Okay, good morning, everyone, and as I keep saying this morning, happy Friday the 13th. But on a serious note, we're delighted to be hosting our Virtual Immunology Symposium. This is David Amsellem from the Piper Sandler Biopharma Research team, and we're delighted to have Biogen with us for the next 25 minutes or so. So we have Dr. Diana Gallagher. She is the Head of Clinical Development for MS, Immunology, and Alzheimer's. So thanks so much, Diana, for taking the time to chat with us. Certainly there's a great deal going on regarding Biogen's immunology pipeline and some late-stage readouts that are coming. Maybe I'll start with your lupus programs.
So you have dapirolizumab and litifilimab, both in late-stage development. But I wanted to ask a high-level question on the strategic rationale of prioritizing lupus, specifically SLE and other manifestations of the disease, given that it's historically been such a challenging space in terms of drug development. So, you know, I guess with that in mind, you know, why such a big priority to lupus? Obviously, it's a major unmet medical need, but just given the challenges, maybe talk about your thought process here.
Sure. So, we've been working. First of all, thanks for having me, David.
Sure.
We're really excited to be here. You know, you're right, lupus remains a very underserved, heterogeneous disease area, major unmet need-
Yeah
-where patients need more treatment options. We have been working in lupus, it's not new, you know, for Biogen.
Mm-hmm.
BDCA2 program, or BIIB059, now called litifilimab. You know, we've had, you know, we did the IND now, you know, over a decade ago. So we've, we've been in this space a long time. We've had our collaboration with UCB, looking at CD40 biology for a long time, so-
Mm-hmm
-two decades, and we've learned a lot, as has the field, over time, I think, about the biologies that we're going after, as well as, you know, sort of right target, right patients, and excellence in execution.
Yeah.
I think we feel like now those three pieces are really lining up for us, and we have, you know, iteratively discharged risk, you know, along the way as we've gone from, you know, sort of research to early development, to late-stage development, with these specific assets.
Yeah. Just a general question on dapirolizumab and litifilimab. How do you think each of these. And we have more data, late-stage data for dapirolizumab, I'll concede that, but how do you see each of these addressing the limitations of, you know, the existing biologic treatment options, specifically belimumab and anifrolumab?
Yeah. It's a great question. I think we know that lupus is seriously undertreated.
Yeah.
Even in the United States, we're only seeing anywhere from 20%-30% of patients get on biologics therapy. Of those, you know, most of them don't reach what our American College of Rheumatology targets of lower limits of disease activity and steroid-sparing. Because, you know, you can be diagnosed with lupus 15, 20, 25 years old. If you're heavily reliant on steroids, the comorbidities you're going to develop over time are substantive. You know, you really start to have a lot of side effects. So we think people are undertreated. We think that the drugs that are available are manipulating biology, but we may be able to bring even more compelling, you know, efficacy. And the patients say it best: "My lupus is not your lupus," they say to each other.
Right.
I think people are going to have to. You know, often, you can't be diagnosed with something at 18, and it works for you until you're 88, right? You might have to cycle through different drugs. We know they have different organs manifesting at different times. They may be flaring and need a certain sort of efficacy profile, and then they quiesce because it's-
Right
-this relapsing and remitting. So you're constantly wanting to titrate their medication, and more options are going to allow you to bring all the efficacy and limited side effects for a lifetime, you know, of treatment in lupus.
So, maybe, you know, paraphrasing you, great deal of disease heterogeneity ultimately lends itself to, you know, the need for a multitude of different advanced treatment options. I mean, is that a good way to think about it?
It's a great way to think about it, and it's very exciting. You know, not only our work, but you see the field really moving. I think you're right. Lots of times people thought if five, ten years ago, it was very difficult to execute in this space. I think we're starting to show, the biology's breaking, the clinical trials, you know, are moving in the right direction in terms of execution, and hopefully we'll bring a lot more options for these patients.
So diving into litifilimab, this is a BDCA2 receptor-directed therapy. Can you talk to the underlying mechanism here and its role in disease pathophysiology, not just in SLE, but also in cutaneous lupus? I know there's a trial, a more advanced trial in CLE. So maybe talk about, you know, mechanistically, its applicability both in SLE-
Yeah
- and CLE.
Sure, it's a great question. So we've, you know, as I mentioned, have been working on this program for quite some time. It's manipulating this BDCA2, so that's something expressed on cells, often a particular type of cell, but not exclusively, called the plasmacytoid dendritic cells.
Mm-hmm.
We know that those cells are big producers of interferon, and we know that interferon drives a lot of sort of these interferonopathies or these complications that you start to get with inflammation, with bringing in other cells responding to inflammation, which is causing tissue damage. And so if we can break that cascade, so we bind, you know, when we break this idea of the BDCA2, you know, we'll stop that biology. And it's not just interferons. We believe, you know, downstream of that, we have TLR7 and 9.
