We'll go ahead and get started with our next fireside chat. My name is Ben Burnett, biotech analyst here at Stifel. Pleased to be with Ronald Martell, CEO of Jasper Therapeutics. Ronald, thanks for doing this.
Ben, thank you. And on behalf of all of my colleagues at Jasper, I really appreciate the opportunity to speak with you today, and thank you to Stifel.
Fantastic. Maybe start just by giving a brief overview of Jasper, and we'll get into it.
Sure. Jasper Therapeutics, we are a clinical-stage biotech company. Our lead asset is a monoclonal antibody called briquilimab. Briquilimab is an antibody that was specifically designed to target c-Kit, and with that as a mechanism of action, we are conducting a handful of clinical trials in mast cell diseases, specifically chronic spontaneous urticaria and inducible urticaria, and we're about to dose our first patient in our asthma study.
Let's start with chronic inducible urticaria. You just had some data presented from your Spotlight study. Maybe talk about those data.
Sure. So inducible urticaria, there are a number of different environmental conditions that can induce urticaria. And a couple of those are life-threatening, like cold urticaria. In our Spotlight study, we specifically enrolled two types of inducible urticarias: symptomatic dermographism, which is a condition where even a potential light scratch on the surface of the skin can lead to significant hives and wheals in these patients. And the other patient population we enrolled was cold urticaria. And that condition can actually be life-threatening. There was a case at an academic center where one of the techs didn't know that they had cold urticaria, walked into a walk-in freezer, and unfortunately, they succumbed to the disease because the mast cells in the airways constricted. And unfortunately, that patient died. So it can be life-threatening.
or if you're living in Florida and come from a really hot outside into a really air-conditioned space, so we enrolled the two populations in that clinical trial, and we recently announced, as you stated, the initial data from the first six weeks in that trial, and we were very pleased to see that we had nearly 93% of the patients who had a clinical response and 83% of the patients that had a complete response to briquilimab.
Fantastic. Just to kind of get right into the heart of the investor debate, there's another drug out there being developed for urticaria that inhibits KIT signaling. This is Celldex barzolvolimab. I think a key difference that a lot of people focus on is that it has a longer half-life. So I guess the question is, just given the implications, what are the implications, I should say, of Jasper's briquilimab's shorter half-life? And why shouldn't we expect less efficacy with a shorter half-life drug?
Sure. So first, let's start with the biology of the mast cell. So what is known is that c-Kit is the primary survival pathway for mast cells. If you shut down c-Kit, you shut down phosphorylation. And at the end of that cascade is something called FOXO3A. And FOXO3A is responsible for regulating BIM. And when BIM is unregulated, BIM initiates apoptosis and makes the mast cells die. So with that as the primary mechanism, it's great that Celldex has really strong proof of concept data here and really proves to us that we have an opportunity to do the same thing and repeat similar efficacy that they've generated. To your point, though, we think that drugging this disease is more about Cmax as opposed to AUC. So if you reach that Cmax, that concentration to initiate the apoptosis, then those mast cells will die and leave the skin.
We think that's where we can then lean into our half-life, because c-Kit is also present on four other important cell types in the body. They're present on stem cells, melanocytes, taste buds, and the progenitor of the spermatogonia. If mast cells are the largest sink of c-Kit in the body, and if you deplete those mast cells or substantially deplete those mast cells, if you have free antibody on board, then that antibody is going to hit those other c-Kit presenting cells.
We think in a combination of an optimum biologic dose strategy along with our shorter half-life, ours is about nine days, theirs is about 22 days, that we can deplete those mast cells but give patients a drug-free interval by which the stem cells can recover, or you're not hitting the melanocytes where you might get graying or the hypopigmentation that Celldex has seen with Barzo.
Excellent. And I think maybe just kind of get specifically into some of the data. So as you mentioned, briquilimab and CindU, you're seeing a high CR rate at four weeks. You're seeing a high CR rate at six weeks as well, but there is some attrition to that efficacy, at least the CR rate. What does that tell you about durability? And I guess, do you have a sense yet as to what dose schedule you think could be supported by briquilimab in urticaria?
Yeah. So again, to your point, we're really encouraged by the data we've seen to date. So in a really hard-to-treat disease of CIndU, and specifically in these clinical trials, so in inducible urticaria clinical trials, you're actually provoking the disease. So when these patients come in and enter in a clinical trial, if they have symptomatic dermographism, there's this scratch test that you do to their skin, and you're provoking the disease. Or with cold urticaria, you place these cold metal rods at different temperatures on the skin, so you're provoking the disease to respond. So there largely is not a placebo effect here. You can't fool that, right?
