Thank you so much for joining us in Miami, and glad to have you.
Yeah, thanks for the invitation. Great to be here.
All right, let's start with the PD-1 CTLA4 bispecific. Obviously, we've got a lot of programs to cover, but I want to make sure we spend a couple of minutes talking about that. We recently heard that you discontinued lorigerlimab in prostate cancer and decided to pursue opportunities in ovarian and clear cell gynecological cancers. So can you give us a little bit more detail about the context for that decision, and what you saw that wasn't meeting your barriers for success in prostate?
Yeah, so Lorigerlimab, this is our bispecific PD-1 CTLA4 molecule. We had run a randomized phase two study called the LORIKEET study, and as we looked at the interim results, based on an October data cut, we made the assessment, primarily looking at the radiographic progression-free survival, that we weren't going to meet kind of what we had targeted as a threshold for differentiation from the dose of Taxol control arm. So that was really the driver of that decision. And then obviously we have a broad portfolio of very innovative, very promising programs across ADCs, T-cell engagers, and as we assessed, you know, where do we want to really shunt our resources and concentrate the investment, we decided to really move away from the prostate cancer arena. And that regimen was really a combination of Lorigerlimab on top of systemic dose of Taxol and prednisone.
So that's obviously a fairly complicated regimen in a pretty challenging population. We are continuing to evaluate our LINET study, which is exploring lorigerlimab in a mix of gynecologic indications, both platinum-resistant ovarian cancer, that's serous ovarian cancer, and then a separate cohort looking at a clear cell gynecologic oncology. So that continues to be an active area of investment for that molecule.
Mm-hmm. Now, when we think about the mechanism of action for the bispecific here, part of the argument was always that, dual-positive T-cells were going to be a unique driver of efficacy, above and beyond what you might see with a combination of monoclonals. So can you talk to us about the biology of these indications a little bit? How does the proportion of dual-positive cells in PROC or gynecological cancers compare to prostate?
Yeah, so you're right, and really the underpinnings of our interest in this molecule was based on the early phase 1 experience where we had looked at monotherapy across a mix of tumors. Actually, ovarian was represented in that population. We had some early anecdotes of activity across both ovarian, prostate, and other indications. The design of the molecule is a tetravalent structure. So you have two binding moieties for PD-1, two binding moieties for CTLA4. That's actually a different approach than what, for instance, AstraZeneca has employed, where they have a one-by-one configuration. We think, and we've done actually some preclinical work looking at comparative data, and we do see that the dual-positive cells do get preferential benefit and efficacy with this two-by-two format. And that was actually manifested in that early phase 1 data.
Prostate cancer, which is historically more of an immunologically inert indication, we had, you know, very robust activity, single-agent responses with a confirmed ORR of 26%. If you look at historical benchmarks for PD-1 agents in that setting, it would be single-digit activity. What was also noteworthy is the ability to really give prolonged exposure to our bispecific molecule. When you look at, again, IpiNevo combinations, the Ipi regimen is typically only administered for two or three cycles, and then they really have to pull back. And even with that short exposure to Ipi, they've seen, you know, major events and, you know, grade four, grade five, colitis and pneumonitis. In our phase one experience, we only saw, I think, one or two episodes of grade three colitis out of over 150 patients.
So that also is really based on the design of the molecule, the fact that we can localize the effect to these double-positive TILs. So ovarian cancer, also an indication that has had some challenges in terms of conventional PD-1 therapy, also had reported single-digit response rates with just conventional PD-1. But what we've also seen, based on some of the early data with IpiNevo combos in this setting and even other molecules where they've done a combination of PD-1 blockade and CTLA4, they do see pronounced improvement in that ORR, but also that enhanced safety challenge. And so the hope is that we can, again, thread the needle there, deliver a meaningful effect, avoid the safety, and potentially also drive much better durability, whereas, you know, durability in ovarian cancer, especially these later line settings, is quite poor.
Even with the advent of all these emerging ADCs for ovarian cancer, and there've been a number across a different, a slew of different targets, one of the common limitations has been the durability of those responses.
