Biogen Inc. (BIIB) Earnings Call Transcript & Summary

Great. Good morning, everybody. I'm very excited, and it's appropriate that the first panel of our CNS conference this year is with Biogen's Head of Development, Priya Singhal. So thank you, Priya, very much, for joining me again this year. It was a great discussion last year, and now I have a whole page-and-a-half of questions written out. I'm hoping we can try to get to as much as possible. For everybody joining, you can always feel free to shoot me a note if there are any specific questions you want me to ask, there also should be a link in the webcast for you to type in any questions. But maybe we can start and have a fulsome discussion on Alzheimer's, Priya, and thank you, again.

I think one interesting topical question is related to the lecanemab Ad Comm. And candidly, I was surprised that there even was an Ad Comm simply just because the data looks so unequivocal. To that point, were you surprised that there's going to be an advisory committee? And what key topics are you preparing for on your end?

Sure. So it's a pleasure to be here with you, Paul. Thanks for the question. I think overall, we're not surprised that the FDA has decided to hold an Ad Comm. I mean, after all, lecanumab is currently the first molecule in the class with the potential to obtain a traditional approval and the first with the complete Phase III trial results, which could support translatability of amyloid plaque removal to slowing of clinical decline in early AD. So we believe that the Ad Comm will provide the opportunity to review the strength of the data. I agree with you the Clarity AD data was really rather unequivocal, but it's an important discussion. I don't think we can speculate on what the FDA or the advisory committee may choose to focus the discussion on, but I do think that overall, I mean, I think there's a question of whether ARIA is important. I think it continues to be important. It's always about benefit/risk. And -- but we've learned a lot about how to manage it. And it can be serious, and I think needs to be appropriately weighed in. So we think it will be a totality of questions across benefit and risk, but we don't believe that it's a surprise at all.

Okay. Okay. Great. And we were just talking offline and I thought I would just throw in more question about it, even though we're going to focus more on the development side. But just on the NCD, the CED, I think most investors listening in, right, have followed everything that CMS has said and tried to analyze it very, very closely. But I guess on my end, and again, if you can't comment much, no worries, but one question that I get regularly is when we read this recent CMS release, and they're speaking to kind of broad access, what do you envision that, that might look like? And when we think about evidence development, are there any analogues we can look to? Or is there any sense of what we can get as it relates to the burden that's going to be on physicians treating these patients?

Sure. So let me tackle the first part first, which is what do we think is going to be the -- what the access could look like. So I need to address that, it's important to kind of underscore that Eisai is leading this discussion and engagement with CMS. We are working very closely. They're sharing the data. They believe that discussions are very constructive, and we believe that it's quite positive to see CMS saying that they will provide broader access on the day that lecanemab, if it receives traditional approval. So we think this is very positive. Now as you know, the broader access could be a range of options, registry and registries could be really quite light, they could be online. They may not be burdensome. So I think we do need to wait and watch on how that is. But I see this as a commitment from CMS that they will provide broader access. And that's what I would underscore at this point. But I think beyond that, it's hard to tell.

Yes. Okay. Fair enough. So let's switch gears to the subcu formulation. Obviously, it could be a big deal to kind of broadening access, right, making it easier for patients that aren't like the cities and treated academic centers to get the drug, can you just set the stage Priya and you and talk about the various studies and formulations for lacanemab subcu that are under development today?

Yes, sure. This is a very important part of -- it's a multipronged development pathway for lacanemab beyond Clarity, and this is a very important pillar. So Eisai has presented the bioavailability data from the Phase I study that compares the IV versus the subcutaneous dosing. They've also presented modeling and simulation data that illustrates that a fixed subcutaneous dose of 720 milligrams administered weekly may potentially result in the comparable exposure and efficacy to the current IV formulation. Also, the subcu substudy is currently ongoing in the open-label extension portion of the Phase III Clarity AD study. This study, the substudy that is, is designed so that the individuals completing the 18-month placebo-controlled portion, both the treatment and the placebo group, transition to the subcu sub study, and they can receive either the IV formulation or they can switch to a direct start of subcutaneous formulation or they may receive the IV formulation for about 24 weeks and then switch to subcu. So it's quite a comprehensive approach to evaluating subcutaneous. There's also an additional Phase I study that's designed to evaluate the bioequivalence of the subcutaneous dose of lecanemab via vial and auto-injector in healthy participants. And as is obvious, a use of an auto-injector could potentially allow for home administration. So it's really a comprehensive plan. Eisai has also stated that they will be ready to file with this package by Q1 2024. And they believe that we have -- that this study will generate and the total package will generate the PK/PD and the safety data that's needed in terms of the regulatory filing.

