Takeda Pharmaceutical Company Limited (4502) Earnings Call Transcript & Summary

Joining us for the Takeda fireside, thanks, Andy and Julie for coming and joining us. Julie, I just learned walked here. So this is not a hard commute for her, but we appreciate it.

So we initiated a few years ago [indiscernible]. And I remember we came up and met with you, and we were saying, hey, we'll get there. We'll upgrade at some point. We did, right, later last year. And from what we can see, one of the most durable kind of cash flows, we'll talk about that in a second and a great valuation of 4% to 5% yield, I mean, this is one of the more compelling stories. So we're going to get into why, without even getting to the pipeline yet. The pipeline looks very interesting. But maybe, Julie, why don't we start with ENTYVIO? Because everyone is worried about the durability of it. Can you talk about why you think it's going to be more durable than maybe a lot of folks on the Street think? Can you talk about biosimilars and some of the challenges?

Sure. So when you look at the biosimilar situation, we -- at the beginning of this year -- I'm sorry, we provided the information that we no longer thought that the LOE was going to hit us in 2026. So there are a couple of things behind that. So first, when you look at the clinical trials that are in existence, we've seen small studies from China and Iran, but nothing at a global scale that's been registered yet in terms of clinical studies. And so that's the first indicator that there is more time. Andy can talk a little bit more about the challenges of conducting an IBD study. We don't have the other indications for ENTYVIO like some of the competitors in the space do. It's just you see in Crohn's. And so those IBD studies are not easy to conduct. So if you think about that and the fact that there's nothing registered yet in terms of a global scale clinical trial that could come to market in the U.S., you're looking at quite a number of years before you could even file for approval. And then beyond that, our patents go out to 2032, and we would defend those. So a company would have to deal with both of those aspects.

Yes. And one would think there would have to be FDA guidelines here in the States. So they have to run studies in the States? Would that be your understanding? They're running studies right now ex U.S., but would they have to run studies in the States?

So the 2 that we're aware of by the Chinese and Iranian company, we don't believe that those would be registerable -- is that a word, registerable, in the U.S.

Andy, why don't you talk about what the studies may be -- would have to look like here if the agency was to try to give some sense of guidelines?

Well, I mean, as Julie said, so the -- firstly, you have to do a study in ulcerative colitis or Crohn's disease. And the IBD studies are tough, and they're doable. You can do an IBD study. When we run -- and we run many of them. When you run an IBD study, you assume about 0.1 patients enrolled per site per month, 0.1 patients per site per month. So you're talking about a site -- and half the sites typically that you'll bring up in a trial, if you're not good in the area won't enroll a single patient. So you're talking about one patient per site per year. So it's -- so you need 150 sites to run one of these studies, and run a bioequivalent study is probably -- I don't know what the numbers are, 400, 500, 600 patients. It depends what you've negotiated with FDA. So they're long studies, and they're not simple studies. The endpoints -- there are endpoints that you can run into troubles with. So the investment in running that study is large, and the risk of running that study is large. And as Julie is mentioning, you complete one of those studies, and then you have to deal with a legal battle. So there's some disincentive.

And so we're talking about maybe a few years, even if we saw anything show up on clinicaltrials.gov, which I would imagine something would have to show up on clinicaltrials.gov to a certain extent.

It would be 3 to 4 years. And don't forget, there's a 1-year period. So it's going to take some time once the study is done, it's database [indiscernible] to submit your file, and then it's a year of review. And you don't have any opportunity for acceleration. So 3 to 4 years to run the trial, a year for a review. So you're talking probably 4 to 5 years' time something gets out.

And when we first met you all, you were actually the most conservative management team talking about 2026 as the exclusivity. So -- and you said, think 2026. A little bit of a change. Is it just kind of the industrial knowledge, just knowing the landscape or getting a feel for the landscape that there's no one there? Kind of what changed with...

I don't find you conservative, but that's okay.

So what changed? I mean now we feel -- we seem to feel very strongly. And again, it's something that the Street, I think, appreciates, but maybe not fully appreciates. We really have a tripwire here. I think we would know if there was something that was moving forward. So anything that kind of changed fundamentally that you saw that made you all feel differently about it?

So I guess I would say part of it is the fact that we haven't seen anyone enter into clinical trials. So that gives us some level of confidence in terms of the extent to the time line or the extending of the time line. And then I think we got more comfortable with -- also with the patent landscape as well.

Okay. All right. Why don't we move to immunology, just kind of a little bit of a background. You're exhibiting really nice growth. Can you just talk about that franchise, some of the puts and pulls maybe as we look forward. Is there any reason to believe that we're not going to see the same consistency we've been seeing going forward? And some of the challenges maybe you see ahead.