Yeah.
We're starting to affect interferons and other relevant cytokines to really break this cycle. In terms of what does that mean? How does that manifest clinically?
Yeah.
I think we've shown it in multiple different spaces, but, I would think about it as overall disease control. So we hit overall disease control when we looked at SRI-4, which is a composite endpoint, but we also looked very specifically at two critical manifestations: skin and joint.
Yep.
And so we showed in the joints, you had reduced number, you know, of joints impacted in terms of tender and swollen, which allows people to sort of function much better. And in terms of the skin, and we can get into it because we're super excited, we got breakthrough designation for CLE. You can see, you know, anywhere a significant clearing of the skin disease, and the skin impact in cutaneous lupus is profound.
Yeah.
We're talking about massive alopecia or hair loss, often big flaking, scaling, and even scarring lesions, often on the face, but throughout the body. So the ability to, you know, calm that down and allow the skin to heal has obviously, you know, is physical improvements for them, but major mental, you know, health-
Yeah
and quality of life improvements.
So I wanted to switch gears a bit and talk about the heterogeneity of trial endpoints in SLE. So litifilimab, your primary endpoint is SRI-4.
Yeah.
I think dapirolizumab, the primary was BICLA response. So I'm just wanna better understand the rationale behind the different endpoints and the extent to which there's buy-in from the FDA here. I also know that these are accepted outcome measures, but would it be helpful to understand the differences between the two endpoints?
Sure. You're right. They are both, well, sort of characterized, approvable endpoints that have a lot—some differences and a lot of similarities.
Right.
So BICLA uses, it's like a BILAG composite sort of endpoint. It requires partial improvement across all sort of affected organ systems without any worsening.
Mm-hmm.
Well, SRI-4 uses this SLEDAI-2K composite score, and it requires a 4-point improvement. So it can be a little more sensitive to specific changes in specific organ systems. You don't sort of have to have across all sort of organ systems. You can also achieve efficacy by seeing specific organ systems.
Okay.
So I will tell you that in both our trials, we measure both. Both, like BICLA is primary, you know, for DZP, as you said, but we're also measuring SRI-4 as a secondary, and conversely, in litifilimab, SRI-4, we've chosen. We had, you know, been examining that. Both of them were the POC sort of endpoints, and we kept them for the phase III endpoints because we understood how to power and think about it.
Yeah
But we're measuring both in each case.
Okay. So it's the, it's really just a function of, I guess, the signal you saw in your proof of concept study, and you wanted to carry that forward in your pivotals. It's really nothing more than that.
That's right.
Okay. Okay.
Yeah.
That's helpful. So just moving on to, so there's the TOPAZ phase III program, which, you know, that's, that's reading out. That's a, that's an SLE. But you also have, AMETHYST in, in CLE for, for litifilimab. I guess one question I had here was, I think in, in part B of the study, it's a 24-week endpoint. It's a shorter duration, relative to the SLE study endpoints in, in TOPAZ. So, and I realize it's a CLE, not SLE, but wanted to better understand that difference in, in measurements in terms of duration.
Sure. It's a great question. We think about it in two ways.
Yeah.
In both the studies, we will go out to 52 weeks.
Okay.
So they're both looking ultimately over a year. In systemic lupus, of course, we wanna see the patients improve as quickly as possible. We, we all want that for them.
Mm-hmm.
We also wanna see durability, you know, of effect. So that is something that, particularly as we're entering that space, you know, and where we're sort of differentiating on options, some of which you mentioned are approved and more coming, we wanna see that onset, you know, and durability of effect in SLE. In CLE, we also wanna see. Again, we just talked about your hair is falling out, your skin is, you know-
Yeah
-massively inflamed. It's a more dermatologic-based condition. Speed of onset, you know, and resolution of those symptoms is something that we've heard from patients, you know, is, is critically important. So we will look, you know, at that 16-24-week endpoint, and then we will also look at durability of effect.
Okay, but to be clear, in part B, the endpoint, the primary is at 24 weeks. Is that right?
That's right. Yeah.
Okay.
As we went on that CLASI. Yep, looking at-
Got it. Okay, so I wanted to move to DZP. And regarding the successful phase III, and I know you have the confirmatory study that's ongoing, but I wanted to ask—just look backwards at the successful study. There was the BICLA response, but can you just talk about the steroid tapering profile that you saw for dapirolizumab?
Yeah, and this, you know, as you said, what are the lessons learned? You know-
Yeah
-from many, many sort of challenging clinical development programs in lupus. One of them is managing steroid utilization-
Mm-hmm
-particularly in large, multi, multi-center global trials, where clinical practice is different in different countries and, you know, and even with different physicians. So you really have to be very clear about what the steroid taper expectation is. Like, how much steroids are you on?
