We're good? Okay. All right. Let's start back. Thank you everybody for joining us for our next session. I'm Marc Goodman, one of the biopharma analysts at Leerink Partners, and we have Biogen next. Very interesting, Head of West Coast Hub, Utpal Patel. I'll let him give a little bit of background of how he got to the company and how this West Coast Hub has been started. Very interesting for the company to do that, you know, through this acquisition that you'll hear about. Obviously a very interesting asset that we're gonna go through all the different indications and stuff. I do think maybe just for 60 seconds, just give your background and how the West Coast Hub is.
Like, what does it look like and how it's evolved, what the goals are.
Sure. Well, my name is Utpal Patel, as Marc mentioned. Thanks for having us. We'll be making some forward-looking statements, so just the usual disclaimers to look at the risks in our SEC filings, because those results might end up differing materially if I talk about any future risks. I'm a nephrologist. I was in academia, took a career detour into industry to try to develop new treatments for people with kidney disease, and joined a company a few years ago called HI-Bio, or Human Immunology Biosciences, that was really focused on developing targeted immune therapies for severe unmet needs. They had licensed a molecule, felzartamab, from a German company called MorphoSys, that had started proof-of-concept studies in three different indications.
All of those read out positively, and we were looking to advance them into phase III and get this to patients. Biogen was a wonderful partner that emerged, aligned with our vision of advancing all of these and saw the broader potential, potentially for this targeted anti-CD38 approach. Decided to build a unit around it, around the original HI-Bio team that formed in South San Francisco that gave Biogen a connection to the West Coast that they had lost with the IDEC campus years ago, allowed us to retain some of that startup feel, and act quickly. In the past year, we launched those three phase III studies. We were 45 people initially, and we've hired over 100 people, and establishing a bigger team as well while we pick up new programs.
There's also a connection to the research unit that Biogen's been evolving with its new focus in immunology that goes back many decades, but a more dedicated one with the pipeline that is bicoastal. Part of the research team sits in the West Coast as well as the East Coast.
Thank you. You mentioned felzartamab, you know, as the key asset, or I don't know if you mentioned the name, but that's the name that you got. Let's talk about that product. Let's talk about the different indications. What was the first indication that was the most obvious?
The most was actually primary membranous nephropathy.
Mm-hmm.
That's a quintessential autoantibody-driven disease. 80% of people with that have an autoantibody that's very specific to a specific protein on the podocyte, one of these cells in the kidney that helps form the filtration barrier, and that's to a protein called PLA2R. Anti-PLA2R positive membranous nephropathy was an indication where we had a few different proof-of-concept studies. They were our initial readouts, and we were very excited about moving that forward, but investors actually didn't like the two-year endpoint that was required. This was during a tough funding environment. We still believe in it and have advanced that program to phase III, see it as an important opportunity. What kind of stepped in front was antibody-mediated rejection.
Some really compelling results from our phase II proof-of-concept study in AMR kind of put that as the lead indication, and that indeed is the one where we'll have the data readout most early.
Should we start with AMR?
Sure.
Kind of go through that, and then we'll come back to that one. That was the idea. That was the engine. Okay. Let's go through AMR. Talk about.
Yeah. AMR stands for antibody-mediated rejection. It's a complication in people who receive kidney transplants. It is one of the leading causes of late kidney transplant loss. Once people develop it, over 75% will lose their grafts within a matter of years. The median time to graft failure is about two years. Classically, it was believed to be caused by donor-specific antibodies, so antibodies that the host develops against the recipient's organ. There was evidence that anti-CD38 approaches could work, and a group of investigators approached MorphoSys, asked to be supported for an investigator-initiated trial, and they ran that trial in 22 people at two sites in Europe.
It was a small study, but very well done by two key investigators who had been part of the AMR trials for the prior few decades, knew what they were looking for. All of those other proof-of-concept studies were 20-40 patients, so similar size. They designed it very well to include serial biopsy samples. They had AMR diagnosed prior to inclusion at six months and one year. It was a one-to-one randomized trial where people were dosed with felzartamab if they were randomized to that arm for about five months or a nine-dose regimen given over five months.
The biopsy assessment at six months, sort of shortly after stopping that course of therapy, was the primary endpoint, and that showed dramatic reversal of AMR by histology, and that's a diagnosis that is defined by some criteria called the Banff classification criteria for rejection. The key score in it is a component called the microvascular inflammation score, which scores the inflammation around the vessels of the glomeruli and the peritubular capillaries. What we saw in that small phase II was that not only did over 80% of people have reversal by histology, but over 2/3 of the participants treated with felzartamab had scores that went down to zero, and that had never been seen in the field before.