Sure. So what everyone is talking about here is the entrance of the anti-FcRns into the marketplace in terms of myasthenia gravis, which they received approval for, and they're on the market now. So the big question is how much of an impact they'll have in CIDP, which is a much larger indication than MG? So right now, they still don't have approval yet in CIDP, but we believe that there's still a long runway for growth for the immunoglobulin portfolio. If you look at the biggest uses, so I'm going to combine primary immunodeficiencies and secondary immunodeficiencies, there's big drivers of growth outside of CIDP. They cannot be -- or immunoglobins cannot be replaced by anti-FcRns for those 2 areas of use. And they represent, combined, roughly 40%, and there's still a long runway for growth in primary immunodeficiency because of the level of under diagnosis and treatment levels. So that's why we still feel confident probably in the 5% CAGR range for long-term growth of the immunoglobulins. And that's the same if you look at external research as well.

So you touched on this a little bit. But as we think about argenx' potential Q2 results in CIDP, how should we think about the potential moat that immunoglobulins might have? And just you alluded to heterogeneity of this disorder. So just can you talk about what split you might see?

Sure. So we haven't seen anything to date that would change our perspective on this. The CIDP population is a heterogeneous population, and today, immunoglobulins are the gold standard for treatment. And if argenx or other anti-FcRns demonstrate some level of efficacy, it's great for patients to have an alternate option, but I highly doubt that there would be a treatment option for 100% of patients just given the nature of the disease and how it shows up. So when you look at that, there's going to be room still for immunoglobulins to play a role in terms of therapeutic options for these patients. And we'll just have to wait to see what their data shows to see how that decision-making will turn out in terms of treatment options for those patients.

Okay. And you have a development pipeline in PDT. So recently, you disclosed positive HYQVIA results. Do you want to provide some background in CIDP and how you think it might work against other subcus in the space?

So we are waiting to see regulatory approval for CIDP indication for HYQVIA. So this is based on the GAMMAGARD LIQUID or KIOVIG as it's known outside the U.S., molecule. So it's the same molecule that has demonstrated years of efficacy in this space, and it is just a subcutaneous formulation. So we're looking forward to this. It provides another option for patients. So instead of having to have an IV infusion, you can have the option for subcutaneous, which has some benefits for patient side effects as well as convenience not having to go into physician's office or hospital outpatient setting in order to get your treatment.

Okay. And what might be the potential administration profile? Is it going to be monthly? Or have we disclosed any other details?

Sure. I don't know what we've disclosed, to be honest. But in the trial, what was tested was every 2 weeks.

Okay. So if we could move to Andy. TAK-279, I think, is now what it's called. Just very briefly provide an overview on the Nimbus acquisition. Was it a competitive process? Provide some background on the asset before we dive into some upcoming data in a week, I guess.

Sure, sure. So this is a TYK2 inhibitor. It's the -- it will be the second in class TYK2 inhibitor. But as we've said, it has all of the opportunity to become a best-in-class. And we firmly believe based on the pharmacology and the data that we've seen, the Phase II data in psoriasis that we've seen and that you will all see in the next couple of weeks, we think it has really great potential not just in psoriasis, but broadly. So you asked about the process. So over the last year, following some of the setbacks that we had in '21, we made 2 decisions. One is just to double down our investment in our innovative pipeline, which I know we'll talk about. And the second was to go out and look for strategic bolt-ons to drive near-term growth for us. And so about a year ago, we saw the TYK2 program, it made a lot of sense for us as an IBD company given the potential of this mechanism in IBD. And so we started engaging with Nimbus in a conversation. There were still very significant risks to a second-in-class at that point. One was that -- so TYK2, the BMS competitor hadn't gotten its label yet. And there was some concern that the TYK2 class would actually receive a black-box label aligned with the JAK class. That didn't happen. And the second was that they hadn't read out their Phase IIb study. So while the pharmacology suggested they could be better than to TYK2, there's no activity on JAK for TAK-279, whereas at higher doses there may be with the TYK2. So we felt that there was an opportunity to dose higher and drive more efficacy, but we haven't seen the clinical data yet. So we waited for the Phase IIb data to read out. When that did, we were then in a very rapid process. It was extremely competitive. And we've been doing a lot of this over the past 5 or 6 years, and the management team has gotten quite proficient, worked very closely with the -- our Board to ensure that we had degrees of freedom as we went in. We were very disciplined in terms of the numbers that we were willing to go up to. And then we put a deal in place that had a couple of very large milestones and very big commercial inflection points, $1.4 billion in sales and $1.5 billion in sales. And I think that, combined with the fact that we knew the team quite well, we had a good relationship, they trusted us that we won it. It was a really intense weekend.

