All right, good day, everyone. Welcome to day one of Cantor Global Healthcare Conference. My name is Prakhar Agrawal. I'm a biotech analyst at Cantor, and for our next session, we are very excited to host the team of Q32 Bio. Representing Q32 Bio, we have Lee Kalowski, Chief Financial Officer, and Jason Campagna, Chief Medical Officer. Gentlemen, thanks for joining us.
Thank you for having us.
Thank you for having us.
Maybe to start off, for those who are not familiar with the story, start off with an overview of the company and the pipeline, please.
Sure. The company was founded about seven years ago. Q32 Bio stands for chromosome one band 32, which is where most of the complement proteins are coded, and the original thesis of the company is that we could design sort of a better, smarter complement inhibitor, and the insight, which is deceptively simple, which makes it somewhat elegant, is that the way in which complement sort of regulates itself is by using these sort of complement fragments that end up decorating the surface of cells, and those complement fragments help the body distinguish self from non-self, tissues that are damaged or organisms that are foreign.
The great insight that the founders of the company had, one of whom is our Chief Scientific Officer, was that you could target those complement fragments with an antibody, and then couple to the back of that antibody, naturally occurring endogenous regulators of complement, and that therefore, you can deliver to the cell surface only where complement is active, the exact negative regulatory proteins that the body uses to control complement to sort of reestablish control of that pathway. As we were advancing that molecule through its preclinical testing and finishing up toxicology work, we had an opportunity, as part of our, the founding venture capital company, Atlas Venture, actually Atlas Life Sciences, to meet with Bristol Myers Squibb, and we had an opportunity to bring in the IL-7/TSLP asset, which we have termed ADX-914, which is now known as benpicobart.
The program, the whole company program consists of two phase I, two phase II clinical trials, excuse me, that are ongoing for benpicobart, one in atopic dermatitis, one in alopecia areata. They are both reading out in Q4 of this year. The complement program has a phase II study ongoing, a renal basket study in IgA nephropathy, lupus nephritis, and C3G. Beyond that program in complement, we have an entire platform of a diversity of molecules that target different aspects of the complement system.
Got it. Thank you. And for benpicobart, I just call it benpi for ease of use, but maybe talk about the history of the asset. You said it came from Bristol, but it also changed hands in between. So if you wanna put that, provide that overview.
Yeah. So you're right, it was a molecule originally discovered at BMS, and we were able to in-license it. We had a co-development and option agreement with Horizon that we had executed, and then following Amgen's acquisition of Horizon, we were thankfully able to reacquire all of the rights back. So it is now a wholly owned asset.
Right. And why did Amgen decide to return this asset?
Oh, I don't think that we would necessarily be able to speculate on that, but we had certainly wanted to reacquire it, and we were fortunately able to do so.
Got it. And so maybe talk about the mechanism, how IL-7 and TSLP works, and, yeah, why did you decide to take into atopic dermatitis and alopecia?
Yeah. So, ADX-914 is a bifunctional antibody, and it binds to a domain on the IL-7R alpha subunit. That subunit forms a heterodimer and makes either the IL-7 receptor or the TSLP receptor, so that the antibody binding effectively antagonizes both signaling pathways, which gets you broad-based Th2 immunophenotype coverage, in the case of TSLP, or Th1 coverage, in the case of IL-7. Depending on which indication we're talking about, the underlying biologic rationale is slightly different, but in atopic dermatitis, where the field has sort of declared in the current era that both Th2 and Th1 immunophenotypes are important ultimately to getting full control of that disease, clearly, we think both of those pathways are relevant. In the case of alopecia, our other indication, that's much more of a focus on the CD8 positive lymphocyte, which is really more Th1, and therefore, the IL-7 pathway.
We do think about them slightly different, although the antibody is capable of antagonizing both of those pathways.
Got it. And there are a lot of IL-7 antibodies, OSE, Zura, GSK had one previously, so maybe talk about the landscape and how is your IL-7 different?