They knew that this therapy was potentially transformative, and we quickly tried to get that moving forward into a phase III, which is now being run and look forward to sharing updates about.
Yeah, let's talk through. What is the design of that?
The phase III design is larger, 120 patients. It's global, mostly Europe, North America, South America, Australia, New Zealand. People will be randomized to felzartamab or placebo. Similar design, biopsies necessary to inclusion. Primary endpoint is at six months, and people will be followed to one year. Same dosing regimen for the first six months for felzartamab, but what we saw in phase II is that the AMR activity came back in those who had therapy that was stopped, and so we're gonna continue dosing into the second six months for those originally randomized to felzartamab. Because of the overwhelming efficacy we saw in phase II, the people in placebo will cross over to active therapy at six months.
That was really important because dropouts have been an important part of these trials. We didn't want that to happen.
They wanna make sure they actually wanna be in the trial. Yeah.
Wanna make sure the patients stay and complete the study.
Yeah. Interesting. Okay. The study is just.
The study is enrolling well.
Enrolling well.
We'll share updates as we get to the end of that. That'll allow us to start the one-year clock, but we expect to have a primary top line readout next year.
Which-
With filing next year.
Right. Sometime next year. Give us a sense of the market for this indication. What does it look like?
In the U.S., where we have very good data, there's about 300,000 people plus who are living with a kidney transplant, and somewhere around 23,000 people have AMR. The group, the subset of those that meet the criteria for this trial that are generally have had the transplant for at least six months have donor-specific antibodies that are positive is about 11,000 people. We know that pretty well 'cause this is a population that's followed very closely, and there's you know routine monitoring. People usually don't drop out of care. It's 11,000 people roughly in the U.S. alone.
Okay. Well, first of all, this one study should presumably be enough for an approval?
Correct. We have breakthrough
In the U.S.
designation.
Right
... Orphan designation, and have the ability to interact with the agency.
How do the other regulatory agencies around the world feel about this?
Similarly excited.
This should be good enough for the Europeans. It should be good enough for the Japanese as well, just as far as.
Yeah. We're not running the trial in Japan.
Mm-hmm.
The transplantation programs are a little different there.
Europe.
Europe.
For sure.
For sure.
Yeah, Japan might make you do something with their own patients, right? They like to do that.
Yeah. That's okay, 'cause we have data in Japanese participants from our IGNAZ study.
Mm-hmm
We can do that. Transplantation's a little different. They don't do as much deceased donor kidney transplantation, where the rates of AMR are higher.
Oh, I see.
Um, so the-
The market's just completely different.
The numbers of people who are living with a kidney transplant are much smaller.
Right. Okay. It's 11,000 that are right now and is that a growing-
That's a growing number.
Yeah.
There's over 100,000 people on the wait list.
Yeah
For a kidney transplant. It is the preferred treatment for kidney failure. People can survive on dialysis, but the five-year survival is 20%, so people don't do well on dialysis, versus transplantation can prolong life to almost near age equivalent.
Yeah
That'll continue to grow.
What's the competition look like? What's the standard of care? What are people doing?
The standard of care is really anchored on this older idea that donor-specific antibodies drive the disease. Nothing's approved, but people have essentially developed a routine of trying to extract the antibodies through plasmapheresis or interfere with their activity through administering routinely scheduled intravenous immunoglobulin. Neither of those are really effective in reversing AMR, but it's all people have, so they're sort of used in practice. I think the evolution will be now that there's a potential therapy, like a targeted therapy like CD38, you know, that'll change. The other therapies in the pipeline are really complement-focused around complements. There's a C1s inhibitor. Alexion has their own targeted complement inhibitor.
These you know are downstream from the pathogenesis of AMR, where targeted CD38 therapies deplete not only the autoantibody-producing cells or the alloantibody-producing cells in this case, but they also remove natural killer cells, which also express CD38 and are the drivers of this disease. That's sort of a newly recognized part of the pathogenesis that our studies helped elucidate.
We're gonna talk about the other indications in a second, but when you think about them, is this the indication that has the least amount of so-called competition, you know, probably?
I think so.
the one where you're probably the leader if it executes on the study, you know?
We believe so. The other studies that are out there are in phase II. Us being in phase III, I think we've got a good lead.
They're complement inhibitors too, so this-
Correct
completely different.
Completely different.
Yeah. Interesting. The pricing for this product?
We haven't gone into details about it.