Yes. Okay. Okay. One interesting question that a KOL raise on a physician panel that we moderated at conference in January. Was this idea that CMS could be relevant for getting more drug in the brain, like maybe there's some sort of grading effect and the subcu obviously has a much lower Cmax and has been modeled more based on C average and AUC. I guess to that end, what evidence do we have at Cmax that doesn't matter for both brain penetration and potential target engagement?

Yes. So basically, the exposure response modeling of the Phase II data, the lecanemab data suggests that the [ C-average ] is the one that's correlated with PET SUVR and a model predicted that the greater steady-state concentration of lecanemab, the greater the change from baseline in PET SUVR at 12 and 18 months. So that gives us a certain degree of confidence. The modeling has also suggested that Cmax is actually correlated with the incidence of ARIA. And at similar exposure, subcutaneous lecanemab has a lower Cmax than IV after each administration. So it's possible that subcu formulation can give us if these [ C-average ] correlation with SUVR, can you give us the plaque reduction, but also result potentially in a lower incidence of ARIA. Of course, we have to wait for the data, but that's how we're thinking about it. That's the data that we are anchoring this hypothesis on.

Okay. When you talk about a bioequivalence study, is that looking at bioequivalence in serum or CSF or both?

It's a bioequivalent serum.

Okay. Okay. And how do you think about the regulatory hurdle. Do you think you can get approved on plasma, bioequivalence and safety? Or do you need to show hard engagement and flat lowering or let's compare or what?

Well, we believe that we'll just see that Eisai has stated, I think, several times now that they do have general agreement on filing strategy with the key regulators and that the subcutaneous sub-study will provide the necessary PK and PD. And safety information. So PD will really be block. So I think it will be a total package and they will file this by end of Q1 2024.

Yes. Okay. Do you have a view of when it might -- when we should expect some data? I guess if they're filing it in Q1, there's a bunch of medical meetings later this year. Is that a realistic expectation?

Well, they haven't commented. So really no comment from me on that topic because they haven't commented.

Okay. Fair enough. Maybe separately, I think one interesting question, it's just about blood-based biomarkers in this space. And there's a number under development. We put together a time line recently of this. I'm not a diagnostics analyst, so I'm trying to kind of learning the job when I look at these and look at some of the data and look at the correlation data, I guess can you just start by sort of setting the stage on where we are with blood-based biomarkers. And in your view, how important is the development of a credible blood-based diagnostic to achieving lecanemab's peak potential if they can truly replace PET SUVR.

Yes. It's a very important question. And really, we believe that the accurate diagnosis today is a key challenge. We believe it's a challenge. And we think that the availability of accessible diagnostic tests are one of the key contributors. And as is common in other disease areas and other fields, when you don't have a lot of therapies that can be meaningful or be disease modifying, you don't see a lot of momentum in diagnostics. And we think we're already seeing a lot of diagnostic momentum. And the field is making progress. But we're not at the point where a blood test alone is adequate to confirm amyloid pathology for an Alzheimer's diagnosis, which is the target for lecanemab. So that remains very, very critical. Of course, we have PET imaging and CSF testing to confirm amyloid beta pathology, but this is hindered by infrastructure challenges and ways of burdensome procedures, high cost, limited coverage and reimbursement. And the goal really is to achieve regulatory approval and reimbursement for a blood- based diagnostic that can be validated against the gold standard, which currently is PET imaging. That can, I think, really change the potential and improve access for patients and very much streamlined. So while many challenges are invoked, when you talk about treating Alzheimer's patients, we believe blood-based biomarkers is really quite central. Today, we think that there are very limited blood test available, but these are now being called lab developed tests, so they're non-FDA regulated and they have a limited clinical uptake primarily due to challenges with the ability to correctly predict Abeta status and commercial scale limitations and of course, the high cost. So all those factors are really precluding this from getting to the main stream. Now there is momentum. We've seen in the U.S. C2N launched in 2020, C2N again, launched in 2022 with an updated version. Quest launched in 2022. In Japan we've seen this approved in December 2022. There's more tests that are coming up. We've been hearing more about the Quanterix with Eli Lilly, Fujirebio, Roche Diagnostics. So there's momentum, but we need this to really be sorted out for us to achieve the true potential and to get to patients in time.

