Analysts here. Our next presenting company is Climb. From the company, we have two executives here. We have the Chief Executive Officer, Aoife Brennan, and we also have Susan Altschuller. She's the Chief Financial Officer. Ladies, thank you so much for joining us. I was just discussing, it's been a very busy year for you guys. Aoife, why don't you make some opening comments, maybe recap a little bit, and then focus more on the things that we should be focusing on, and then we'll go into sort of some Q&A that I have prepared for you.
Yeah, delighted, and thanks so much for being here. We're a local Boston company, so it's always a highlight conference for us where we don't have to get on an airplane, so it's wonderful to be back again. Climb Bio, for those of you who don't know us, we're a public biotech company focused on developing B-cell targeted therapies for autoimmune indications. We believe that there's tremendous opportunity to continue to advance on some of the science around specific B-cell targets, particularly in diseases that are undertreated or haven't had very many therapeutic approaches. That's kind of our overarching strategy. Underlying that, we have two assets. The first asset is a CD19 targeted monoclonal antibody, and then the second asset targets APRIL, which is a circulating cytokine that's an important mediator of B-cell differentiation and maintenance. So two clinical stage assets that are advancing very rapidly.
Yatin referenced a busy year, and we've literally been going from one data readout to the next. We haven't had a break pretty much for the last six months. So just a very active pipeline, a very active portfolio of studies that are now starting to yield some really interesting data that helps us to understand the potential of both assets, and helps us to really understand dosing as we think about advancing to one or more assets to phase III development over the next 12 months.
Got it. Very good. Let's maybe start with budo. First, maybe recap for us the PMN data that was recently presented at the Kidney Week. What were the learning in your view? How much more we could learn from the additional doses, the 600 and the 1,000 that you're testing, and what will be the next readout for the PMN?
PMN is a rare renal disease mediated by autoantibodies. There is currently no approved therapy. There is a therapy that is under regulatory review, which, if successful, would become the first therapy that has been approved for PMN. It is a very difficult disease for patients who are diagnosed with the disease because we are used to talking about proteinuria for IgA nephropathy, but these patients actually develop nephrotic range proteinuria, so they are having proteinuria excretion of like 5-10 g per day. When you have that amount of proteinuria, you end up with lots of secondary impacts, like they get swelling, you are predisposed to clots because you are losing your protective clotting factors in your urine, you are losing a lot of your immunoglobulins in your urine, so you are going to get infections.
These patients are often in disability, so it really is a life-altering kidney diagnosis, and that can be very, very challenging to treat. When we in-licensed budo, there was a study that had been started but had not been finished by the prior sponsor. It was just discontinued for business reasons. There was no study report written, but we kind of gathered the data that had been collected up until the point that we in-licensed the asset, and we saw a really interesting signal. This was a phase I-B study that was performed in patients with PMN. Eight patients had been enrolled. We had follow-up data on five of the eight, and what we saw was a 60% complete renal response at 12 months in this small dataset. That was really best in class of any product that had been studied in PMN before.
This was a really transformational efficacy signal. We thought, oh, that is really intriguing, but we want to finish the study. We want to get higher N. We want to be able to really explore the range of doses in this population. But we had this really encouraging early signal. We went back to the sites that had enrolled those five patients, and we asked, h ey, how is the patient doing now? It turned out that three of the four patients where we were actually able to kind of get anecdotal follow-up had continued to be in remission even though they were not continuing to get dosed with the monoclonal antibody. That was very intriguing to us, but obviously, we wanted to replicate the data and bigger N, make sure it was truly representative of the phase III population.
The data that you are referencing that we shared at ASN was really the first look at the data from the kind of continuation of that study, if you will. We restarted a study, a phase II study called PrisMN. It was evaluating three different doses. The first dose was 200 mg. That was really the only dose group that we had sufficient follow-up to look at some of the endpoints that are important in those patients. What we saw was that we enrolled a severe population of patients. They had very high mean proteinuria with 6 g per 24 hours at baseline, very high PLA2R levels. These were patients who were very resistant to treatment, unlikely to remit, and we were able to get a nice proportion of them to an immunological remission. We saw about a 73% reduction in PLA2R levels at 12 weeks.
These patients continued to be followed, but really encouraging early signal. When we went back and compared how these patients looked to the patients in the phase I-B at the 12-week endpoint, it looks like it is exactly in line with the early kind of looks at those data. So, it is really nice when you are doing clinical development that you can replicate data again in an independent study. It kind of makes you feel like, okay, there really is something real going on here. We are really encouraged and are continuing to follow the first cohort.
Yeah.
