Akash Tewari. I am a Farm and Biotech Analyst here at Jefferies. Day one of our London Healthcare Conference, and I got the pleasure of hosting the Jade Management Team. Why don't I hand it off to you for some intro remarks, and then we'll get started with Q&A?
Absolutely. First of all, thanks so much, Akash, for hosting us here and all the support in our recent financing and just helping us essentially get the company off the ground. Yeah, very pleased. I'm Tom Frohlich. I'm the CEO here at Jade. We're a fairly new company, actually. We got founded officially in June of 2024, but we've made exceptional progress. We have a really high-quality team. Andrew and I actually both come from Chinook Therapeutics, so a lot of experience in the IgAN space. We've managed to recruit across most of the experienced development team from Chinook, so have a lot of experience moving the programs forward. We've founded the company actually off of three assets that we accessed from Paragon, which many of you probably know is a very high-quality protein engineering company with half-life extension capabilities to develop best-in-class therapeutics in autoimmune disease.
Our lead program is an anti-APRIL, initially going to be developed for IgA nephropathy, an area we think is a very large unmet need. I believe it's a $10 billion+ opportunity in the U.S. alone. We have strong conviction the anti-APRIL is going to move to become foundational frontline therapy because it has disease-modifying potential in that indication. We just initiated a Phase 1 healthy volunteer study there in August of this year, moving towards a very, very important readout in the first half of next year, which will allow us to move, pending positive results, into patient studies very, very, very quickly. We've also recently just disclosed JADE201, which is our second program that we've also accessed from Paragon. It's a eufucosylated antibody targeting BAFF-R, so following in the footsteps of ianalumab at Novartis, potentially targeting many, many different autoimmune indications.
Basically, anywhere where rituximab is responsive, we believe we can have better B-cell depletion for a longer duration of action to get better overall efficacy with a more convenient dosing profile. That program, we anticipate getting in the clinic in the first half of 2026. We have a third program, which we have not disclosed yet, which we anticipate getting into the program in the first half of 2027. That is all underpinned with a strong financial position. We're well-resourced to fund all of those trials into the first half of 2028.
Understood. Thanks so much, Tom. I'm going to start off with kind of we just had ASN, and your team has taken—I frankly would agree with you—that you don't really need BAFF in IgAN. Can you comment? I mean, we got some POVI data. I think we saw data from anti-APRILs. We saw data from APRIL BAFF. We saw data from maybe weak BAFF inhibitors, like some assets from China. Help us just kind of do a review for the sake of it. There was a ton of data that came out, and let's do it on a couple of things. Number one, do you see any proof that you need BAFF to have remissions in IgAN? Number two, do you see BAFF contributing any way to eGFR slope function?
I think lastly, when we think about therapeutic window and infection, do we expect the APRIL BAFFs at their go-forward doses to actually have an issue with infection, or they're largely going to get around that issue?
Yeah, great questions, Akash. Maybe I'll just do a super quick recap of the ASN data and how we fit into that. Then Andrew, you can take the questions around the role of BAFF. Yeah, it was an exciting time. Actually, ASN gets more and more exciting every year. I've been going every year since 2018. I kind of joke that when I first started going there, they were selling dialysis chairs in the exhibit hall, but now people are very excited. There's actually disease-modifying therapies that are coming out that they can start using. It really reaffirmed our idea that IgAN is going to be a large prospective market. Key data updates there from Vera, Vertex, and from Otsuka. I would characterize the Vera update as very consistent to their Phase 3 top-line disclosure. They showed 42% placebo-adjusted proteinuria results.
Subgroup analysis that were largely consistent with what we anticipated. Vertex had some really interesting data from their Phase 2. It is Open-Label, not placebo-controlled data, showing good results at 48 weeks. They had a 64% proteinuria reduction. No placebo there, so it wasn't placebo-adjusted. If you go actually look at the 36-week time point, which most people are comparing to, it was about 56% reduction. Right in line with kind of what we would expect. The data there that was actually the topic of discussion, I would say, is in that Phase 2. They had five cases of hypogammaglobulinemia. People were trying to dig into that a little bit. The nephrologists and the KOLs didn't seem too concerned. It wasn't involved with an overall increase in infection, but that was sort of the question that came up there.
Kind of leads us to believe, though, with the sibeprenlimab data, that that's really what we want to be focusing on, those selective anti-APRILs for the reason you pointed out. And the sibeprenlimab did have an update there. Good news was there's continued decrease in proteinuria. Their data update in June had a 51% placebo-adjusted reduction in proteinuria at week 36. Continued to decline. They had a 12-month data set showing a 54% decrease in proteinuria. As with all of these agents, you get continued improvement in proteinuria over time, which is very encouraging. What did stand out from the sibeprenlimab data was when they did look at the subgroup analysis, there was no difference in terms of age, sex, or race on proteinuria reductions, but there was a difference when you looked at geographic regions.