So for us to see this high rate of complete response at the 120-milligram dose level and the durability of that, so again, back to our half-life, if you're thinking about an antibody in three or three-and-a-half half-lives being the drug cleared, so at essentially a month, briquilimab is cleared from the system. And we still saw 83% of the patients have a complete response and at six weeks where the drug is gone. So those responses can only be driven by mast cell depletion. We still saw a 50% complete response at six weeks. So it tells us that with a single dose of briquilimab and a really hard-to-treat disease, that we're seeing significant durability because we are depleting those mast cells.
There's a lot of focus also on the tryptase signal as a biomarker. I think we've talked about just the biology there and kind of the complexities associated with this. Is tryptase, in your mind, a good biomarker? And maybe what are some of the caveats we should be focused on?
So tryptase is certainly a good biomarker, and it correlates with efficacy, but it's not predictive of efficacy. So maybe it's important to step back and talk about what is tryptase and what it's not. So serum tryptase, as the name implies, is a measure of total body mast cells, so not just skin mast cells. So mast cells are also present in the lung, in the gut, high concentration in the pancreas, and in females, also in the uterus. And remember that in these urticarias, this is predominantly a disease of female. About 70+% are female. And what we also know is that there's a growing body of data to suggest that the body preferentially replenishes the tissue, like the lung and the gut, for the mast cells over the skin. So mast cells are a fairly antiquated immune cell.
Their primary role is to fight parasites and for venom, and so we really don't need skin mast cells that much anymore. And in fact, because of that, evolutionary biology has taught the body that mast cells can be really long-lived. In fact, they're one of the longest-lived cells in our body. You have mast cells in your skin that you were born with, so the other piece about tryptase is that serum tryptase, unfortunately, the assays that are currently available don't differentiate between alpha tryptase and beta tryptase. Alpha tryptase comes from progenitor mast cells, so immature mast cells. Those are mast cells that are either normally circulating in your body, waiting to be called upon, or they're circulating mast cells waiting to migrate to their corresponding tissue, but progenitor mast cells can't degranulate like a mature mast cell.
When we see the tryptase coming back after inhibition or depletion, what isn't known is what percent of that tryptase is actually alpha tryptase. You've depleted mast cells. The body's telling itself that it needs more mast cells. It's producing progenitors. What is that ratio when we see mast cells coming back? The last thing I'll say about tryptase is we know, and when we looked in Spotlight, as an example, we had one patient who had a 50% reduction in tryptase but had a complete response. We had another patient whose tryptase nadir'd. They had a complete response. The tryptase came back 70% off of that nadir, yet they maintained their complete response. At this point, it's not possible to say you have to have a 50% reduction or a 70% reduction in tryptase in order to have a response.
Or if tryptase comes back 25% or 50%, you'll lose the response. It definitely correlates to efficacy, but it's not predictive.
Okay, and kind of going back to some of the discussions around Cmax and kind of the implications of that for mast cell depletion, just theoretically, I know you're testing this, but do you anticipate there being a dose response with KIT inhibition?
Absolutely. We saw that in our healthy volunteer study as well, so in our healthy volunteer study, we studied dose levels of 42, 84, 158, and 280, and we saw a definite mast cell depletion response to dose, and so we would expect that the same thing happen in treating of diseases. Now, one thing that's interesting there, though, is, and I think this also goes to the tryptase, is you mentioned Barzo, so they're currently dosing at 150 every four weeks or 300 every eight weeks, and yet the efficacy is almost identical between the 150 and the 300, so what it could potentially imply also is that you don't necessarily have to deplete all the mast cells on the first dose, but maybe there's a way to build up to that, and if we look at their 52-week data, in fact, that's sort of what you see.
You see they get there a little quicker with the 300, but after a couple of doses of the 150, the efficacy looks very, very similar. So we potentially could see the same thing as we're dose escalating in our Beacon study.
Okay. Great. And I want to get to that Beacon study in more detail in just a minute. But just while we're kind of on the mechanism of action and everything, I want to maybe just touch on toxicity, which you kind of spoke to a bit ago. But what type of tox would you expect with chronic KIT inhibition? And I guess, how would that tox sort of manifest in an adverse event table?
Again, c-Kit is present on those four other cell types. And there's probably two different ways to get to that toxicity. And let's start with the stem cells. Stem cell is arguably the most important cell in the body. The good news is that c-Kit is not the primary survival pathway. Inhibiting c-Kit on stem cells does not make them apoptose. We presented some really interesting data earlier this year where we demonstrated that stem cells have redundant survival pathways. When you block c-Kit on a stem cell, those stem cells, let's say, become a little quiescent for a moment while they're attempting to upregulate other survival mechanisms. It's also known in the stem cell field that only about 10%-20% of stem cells are actively cycling and necessary for maintaining normal hematopoiesis. And we've seen this in NHP studies as well as human studies.