Mm-hmm. Yeah, fair enough. You mentioned the competitor PD-1 CTLA-4 bispecific from Astra, obviously with a slightly different architecture, but they've been pursuing those programs aggressively, primarily in tumor types where IO has a good response or has had, I should say, is more central to the thesis of those indications. Can you talk a little bit, and I think you alluded to this, but can you talk a little bit about the differences between your two molecules that drive you to these indications that maybe are on the edges of what we would historically think of IO as working well?
It wouldn't be that we're adverse to looking at both these immunologically sensitive indications. That is clearly an area that we could also have utility. Those are likely going to require much larger studies, especially if you're going to do a head-to-head study against an existing agent. So that may be, you know, where we go as we think about the broader franchise strategy for this molecule. We have had, you know, anecdotes of experience in some of those indications. Even in our phase one, we had some melanoma patients. Those would be primarily checkpoint-experienced patients. We've done some IST work, actually with a group at MD Anderson in cervical cancer. So I think we do have a broader gestalt in terms of where the utility of this molecule is.
I think we actually are encouraged both on these more refractory populations as well as in, you know, the ones that are typically more sensitive. Ovarian cancer was also an indication that historically, again, has had very limited success, but Merck has also recently reported that in the context of a combo regimen with, you know, plus or minus Bev and chemo, they actually are seeing some encouraging activity.
Let's continue down this road in PROC. You've mentioned a potential to combine with ADCs in the indication. You mentioned some of the lacunae of existing ADCs in that space. Can you talk a little bit about the safety bar of a pretty active IO molecule with ADCs that have their own safety limitations? What are the overlapping issues you might have to worry about in there?
I mean, the hope is that those toxicities aren't necessarily overlapping in terms of, you know, the heme toxicities, which are primarily associated with the ADCs. And obviously there's different classes of payloads. The topoisomerase agents that are continuing to have more and more visibility typically are very well tolerated. We have our own portfolio of ADCs, which we'll I'm sure talk about. Those have also had, you know, very good, you know, safety and tolerability. And that's predicated on the drug linker system that we've employed, which we licensed from Synaffix.
Let's move to those ADCs after a brief word on the ongoing study. Can you walk us through the timeline of the study and where your internal bars are?
For the LINET study?
For LINET.
Yeah. So we're, you know, recently initiated the study. We're ramping up nicely. The design of the study is a Simon two-stage study. So the first stage would be looking at 20 patients needing to clear a requisite, you know, threshold in terms of activity. And then we'll add an additional 20 patients. And then there's a separate arm, which is really focused on that clear cell gynecologic indication. That is an indication that is typically more prevalent in Asia, probably about two to three-fold more prevalent. So we've also incorporated some international sites, including some in Korea. So that study is moving nicely, and we're encouraged by, you know, the direction, and we'll be providing updates probably middle of next year.
Middle of next year. Great. Now let's talk about that ADC pipeline that you alluded to. The lead here, I think in terms of our interest, has been B7H3. You've been working on this target for a long time, and by now it is a highly competitive landscape. So can you talk us through the evolution of your programs here and where you're going to fall relative to the competitors in the space?
Yeah, so, I mean, we did have an earlier asset called vobramidomab duocarmycin that was using a payload based on this very potent DNA alkylator, duocarmycin. There were some challenges in terms of threatening the therapeutic window there and the safety profile. So we've really moved towards the Synaffix platform, which is being more and more recognized as a best-of-breed solution, where a number of other partners have, you know, started to leverage that and license that program. We were an early adopter of that platform, actually secured broad access to up to seven different programs, and we've now already started prosecuting three of those to our end of clinic. The B7H3 asset is the furthest advanced. Yes, it is a competitive climate, but we do think we have a very good antibody, and again, we've done some comparative testing even with the Daiichi Sankyo specificity.