There was a lower proteinuria response in North and South America compared to the rest of the world. Not fully explained through the data set. It was a small number of patients, about 20 patients. We've had a theory that they're not optimally blocking APRIL at their Phase 3 and the dose that they're taking for commercially. They switched from IV body weight-adjusted dosing in Phase 2 into a flat subQ. The one difference you could imagine with North American patients is that they're typically heavier, a bit bigger. Potentially they're not getting that same level of response. That said, we'll have to see more analysis. The data set was small, so it could just be within the margin of error. We do think it leaves a lot of room for further improvement in the dosing interval.
The last update from ASN before I hand it over to Andrew was that I think the importance of convenience in this market was really highlighted. Vertex and Vera were spending a lot of time trying to differentiate on convenience, talking about a 0.46 ml injection versus a 0.5 ml injection and what's better for patients, the prefilled syringe versus auto injector, where it really highlights that in this patient group that are typically diagnosed in their 20s and 30s, have very few comorbidities outside of their kidney disease. They need lifelong treatment. That convenience is actually going to drive a lot of differentiation. That is where we feel with JADE101, we have another really good opportunity where we think the largest differentiator on convenience is going to be dose interval.
If we can get to the Q8 week dosing, so six injections a year or less, we think that that's going to be very valuable if we can get to that point. That was sort of the highlights of ASN. Do you want to talk a little bit about the questions around BAFF?
Yeah. What we've seen with APRIL inhibition clinically, whether it's selective APRIL inhibition or dual APRIL BAFF inhibition, is really remarkable disease-modifying impact in IgAN. Significant depletion of pathogenic Gd-IgA1, large reductions in proteinuria, and most remarkably, eGFR stabilization. We believe the clinical data supports that APRIL is driving that disease-modifying efficacy, and adding BAFF does not provide additional clinical benefit. When you add BAFF on top of APRIL inhibition, you do not get deeper pathogenic IgA reduction. You do not get deeper proteinuria reduction. Most importantly, you do not get better eGFR stabilization. The reason we believe this is the case is that IgAN is a plasma cell-mediated disease. This is an APRIL responsive cell type and not a BAFF responsive cell type. Historically, rituximab has not worked in IgAN. Selective BAFF inhibition has not worked in IgAN. APRIL inhibition, whether alone or in combination, provides disease-modifying benefit.
We believe that targeted APRIL inhibition provides the full efficacy available to B-cell modulation without unnecessary broader immunosuppression that's accompanied by BAFF. We know what BAFF inhibition does with Benlysta approved in lupus and lupus nephritis, and it does result in significant B-cell depletion over time. Without the ability to contribute to better clinical benefit, we just think this represents a potential liability relative to targeted selective APRIL inhibition alone.
Understood. Now, there is something pretty, I think, provocative about the sibeprenlimab. I can never pronounce it, but that data set, because your team has always talked about.
Sibe, yeah, you're right. You're 100% right.
You guys have talked about, hey, I want exposure to be kind of at that eight-meg dose. Did you guys prospectively think that there was going to be an issue as they went from IV to subQ in terms of anti-APRIL inhibition? Number two, how does that kind of change your own markers in terms of the dose and the exposure that you want to get? Maybe lastly, and I think this is where it gets a little provocative. My team and I, we've really struggled to. Anti-APRIL doesn't look like a great PD marker. I just haven't seen it correlate super strongly. Is there something about the not only depth of anti-APRIL knockdown, but the duration that might be critical here that you can read with the sibe data that came out at ASN?
Yeah, so what we saw in the sibe P hase 2 study was three different dose levels, 2, 4, 8 mg per kg, IV body weight-adjusted dosing. All three of those doses at peak produced max APRIL suppression, but they had different durations of APRIL suppression such that only at the high dose, the 8 mg per kg dose, did you maintain full APRIL suppression in all patients through the dosing interval. It was that dose that was associated with the best clinical response, the largest reductions in proteinuria, and the highest rates of clinical remission, returning proteinuria back to the normal range. We believe this data set suggests it's not just the magnitude of APRIL suppression, but the duration of APRIL suppression that's important in driving the full disease-modifying efficacy. That can be achieved safely.
The high dose, 8 mg per kg, which wiped out APRIL in all patients, was safe, well tolerated, no increased risk of infections relative to placebo control. That really supports our approach with JADE101 and ultra-high affinity half-life extended anti-APRIL, where our goal is to provide the full efficacy available to the APRIL MOA with a convenient, infrequent subQ dosing schedule.