We just observed the same thing in the Spotlight study, is that when you block stem cells with a dose of briquilmab, the heme indices nadir at about day eight, day 12. In Spotlight, it looked like about day 15. By day 28 or 29, you're back to baseline. The stem cells have a way of figuring out how much and what do they need to upregulate in that other 80%-90% to get back to normal hematopoiesis. The other thing that we've observed is that when you block stem cells, as an example, at least with the neutrophils, you see about a 10%-20% decrease on that first dose.
But the good news is if you start with a healthy reserve, so above 2,000, let's say, the lower level of normal, a 10%-20% drop in the neutrophils is really more of a lab value than an AE. You're not going to get a grade 3 or 4 AE. And again, if they bounce back by day 28 or 29, you're back to normal. And again, this is where we think our dose and strategy and our half-life can be really beneficial as opposed to constantly keeping drug on board.
So that makes sense. So by having a different half-life, you have less drug on board throughout the sort of AUC curve. Do you know, I guess, what level of sort of drug-free period would maybe confer a safety advantage? And I realize I'm asking a very forward-looking question, having you pontificate there. But what do you think? Is Q8 weak? Would that be good?
Certainly, if we're at the Q8 week level, that would give an average patient four-ish weeks of a drug-free interval. It would give, whether that's the stem cells' time to recover or melanocytes. We talked about that as well. What's known about melanocytes is that the highest concentration of melanocytes in the body are around the hair follicle. Those melanocytes serve a double duty. They produce melanin to color the hair as well as to pigment the surrounding tissue. And what's also known is that those melanocytes around the hair follicle cycle on and off. Certainly, if you're dosing at high enough levels where you're hitting all those melanocytes, then you could get some graying of the hair. If you're constantly blocking those for a longer period of time, then you could see some hypopigmentation as well.
So we would think that with our half-life and our dose schedule, that we might be able to reduce or eliminate both of those side effects.
Maybe just one more question on toxicity. I think we've seen some evidence from competitors that there may be some accumulation effect toxicities. Would you anticipate seeing kind of being able to differentiate on toxicity at sort of the 12-week mark, or would you want to see kind of longer-term data?
I think at 12 weeks, you'll start to see a trend. Having said that, I think specifically for the hypopigmentation, that's probably something where we'll want to see longer exposures in these patients. Again, the pigmentation in the skin. Also, the other confounding variable there is the amount of sun. You would expect that you probably would see less of the hypopigmentation in the winter months as opposed to the summer months. It's sort of if you put sunblock on the back of your hand, the tissue where the sunblock is will not tan the way that the tissue without it. And so similarly with the hair follicles, that if you're decreasing the melanin production in the wintertime, you may not see it as much, but it may be more stark in the summer months. We'll want to see longer exposure here.
But having said that, again, with our half-life, we think that in our potential dose and schedule, that we can either reduce that or see less of that.
Great. So let's move to your next readout will be in chronic spontaneous urticaria, CSU, the Beacon study. Give us a sense for the data that we'll be getting there and kind of the dose cohorts and so forth.
Sure. So what we've publicly stated is that we will have the top-line data from the Beacon study in chronic spontaneous urticaria the week of January 6, and what we will have is on all cohorts of patients from the 10-milligram dose through the 240-milligram dose. We'll have 12-week UAS7 and UCT on all those patients. We'll have serum tryptase over that course as well, and we'll also have longitudinal safety on all patients for their time on study, so we'll have safety beyond the 12 weeks, so as an example, we dosed our very first patient almost a year ago now. The end of this month, it will be one year, and so some patients will have almost a year or more than a year's worth of safety data, so we'll have longitudinal safety data on all patients in all cohorts.
Great. Okay. You also recently announced that you're testing a higher dose, 360 mg. Why did you add that cohort?
Well, quite frankly, because we could. So the study, first, maybe back to the design. So again, the way we think that the way we believe is the best way to treat these diseases is in an optimum biologic dose strategy, follow the biology of the mast cell. And in that design, in the original design, we put a 240-milligram dose in there as a single dose because we wanted to look at that maybe as a loading dose or an induction type of a dose. And when we safely cleared the hurdle for the 240-milligram dose, we made the decision, too. Let's push it a little higher and see if we get any differential in safety or efficacy.
Okay. And then how much read-through from inducible urticaria do you think there is to spontaneous urticaria? Because we've seen translational data that maybe speaks to that, but just curious on your view on that.
Sure. So we think there's a high degree of read-through as well as our competitors do as well. It's important to remember that in CSU and CIndU, it's a disease of mast cells, but the mast cell is actually not diseased. It's the same mast cell that you and I have if we don't have urticaria. Something in the immune system, though, is triggering that mast cell. So in CSU and CIndU, it's the same mast cell in both diseases. So being able to inhibit or deplete mast cells like we did in CIndU corresponds or has a strong read-through to CSU.