Sure. I mean, big pharma has been interested in this pathway, the IL-7 pathway, for a very long time. GlaxoSmithKline ran an early clinical development program with a similar antibody, and they discontinued it due to... They were not happy with the pharmacology or the other elements of that profile. Pfizer also ran a very nice phase I program and a phase I-B in patients with diabetes. That drug is now owned by Zura Bio, and they are considering advancing that drug in similar indications, particularly alopecia. I think they're waiting, sort of not surprisingly, for additional data to play out in the field. Then, in the case of OSE, they have an antibody that's very similar to ours, except clinically, its potency is very different. But in terms of its binding characteristics and inhibition of both TSLP, IL-7, pretty similar.
They just completed a successful phase II trial in ulcerative colitis, read out over the summer with a positive result on the modified Mayo Score. We're obviously very encouraged by that. We're anticipating, I think, as many people, our additional data from that trial, which we understand might be coming out later this year, but things around what the mucosa looks like on endoscopy and other elements, clinical elements, like remission. But we clearly think that a drug like ours, which is much more potent, given in the form of sub-Q at low milligram per kilogram dosing, we're at roughly 2.5 mg/kg in our clinical trial now, that may offer a pretty compelling competitive advantage to OSE, which is closer to it. It's an IV formulation and much higher up on the dosing ladder.
... Got it. And none of these are testing it in atopic dermatitis, right?
I'm sorry?
None of these companies are testing the IL-7 in atopic dermatitis?
Not currently.
Correct.
Just us, yes.
Got it. Okay, so moving on to atopic dermatitis, maybe is there any preclinical or genetic evidence that IL-7 inhibition by itself reduces atopic dermatitis, or it needs to be in conjunction with TSLP, like mechanism to work in atopic dermatitis? Just talk about the rationale there.
I think that there's a fairly large diversity of evidence, ranging from genetic to data on T cells, cytokine profiles, et cetera, which strongly suggest that benpicobart should be effective in the indication. An example, when you look at mouse experiments where you give a generic IL-7R alpha targeting antibody, very similar to what we have, you impair both Th2 and Th1 cytokine signaling, consistent with where the AD field has gone, that you need to get control of both. So I think in summary, there's a reasonably strong base of data supporting that indication, meaning dual Th2 and Th1.
where in alopecia, it's much more direct than I think even recently in the last year or two, there've been continuing data from preclinical mouse models, for example, showing that the role of the CD8 lymphocyte and, more importantly, the role of IL-7 and those cytokines are really critical to the pathogenesis of the disease.
Got it. And on TSLP, Tezspire had some data in atopic dermatitis, which is Amgen's TSLP. Talk about what the efficacy was more modest. So maybe talk about what happened over that trial and what's related to your approach.
I think the tezepelumab study. I think we agree with you. It showed some data evidence that the drug was having a treatment effect. I think in that era, development was a little different. Tezepelumab and lebrikizumab chose an approach which utilized combination therapy, topical corticosteroids alongside of the treatment. Those can be difficult studies to run, particularly early in development when you're not sure of your treatment effect. In the case of tezepelumab, their combination therapy study did not meet statistical significance. I think as you know, Prakhar, the data looked okay in terms of clinical evidence. The one endpoint that it did hit on statistically was itch, which is consistent with the mechanism of action. When you look at the lebrikizumab study, which was also a combination therapy study, they had statistical significance on their primary endpoint.
The effect sizes were about the same, and similar to the tezepelumab study, the key secondaries were directionally positive, but nothing that you would look at and say, "Oh, that was a clear home run." Yet tezepelumab ultimately has now gone on to be an approved therapeutic, both in here and Europe, so I think we can only look back and say, probably confounded a little bit by those topical corticosteroids and of the era, but beyond that, I'm not sure there's anything more to offer.
Right. So if you can elaborate on what exactly on the topical corticosteroids that happened in that trial, was there any imbalance?
in short, they, those trials in that era not only allowed people to stay on topical corticosteroids, but sort of optimized their regimen prior to randomization. And then the issue within, while you're running the clinical trial, is if your drug is actually showing a treatment effect, are you tapering down the steroids or not? So I think in that particular trial, what you found was fairly similar use of steroids across both arms as the trial went on, which certainly, I think, contributed to the confounding there.