Okay. All right. I'm going to hit you with my wonky theory, which I've alluded to. I want to get it on a transcript. This goes back to actually the telitacicept, the RemeGen data. I think a lot of investors look at that data and they say, okay, they're never going to replicate a 0.9 mg ADL response, and that kind of is it, right? When I look at that data set, I can't really explain the amount of data they have, you just can't ignore. I mean, I know it's in China. There might be a question of how it extrapolates, but it's not something you can ignore. You have a drug that drops IgGs 20%-25%. You have a drug that drops B-cells 20%-25%. There's no infection. I can't help but look at that drug and say that is a weak BAFF inhibitor.
There is also a dose response with that drug. And you're getting, or at least that drug is getting mg ADL responses and drops that I think are very, very competitive in the class. How do you interpret that data? Do you feel like, and this is for, by the way, for gMG, do you feel like that's a sign that even incremental BAFF inhibition in gMG is adding something, or is it a sign that maybe anti-APRIL has a more profound effect in a disease like gMG than we maybe have thought?
Yeah, it's a great question. We wouldn't have a priori thought of an exciting opportunity there because the autoantibody in that disease is largely IgG. And APRIL inhibition has relatively modest effects on IgG, maximum reductions of 30%-40% from baseline relative to the 60%-70% reduction you're seeing for IgA and IgM. Historically, Benlysta has not worked in that disease, suggesting that it's really not a BAFF-driven disease. And could there be an unexpected role for APRIL inhibition? We'd love to see that data set replicated outside of China just to ensure that it's robust and reproducible.
It does highlight the potential for APRIL to have broader therapeutic potential beyond IgAN, where we think it's just really tailored as this master disease driver, but not something we've yet considered exploring. We'll be very open to the opportunities from both the dual APRIL BAFF inhibitors as well as lifecycle management strategies from sibeprenlimab, where they are evaluating sibe in a Phase 2 Sjögren’s disease study, an indication that's typically been thought to be B-cell mediated, but going after the plasma cell could be an interesting strategy. We'll definitely follow where the data leads us.
Yeah. So what we've disclosed is what we're going to do with our clinical development plan for JADE101 is we're currently in a Phase 1 healthy volunteer study, as I mentioned. The readout is in the first half of next year, which we think will be very de-risking for the asset and extremely informative for us because in IgA nephropathy for that development pathway, the translatability of healthy volunteer data to patient data is extremely high. We'll be able to look at that depth and duration of APRIL reduction, understand the IgA curve and the reductions. Coming out of there, we'll have a really good degree of confidence in what we expect to see in terms of clinical activity in IgAN patients. Importantly, we'll be able to pick our dose and our dose interval to allow us to move really quickly.
We won't have to do dose range finding in Phase 2. We'll be able to move really quickly in IgAN. What we have said as well in terms of lifecycle is that we will start exploring once we have that data and we've started the trials for IgAN, that we will explore different indications. We've talked about IgM-mediated diseases, so things like multifocal motor neuropathy. We have a conviction that we can have a benefit there, but we're open to looking at other indications as well. We'll look at how sibe is performing in Sjögren’s and explore other areas as well to understand how do we optimize lifecycle.
I'm going to put you a bit on the spot here because I don't think we're getting another gMG data set with anti-APRIL, right? We aren't. We're going to get Sjögren’s and that's probably going to be more reactive T- cells. You know what I mean? When I look at very potent anti-APRIL inhibition, the interesting downstream benefit is you render BCMA functionally silent. I don't think that's well understood by people. Again, you look at even the Cartesian data where that's another drug where you have 20% B-cell reduction, you have 20% IgG reduction, and they seem to have efficacy that, again, maybe there's a subset of dendritic cells that are really driving the disease. You're reprogramming the immune system. I mean, why couldn't this be the ideal drug to give after an FcRn? You're not dropping B-cells. You're not causing an infection risk.
I don't think you're going to get another data point at this point outside of your drug working, which I hope and I expect it to. Are you guys ready for the capital lift if, let's say, you do want to look into broader indications? If it is, it sounds like MMN, but what would you do? What would you have to see to pull the trigger in an indication like gMG?
Right. Do you want to talk a little bit about the sBCMA and then how we're thinking about that? Before that, yeah, from a capital point of view, I think we'll need to see the Phase 1 data readout. We're moving 201 into the clinic next year as well. We'll be looking at 03 as well in the first half of 2027. In terms of the scope and extent of lifecycle exploration, you're right, it'll be capital-driven. If we feel like we're in a good position to explore, then we're definitely open to it. We'll have to see kind of what the situation looks like at that time.