Okay. Great. And then so if the Beacon data look good, so it sounds like we'll get some information on safety, including some longitudinal data, long-term data for a few patients. Efficacy, I guess, what is the next step following that?
So if we have a dose and schedule in the Beacon study that's comparable to Barzo, we clearly have a drug. And we're only 12-ish months behind them. So we are really the definition of being a fast follower. And if, in fact, we can generate that kind of data, it's our current plan, and we're already working with the regulators to initiate a registrational program in the second half of next year.
Probably hard to answer without seeing data, but do you have a sense at this point if you would take multiple doses for the way that Celdex did with Barzo?
As with any clinical trial, the data will tell us what to do, and I think if we have a clear winner, then that's the easy answer. What we may want to do is do a phase II B run into a phase III where we take that clear winner, but maybe also along with a loading dose. We mentioned the 240 and the 360. If you have seen what they're doing with Barzo, they've now added a loading dose to theirs as well, so we may want to do that in a phase II B, 3 run-in and then pick a single dose, but the data, I think, will tell us what to do.
Great. Great. I think another question that's sort of out there is the commercial opportunity. A lot of sort of moving parts. We have the c-Kit antibodies, I think Xolair is going generic, excuse me. Some expectation that Novartis' remibrutinib, the BTK inhibitor, will be approved. And then behind all that, we have sort of oral KIT inhibitors being developed. So I guess just where do you see kind of the CSU market evolving and where is briquilmab's position within that?
Sure. So first of all, I think this is fantastic for urticaria patients. They unfortunately have lived decades with really only one option or two options in antihistamines or omalizumab. So the potential for down the road where patients may have options, I think that's fantastic for patients. Having said that, we clearly believe that the apex or the treatment option at the top of the cascade, if we're truly able to safely deplete mast cells and have a significant durable response where with briquilimab, if patients only have to have a 2-mL subcu injection every eight weeks or 12 weeks and you forget about your disease, that should be the therapy of choice. All the other therapies that you've mentioned in development so far, their efficacy doesn't come close to the efficacy that's been observed with a c-Kit antibody to date.
I think you kind of separate the world into drugs that can deplete mast cell and those that inhibit mast cells. Whether that's omalizumab and its effect on IgE, DUPI and the IL-4/13 pathway, Remi, all of those drugs, or even the c-Kit wild-type small molecules, they only inhibit the mast cell. It means you need to maintain 24/7, 365 inhibition, or as soon as you fall below those inhibitory concentrations, the disease is right back because you have not depleted the mast cell.
Great. In the last sort of three minutes or so, I want to move and just talk about your asthma program. I guess start off, talk about the design of the phase 1 study.
Sure. So again, the hypothesis here is that the mast cell is the conductor of the orchestra in asthma. It's well known that mast cells are the dominant cell in the release phase of asthma, whether it's releasing histamine or prostaglandin or R2. It's the cell that starts the cascade. So with that, we've designed a true proof of concept phase study in asthma where we're taking mild asthmatics. And in this study, these patients all have a known allergen, like let's say cat dander. And so whatever their known allergen is, the patients come in, we'll measure their FEV1, then we provoke their asthma with their known allergen, measure that response. Then two weeks later, they'll come back, get a dose of briquilmab. Six weeks later, the patient will come back, receive that same allergen again to provoke their disease, and then at 12 weeks.
So what we want to look at is, are we able to suppress that release phase over two different provocations with that allergen at six weeks and at 12 weeks? We'll measure FEV1. We'll be looking at all the biologic markers as well. I think one of the interesting things that we'll be looking at here as well is it's also known that mast cells are involved in the recruitment phase, things like TH2, but importantly, eosinophils. And as you probably know, most of the endotypes for treatment are driven by eosinophil level. And what would be really interesting is if by depleting mast cells, if we're able to reduce the eosinophil recruitment, then down the road, this potentially could mean that if it works here, that maybe briquilimab is applicable across endotypes.
Maybe just last question here. Presumably, the safety bar is higher in asthma than urticaria. I guess do you agree with that? And I think there's maybe some focus on an IgG1 antibody and kind of the anaphylaxis risk and sort of what we've seen in others in the space. Maybe talk to that a little bit.
Yeah. I would say that the safety bar in asthma and urticaria are probably very similar. It's a pretty high bar. I mean, with the exception of the cold urticaria, patients either can largely control their asthma or it's not really life-threatening. Having said that, this is a unique opportunity here where the very large patient population and the read-through here also could be to other allergic conditions like food allergies as well.
Excellent. Okay. I think we're out of questions, but Ron, thanks so much.
Thank you, Ben.
Great.
Appreciate the time.