Is this something that could be see -- could we Eisai and Biogen partner with companies or make investments here?

Yes. We actually already have. So Eisai and Biogen have been using both in Clarity AD and in the presymptomatic AHEAD 3-45 trial, we've been using C2N tests for screening prior to amyloid, PET and CSF confirmation. So this is an important data source. Eisai separately outside with collaboration with Biogen has also funded the development of blood test with C2N, Sysmex and Shimadzu and then Biogen and Lilly are sponsors of the Bio-Hermes trial, which aims to compare blood tests alongside digital and other tools in MCI and AD. And that adds prospective data to [ AIDS ] tests validation. So we think that we are trying to do everything we can but it will really take a large momentum to get this into mainstream. But it's going to be very important.

Of all the data you've seen so far from the test that you've been kind of -- you've been invested in and partnered with and then others externally. Have you seen anything yet specifically that has a high enough correlation with PET that it could be ready for prime time? Or are we really just not there yet?

I think we are not there yet, but we have seen a lot of important data, and this has been shared, for example, with the plasma Abeta 42/40 ratio. That has been very important that C2N is that this has yielded very important data about how long do you continue to treat and why would you continue to treat. So we're seeing that, but can it replace PET and CSF were not quite there yet because you have to think about the fact that this is a serious disease. And when we talk to physicians, we do want to limit any false positives because they will be putting a patient on a beta amyloid therapy. And that's really the question here.

Okay. Okay. Great. You alluded to my next question, which is one of my favorite topics in this space, and it's the whole concept of dosing continuously, non-continuously. I feel like, by the way, I've lived this story twice now with following stage since they IPO-ed with zuranolone and that whole debate as well, which we can get into. But I guess how do you think about the need for chronic dosing with lecanemab? I mean you have the data, and we can talk about the data. But just like more broadly, did you ever consider treating to PET negativity? What data is there that suggests that given this product is the right way to go? Maybe I can just kind of keep it open ended and then follow up, so, thanks.