Right.
Almost have a protocolized, I'll call it force, but, you know, proper protocol steroid taper that they must attempt.
Mm-hmm.
And so we're really we know that's important for overall wellness. We know the guidelines push it, but you have to put per protocol to get it, you know, ultimately to see if it's statistically relevant, and also could be an, you know, something we could get in our label. So we did do that, and you see that we're quite encouraged that up to, like, a fifth of the patients were able to substantively reduce their steroids down to this 7.5 or 5 mg dose, which is really-
Mm-hmm
-where you're starting to get to say the long-term side effects are very differentiated. You know, that's where we really want them to be. So we were able to see that. Yeah.
Yeah. And then, regarding safety, I think and you had a webinar last year.
Yeah
-where you discussed the lupus pipeline, and you talked to the potential for Dapi to be used safely in pregnant women, and you had preclinical data showing that it doesn't cross the placenta. I was wondering if you could talk to that data and how you plan to leverage that in practice.
Sure. So, it is, as we sort of talked about at the top, lupus affects, you know, women predominantly, but not exclusively, and particularly young women who are often contemplating pregnancy or going through pregnancy. And most of the approved agents are not, you know. And all the off-label things people use are not approved for, often not, allowed to be used in pregnancy. Dapi is differentiated because it is a heavily pegylated molecule, so it just doesn't cross that placental barrier, at least as we can see in primates. And so the other piece would be, does it not get into breast milk?
So if you can create an option that allows for both, utilization in pregnancy to not cross to the fetus as well as post-birth, you know, to not get into breast milk and maintain high efficacy for these women, that's really differentiating.
Yeah.
Of course, it's not an approved therapy, so we're working hard, you know, to sort of think about most people go for this in a post-approval setting. You know, we're thinking right now, you know, and in dialogue, you know, with agencies about what would it take to, right?
Mm-hmm.
Start to examine some of these things, in parallel, or, you know, how should we be thinking about it? And-
Sure
-you know, ultimately, you know, that's something we'll have to have an aligned sort of pathway for, but it's definitely top of mind for us because of how unmet the need is.
So, looking at the R&D landscape for SLE, I mean, we're gonna see a number of readouts for orally available agents. There's Rinvoq, there's Sotyktu-
Mm-hmm
-there's the S1P modulator, cenerimod. I mean, all these phase III's are gonna be reading out in the next 12 months, and they're all mechanistically different, but wanted to get your thoughts on the potential for a more varied treatment landscape with if these oral agents or something, one or more of them were to work, and what that could mean for DZP and for litifilimab.
Yeah. You know, I think we don't see lupus, as we mentioned a few minutes ago, as a winner-take-all-
Yeah
-sort of market. We really see that with lifelong, you know, need, with a relapsing and remitting condition, and very heterogeneous condition, you know, there is plenty of room for patients to have optimized therapy that treats the manifestations of their disease as aggressively as possible, but, you know, across the range. So there are patients that will say to us, "I wanna be on as much medicine as I need and no more," you know?
Yeah.
And then as soon as I can come off it, I wanna come off it." So as you're working through that with them, you're gonna have to have, I think, a range of options. Also the organ systems, you know, at different times, and the flares are happening. I think we'll see. Yeah, of course, it would be, you know, the idea they'd love and maybe, you know, science is just probably not gonna be a one-and-done, set-it-and-forget-it biology for them, given the complexity.
Sure.
So that's how we're thinking about it. Of course, more options is, we look forward to that too, and we don't just have DZP and litifilimab. We certainly have an early pipeline-
Yeah
- thinking about moving into orals ourselves so that, so that we can bring a range as well.
Okay. So I wanted to talk about some earlier stage opportunities here. So you've got 122, the LRRK2 directed product.
Mm-hmm.
Maybe talk about that and its role in LRRK2 and its role in neuroinflammation. And, you know, what I kind of look at, an asset like that is the extent to which it could have applicability in other neurodegenerative diseases beyond Parkinson's. Maybe talk about that.
Yeah, I think we've, you know, that is a, a really interesting asset. It's been, you know, something that we have a large, controlled, randomized trial-
Yeah.
trying to figure out what it can do in Parkinson's.
Yeah.
It's not our first Parkinson's trial, nor are we naive to the idea that-
Mm-hmm.
You know, these are very, very challenging spaces to work and-
Yeah
-profoundly manipulate biology. They're hard endpoints, you know, to move, in Parkinson's. And so, you know, I think we sort of see it as that's something that we started pre-POC, high conviction in that biology, but a sort of higher risk, high reward component-
Yeah
-you know, of can we hit POC? And I think we've designed a nice trial that allows us to answer that question. In terms of applicability, you're right, that biology is interesting across. It's very, I think the most risk, you know, forward sort of place to put it, we sort of chose LRRK2 biology for Parkinson's.