Yeah. Just like very naively, focusing on the APRIL biology, you just gravitate towards IgA and IgM-mediated diseases because of the large effect. It is really ignoring the potential you're highlighting that could be more broadly impactful. Pathogenic autoantibodies can tend to drop greater in magnitude than normal antibodies. In these IgG-mediated diseases, there could be potential. We perhaps do not fully appreciate the complex mechanism of action of APRIL, as you highlighted, the receptors like BCMA as shed and serve as circulating decoys and potentially bind APRIL to neutralize and block up, but potentially other downstream pathogenic effects. There could be potential to exploit this additional kind of yet-to-be-defined biology of APRIL. Given the safety profile has been so clean, it would represent an exciting opportunity in any of these autoimmune diseases if it could be disease-modifying like it is in IgAN.
Understood. Now, going back to IgAN, I think the pushback I'll often get from investors is like, look, gosh, like once two drugs get on with accelerator approval, that quote-unquote pathway kind of shuts down. I don't know if your team's ever really agreed with that paradigm. How do you respond to this idea that, you know what, I don't see an accelerator approval pathway for Jade? Why is that wrong?
Yeah, I think the FDA in this division especially is extremely data-driven. The reason why they accepted proteinuria as a reasonable surrogate marker is because there's such a strong correlation between decreases in IgA and long-term kidney function preservation as measured by eGFR. What we've seen is several drugs now from different classes go through that pathway and really demonstrate that proteinuria is probably not only a reasonably likely surrogate, but maybe even like a full surrogate over time. We see that as that going away is extremely unlikely. One thing that's actually very exciting actually also coming out of ASN is the FDA is starting to recognize it's harder and harder to keep patients on a two-year eGFR placebo-controlled trial. You've had some conversations with investigators. I don't know if you want to describe that.
Yeah, the FDA has requested to reconvene the Kidney Health Initiative, which is that group that led to the validation of proteinuria as a surrogate, a partnership between FDA and ASN, in the recognition that maintaining patients on a two-year placebo-controlled trial in the setting of multiple approvals is becoming increasingly challenging. They really want to explore new study designs in this evolving landscape that can still support innovation in IgAN. In conversations with KOLs, we believe the proposal to the FDA is going to be shortening that eGFR confirmatory part of the study from two years to one year, which sets up well for the anti-APRIL mechanism, given that you get large and early separation in eGFR from placebo. You do not have acute hemodynamic effects that confound the interpretation of those early eGFR changes.
We think that this is a very encouraging sign that will support continued efficient development of IgAN programs into the future despite these early approvals.
Understood. Now, kind of going back to that VOR data, I think the provocative angle is also you can fine-tune your level of BAFF inhibition and APRIL inhibition, right? You think about a disease like Sjögren’s where maybe reactive T- cells play a bigger component. When you think about how much BAFF inhibition do you quote-unquote need, like Spire, Apogee, these are areas where you might be able to fine-tune OX40 versus OX13 versus TSLP. We do not talk about that yet for Jade, but are we making a mistake? What is your team doing in terms of figuring out the right level of inhibition for Sjögren’s so that you get the right recipe here, right?
Yeah. Sjögren’s is a potential indication for JADE201, our anti-BAFF receptor monoclonal antibody, really following in the footsteps of ianalumab from Novartis. They did report out positive Phase 3 Sjögren’s data recently at ACR with large reductions in SDI, the primary endpoint from baseline, but relatively modest placebo-corrected indications on disease activity, despite showing in other studies really deep peripheral B-cell depletion, as well as significant B-cell depletion within the salivary gland of Sjögren’s patients. That's a data set that was a little bit underwhelming from an efficacy perspective. Two things we were encouraged by in that data set was the very good safety profile of long-term B-cell depletion with a BAFF receptor monoclonal antibody in Sjögren’s patients.
Novartis's data showing acute monthly resulted in better data than a Q12 week dosing interval with JADE201 with incorporated half-life extension to provide more extended BAFF receptor coverage with a goal to potentially drive better efficacy with a more convenient subQ dosing strategy. Right now, we're not sure if there's an opportunity for JADE201 in Sjögren’s given that underwhelming Novartis data and see potential additional readouts in other indications like ITP, lupus, lupus nephritis, systemic sclerosis, or other first-in-class indications where rituximab is the standard of care and ianalumab is not being evaluated. Right now, we're focusing on delivering JADE201 into a first-in-human study in RA patients to generate the PKPD and safety tolerability to support development across this broad potential autoimmune program.
Understood. We're out of time. Thank you guys for humoring me. I really do appreciate it. Thanks so much.
Much appreciated. Thanks, Akash.