So it's a very important question. I mean I think it's both a scientific question and of course, then you have to follow that through with the therapeutic strategy. So overall, I think it's very important to remember that there's the aggregated amyloid plaques in the brain that gets visualized by PET and picked up by CSF and of course, also by blood biomarkers, hopefully in the future. But there's also the soluble oligomeric species that specifically the protofibrils, that literature shows that the soluble oligomeric amyloid species impact synaptic function and learning and memory. And these can be visualized. So when we -- when lecanemab was designed, it was actually designed to address not only the plaque, which is aggregated and can be visualized, but also the soluble species. And we believe that, that's the therapeutic strategy that can, in totality, address this disease progression. Now the data that we have that supports that you need to continue to treat with lecanemab, even after the removal is the data that's important. And I'll sort of touch on that data, Eisai presented the data from the lecanemab Phase IIb study that included a gap period. The average time of off-drug was about 2 years. Before previously treated patients resumed or placebo patients started treatment in the open-label extension for the Phase II study. So what we saw was that lecanemab resulted in fast and deep plaque clearance during the 18-month placebo-controlled period, and we saw an increase in the plasma Abeta 42/20 ratio during this time, which is indicative, we believe, of a reversal of the disease biology. And you know the hypothesis here is that Abeta 42/40 gets sequestered by the amyloid plaques in the brain. So when you remove the plaques, it allows more Abeta 42/40 to circulate. And so you pick up an increase in the plasma Abeta 42/40 ratio. Now when plaque reductions appear to have been maintained -- what we saw was that they appear to have been maintained during the treatment gap period. However, this ratio declined, indicating that the Alzheimer's disease biology was returning. And then when lecanemab was restarted, we saw the trend reversing. So our conclusion at this point based on the data that we've seen is that while plaques remain relatively stable during the treatment gap period, we do see signs of returning disease biology. So as we think about what's well, so therefore, what's the -- so we have a molecule that addresses both these aspects. We've got the data that shows that, yes, it does come back, sort of the soluble species stop coming back. So the question now really on the table is, how do you -- how often do you need to administer lecanemab, after the initial 18-month period where you get to that amyloid negativity as you referred to it. I mean you remove majority of the plaques, do you need to continue it? We believe, yes. How long and how often do you provide lecanemab, is the question. And this is being answered. We believe that you need data for this. And this is that other pillar of the clinical development plan for lecanemab and it's being evaluated in the Phase II open label extension. And the 2 maintenance dosing is being tested as Q4 or Q12, and that also Eisai has stated that they expect to submit a regulatory filing by the end of Q1 2024. So hopefully, that answers both the scientific hypothesis, how lecanemab addresses it. and what we're doing to generate data to really evaluate the question.

Yes. Okay. Great. One last Alzheimer's question that just came in before we switch gears and talk about zuranolone, which is how do you think the subcu is most likely going to be positioned in the real world? I know you kind of covered some of this earlier on the different studies. But do you think it's going to be something where when it's used in the real world, it's a switch from an initial IV course? What are your thoughts there?

Well, I will say that the data that we're generating right now that Eisai is generating will allow evaluation of all the situations, because as I mentioned, the sub-study is testing 3 aspects. One is you just start, you continue on IV and you switch or you start on subcu. And remember, people -- patients who were on lecanemab during the 18-month period, they're going to switch to the subcu. And so that is going to give you all those sort of use options. So you will be able to see what the data shows in each of these situations. Now how would you exactly get adopted? I think remains to be seen. Certainly, we will be launching with IV, and then we'll be filing with this. So there's a period where just the IV will be available. And by that point, we'll have this in review. And I think we can then comment on how it could be used. But the way the data is being generated, I think it could answer a lot of the questions that are outstanding today.

Yes. Yes. Okay. Great. Maybe let's flip back to zuranolone, it's interesting, right? Like I followed these drugs and take the time in Phase I and Phase II and the whole concept of noncontinuous dosing with this drug. On the Wall Street side, right, became a kind of bull case and optimistic case and then as the data approved and investors got focused on the FX side and some of the day 42 stop, it's almost flipped back and there's a lot of skeptics. We think that it's a challenge with this product. I guess, in your view, what makes you confident that this is the right way to dose this drug. And how do you envision zuranolone being used in the world?

Yes. I think -- we think that there's a very significant opportunity. I mean, obviously, we all know that the data from major depressive disorder is that there's millions of patients who are currently on therapy and are in need of a drug that can add to their treatment plan. So that's one aspect. The other is that we have seen repeatedly across the entire landscape and NEST programs for both MDD and PPD that the rapidity of onset of action by day 3 is really very meaningful. We also believe that it is sustained and that it is durable and we believe that we have data to show that the safety and tolerability is really consistent, and it does not come with the SSRI and SNRI burden of safety effects. So we believe that this is really potentially can be a paradigm shift where you could have a patient with MDD who needs treatment once and potentially twice in a year because that's what we've seen with SHORELINE, which is the largest naturalistic study that's been done in MDD. And with the 30 milligram, I believe it was 4.5 months that we saw for patients who needed a secondary treatment. And in -- with the 50 milligrams, it was 8 months. So we think that, that is really meaningful, and that is going to add value to both HCPs and patients who are looking to have benefits and disease-modifying treatment in this area. So we think it's very meaningful. With regards to PPD, it's the same thing. It's highly prevalent, highly under diagnosed, and we think that the data are compelling. Obviously, you know that FDA had given a big through designation. We did a single filing to make it very simple. And now we have priority review with the PDUFA date of August 5. So priority review is also a very good outcome in terms of where the FDA has started their review. On the potential that the drug could add in terms of impacting or being a meaningful and significant difference between currently available therapies. So I'll stop there, happy to answer any other questions.