Yeah
Just if you took a back-of-the-envelope calculation, you know, current IgAN pricing as an analog for a rare kidney indication somewhere, you know, north of $200,000, just approximately. You could do the math, but essentially for an indication with a defined population of 11,000 people, that's over a $2 billion market.
Yeah.
Like you said.
You get half of them, you've got a billion-dollar indication.
Exactly. You know, the goal is to continue to suppress the AMR activity in those who we can treat, the prevalent patients we can treat, and there'll be new incident patients along the way.
Yeah, I was just gonna say, to me, like this seems like the one where you can check the box and feel the best about the opportunity in addition to it's probably gonna work, but, you know.
Yeah. What we're really excited about is what we hear from patients and clinicians.
Yeah.
You know, it really has restored hope for a lot of people. Losing an allograft once you've got this lease on life that you know helps you avoid dialysis is devastating for patients. We're very excited about that.
Good. Okay. That's AMR. Where do we go next? IgAN?
Well, before we leave AMR, we'll talk about MVI real quick.
Yeah, let's do that. Forgot.
So that's a-
Yeah.
That's a-
I like that indication.
Newer recognized indication. It stands for microvascular inflammation. Again, with the Nature Medicine paper we published last year based on the phase II studies, we showed that NK cells were directly responsible for this, AMR pathogenesis. MVI is a newer entity where the donor-specific antibodies are negative. They can be negative for a variety of reasons. They haven't met the threshold yet of being positive. It's earlier in the phase of developing full-blown AMR with DSA positivity. A really nice epidemiologic study was published in late 2024 in The New England Journal that was from a number of international registries, and they looked at the outcomes of people who have this MVI, which was identified with an updated classification of that Banff criteria that I mentioned.
The 2022 classification included specific criteria for this group of patients 'cause there was growing recognition that their outcomes were almost as bad, and that's what this very nice epi study showed, that they have graft loss rates almost as bad as DSA-positive AMR. The size of that population in the U.S. is about 5,000 patients, so again, the opportunity to have an impact in a large number of people.
The plan is what? We're starting a phase II study.
The plan is that we've started a phase II study. We've enrolled the first participant this month. Very excited about that. It's gonna be at the same centers that we're running the phase III. We've got some synergies and efficiencies there. That's a phase II study that'll, you know, potentially be registration enabling that we're excited about.
Could be pivotal. Interesting. How many patients did you say in that study?
That one has 81 patients.
Okay. The other one was like 100.
120
20 or so. Okay. Got it.
slightly smaller.
Slightly smaller.
Yeah.
Okay. Very good. The pricing on this indication would mesh with the other indication, you think?
Yeah. AMR, we expect that people will require ongoing dosing, and so that's sort of the context for AMR. IgAN, which is probably the next indication we can talk about.
Okay. Yeah.
You know, a little different, larger population, a lot of other therapies, and some competition. What we saw in our phase II IGNAZ study, that was published, the people who received the nine-dose course over five months then weren't given treatment again, through two years, and they had durable efficacy from the nine-month assessment of reduction in proteinuria all the way out to two years off treatment. That is, you know, a really compelling additional therapeutic opportunity for patients. The pathogenesis makes sense, so rather than suppressing the maturation of, the B cells into these, professional antibody-producing cells, the plasma cells, plasmablasts, felzartamab depletes them.
Gets rid of them entirely until, you know, they reform either from maturing from memory B cells or there's a new activation of that person's disease that puts them there.
Let's talk about IgAN a little bit. What kind of proof of concept do you have so far?
The phase II study was a modestly small, 54 participants across four dosing arms and an additional Japanese cohort. The four doses were placebo, two doses over two weeks, five doses over two months, and nine doses over five months. A Japanese cohort that got the nine-dose regimen was followed up to only one year. The other participants, we have two-year data on. When we look at the results, you know, what we see is again about a 50% reduction, placebo-adjusted reduction in proteinuria, which is on par with the other therapies that are out there with, you know, durable effects out to two years. No suggestion that they're gonna increase. We saw very good safety.
We saw a pattern of immunoglobulin decrease that's different than some of the other therapies out there. We see modest drops in immunoglobulin G, total IgG, with return to normal a few months after dosing. That gave us confidence that in the long term, this could be really potentially differentiated. We have you know, the ability to not treat chronically. We don't interfere with the earlier B cells. We also showed during our phase II study that was run during COVID, that people would mount a normal immune response to COVID vaccinations, for example. This is important because, you know, some, there's obviously, you know, all sorts of risks that people might be susceptible to with chronic therapy.
