field, that there's been a very positive reception by physicians in Japan.

Great. Thanks, Chris. Next question, please, operator.

Thank you. We'll go next to Salveen Richter with Goldman Sachs.

Good morning. Thanks for taking my question. I have one with regard to the bottlenecks on the LEQEMBI launch. Could you speak to maybe two of those aspects? One is your expectations for Medicare Advantage to get to the same level of coverage as traditional Medicare and over what timeframe? And then secondly, just an update on the patient access to neurologists. Thank you.

Yes, so I'll have to get back here on the -- I haven't heard anything that Medicare Advantage is any different than Medicare. So I haven't ever asked that question before, but I'll go check. But as far as I know, it's the same. The bottlenecks, I still -- if you think about it, if the data from the patient registries are accurate, and again, we don't have direct access to that, but it suggests that we've got almost twice as many people on the registry as we do on treatment. And so that says that in addition to the bottleneck of getting into the neurologist, that there's -- when you get to the registry, you've got a clear intent to prescribe, because on the registry, at least for CMS, you have to describe how you actually validated the diagnosis. So by then, you've triaged the patient, you've done either the PET scan or the CSF markers, and you're looking for reimbursement. And what we're hearing a little bit is, is that there is some challenge in just scheduling the first MRI, because when we initiate the infusion, you have to have the first MRI within the first two weeks. So people don't want to initiate the infusion until they've got that MRI scheduled. And the MRI -- there isn't an MRI capacity constraint per se, but you are looking for a specific date, and then you have to back up the infusion. So there's just, I think, until people get the hang of this, getting all that coordination, I think that seems to be where the -- where one of the bottlenecks is.

Great. Thank you, Chris. Let's move to the next question please.

We'll go next to Umer Raffat with Evercore ISI.

Hi, guys. Thanks for taking my question. I thought I'd ask for something a little different today, your CD40 Phase 3 in lupus. And my question is, two things. One, the trial size, this was shrunk from 450 down to 320. Could you speak to the recruiting challenges and whether they bode well or not well on efficacy? And then secondly, the primary endpoint, this one has three components, but the FDA guidance appears to want one clear index like a BILAG or SELENA-SLEDAI et cetera. Is there alignment with regulator on that? Thank you.

Thank you, Umer. I'll take that. So just starting off, I think we expect our results from the first Phase 3 mid-2024. We expect that we'll need a second Phase 3, if this is positive, to generate the safety and efficacy to support a Reg filing. We did make a protocol amendment, and this was really working very closely with Biogen and UCB, looking at the study design, balancing our commitment to execute a well-designed, informative study with a desire to potentially expedite the delivery of dapi, if positive, to patients in need. So we do think it's appropriately powered, and we continue with regulatory engagements and facilitate a discussion on the next step. So we think, yes, we -- it is positioned to give us a clear readout on the therapeutic potential as of now. Yes.

Thanks, Priya. Let's go to our next question, please.

We'll go next to Evan Seigerman with BMO Capital Markets.

Hi, all. Thank you so much for taking my question. Chris, maybe can you walk me through some of the rationale for adding more Biogen resources to the LEQEMBI launch and maybe kind of what's changed or evolved with your partnership with Eisai where you think you needed to add more Biogen resources in the United States? Thank you.

Yes. Thanks, Evan. I mean, to be clear, we're adding both more Biogen as well as more Eisai. A year ago, the CEO of Eisai and I talked about the launch of LEQEMBI, and for the U.S., just discussed the complexity of the launch, and we've been through all that, and I won't necessarily bore everybody again with that complexity, but we just felt that we wanted to really make sure we understood the go-to-market model. In addition to these neurology account specialists, you've got MSLs, you've got some patient care navigators, you've got some people looking after KMEs in the region, and there's probably -- for every NAS, there's another two or three people who are actually out there in the field. And there's an awful lot of coordination that is needed. And even the role of the NAS is quite complex because you've got to go in there, you've got to work with the office around helping them to understand the safety. You have to help them understand what the care pathway is. You have to help them to understand the reimbursement, not just for LEQEMBI, but there is the reimbursement for the PET scans, the MRIs, and for the care. And then finally, there's what people in the field are -- have as a principal objective, why LEQEMBI? So we wanted to make sure we understood all of that. And to be honest, whenever you do these copromotions, they require an awful lot of coordination between the companies. And we just felt that it would be simpler if one company went out at the start. We were sure that we knew exactly how the role of the NAS was going to work in relation to the other accompanying roles that are out there in the field. And we also needed to get a certain number of core IDNs ready and signed up because there's not a lot of point in increasing the number of people out in the field unless you've got enough sites that are activated and ready. So now we're more than six months into the launch. I think we feel very comfortable about how the role of the NAS works. We understand how long it takes between going to visit a neurologist or an IDN and how long it's going to take for them to be activated, because, as I say, there's -- you can put an awful lot of resource out there, but if you're not able to pull the drug through, it's not a very efficient process. So that's just where we are. We're confident in that model. Obviously, it is -- we need to now reach out to more sites. So we're looking at this from both a geographic expansion, but also, I think, even within certain geographies, perhaps reducing the territory side, because when these NASs go in, they spend quite a long time with the specialists. So it was always the agreement between the two CEOs that when we scale up that Biogen would come in, but we both -- our objective is to make the joint venture as efficient as possible. And so we just felt that the efficiency at the start would be maximized if we just had one company on the field. Now, we've obviously learned from that, and that's what also gives us the confidence to put two companies out into the field immediately in Japan, for example, because while there are differences in the market, a number of the dynamics would be the same pretty much in those markets. So it is an increase. Eisai is increasing their resource and so -- and Biogen will be out there as well. And that could still evolve over time. We're going to be in this business together for many years to come.