So as we think about the benchmarks where we're going to get the Phase II data at AAD. You've talked about the TYK2, what has been seen in their Phase II. Do you want to remind us what range of efficacy we might expect in terms TAK-275 for the primary endpoint? And then as we think about the more selective TYK2 inhibition, what kind of side effect profile should we also be looking at?

So firstly, in terms of what to expect. So if you -- so to a large extent, BMS has already done the experiment, right? Because they've actually -- they have a Phase IIb study where they go up in a dose that's essentially fivefold higher than the dose that they brought into Phase III. So you can go back to their Phase IIb data, and you can see what they see across the PASI 75, 90 and 100. And those are just endpoints looking at 75% clearing of [indiscernible] skin, 90% clearing and 100% clearing. Whole field is moving towards the right, focus on really truly essentially functionally curing these patients with their psoriatic plaque. The -- so TYK2 data, you do see a dose response on PASI 75, but that dose response becomes even more robust as you go to PASI 90 and even more robust as you go to PASI 100. So that's kind of a benchmark for all of you to think about when you see our data. In terms of side effects, we don't hit JAK. So there's no -- there's -- just biologically, there's no plausible reason to think that you'd ever pick up a JAK side effect. The -- you'll see the safety profile, but we know this is an interferon signaling pathway. We know that there are multiple different drugs that inhibit signaling through this pathway. They all have. And so TYK2 has this in their label. There are issues with respect to mild viral infections, upper respiratory tract infections, very mild COVID infections. And those are all now in the TYK2 label. Those are the kinds of side effects that we're expecting to see. Of course, if you would go up to 100% inhibition, and we know this from the genetics, you could put patients at risk for more severe side effects. But there's a window where you can go up high enough to drive more efficacy, but not towards 100% where you start to see more severe side effects.

Okay. And if we could think about the potential competitive landscape, there are other oral TYK2s in development. So to the extent that you're willing to comment, how should we think about your due diligence when you're thinking about Nimbus versus others?

Well, first, we're significantly ahead of the next in class. That's big. And then secondly, based on what we saw within this molecule, I don't think you can develop a better TYK2 inhibitor.

Okay. So psoriasis only at the beginning, and I believe there's also psoriatic arthritis. Potential results, I believe this year -- second half of this year. So do you want to talk about that opportunity, the next development steps as we think about other indications?

Sure. And Julie can comment on some of the commercial implications of working across such a broad range of indications. But psoriasis is clearly the lead indication. We'll start Phase -- 2 Phase III studies later this year, and the intent would be a launch. We've said so far, in the '25 to '27 time frame. But you can look at how long it took BMS to do their studies, and you could figure out our more precise timing. Psoriatic arthritis will be a little bit delayed. The Phase III studies will take longer than the psoriasis Phase III studies. Once we see the data from the Phase IIb study, we expect that those data to be positive based on what we know about the mechanism. We'll kick off Phase III studies likely in early FY '24. But then as you've said, there's a whole host of indications where we have either very strong genetic rationale or, more importantly, pharmacological rationale either from -- so TYK2 as in the case of lupus, for example, or in the case of the IL-12 and IL-23 inhibitors, which are upstream in the past, right? So you could imagine a dozen indications. Our initial focus will be on psoriasis and psoriatic arthritis and then on IBD, Crohn's and ulcerative colitis and lupus. And our hope is to really gain, this year, substantive momentum across those 5 indications.

Okay. And are you going to discuss timing for any of these programs?

Best. I mean we're just getting our head around it. We just -- I don't know when we announced the deal, it was about beginning of February. So we're in week 4 of having the ability to actually be primary drivers of this. And so our hope is that this calendar year, we have our Phase III studies in psoriasis up and running. Nimbus did a great job pushing momentum in those -- in that program. Our hope is that this year, we'll also have data in-house for the psoriatic arthritis studies. Crohn's, lupus and UC maybe slightly longer, but our hope is to really place those and get those going.

No. I know you all are not the finance people, but is it within the framework of kind of the current R&D spend that we're able to sneak this in and continue to kind of run the spending kind of as we're at right now? Is that really the go-forward goal?

That's the intent. Yes. Just tweaking for inflation. There's a little bit here and there, but we don't expect to have any significant increases in investment in R&D, certainly not to cover this program.

So I think this question might go to both of you. But as we think about the psoriasis Phase III program, what might a [indiscernible] design look like? Are we looking at versus OTEZLA? What are you trying to establish? And Julie, what do you think about the positioning within psoriasis? How should we think about an oral TYK2 versus other agents? What are you trying to establish? And do we need other synergies? Do we need to add other presence in dermatology for this to work?