As well as continuing to dose escalate. We have completed enrollment in the 600. We are enrolling in the 1,000. We will continue to provide updates from those patients as we go into next year, but certainly off to a good start in terms of being on a solid foundation for the program.
Got it.
One additional piece of info I would add is that in the 600 mg dose, while it was less follow-up, you were really seeing silencing of B-cells.
Yeah.
There was a dose response. In a renal population where patients have baseline proteinuria of 6 g, you are losing drug in the urine.
Yeah. Yeah, that is what I was about to come to. At least on the B-cell kinetics, you were seeing a dose response. Do you think, I mean, when would you have an idea of the dose that you would take forward in phase III? Do you think 200 is the dose? It seems like most likely it is 600 or 1,000.
Yeah, I think that is a fair assumption. We are continuing to follow patients. What we have shared previously is we will make a decision about the phase III dose based on the PLA2R antibody levels. What we are really looking for is when do we hit that plateau in terms of dose response. We will continue to follow the patients for the proteinuria, which takes about a year to mature.
Yeah.
We are not going to wait for that to pull the trigger on moving forward to phase III. I think the 12-week endpoint would be a good time point to compare all three doses based on the PLA2R endpoint, and that would make our decision for us in terms of what dose or what exposure is required for optimal efficacy in phase III, and would make a decision on which regimen to take forward based on those data.
How would you characterize the phase III? What would be the size and scope? Do you need one study, two studies?
The precedent has been set that it is a single study, and the endpoint is a complete renal response.
Yeah.
That would be how studies are done and conducted. I mentioned earlier there is a product currently under review called obinutuzumab, Gazyva. They executed a study called MAJESTY. I think in the absence of additional information, that is a good proxy for what phase III looks like. It was a single phase III study. It is about 150 patients, an active comparator type of trial design. I think that is kind of our placeholder for now until we engage with regulators around the specifics for our program. Despite the fact that there are not many approved products, there is really a well-established regulatory pathway in PMN, and FDA have been very consistent in what they want to see.
Got it. Very good. The second indication, ITP, again, there was data recently that we have seen. What is your interest level in that, and what do you expect to present at ASH?
Yeah, we have upcoming data at ASH in early December. We shared some data in the first half of the year. Our understanding of the unmet need in this phase III population is there's about 18,000 patients in the U.S. currently
Yeah.
who've exhausted all available therapies for ITP, still have a low platelet count, have failed to respond to anything that's currently available. That's the group that we're targeting initially, and that's the population that we're enrolling in our phase I-B study. We had some very early data at EHA in June of this year, and we'll be presenting an update at ASH. What we're really looking for there is to do something transformational for these patients. Right now, in studies that enroll this kind of third-line ITP population, they achieve about 20% durable response. Often patients will have a blip in their platelet count, but it doesn't stay in the safe range. What we're looking for is platelets that increase and stay up.
Sure.
That's really the rate that we need to focus on, not just the single spike in platelet count, but the durable response data. We're looking for something that achieves that kind of a very high bar of durable response in a good proportion of patients, and I think that could be something that's very useful for this patient population that currently really has exhausted everything that is available.
Got it. That is an indication of interest, right? Provided you are able to show transformation efficacy, you would conduct a phase III?
Yeah, I think there is a commercial opportunity there. I think the phase III path is well understood.
Yeah.
What FDA want to see for approval. I think it is a very interesting opportunity for patients, a very interesting opportunity commercially. I think if we can achieve what we believe is a target product profile, it would be a go.
Got it. Very good. Moving on to the SLE, I mean, there was some new disclosure, right, recently. What were the key takeaways from there?
Excuse me.
Bless you.
SLE is a very devastating disease.
Yeah.
It's also been a disease where patients are more medically frail going into some of these immunotherapies. When we look at some of the other B-cell targeted therapies, often the SLE patients are the group that have the most issues around adverse events, and some of those adverse events have been unfortunately tragic in this patient population. What was really important to us, and also is a requirement of FDA, is that you start with very low doses. You're starting with minimally biologically active doses and then very gradually dose escalating, because these patients are coming in with immune systems that have been flogged by multiple lines of prior therapy. They're often on concomitant immunosuppressant therapy. The data that we shared last week is sharing the initial safety and B-cell depletion data from some of those very low doses. And we were really encouraged.
We are able to get B-cell depletion with very good safety and tolerability in these SLE patients. It does appear to be translating into some efficacy signals, albeit those very early.
Yeah, preliminary.
Not fully mature. We are really encouraged by the kind of benefit-risk profile that we see emerging for this naked monoclonal in SLE. Having said that, SLE is a difficult disease to take forward independently as a small company. We think it is very important, it is very de-risking for budo, but not necessarily something that we are rushing to take into phase III development, just given some of the complexity and resources required for that.