Okay, got it, and since IL-7 and TSLP are quite upstream, what do you think about the safety implications?
I think we feel very good about the safety profile of these bifunctional IL-7 TSLP agents. We have our own preclinical data, which at dosages well in excess of where we are clinically, 40-fold higher. We had no dose-limiting toxicities. I think we see data from Pfizer that have been published in their phase I experience and their patient experience, which are completely consistent with that. We have now OSE that's reported, although with no specific data, they did note that their data safety monitoring board was very comfortable and found nothing but, a benign safety profile. I think that's directionally helpful. And in our ongoing clinical trials, we've talked about in other public settings that in our phase I and in our Part A, our dose selection portion of the atopic dermatitis trial, that the safety profile looked quite good, and we were very satisfied with it.
So I think the data out there support that it's a relatively benign safety profile, but we are paying attention to the things that are on mechanism, reduction of lymphocytes, and whether that reduction is associated at all with any evidence of either increased infection risk or reactivation of infection.
Got it. And before moving to the phase two, talk about the phase one data. What were some of the key results on the PK/PD and some of the target occupancy data that you have disclosed?
So keeping it very direct, benpicobart is a fully human IgG1, which is Fc inert, and the preclinical data suggested that it was going to be highly potent in man at dosing between 1-3 mg/kg to get full receptor occupancy and signaling inhibition. What we showed in the phase I was exactly that. The drug at dosages of 0.3 mg/ kg already had full receptor occupancy and signaling inhibition, and at dosages of 1 mg/ kg, we were able to get full RO and signaling inhibition, the entirety of the two-week dosing interval. So a very potent molecule, and that potency was coupled with a very favorable safety profile, as we've just talked about. And the ADA profile, although we did see ADA, and we've talked about this previously, the titers were low level and no impact on pharmacology or safety.
So I think in summary, we went from talking about a preclinical molecule, which we believed would be best in class, to clinical data, which supports that statement that it's likely a best-in-class antibody.
Right. What was the level of the ADAs in phase I?... the ADAs?
We've not disclosed that publicly, but I can tell you it was fairly common.
Okay.
But, more importantly, wherever it was seen, it was almost exclusively low titer.
Okay, got it. And so you're in a phase II right now in atopic dermatitis. Walk us through the trial design. There's two parts: Part A and Part B. What, what do these entail?
Do you want to pick any of this one?
Yeah. Sure. So, you are right, there are two parts, for the atopic dermatitis phase II trial. Part A is completed but remains blinded. So that was about 15 patients in Part A, and then the remainder is Part B, which will be the subject for the efficacy readout, and there's about 106 patients in Part B, so 121 in total in the atopic dermatitis trial. It's a 14-week endpoint on the primary endpoint of the mean change in EASI score. We'll be looking at that, as well as key secondary endpoints, such as, you know, what would be typical for a trial like this, percentage of patients achieving EASI thresholds, like 50, 75, 90, IGA response, you know, as measured by a two-point change to 0-1.
You know, very typical for a phase II atopic dermatitis trial.
Right. And I think in Part A, the data was reviewed by a third party on a blinded basis, specifically on the PK, PD, and safety. Maybe talk about that.
That's correct.
What doses are you testing in Part B, basically?
You have that exactly right. So Part A was a dose-ranging study in patients with atopic dermatitis to allow us to select the dose for both of the current ongoing phase II trials. The primary endpoints of that small 15 patient experience were safety and pharmacology. Those data were submitted to the FDA and allowed us to select a dose of 200 mg flat, which is approximately 2.5 mg/kg depending on the weight banding for both of the clinical trials. And I think back to the pharmacology question, what was incredibly de-risking about those data, I mean, we were obviously private then and in partnership with Horizon, but it was a big celebration for us.