We think ours is a very rapid, efficient internalizer. We have a very good linker, and this is actually a site-specific conjugation approach that binds to the native glycan that enables you to have a much more uniform species of DAR4 construct. And by binding to the native glycan, we also render the Fc domain inert, which also potentially helps with some of the safety liabilities with some of the other topo I's that have shown ILD and pneumonitis, and some of the data that's already been published with other Synaffix-based molecules suggest that that liability doesn't exist. And the notion there is that the Fc gamma receptor binder enables non-specific uptake of these alveolar macrophages, and that is actually a driver of some of that toxicity. So very good linker. We also have a very good payload, and not all topo I's are the same.
So this is based on exatecan, which has been shown to have two- to fivefold higher potency than deruxtecan and some of the other deruxtecan derivatives, better bystander killing effects, as well as being less prone to multi-drug resistance and efflux pump escape mechanisms. So we think it's a great system in terms of the antibody, the linker, the payload. And then the last piece is really where do we craft a differentiated development strategy? It is competitive. There's been a lot of convergence on a few indications, with small cell lung cancer being probably the most popular, where there are a number of ongoing registration studies. But given the broad expression profile of this target, we think that there are a lot of legs to really look at other adjacent areas.
There's a lot of white space, and we have now kicked off two expansion cohorts in two different solid tumors. Those are enrolling, and, you know, next year we'll have some additional updates on this program.
Obviously, the vobradib program was very focused on prostate, but you mentioned there are a lot of places to go here, a lot of white space. Can you walk us through some of those indication selections?
So we've not yet disclosed what those indications are, partly just given that competitive environment that we're working in. So we're moving very aggressively.
But you're looking specifically for places where others aren't running large registrational trials?
That is right. I mean, it's a little bit the Goldilocks indications that have some level of validation, but not so popular that there are already multiple groups, you know, well into, you know, registration studies. Beyond the monotherapy development path, obviously the other excitement around this molecule, and again, given the fact that top one tends to be much more tolerable than some of these other classes of agents, is thinking about where combinations could also enable some differentiation. So both indication selection and then ultimately determining what that winning regimen is, whether monotherapy or combo could all be part of a strategy that really enables us to differentiate.
Yeah. It's interesting that you say that. I feel like combinations of ADCs have historically been very challenging and only recently have started coming to the forefront of the discussion. Can you talk about some of the combination agents that are actually attractive with the safety profile that you have?
You know, I was out at ESMO a few months ago, and that was a very popular theme, you know, all the excitement around combinations, and it does span many different classes of molecules, including checkpoint molecules, both some of the approved checkpoints as well as the emerging classes of checkpoint molecules. Obviously, we have our own bispecific checkpoint in the pipeline. Some groups even exploring combos with systemic chemo with other types of chemo regimens that might be again synergistic. There's combinations with, you know, PARP inhibitors and DDR agents. That's been again shown to have some synergistic biology, so I think there's a lot of latitude, and actually the other emerging area where we again have some capabilities within the pipeline is combinations with T cell engagers.
And there's, I think, already three examples of groups with B7H3 ADCs that are now thinking about combinations, for instance, with DLL3-based bispecific molecules, DLL3 by CD3 constructs. So there's a lot of, a lot of opportunity there, and we're eager to take advantage of that as we progress the program and obviously first solidify the signals of monotherapy and then potentially expand from there.
All right. Well, I won't rush you into combinations before we've seen mono data. Maybe we should move to the second of those ADC programs that you mentioned, ADAM9, another target that you've been working on for some time now, with a new molecule based on that Synaffix platform. So can you talk us through the ADAM9 history here and what's making you excited about the targets?
Yeah. So here again, this is a first-in-class molecule. The hope is the O26 might be a best-in-class approach. This is a first-in-class approach. We've had a lot of learnings from this molecule and the ways to target it as an ADC. We had an earlier, first-gen molecule that was using a maytansine-based payload, which was associated with ocular toxicities. That was a class-based toxicity that was actually very predictable. We saw it in the early cyno models. We hope we could manage that in the clinic through some supportive care measures and alternative dosing, including fractionated dosing. Ultimately, we didn't get to the doses that we really were targeting, and the dose-limiting toxicities were some of these eye toxicities.
Payload related.
Payload related.
Payload related eye toxicity.