Yeah.
I think that's where the best biology is. You see it in a couple other inflammatory conditions, but I don't think right now that's where we would put it. We really want to take our shot here based on our conviction with the genetics and the preclinical data.
Okay, that's very helpful. And then switching gears to O91. So, you know, the BTK inhibition, you know, is certainly, I guess, not new. But maybe talk about its utility in MS specifically, and how you're thinking about. Maybe the right way to ask the question is, just given how crowded MS has become, you know, what do you need to see here to really, I think, capture your attention and say, "Okay, this is something we really should move forward and really invest, you know, precious R&D resources in?
Yeah, great question. I think it is, as you said, it's a really interesting biology in the sense that, we know it manipulates, findings in MS.
Yeah.
We are certainly, you see, both the covalent molecules as well as these non-covalent molecules all having different degrees of impact, you know, on biology in MS. So we have the ongoing phase II study.
Mm-hmm.
That study is in relapsing MS. That study has a comparator even in it, which is pretty unique, right? We have, like, two doses and then Vumerity in it-
Yeah
-to really see where we are. So that allows us to get a very good sense, to your point. RMS is, it's a crowded space.
Mm-hmm.
So our threshold, you know, to enter into that space, will be appropriate to that crowding, you know, and needing to see what we need to believe that, that it's, differentiated. And so we'll get that full data set later this year and be able to take, I think, a really, informed decision, on that molecule. We also have initiated, a phase I study of our BTK degrader.
Yeah.
So we have, you know, that's in the clinic now too. So we have sort of two that would be differentiated, sort of, degrader biology that we'll have to sort of think about how we want to position that. So we still are very intrigued by BTK biology.
Yeah.
It works in lots of things, not just MS, as you see.
Mm-hmm.
But it's really to your point about proving out the differentiation so we know where to, you know, where to put the resources behind it, and it's likely to have the biggest impact.
Yeah, and I'm curious, just a follow-up question about the degrader. I know we're in early stages here, and you know, you mentioned MS, but just you know, just understanding the biology and mechanism here, you know, how are you thinking about, to the extent you can talk about it, you know, other autoimmune disease settings here? And again, bearing in mind, these are early days, yeah.
Definitely early days. You know, but I think we've spoken publicly, you know, on that idea.
Yeah
-that we are moving, you know, into this ideation of, like, these assets are not one sort of-
Mm-hmm
-one drug, one disease, but-
Sure
-you know, are sort of products which can create a whole portfolio. So multi-indication strategy, you know, is definitely on the table for you know, assets like we call it 145, the BTK degrader-
Right
-as well as 142, the IRAK4 degrader program.
Yeah. Okay. Wanted to spend just a little bit of time on felzartamab, and I know that, you know, over the next couple of years, we're going to have some, you know, really important data milestones. But maybe a high-level question. I know we have about a minute or so left, but, you know, looking at CD38, and you have, obviously, there's a big focus on autoimmune diseases in the renal setting. But maybe talk more broadly about, you know, CD38 biology and how you're thinking about broader development, not just the felzartamab, but I think you've started talking about a next-generation CD38 that came out of HI-Bio. I mean, how are you thinking about, you know, that target more broadly?
Yeah. So B-cell biology is a huge, you know, area of interest for us.
Yeah.
You've probably heard, you know, Jane Grogan, our head of research, and Nick Wilson, our head of immunology research in particular, talk about it. So you're right, antibody-producing B cells that express the CD38 are implicated in multiple autoimmune diseases. So it was a very sort of intentional choice that, you know, our legacy HI-Bio colleagues made to go after immune-mediated kidney disease.
Mm-hmm.
But that does not preclude going after, you know, multiple other indications.
Sure.
So, we definitely think that it's going to be involved in, you know, multiple other plays we could take, and that's why having, as you mentioned, a sort of additional asset, earlier asset, maybe, that we can tune up and tune towards different diseases, would be really great. So we're really looking forward to where we believe it can have an impact. And it may even be with the lead. You know, we can maybe do some more-
Yeah
-with the lead, but with the backup or the sort of next gen-
Mm-hmm
I think, we can sort of think about moving it into other inflammatory, you know, other autoimmune-based diseases. And it's, there's a lot of biology and reasons to believe-
Yeah
-there too.
Well, definitely more to come there. Wish we had more time, but I'll leave it there. But thanks so much, Diana, for you know, a really wide-ranging and deep discussion. Really appreciate it, and lots, lots, lots certainly going on, and you know, certainly an exciting year ahead in terms of data milestones. So really appreciate the time. Thanks everyone listening in, and we'll conclude. Have a great rest of your day.
Thank you, David. Have a great day.
Bye-bye.