So look, I think the way that we're going to approach this is similar to the way that we've approached, for example, bringing transplant on. It's not an area that we necessarily have a commercial presence in today, but we know how to build it. And we believe that with TAK-279 and given, hopefully, the differentiated profile that it's going to have, differentiation is how we're going to win when it comes to patients. Patients want clear skin, full stop. So that's what we're going to be focused on, and we'll be positioning it, hopefully, as the product that delivers that to individuals who suffer from psoriasis.

Okay. So moving on to orexin. I know on the last earnings call, you disclosed some information about starting your Phase IIb study. So do you want to provide some background, what you've seen -- or willing to discuss what you've seen so far in the Phase I. Why you decided to launch at risk, I guess, the keywords you guys used.

Yes, yes. The -- so this is TAK-861, which is our second oral orexin 2 receptor agonist. We're developing it right now in Type 1 and Type 2 narcolepsy with the potential to expand into idiopathic hypersomnia and other sleep weight disorder cycle -- sleep weight cycle disorders. So we actually accelerated this program right from the beginning because we knew once TAK-994 had been discontinued because of liver toxicity -- this was a lead molecule. We're quite excited about the molecules. It's quite potent. The dose is significantly lower than the doses that we studied for TAK-994. And we set up a set of criteria, standard Phase I, PK tolerability. Of course, liver safety was a criteria that we used. We actually did studies both in sleep deprived healthy volunteers and in Type 1 narcolepsy patients as part of our Phase I program, and we set up an efficacy bar that was equivalent to the one that we had set up for TAK-994 to make a go decision. And then importantly, because drug-induced liver injury is a function of exposure, we set a dose back. So it had to be efficacious at a dose that was in aggregate over the course of a day 10 milligrams or less. And so we achieved all of those parameters, and we, at risk, have been setting up our Phase IIb study within a week of unblinding the Phase Ib data. We had our first site activated. And then within a month, we enrolled both our first patient for Type 1 narcolepsy and our first patient for Type 2 narcolepsy ahead of our neuroscience group. So it's not just the industry competitive. It's industry bashing.

Wonderful. And so I know it's been asked before, but we'll ask again. The Phase I disclosures, I know there's more of a competitive landscape now, but would you be willing to provide any updates [indiscernible] on that?

Not here, sorry. I mean we're still -- the issues, I think, are around -- as you said, they're around the competitive landscape and trying to also put together a more complete story that we can present. So we're in the process of, over the course of this year, mapping out the time line for disclosures, but we're not going to push -- keep pushing it out. And if there's an obligation to share data at some point that goes beyond competitiveness is good for the field, and it's good for patients. So we have TAK-994 data that we haven't shared yet, our Phase IIb data, very extensive data sets. Now the TAK Ib -- the TAK-861 [indiscernible] data and then also TAK-925, we're pursuing in hospital indications in patients who are at high risk for post-anesthesia complications during surgery. So we have data sets from each of those 3 that over the course of this year we'll be rolling out.

Okay. Wonderful. And the Phase II for the narcolepsy patients. I believe on clinicaltrials.gov, we have primary endpoint in the middle of 2024. Is that when we should expect next data or...

So I'm not sure again when we'll be presenting those data, but we'll do an interim analysis as part of the study. And we're going to -- our goal is to push that study as quickly as possible. And then we'll provide a little bit more granularity at Q4 with respect to time lines for that program now that we're in Phase IIb.

So Jazz and Sumitomo, they initiated their Phase I healthy volunteer study, I believe it's also sleep deprived, in Q4. So they're going to get updates this year. Are you going to provide any commentary on the competitive landscape? I believe there's others in development as well.

Well, I think it's a really exciting mechanism, and we were the innovators here. And I think that our learning through multiple molecules will help us, but it's also very competitive. And so we're very aware of the competitive landscape. Of course, we have a sense for the molecules that we're competing against. And I think we still believe that we have not just the forerunner, but the best molecule.

Okay. So ahead of your March 15, I believe, Qdenga Investor Day, just remind us the timing of the planned launches. You've taken the time to get 4.5 years of data. So in the meantime, discuss the level of preparation you've made just as we think about the safety overhang of potential -- of previous dengue vaccine launches.

So I think this is an area where we've been very careful given the previous situation to make sure that, as you've mentioned, that the safety data is there to support use in both exposed and nonexposed individuals. So we're launching in Indonesia, I believe, is the first market, which is outside of my remit, but very excited for that launch. In the U.S., we'll be looking at the travel and military markets.