Got it. Would you expect a lower dose here in general? Do you think the 200 mg is sufficient in SLE versus, let us say, PMN, where you need a little bit higher dose?
Yes. So it's possible that there's a renal and non-renal dose.
I see.
That's not unusual for monoclonal antibodies, where because of the urine protein losses, that you need higher doses to get equivalent exposure.
Where there's a lot of protein spilling in the urine. So that's something that we've designed the protocol to address that specific question, and we're getting pretty close to being able to answer it, just based on the PK that we're seeing in both groups.
Got it. Maybe final questions on budo. Where are we on the subcu formulation? And as you move into the pivotal, will you run it with a subcu or you bring subcu later?
We are working towards having a subcu formulation. I think that it's not table stakes for any indication, but we like the optionality.
I see.
We haven't given a timeline exactly yet, but could we potentially start a pivotal study for pMN with a subcu? That is a possibility. More to come as we kick off 2027 and lay out all the 2027 catalysts.
Got it. Got it. Are we going to get any data from the subcu study that you are running next year? Is there any data coming?
Yes. Yeah.
Okay. There is. Okay. Moving to CLYM116. Maybe, I think the data that you have, I think you have two cuts of the data, right? You presented in September and then more recently. Just preview to us, what are some of the key learnings from that? Where are you on the hypothesis of depletion, whether it is free APRIL suppression or IgA reduction? How comfortable you are with Q8W and Q12W dosing?
Yeah, so for those who are new to CLYM116, it is an APRIL-targeted monoclonal that has a novel mechanism of action. It does not just bind APRIL, it is actually a sweeper, so it degrades APRIL. We believe, based on all of the data that we have seen to date, that APRIL is the best target in IgA nephropathy, which is going to be a big market for a renal-focused therapy. We have shared data now from two separate studies that are phase I in healthy volunteers, one that was based in Australia, one that was based in China.
So in totality, we have dosed about 90 healthy volunteers with CLYM116. We have taken it up to a dose of over 1,000 milligrams, really good safety, and a very solid foundation, I would say, for future development. I mean, as a drug developer, I really feel that the foundational elements of any program are PK/PD.
Yeah.
And we have a really good, solid understanding now, I think, of the behavior of this molecule in humans based on both datasets. And we've seen very consistent data across the, we'll call it the Caucasian and the China datasets. I think some of the key learnings from us are that we have a really long half-life. We've 33 days half-life in humans, which is the longest of any naked monoclonal. It's three and a half times the sibeprenlimab half-life. And we've been able to overcome this kind of very geeky PK concept called TMDD.
Yeah.
But it's a phenomenon that has acted as a ceiling for all other APRIL monoclonals, where you can't kind of get, no matter what modification you make, you can't exceed a certain half-life limit. We've been able to get around that with this sweeper mechanism. Downstream of PK, we see really good target engagement as measured by free APRIL suppression. So we're really aiming to take something into phase III that's a Q12W dosing interval. And to do that, we've always believed that you need to get free APRIL suppression through the dosing interval. We've been able to achieve that. Downstream of APRIL, you have Gd-IgA1, which is the pathogenic form of IgA that actually forms these complexes in the kidneys in patients with IgA nephropathy.
And we've seen best in class Gd-IgA1 lowering, both in terms of the magnitude of the lowering as well as the duration of the lowering. So I think this is a molecule that has great safety, long PK, really good PD, and we're excited to advance it to phase III. Before doing that, though, we have this check-in, which is the phase II data. So we do want to take it into a cohort of patients with IgA nephropathy. That study is ongoing, and we'll have data from that trial in the first half of next year, and then subject to regulatory alignment, starting a phase III study shortly thereafter.
Got it. So the meeting with the FDA is ahead of that phase II completion, and after this, when you'll meet with the FDA on the IgA side?
I will never tell you when we're meeting with the FDA. But as soon as we do get alignment, we'll absolutely disclose that and talk about our plans and what the design of the phase III study is.
Got it. And then the reason to use the 800 mg loading dose is to do what?
To get patients to steady state more quickly.
More quickly.
Without the loading dose, when we look at our modeling, what happens is it takes about three or four doses to get patients to steady state exposure. With the loading dose, it allows us to give them a jumpstart on that, so you get to steady state by about 12 weeks. In a study where you have a 12-month endpoint, taking that amount of time to get to steady state is a bit of a problem. If we get to steady state faster, we just have the effective concentration for a much longer period of that kind of follow-up interval of one year. That was important for us to get there and to ensure we have optimal success in phase III.