Right, thanks, Chris. Now let's move to our next question, please.

We'll go next to Paul Mattias with Stifel.

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.

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.

Thanks, Priya. Next question, please.

We'll go next to Phil Nadeau with TD Cowen.

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.

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.

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.

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 SPINRA

Great, thank you. Next question, please.

We'll go next to Michael Yee with Jefferies.

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.

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.

Great. Thank you, Chris. Let's move to our next question, please.

We'll go next to Colin Bristow with UBS.

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.

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…

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.

All right. Thank you, Priya. Let's go to our next questioner.

We'll go next to Chris Raymond with Piper Sandler.

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.

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. So we'll be looking at that. as well as clinical endpoints. And very specifically, there are quite a few clinical endpoints. There's the Bayley score, there's the CGI and there's a Vineland. We'll be looking at all of them. Stepping out into what do we feel about the competitive landscape? We feel that this as designed the program is well positioned. Just from an ASO perspective, the backbone of the BIIB121 ASO, we believe, is different. That's 1 from the Ultragenyx ASO. Second, we believe that the dosing may be needed at a quarterly level to really see the PK/PD impact that we need to have -- make an impact in this disease. And we do have a 3 monthly dosing in the LTE. So the MAD is 2 doses being given 1 month apart. And then the third dose, 2 months later, and then patients go into a 3-month dosing. So we are -- we feel that we will have a data set that we can look at and really assess whether we see an adequate signal to really take it into a Phase 3. And with regards to Roche discontinuing their program, we believe, again, that this is a different product, and we believe we may have a competitive advantage. Ultimately, of course, we need to see the data.

Thank you, Priya. Let's move to the next question, please.

We'll go next to Mohit Bansal with Wells Fargo.

Great. Thank you very much for taking mu question. Maybe I can -- if you can comment a little bit on the previous comments you made regarding SPINRA

Sure. So as you know, we have an oral therapy out there. We have a gene therapy, and we have SPINRA

Yes. And I'll just quickly add to that, Mohit, that in the -- as we mentioned in our prepared remarks, there tends to be some lumpiness quarter-over-quarter, particularly outside of the U.S. with shipments. But overall, when you look at the full-year of 2023, we actually saw modest growth in the U.S., modest decline OUS and overall, moving back toward the modest growth trajectory that we're hoping for, and we are pleased with how that franchise has stabilized over time.

Yes, there's a dynamic as sort of the oral comes into a market at one point or the gene therapy comes into a market. If you have 100% market share and the competitor comes in mathematically, you're going to lose market share. But what we see is that there is some churn for a year or two. And then the markets settle out, and that's when people start focusing on efficacy and patient populations. And as I say, so far, we have been able to maintain leadership in SMA despite the competition. And I think that's where they'll be. There'll be different products for different patients, but there's still enough of a patient population and even with the switchbacks that we can find reservoirs of growth.

Great, thanks. And operator, can we move to our last question, please.

We'll go next to Jay Olson with Oppenheimer.

Hey, guys. This is Matt on for Jay. Thanks so much for taking our questions, and Jay sends his regards. So we were wondering, I guess it's still early, of course, but the PPD launch still far, just in terms of any metrics or signals that you see that support your confidence in the launch so far? And of course, over the next few months to quarters, what kind of metrics do you believe will become meaningful and that you might plan to share? And maybe just your overall longer term goals for that PPD launch and your general interest in the psychiatry space would be interesting to hear as well. I really appreciate the question.

Sure. Thanks, stunt double. We -- so there are a number of things that I think are quite encouraging. One is our initial target has been high-prescribing psychiatrists in this space as well as OB-GYNs. And one of the things that we were wondering about is, are the OB-GYNs really going to be willing to prescribe? And so one of the encouraging signs is that they in fact are doing so. So we're seeing quite a high percentage of the prescriptions coming from them. Another has been, I think, as I mentioned earlier, that payers have really wanted to ensure access to patients, and I'm quite thankful to them. I think Medicaid, for example, where 40% of births occur, have moved very quickly on that in a number of states. And some of the large -- at least one of the large commercial insurers is moving much quicker than we expected as well. So I think the reimbursement is a key statistic. Now, personally, I'm interested in knowing how many patients are treatment-naive versus people who have been on treatment. What is interesting is, is there a warehousing effect here as well? There's been an awful lot of media coverage. The product was approved in July. We were not able to launch because of the DEA inspection until the very end of 2023. So what we don't know is, are we seeing a bolus of patients come in because these are patients physicians have been following for some time who've been identified as being particularly important to have

Great. Thanks, Chris. And that will conclude our call. Appreciate you all joining us today.