Okay. Wonderful. So Andy, back to you. I know there's -- recently, we got some Phase IIb results for TAK-999, your collaboration with Arrowhead. So I want to talk about the indication, recent results and Phase III design?

Sure. So TAK-999 is an interfering RNA. It knocks down alpha-1 antitrypsin, and in particular, mutant forms of alpha-1 antitrypsin that is known as PiZ. These are active enzymes that when secreted are active, but tend not to -- gets secreted from the liver. They tend to form aggregates in the liver. And those aggregates in patients can over time cause liver toxicity, cirrhosis, and then without liver transplant, death. And there's no treatment for this disorder. Patients, how many patients are there with alpha-1 antitrypsin 2 deficiency, 150,000, 200,000?

Less than that.

Less than that. And then maybe 30,000 to 40,000 will end up developing as part of their course of disease, liver involvement. So we've seen -- we partnered with this -- with Arrowhead very early on after seeing 2 or 3 patients with the data because what we were seeing in terms of potency of this molecule in terms of knockdown of this mutant form of the protein was just remarkable. And as we carry the program forward to uncontrolled Phase IIa data to now the controlled Phase IIb data, we continue to see 90% knockdown of the mutant protein at an RNA and a protein level, we see 70% to 90% knockdown of liver globules. These are the pathological aggregates that exist. We see benefits on liver enzymes directionally. And even on liver biopsy, we started to see benefits, very small numbers of liver inflammation and even directionally on liver fibrosis. So we're really excited about this program. We're -- any day now, we're going to have our first patient enrolled in the Phase III study. And that's a study that we've had extensive discussions with the agencies on because tracking a new regulatory path in an area that's quite complex, a lot of similarities to NASH. The benefit that we have here is that it's a homogeneous genetic disease. So kind of much easier to understand the pathophysiology, and therefore, a bit easier to understand dose selection and endpoints.

Okay. Can you walk us through the competitive landscape? Now we have a little less insight now that based [indiscernible] brought in-house. So what's the potential opportunity, competitive landscape? How should we be thinking about the market? I guess it's for both of you.

But as Andy said, this is a very specific subset within the alpha-1 antitrypsin group of patients. And so while it is a targeted area, it is an area of very high unmet need.

Okay.

Well, and on the liver side, this -- and firstly there's nothing that looks as good as what we have. There's nothing as advanced as what we have. There are oral agents that have been put into the clinic. You might know of some of them. And I don't think that any of the oral agents will have the combination of the efficacy and safety that we'll have.

Okay. I know we have a lot of other pipeline programs that are moving forward. We asked this last year, so I'll ask it again. Do you want to pick a few programs that you think are interesting that we should be paying attention to?

Sure. So one would be modakafusp alfa. So we've talked a little bit about modakafusp alfa, not a lot. We just missed that crest of accelerated approvals. We're about 6 to 12 months late. It's very frustrating, actually. And -- but we're perseverant. So we have to -- so what is modakafusp alfa? It's a CD38 antibody that targets interferon and antibody drug conjugate to cells that express CD38. So unlike depleting antibodies that -- like daratumumab, which will go and deplete cells that express CD38, like myeloma cells, we don't have a depleting antibody. It's just a targeting antibody. It binds to a very different epitope than daratumumab. But carrying in that payload, major [indiscernible] payload it activates an [indiscernible] response, immune response in these cells. So it's a completely distinct mechanism of action. And what we've seen in next Phase I/II expansion study, it's about a 40% to 50% response rate in very highly refractory patients. These are patients that have been through as many as 10 lines of therapy. And what's quite interesting is, firstly, is those that are very durable, deep responses. So we see durations of response above a year in patients who are responding. And then also really interesting is that patients who have refractory to daratumumab respond to modakafusp alfa. So it's really interesting. We have to step now through a more formal process given Project Optimus, which is the need to dose range. So we're doing that for monotherapy. So we have now single-arm study that we're bringing forward. Right now, we don't have an agreement with the FDA that we can get approval off of that noncomparator study, but we'll see. But our base case will be now in combination settings with daratumumab and other agents. Right now, we're just trying to figure out what that -- what the combination should look like in terms of dose, understanding safety and then we're going to start significant programs, pivotal studies in that. We're really excited about that molecule.

Good. Okay. This is probably a good time to wrap it up. Thank you for both doing this and joining us. I'm just going to repeat that at 4.5% yield, 8x EBITDA, we have no pipeline factored, and the pipeline is meaningfully changed here with Nimbus. It's exciting times ahead. So we thank you, and we're glad to be recommending your stock. And hopefully, things keep working out. Thanks.

Thank you very much.

Thanks.