You know, we showed that in the patient population, there was no change in the modeled and expected pharmacology in terms of the big metrics I gave. The receptor occupancy, the signaling inhibition, and to the extent that we were looking at things like ADA, there didn't appear to be any dose dependency to it. So from a, at the time, an incredibly satisfying and de-risking event, but I think for this venue and the question that we had, completely supportive and almost mirroring exactly what we saw in that phase I healthy volunteer experience.
Got it. And in Part A, the safety was also reviewed by the third party?
In this case, the safety was reviewed by us, but it was part of our file to regulatory authorities to get the trial open.
Okay.
I think it would be fair to say that absent a good safety profile, we wouldn't have been allowed to do that dose.
Okay, got it. And so you're now in Part B. So maybe talk about the population that's being enrolled, the geography. Any differences with other atopic dermatitis trial?
I don't think so. I think it's pretty standard. This is a moderate to severe population, as defined by a combination of EASI, BSA, and IGA, which is very typical for the field. We allow patients in the trial with prior exposure to biologics, as long as there have been a sufficient washout. The same would hold for JAKs. And it's a monotherapy trial, as Lee mentioned, where topical corticosteroids or calcineurin inhibitors are not allowed. Again, very typical for today. I think it's a, by almost every measure, a very traditional atopic dermatitis phase II-A trial.
Got it. And so biologic failures are allowed in this trial, so Dupi failures may be enrolled, and is there any cutoff on what percentage of Dupi failures may be part of the trial?
Not to split hairs, but we refer to them as prior exposures only because the definition of a failure in AD is not clear. Unlike rheumatoid arthritis, where that definition is sort of codified in guidelines, the world of dupilumab, failure or success can be very much in the eye of the beholder. So when patients go on dupilumab, they can have, for example, quite a good skin response, but maybe less response on itch, and that could be deemed a failure or a success, depends on the patient, depends on the doc. We simply say, "If you've previously been on dupilumab or another biologic, it would've only been tralokinumab, and you've had sufficient washout, you are eligible for our trial.
Got it, and this is a U.S. trial? I'm sorry, this is a U.S.-specific trial?
U.S. and Europe.
U.S. and Europe. Okay. And the baseline EASI scores in atopic dermatitis trials has kind of trended down with Dupixent uptake. Any comments you can talk about that on the baseline EASI scores that's in the trial on a pool basis?
I don't think there's too much we could say. I mean, it's in the literature, it's a known phenomenon that EASI scores have moderated somewhat over time. Again, I think we would expect, like a lot of trials, will be in the twenties from a baseline EASI score.
Got it. And placebo response has been also a little bit variable in atopic dermatitis trial. What are you doing to mitigate that? And again, going back to the Tezspire trials, you talked about the confounding factor of topical corticosteroids. How are you managing that?
So, back to our trial, monotherapy trial, so no topical corticosteroids allowed. Some of the things you could do to manage placebo response, ensure that the screening window is long enough to have any topical corticosteroids or calcineurin inhibitor sort of washed out, so that you're not getting the tail end of any of that effect. The second is just being really disciplined with your investigators about the way in which they assess EASI score. Is it the same rater, the same reviewer, the same methodology? Are they trained up? And then lastly, you're picking good investigators that are both competent clinicians and competent trialists. They should have seen these patients in clinical practice and have a lot of experience scoring them at the bedside, and I think we've chosen really exceptional partners.
Beyond that, you know, there's prayer, of course, but beyond that, I don't think that there's much that we can do to control the placebo response.
All right. The readout is coming soon, so what efficacy benchmarks are you looking to move this asset further? Want to start?
Sure. You are right, so it is coming next quarter in Q 4, so everything is on track. As far as efficacy benchmarks, you know, I think we would look at some recent trials. For example, as a modern contemporary trial conducted recently, in OX40 ligand, for example, and in their 2a and 2b , saw a placebo-adjusted EASI change of right around 30%. I mean, if we saw 30%, we would be very confident that we have a drug for sure.