Yes. Great. Thank you, Priya. On -- so one thing that I -- when we try to forecast these drugs and model them as I've had a little bit of trouble trying to figure out, I know the SHORELINE data, right? But just figuring out how it's going to be using the real world, what line of therapy, if you look at the launch of Axsome drug, right, payers naturally push this into the treatment-resistant depression population. When I think about zuranolone I don't know if this noncontinuous dosing at parts really makes sense for patients in that line. I guess, can you talk a little bit about Biogen and Sage's sort of strategy for positioning this drug because it does seem like based on SHORELINE that this could be very clinically successful in the earlier lines of therapy, but I worry that maybe if it gets stuck in TRD, it's not going to get that a state velocity because the initial experience might not be as favorable. What are your thoughts there?

Yes. I think that is very important to note that zuranolone has not been evaluated in treatment-resistant depression. And if approved, think that both Sage and Biogen were already working very hard on what our launch educational strategy is going to be, how to approach physicians? What's the patient journey? Who are the physicians who are going to be treating? So we're looking at that very, very carefully, and we're looking at the appropriate use of zuranolone supported by the clinical trial data thus far. Now what's really important to note is that in this LANDSCAPE and NEST program, specifically for MDD in the LANDSCAPE program, zuranolone has been evaluated as a monotherapy, adjunctive therapy and add-on so -- and co-initiation. So I think that, that gives physicians and data has being generated across all those. So that gives physicians a lot of data to rely on as they look at the patients who walk in through their clinic. And I think that's going to be important. While we don't -- we can't speculate on what the label is going to see. At the moment, we are really focusing on patients who might be needing a switch or an add-on and where they need more power. And we believe that this GABAergic mechanistic action is going to really be important for those patients.

Yes. Okay. Do you -- one thing with SHORELINE right now, I understand it's described as naturalistic study. But I do think one thing that's different about that study versus how a physician might have the impetus to care for a patient in the real world is that between courses of therapy, I think patients weren't allowed to re-dose for 6 weeks. How do you kind of think about that in terms of how it will impact psychiatrist approach of the drug, the technology around it. And I guess do you expect that restriction to be in place in the real world? Or do you expect it to be more open-ended?

Can't speculate really on the restrictions in the label. I think we'll have to wait for that. But I think the important information that SHORELINE provides us is how zuranolone could be used in the real world if approved. And the 50 milligrams, approximately a cohort in SHORELINE, approximately 80% of individuals who responded to the initial course received we see only 1 or 2 treatment courses in total during that time in the 1-year study. And majority of the patients actually receive only the initial 14-day treatment course. And so -- and then I already quoted the data to you of what was the time to retreatment if patients went on to get another rate treatment. So we think that these underscore the potential and provide data. The other piece I want to definitely add here is that as this is a very important launch for Biogen and for Sage, of course. And we are focusing very deeply on what is all the real-world data we need to generate. So we are looking at this very carefully. We have a very systematic and comprehensive plan. We'll continue to generate data to help physicians really understand how the drug works and fill in any gaps. So it's not like this will be it. We have an educational strategy that we're approaching and also what's going to be our approach to generating real-world data.

Okay. And like what would be something that would be your first information on an additional question to help answer for physicians?

Well, right now, what we are doing is we are speaking to a lot of physicians, and we're gathering that and we're prioritizing all the questions that we're gathering both from the Sage and Biogen side so that we can decide how we would approach it. And then we're also looking at whether this would be -- what kind of networks we might tap into. So we're looking at it very comprehensively. I'm sure we can share more in future meetings. We're also looking at additional indications, Axsome strategy. So it's a very comprehensive approach for zuranolone. We believe that this is a very important opportunity, and we want to do the right thing for both patients and physicians.