If we talk about the competitive market, what's it look like?
I think there's three buckets of therapies out there. The first is sort of the foundational class of therapies that, you know, really treats the injury that exists. There are CKD therapies that generically will help minimize the decline in kidney function but not be disease modifying. That's the SGLT2 inhibitors, ERAs, MRAs, on top of ACE inhibitors. The next group is a group of therapies that can help treat active inflammation driven by complement. Complement gets activated because of immune complex deposition in the kidneys, and those immune complexes are formed by the galactose-deficient IgA1 that is the hallmark of the disease, and the autoantibodies to it that plug up the kidney filtering units and cause inflammation.
If you stop the production of those abnormal antibodies and the autoantibodies, then you presumably will have fewer immune complexes and potentially not have the need for a complement inhibitor. That's the benefit of the last group of therapies, the ones that essentially are probably disease-modifying that include the APRIL pathway as well as the CD38 therapies. In the APRIL pathway, there's a lot of them. They have different, you know, features, but they're all looking to have about the same efficacy and safety, but they require chronic administration as soon as you stop dosing them. It's very clear that within three to four months you have a return of your proteinuria and other markers of active disease.
Interesting. Okay. All right, the phase III...
Phase III is underway.
Underway.
Global study going very well. I think that helps us see the enthusiasm and opportunity that patients provide.
It's the same endpoint? Just remind us.
Yes, similar design as all the others. Randomization 1:1, felzartamab, nine doses, or placebo. People followed up to two years with a nine-month interim analysis based on proteinuria. We also have a small sub cohort of people with lower levels of kidney function that we're interested in studying. Those people have GFRs between 20 and 30.
Got it. Okay. Good. Next indication. Should we-
Next we'll go back to PMN.
I was gonna say, let's go back to the start. Yeah. Which we over
Primary membranous nephropathy.
Yeah.
Again, quintessential autoantibody driven disease. What we saw in our phase I/II proof of concept studies was that the nine-dose regimen of felzartamab rapidly depleted this pathogenic autoantibody, PLA2R. The population we studied were high risk, so they had high levels of this autoantibody. That led to kind of a deepening over time, even past the interval of therapy. That, again, consistent with this idea that if you deplete the cells that are causing the disease, you can get durable efficacy. We did see heterogeneity there, and we did see some people have return of the pathogenic autoantibody close to one year. Our phase III design, you know, we took some lessons from the data we had, which was only up to one year.
We have essentially a trial that includes 180 participants randomized to felzartamab or active treatment tacrolimus, and we'll talk about where that fits in the constellation of available therapies. People who receive felzartamab will get the nine-dose course over 5 months at the beginning of year one, and then again at the beginning of year two. The approvable endpoint in this space is complete remission at two years. The available therapy. Today there's nothing approved, but you know, there's sort of three different therapies that people generally cycle through. The first is anti-CD20s wherever they're available. Those do work in a large number of people, but 20%-40% of people don't respond initially to therapy.
About 30% actually relapse after maybe an initial response. That probably reflects the biology that, you know, these plasma cells and plasmablasts that produce these pathogenic autoantibodies don't express CD20. That fits with this idea that there's really a need for something that actually gets that population of cells.
Yeah.
The other therapy that people can, you know, respond to is tacrolimus, or calcineurin inhibitor, which works through immune and non-immune mechanisms to reduce the proteinuria. It can't be given too long, otherwise it can cause some kidney injury, and so that's a real downside for that therapy. The last that generally works, but it can be quite toxic, is cyclophosphamide, essentially a chemotherapeutic agent.
Give us a sense of the size of this population.
In the U.S., about 36,000 people.
Mm-hmm.
It's sizable. There's, you know, I think room to sort of say, it might make sense in a world where there are available generics for CD20s to see if people respond to that. Then felzartamab, what we've shown is that, people who either relapse or don't respond can respond to an anti-CD38. The other patient group upfront that we think, you know, could really benefit are those that are really high risk. People with very high PLA2R titers generally have been unresponsive to anti-CD20 therapy.
Mm.
There's this, you know, I think still a good proportion of patients that would benefit from a targeted CD38.
Right. I didn't ask you, but the other population, the IgAN, I mean, that's over 100,000 patients. That's a big population.
In the U.S. estimate, you'll see, you know, different numbers, but at least 130,000.
Yeah. I forgot to ask you, but I think everybody knows that's a really big one.
Yeah.
Okay, good. What are some other indications besides those that you-
Yeah.
Yeah.