Just to be clear, it's an 800 mg
Yes.
dose, and then 12 weeks later, it's a 400, or eight weeks later
Eight
it's a 400. It's a pretty simple, straightforward.
Yeah
loading approach.
Correct. Yeah. You are just trying to figure out whether eight-week or 12-week, right, with the same loading dose.
Exactly.
How many patients in that study?
The study is on ClinicalTrials.gov. It is 30 patients per arm.
Arm.
We've disclosed that the first look at the data, if you will be when we have 10 patients who've completed 24 weeks of follow-up. That would be three rounds in the Q8W and two rounds in the Q12W.
Got it. Is that data sufficient for you to go to the FDA and figure out, or you need to wait for all 30 patients and have data?
Well, we can't speak for the FDA, but scientifically, our company position is that this study is really around confirming safety, PK, and dose in terms of the APRIL suppression.
Yeah.
We think 10 patients is sufficient to do that, and that should be adequate to de-risk the phase III dose selection. Obviously, FDA may push back and say, no, I want to see proteinuria, which is longer time or more patients. We don't know the answer to that.
Yeah.
But certainly from a company perspective,
Yeah
that's what we think is appropriate for phase III initiation.
Got it. What is your view on the IgAN market? Obviously, it is competitive, but what does your market research suggest? Do you need a quarterly dosing, eight-week dosing? What sort of share you could get under various scenarios?
Yeah, so I think it's an emerging market. My sense is we're probably in the I watch a lot of baseball with my son, so we're in the first inning of what's going to be kind of a 5- 10-year market build in IgA nephropathy. It seems competitive because just there's been this rush in because the market opened up with the FDA alignment around proteinurias and approval endpoint or accelerated approval pathway. So I think there's a lot of market build, identification of patients, getting them to the appropriate treatment centers, biopsying patients who have asymptomatic proteinuria. A lot of the work that needs to be done over the next couple of years is going to be educating prescribers, educating, screening, and making sure patients are finding their way to appropriate treatment.
I do think we likely still underestimate the size of the market. I think there's plenty of room for multiple programs to be successful commercially here. What we hear from investigators and prescribers is that treatment burden is going to be important for these patients. So even without differentiation on efficacy or safety, being able to give something that's less burdensome for patients is going to be important for long-term compliance. These are patients with silent disease until they get renal failure. They're not looking in the mirror and seeing something every day. So something that patients can really easily take for a long time is going to be important. We think there's an interesting commercial opportunity.
Got it. What additional data are we going to get from Mabworks in China for this molecule?
They had some data at ASN.
Yeah, we saw that.
which I think was very consistent.
Yeah.
We had just dosed the 1,200 mg, but we didn't have any follow-up data from that top cohort, so there will be some additional healthy volunteer data to come going forward. Then obviously the phase II data set as well, which is been That's a study that's been done jointly by Climb and Mabworks.
Yeah.
There will likely be a joint presentation in the first half of next year.
And how-
That's one advantage that we also have with our partnership in Mabworks. There's 40 sites for the NAVIGATE-2 study, and that should help us accelerate when we go into a pivotal.
Absolutely. What about the other indications? How you are thinking about other indications that you could consider for CLYM116?
We admittedly haven't done a huge amount of work on lifecycle management because we've been really focused on executing the studies we have ongoing. We know that there are a number of different diseases where APRIL plays a role from a pathophysiological perspective. The work that we need to do is understand where the biology makes sense, but where there's a commercial opportunity that fits with an IgAN pricing and market structure. That's work that we really had to do. We get a lot of ideas from people, have you tried? Have you thought about Sjögren's? Have you thought about IgM-mediated diseases? I think there's a tremendous amount of potential there. It's just a matter for us of sieving and working out what makes sense in the context of moving towards phase III in IgAN. More to come on that.
Got it. Would you move in something like PMN? Because I think other BAFF-APRILs are going there.
Yeah, we believe CD19 is probably the best target for PMN. We're certainly right now, some of the data from some of the BAFF-APRILs hasn't been compelling enough to get us excited about that. But I think there are some other diseases where APRIL biology makes tremendous sense, and yeah, we're doing the work to work up some of those.
Got it. Maybe then just final question. How is the financial health? How should we think about the burn rate as programs move to phase III development? How will that evolve?
Right now, our cash runway gets us into the second half of 2028, but that is also inclusive of all the pivotal startup and CMC spend. We want to make sure that we can move with speed to a pivotal for both CLYM116 and for budo.
Got it. Well, very good.
Great.
Thank you so much.
Thanks so much for having us.
Thank you.