What are -- I think Sage generated some data in bipolar historically. They also have some subset data in patients with high levels of anxiety. What -- if you could pick one, is there one site indication that you're most kind of intrigued by for this?

Well, it's early days because we're still looking at the data. We're kind of evaluating them very -- in their entirety in terms of what the plans would look like and how we would develop these I think generalized anxiety disorder is important. We've already seen that zuranolone is beneficial to patients with MDD with a high level of anxiety and then we're looking at generalized anxiety disorder by -- but we're also looking at bipolar disorder. So we're looking at a lot of these, and I'm sure we'll be able to share more details soon.

Okay. Okay. Great. When I met with Mike and Mike, CFO and -- or Michael or Mike CFO and IR in December, I'd like to ask what's the one R&D pipeline drug that you built that's most underappreciated, or I don't know exactly what was great, so maybe I shouldn't quote them. Most of the radar. And they talked about lupus 059. Can you just talk about this drug and also Chris has talked about immunology as a potential area for business development. Like maybe talk about this drug and just kind of your broader interest as the R&D portfolio is shaped in getting more into immunology after that wasn't more of a core area when you're doing a lot of drug development in MS.

Yes. So we have 2 Phase III programs in SLE. We have 2 programs. One is Dapi in collaboration with UCB, which is also a Phase III anti-CD40-Ligand antibody fragment in Phase III for SLE. And then BIIB059 is also for litifilimab. And this is a more monoclonal antibody that's targeting the human BDCA2, and it's a homegrown asset. So we're very proud to have brought it to Phase III. Both assets have the potential to be first-in-class molecules in SLE, but litifilimab is also in Phase II/III for CLE, which is a skin beast autoimmune disease and can exist in the absence of systemic manifestations, no real treatments approved in the past 70 years and a very high burden of disease, specifically in the diverse underserved population, impairing quality of life, severe skin damage. So we believe this is right in our -- sort of our mission of going after diseases of high unmet need with an asset we believe that has the biology that impacts the biology for this disease. Now the hypothesized mechanism of action and data is coming from the Phase II LILAC study, where we generated proof-of-concept. This was published in the New England Journal of Medicine last summer. And essentially, what litifilimab is, is a humanized monoclonal antibody against BDCA2, as I mentioned, which is a protein that is predominantly expressed on the surface of what we call pDCs or plasmacytoid dendritic cells. What these plasmacytoid dendritic cells do that we are innate immune cells, and it rapidly produce high amounts of type 1 interferon as well as cytokines and chemokines in response to immune complexes and lupus. And what you see in lupus is pDCs is accumulating in target organs like skin, kidney and joints. Litifilimab comes and binds to the BDCA2 and leads to the BDCA2 internalization and inhibition of type 1 interferons, but also other cytokines that are implicated, and we saw the proof of concept. I won't go into the details, but in Part A of the LILAC study, we saw it in SLE and in Part B, we saw it in CLE. So this is really important. I think that overall, we believe that the pathogenesis of lupus is quite complex. There's a constellation of symptoms, and many mechanisms of action are important. But we believe that this actually the litifilimab inhibition of BDC actually works to preserve the protective type of interferon response to viruses in other cells. So it works on the pDCs, but it preserves the other cells. And that's important as you think about benefit/risk. So we need to wait for data, but we're excited about litifilimab.

And that Phase III is reading out in 2024. Is that right?

No, it's later than '24. I believe it's '25 or '26, but I can come back to you and confirm the date.

It's all good, it's all good. Okay, and then...

And actually, I didn't answer your second part of your question, which is we think that we have been experts obviously in MS for many years. We think it's an autoimmune disease. It gives us a lot of legitimacy to explore and potentially move deeper into immunology. We've already generated the first-in-class asset like litifilimab, which has progressed to Phase III. So we believe we have the expertises and the capabilities. We've got a good foundation with 3 late-stage programs in CLE and SLE, and I think as Chris has stated, what we're trying to do in the first half of '23, we're focusing on looking at our current programs and capabilities, but this is an area where we may supplement and build on our foundational expertise in specialized immunology.