Right. And OX40 showed 30% on EASI?
Uh, placebo-adjusted-
Adjusted
... change. Right, right around there, yeah.
Got it.
Thereabouts. Yep.
EASI 50 and EASI 75, will you be disclosing that, too, during the readout?
You mean with the top line?
With the top line.
I don't think that's unreasonable. Those are key secondary endpoints. I would say the EASI percentage of patients achieving a certain threshold, so 50 and 75, and I would say EASI 90 is also one that often is reported as well, and things like IGA response as well, a two-point change, going to 0 or 1. I would think those are the type of materials that we would be, you know, certainly thinking about that for the top-line results as well, the key secondaries-
Right
... in addition to the primary.
For those key secondaries, would OX40 be again the benchmark that you would point to?
Yeah, it... I think that's fair. I think maybe why we're, why we keep referring back to the OX40 ligand is less about the specifics of the efficacy profile, although they're not unimportant. It's that it represents the field sort of migrating away from what we'll call narrowband development opportunities. Dupilumab was very narrowband. It's the IL-4 receptor antagonist that gets both IL-4 and IL-13. We see a lot of people in the field now, I think all of you know this, that we're seeing bispecifics, which are sort of doubling up on that Th2 pathway, even trispecifics, that are sort of tripling up on the same pathway. Go back to what we were chatting about earlier. The disease is really about a sequential Th2 and Th1 immunophenotype. Th2 is always important, but Th1 becomes increasingly dominant later.
So what the OX40 ligand data represent is a sea change of the approach, which is, instead of going narrowband, they're moving up to the level of the T cell, which has had mixed results in other autoimmune diseases, but it seemed to do pretty well here. And the trade-off that you're getting for maybe slightly less skin clearance response, in the case of OX40 ligand, where compared to dupilumab, for example, it's not as apples to apples comparison as you might like. The trade-off is that you're getting a much less frequent dosing interval, potentially as infrequent as once every three months, which is very powerful right now in the field, and you're toggling up addressing other elements of the disease beyond just skin clearance, things like itch. So it's not that skin clearance is unimportant-
Mm-hmm
... but given that we have tralokinumab, lebrikizumab, dupilumab there, the world is now moving towards: Can we get more broadband and dial down more than one element of the disease? That's why we like OX40 ligand.
Right. And you noted that benpicobart could have remittive effects as well, similar to OX40, along with durability. Why is that the case, and will we get data around this, as well, when the readout comes?
We will not have those data at top line. We may, depending on where the patients fall in the, you know, how many of them have completed the study, we may be in a position to comment on some early things that we see. But the full data set for the complete trial, which is the 24 week trial, will not be available till early next calendar year.
Right. Okay, and so what could be the next trial? Would it be a phase II-B, or could you go straight to a phase 3 if the data are positive?
In atopic dermatitis specifically, so, you know, I don't think we've commented too much on this. Obviously, we have to let the data play out. But as we've seen from other trials, you need to get a sufficient number of patients on drug. And for a variety of reasons, a phase II-B may make sense for us, including evaluating some additional dosing intervals. You do have to explore minimally effective doses. But we really do think that we have an opportunity to go beyond every two-week dosing, and so that will be something we would be interested in exploring. But, you know, first and foremost, get the data out and report that.
Got it. And you also have alopecia-
Yes
... a readout coming. So in the upcoming phase two, remind us of the population that's being enrolled because alopecia can have different segments as well.
This is our trial is severe and very severe, so SALT 50-100. So no moderates in there. The distribution of the severe, which is 50-95, versus very severe, 95-100, is approximately 2- 1. And we'll get the specific numbers, obviously, at the time of top line. That's consistent with, in fact, mirrors pretty closely what the JAK inhibitors had done for both of their clinical trials at early stage development. And beyond that, the primary endpoint, the SALT score, reflects only scalp measurements, which right now is the sort of standard for early stage clinical development.
Got it. And so what would be the efficacy benchmarks for the alopecia trial?