A couple things that we're, you know, working on is we recognize felzartamab in the format that we inherited it is an IV formulation. We're working on generating a subcutaneous format to optimize patient convenience and get this to as many patients as might benefit. We don't want that to be a limitation. The other is that, you know, I think we really believe in this target and are working on a next generation anti-CD38 as well.
Yeah.
The goal for that is, you know, that it really would help us expand beyond this initial set of indications. You and I previously have spoken about how, the original, people who developed this molecule, as well as the HI-Bio team that licensed it, you know, recognized that over time, out of desperation, a lot of clinicians have used anti-CD38 therapies that are available for myeloma off-label to treat very, you know, challenging patients with autoimmune diseases. There's an entire series of autoantibody-driven diseases that there's case reports or controlled trials for using available anti-CD38s off label to show essentially Proof of Concept, some safety, and kind of gives us a roadmap for other indications where there may be an opportunity.
Like what? Like, what are you thinking?
There's a number of dermatologic, neurologic, rheumatologic.
Are you really? Yeah.
... autoimmune disorders. Yeah, we're planning to actually start two POCs this year in a few additional indications and look forward to sharing that when we get it.
Still don't want to talk about it yet. Okay. Fair enough. What else? What else should we talk about in the last three minutes? We kind of went through all of that. What else is kind of happening at the West Coast Hub, and what other areas are you involved in and, you know?
Yeah, working very closely with the research team and, you know, thinking of ways that anti-CD38 might be paired either, you know, in combinations or sequential therapy for some of the new immunology indications we're going after.
Mm-hmm.
There's a lot of work there and working with them closely to help build out our immunology portfolio that's becoming quite exciting.
Are you involved, like, with the lupus studies as well or?
We're not directly involved. We've got enough stuff to do. We, although we've grown as a team, we're still much smaller than the development team that has been working on this for a very long time.
Yeah.
Yeah, they've got some exciting.
I'm just thinking, do any of these overlap with that at all?
No.
Commercially? I mean, they all seem.
Yeah, no.
their own little niche.
quite different.
Yeah.
I think, you know, the one thing to recognize is that the, you know, as people might say, "Well, you're looking at a lot of different indications. How are you gonna get this to patients? What's the commercial build gonna be like?" You know, I think if we just take AMR first, there's, you know, roughly 250 transplant centers in the U.S., but really most of the patients, you know, probably north of 80% are followed at, fifty to 100 of those those centers. That's not an unreasonable place to start. Many of those centers are specialized centers that also have, you know, the type of specialized glomerular disease clinics where difficult to treat IgAN patients and PMN patients are gonna be, so, you know, provides a nice foundation to build out further.
As we think about the rare kidney indications, IgAN, PMN, you know, there's about 10,000 nephrologists in the U.S., probably 5,000 are actively treating people with glomerular disease. What's happening in the space is that because of a number of new therapies in development, the community's recognizing there probably needs to be glomerular disease centers of excellence, which might sort of shrink that number even further by the time we get to the launches of IgAN and PMN.
Interesting. That's happening kind of behind the scenes right now.
That's happening in the community organically.
Yeah
because, you know, you want clinicians who are comfortable.
Yeah
helping patients get on the best therapy for them, and if you don't use these therapies enough, you know, you may not be familiar with some of the advantages or disadvantages.
Has there been a lot of consolidation in the doctors' practices of nephrology? You know, I've seen a lot of private equity kind of roll up a lot of industries. I didn't know if nephrology was one of them.
Nephrology's, you know, trifurcated. There's kidney transplant specialists.
Yeah.
There's you know just general CKD docs take care of patients inpatient or outpatient, and then there's some who focus on dialysis, and then there's obviously people who wear all three hats or two of the three or one of the three. There's always been large consolidation on the dialysis side. 80% of the market is-
Yeah
Controlled by two.
Yeah
two groups.
Certainly on the dialysis.
On the provider side, generally, there are larger practices. There's sort of strength in numbers.
Well.
Because of that, a lot of these larger practices will identify one or a few people to focus on glomerular disease, for example.
Yeah. Good. Anything in our last 30 seconds that we didn't hit on that you wanna say, or?
No. Thanks for the opportunity.
Yeah
to chat.
Good. No, it was great. Thank you. Thanks for the overview, and very exciting. I mean, that's a product with, what do we do? Four indications?
Four indications and adding.
Right. Two coming.
Yeah.
Who knows? It's the next DUPIXENT. Right?
Chris would love to hear that.
All right. You tell him that.
All right.
Thank you. Great to see you.
Thank you, Marc. Yeah. Thank you.
All right. Appreciate it.