And then we've now taken this second-gen molecule, which is called O28, again finished the GLP tox, did not see any of the ocular toxicities. That's now moving through a dose escalation. We're very excited about the profile of this target. Again, the design of the molecule, the payload, which we think is also very well suited for the range of indications that we'll likely explore for this molecule. Those would include some GI-associated cancers, which historically, again, are more amenable to topo-1 as a payload versus these cell-cycle-dependent payloads like maytansines. So this molecule's moving ahead. And what we've also now seen, there's been some, again, you know, other players recognizing the excitement of this molecule and the target. DualityBio has recently announced they're going to be moving into a phase one study with an ADC.
And there’s a few other groups that have declared that they have preclinical efforts. So we’re moving briskly and, again, excited about the promise of this program.
Excellent. You talked a little bit about some of those indications that you were interested in GI as well, but I see that from clinical trials that you're also in on small cell, you're also in colon carcinoma. Can you talk about how you approach patient selection and, and what, makes those indications particularly interesting for you?
I mean, a lot of that has been guided by some of the early preclinical work, both CDX and PDX animal models. Also look at the immunohistochemistry expression profile, looking at literature. In some cases, there is association of disease severity and outcomes based on the overexpression of ADAM9. And one thing that we've seen and others have also reported on is across a number of GI cancers, colorectal, pancreatic, cholangio, gastric, you know, very high and very uniform expression pattern. In some ways, it's actually preferable to some of the other popular targets that are being explored in these indications, things like claudin 18.2, for instance, which is a little less uniform in its expression pattern, and also the fact that ADAM9 seems much more restricted in terms of tumor versus normal tissue. So we think it's a great target.
You know, we're moving it forward, aggressively, and obviously we'll have updates on the clinical data as it matures.
Excellent. And then the last of those ADC programs entering the clinic, against an undisclosed target, which I won't ask you to name, but can you tell us a little bit about how you're doing target selection, what sorts of things you're looking for? So maybe we're not totally blindsided when you announce it.
I mean, it's a target that is, you know, there's been some, you know, data reported in the literature. Its utility has been explored in the past. We do think we could be well positioned as a first-in-class molecule with a top one payload, which we're not aware of other active efforts on this target, which is why we're not currently disclosing it. It is expressed across a number of solid tumors. You know, we'll be moving that into an IND next year. That's the plan.
Excellent. So while we're talking about the timeline for that molecule, can you walk us through the cadence of data readouts across those four molecules that we just discussed over the next year and a half?
So as we move into next year, we will provide more explicit guidance in terms of timing of that disclosure, since we're right now just ramping up and trying to also make sure that the data that we have to disclose is going to be relevant, externally, and also that will guide the next up and best decisions for the program. So stay tuned. The one program we have committed to have some updates is the Lynette program, which should be middle of next year. And then the expectation is you'll get more granular guidance as we move into the early part of next year.
But you're already in escalation in the first two ADCs.
We're actually into expansion now for the first and, you know, well into the escalation for the second and moving through the IND enabling studies for the third.
At least for those first two, fair to assume that we could start seeing clinical data next year?
That is what we're hoping to deliver. Exactly.
Great. And I'll ask a couple of.
These are obviously open-label studies that we're looking at. So we know the data. Obviously, that doesn't preclude us from also exploring, you know, with potential partners' data. But I think from the investor disclosure perspective, we want to make sure we get a nice actionable data set before we provide that.
No, we all appreciate that. In our last couple of seconds, can we talk a little bit about cash balance and runway and how much data we can get to see?
So the Q3 cash balance was $146 million. That did not include some subsequent money that we triggered through both a third collaboration molecule with Gilead that brought in $25 million, an additional $50 million that was brought in that will be recognized in Q4 from Sanofi on the continued progress of the TZ asset for type one diabetes. So with those additional milestones, we've now actually extended the cash runway guidance into late 2027.
Plenty of data.
So we think we're in a great position and well resourced with that cash to really execute against the plan and deliver on some of these data inflection points.
Excellent. Well, thank you so much, Eric. We appreciate you joining us.
I appreciate it, Jon. Thanks.