So in alopecia, there really are not a lot of treatment alternatives. There are the JAKs. They, of course, have their class-wide safety and toxicity issues. And, you know, as I'm sure you've done as well in talking to, treating physicians, they are clamoring for safer alternatives. So, you know, again, we'll have to let our data play out, but, a better-tolerated drug, a drug with a better safety profile would be a significant differentiator. There haven't been a lot of-
... JAKs that have looked at data out at 24 weeks, most of them go a lot longer, and it's pretty important that you're apples to apples on that, because hair does continue to grow past that point. There is one that has shown around a 30-ish%, placebo-adjusted, SALT change at 24 weeks. In talking to the KOLs that, and again, as I'm sure you do, we would not have to be that efficacious to really have, you know, proof of concept that we are working, and that we would be a meaningful drug in alopecia. You know, from our conversations, north of 20% would give us confidence, and obviously, we would then be looking at, you know, additional things beyond that, adding in a loading dose, going beyond 24 weeks.
We'll have to look at the totality of the profile, but from a proof of concept standpoint, north of 20% will give us confidence that we have a drug.
Right. And that's at 24 weeks?
That's at 24 weeks.
And the doses are same for-
Yes.
Atopic dermatitis and alopecia?
That's right.
Correct. Got it. And you have both readouts in Q4, so maybe in terms of the timeline, will you be disclosing both alopecia and atopic dermatitis together, or will it be separate, or you haven't decided yet?
As it so happens, the trial timing are very close to each other, so most likely, yes, that we will likely be getting the data and reporting the data, simultaneously.
Okay. Good. You also have ADX-097, which is your second asset. So maybe talk about what unmet need you are trying to solve with that asset.
You mean in terms of data?
In terms of the-
So the-
In terms of the mechanism and the indications you're going after.
Yeah, I mean, I think the most appropriate way to think about complement, it's a very straightforward three-step story. Number one, when complement becomes active and is causing damage, it's a cell surface phenomenon. Many of us have in our head when we think about complement, these kind of vertical pathways and that it all happens in the fluid phase. It doesn't at all. The proteins, many of them live in the fluid phase, but the action happens at the surface of the cell. Second, ADX-097 is a cell-targeted bifunctional fusion protein, and it only goes where the alternative pathway is active. And third, when it goes there, it will bring factor H to bear on those convertases, which will lead to their catalytic inactivation.
So we're talking about completely shutting down the alternative pathway in the tissue where injury is happening, at dosages that do not impair, at all, systemic alternative pathway. So not only is there potential for a deeper efficacy profile, clearly the other side of the benefit-risk calculus would come into play as well, without any impairment of systemic alternative pathway. Different indications have different relative weighting of those. Example, in diseases now, where we're looking for things like lupus nephritis or C3G, where getting proteinuria under control is very important, people will tolerate things like twice-weekly sub-Q infusions to get that. On the other hand, diseases where you're using a lot of autoimmune drugs that are already suppressing the immune system, high-dose corticosteroids, like ANCA-associated vasculitis, for example, or lupus nephritis, the ability to deliver a drug that may not add to that burden of safety could be incredibly valuable.
So we think that depending on the disease indication, each element of that biology might be relevant.
Got it. And what will we get for the upcoming renal basket readout by year-end 2024?
Lee, do you want to pick that up or..
Yeah, so the renal basket is open label. That trial is open. So, you know, top-line data, as we've said, would be in 2025, but given the nature of the trial, there's the opportunity to show, which we've seen in other cases, to be relevant, to have some early data, to show us, you know, some early findings from the trial, and so that's sort of the order of magnitude that we would be contemplating.
Got it. And in the last minute, cash runway, and what does the guidance envision?
Yeah, runway, we've said is to mid 2026, so that gets us through our four phase II readouts. So, the two with benpicobart that we've talking about in Q4, the ongoing renal basket, and then we're also gonna be starting phase II in ANCA-associated vasculitis, AV. So all four of those are funded under that runway guidance.
Okay. That's all the time we have today, but thank you for joining us.