Yes. Okay. What should we expect, Priya, in terms of just an R&D update from Biogen this year after you're done kind of taking a closer look at your current portfolio, the risk profile and how you're positioning the phase, might evolve going forward.

It's a very important and central initiative. And Chris is very much supportive and also wants us to continue to do what we've been doing all through 2022. So it's an ongoing effort because what we're trying to do is look at our portfolio look at the inflection points for data internally, but also scientific advances externally and help us guide how we would either go to next decision point and spend until that point or we might actually terminate or accelerate. And I'll give you a few examples. So we have kind of dynamic prioritization. So first, I'll just speak about -- a little bit about how we've approached it in the process. We want to essentially rebalance the risk profile, but also increase the productivity. And we want to have the -- prioritize the programs at the highest risk/reward profile. So to do this effectively, we've taken 3 high-level steps. Number one, we've identified the programs where we believe we have the highest attractive risk/reward profile, and we've developed what we call internally, a clinical investment framework that helps us guide decision-making, helps make sure that our spend is commensurate with risk, and that we are being very clear about what's the derisking experiment and how we can get to that very quickly. This is primarily for our pre-proof-of-concept portfolio, but also applies to actually our pre -- our discovery and research portfolio. Now we have identified programs where we committed to investing to win. BIIB080, which we haven't talked about, which is our anti-tau ASO is one of those where we are really investing to win. But we've also discontinued programs where we believe that there's significant challenges either with the development, commercialization of regulatory effect. One is vixotrigine, in neuropathic pain, the other is oral ibrutinib in MS. And the second piece here is that we've taken a lot of steps to increase the productivity of the per POC pipeline because we've noted, right, we fail certain POC programs. So the question is, how can we do better? What we've had is genetic targets, but we are increasing our translational science capabilities to increase the focus on generating value by focusing on the translational biology, the totality of it, not just the targets versus operational milestones. And the final one is that we are -- as we do this, we make -- as we kind of bring assets forward or retire some, what we're trying to do is build areas beyond neuroscience, like neuropsychiatry, specialized immunology and rare disease. And all of these are built on foundations that already exist. So with zuranolone, we've already got neuropsych, with litifilimab, as I spoke, we've already got specialized immunology. And with SPINRAZA, we've had a very successful run in rare disease. So we're building on all our expertise to kind of branch out, and the reason to do that is not because we don't want to do neuroscience, which remains very important, and we will continue to do that. But we just want to make sure that we balance it so that the risk/reward maybe in the other areas is not as steep. The risks are not as steep. We'll still continue to take a very calculated and informed targets and biologies forward and be pioneers. I mean you've seen the example with amyloid, hopefully, with tau. We're taking that to the next level. And you've seen it with neurofilament and ALS and tofersen. So that's how we're trying to think about this.

Okay. Great. Last thing before we wrap up. So my expectation from here that you said, we heard it first in the earnings call is that maybe on the Q1 call, the Q2 call, we may get some kind of updates on how you're reframing things or reprioritizing. And then after that, the deck is clear to maybe do more business development in these 4 areas. Is that the right interpretation?

I think business development is always on the table for us. At any given time, we're looking at a lot of assets, but I think it needs to have a combination of the high science and it's got to be really attractive, and it's got to be at the right economics. And I think that what Chris -- I'll just quote him here. He said, we don't have that high desperation quotient. We will continue to evaluate the business development opportunities. So yes, you're right. In the first half of the year, we really want to do everything we can to streamline within. And yes, our focus might be higher in the second half, we're continuing to look at it at any given time. So we don't anticipate specific hard line. But yes, it's going to be more and more important.

Okay. Okay. Great. Well, thank you so much. This is an awesome conversation, and thanks everybody for joining, and I'm excited to be talking to Ryan Watts from Denali in just a couple of minutes. So hopefully, everyone continues to hang out. And thank you again, Priya.

Thank you, Paul. Thanks, everyone. Goodbye.