All right, welcome back. My name is Silvan Türkcan. I'm a Senior Analyst at Citizens covering precision medicines. Thanks so much for joining us at our healthcare conference. Now it's my pleasure to host MacroGenics. With me is Eric Risser, COO of MacroGenics. Thank you so much.
Great, thank you. I appreciate the opportunity to present here today at the conference and talk about MacroGenics and all the milestones and upcoming events for the company over the course of this year.
Yeah, great. No, looking forward. Maybe can you provide us some background of how you're redirecting MacroGenics now after the R&D engine, and specifically after the robot duo?
I think the operative word there is R&D engine. We've had a history of being a very prolific drug discoverer developer. We actually have four assets in the clinic, which were all homegrown assets, some cases leveraging platform technology that we developed internally. We have also licensed in for our ADC portfolio some proprietary drug linker chemistry. Four assets in the clinic actually spanning three different mechanisms. We're very excited about the prospects of each of these. The lead asset in that portfolio is lorigerlimab, which is a bispecific molecule that blocks both PD-1 and CTLA-4. We actually fully enrolled a randomized phase II study. We'll have some data coming up latter part of this year on that program. We also have two ADC programs leveraging a topo I-based drug linker that we licensed from Synaffix.
Those are in the clinic in phase I going through dose escalation. Again, we're excited about prospects of where those studies might be later in the year. We also have a bispecific molecule, which is predicated on a T-cell engager mechanism, so CD3 by CD123 that is part of an option-based deal with Gilead. That's also going through phase I dose escalation. In our earlier research labs, we continue to innovate and advance additional molecules, the first of which will be now in the clinic next year. That's another ADC program called MGC030. A lot of activity in the portfolio, multiple mechanisms, many of which are actually quite complementary with one another. We think we've never been really reliant on a one asset kind of investment thesis. It's really been a portfolio approach.
We think the portfolio will do very well over the course of this year.
Great. No, thanks for this overview. Obviously, maybe I'd like to start with the bispecifics because it is obviously a very growing or hot topic right now. We're waiting some very important readouts, I think, from summits and others this summer generally in that space. Can you just give us an overview of lorigerlimab and how you came up with what you designed the molecule for and then how it fits, what data we've seen and how it fits in the prostate cancer?
Yeah, so we're very excited about that molecule. Obviously, the whole field of checkpoint inhibition has gone through a little bit of an evolution with the first introduction of pembro and evo about 11 years ago, a flurry of interest in alternate checkpoint molecules, which in some areas did disappoint. We have seen a reemergence, particularly in the context of bispecific formats and actually working on validated targets. PD-1 VEGF obviously has restored some excitement in the category. Our PD-1 CTLA-4 molecule, we're also very excited about. The promise of that was initially highlighted at ASCO-GU when we had some monotherapy data. That was highlighting experience in a late line castrate-resistant prostate cancer population where historically immune checkpoints have not worked. This has been more of an immunologically inert indication. Pembrolizumab in some of their early studies only had single-digit response rates.
In that study, we actually reported 26% confirmed ORR. We also had pretty meaningful PSA reductions, about 29%. There was also very good correlation with PSA 90 as well as the responders in that study. Great that we had early induction of response, but what was equally important is we actually had pretty long durable responses with, in some cases, patients staying on study for over two years. That is really unprecedented when you think about some of the prior experience, for instance, with IpiNevo. When those molecules were combined, the toxicity really required them to limit the ipilimumab dose to only two or three cycles. The fact that we can get continuous blockade of PD-1 and CTLA-4, in some cases going out two years plus, is pretty provocative.
That really led us to kick off the LORIKEET study, which is a phase II. It is a 150-patient study with two-to-one randomization. There we will be actually combining on top of docetaxel as kind of the prevailing standard of care in a second line population and then doing it against docetaxel as a monotherapy. That was fully enrolled late last year. It is an event-based endpoint with median PFS as really the lead endpoint. We are obviously continuing to accrue events and hope to have some updates on that program later this year.
Great. Maybe just to clarify your monotherapy data, that was post chemo, right? Or a significant amount of patients?
That was a late line population. Vast majority had both ARAT as well as docetaxel, primarily probably third, fourth line. Actually, we had about a quarter of those patients that were at least 4+ prior lines of therapy. Pretty late line population and again, pretty provocative early signals. Now we're building on that with what would be primarily a second line population. In the LORIKEET study where we're combining it with docetaxel, these are patients who have progressed on prior ARAT therapy. They're all by definition chemotherapy naive. Potentially a little bit more responsive patients, especially for immunological intervention where earlier lines sometimes can drive an even more pronounced benefit.
Great. Maybe can you outline a little bit kind of, I mean, I guess what we'll see in the data? I think you alluded to some PFS or at least what we'll see in terms of durability in this data. And then kind of what the bar is, obviously prostate cancer is evolving quickly, right? We got the radio treatments coming in here, cabozantinib, which is trying to find its space there. Obviously, we had some difficulty with the control arm here, right? We do not know if it is going to be filed or not. You have a chemo control arm. Would you think you are coming a little bit later with respect to those new treatments or maybe at the same level?
It is a very heterogeneous population. It's also a very competitive category, which is also why we really were adamant to make sure we had a control arm in that study. If you look at some of the historical efforts with docetaxel, for instance, the KEYNOTE-921 study, which was pembro + docetaxel versus docetaxel, in that control arm, they had about an eight-month PFS value. That's a little bit higher than what has been reported. We look at real-world evidence. There were some features of that study where it was again immunotherapy-based where some of the investigators were potentially treating even beyond initial study progression. We will see where we end up with that.
We do have that control arm to really give us a clear benchmark that we're going to look to beat and see if we can meaningfully extend PFS there and also have overall acceptable safety tolerability profile.
Okay. That's very helpful.
It would tee us up for potentially a future registration path that would likely be again recapitulating that regimen. That would be primarily a second line population.
Okay. Great. You also have another study, the LINNET study in ovarian cancer and other gynecological cancers. Could you just tell us about what motivated this trial and where you are with it and when we could see, I guess you're just ramping it up, but when could we see data?
Yes. Really excited about this program. It's in some ways a little bit of the same playbook as prostate cancer, another indication that has been historically not very sensitive to immune therapy. Again, the benchmarks there for traditional PD-1 monotherapy were single-digit response rates. Checkpoint therapy has had limited success, although there has been evidence that PD-1 plus CTLA-4 combo has actually meaningfully raised the bar there. They have generated 25%-30% response rates in some of the studies that have reported. Again, the safety liabilities are always a challenge there. That is where we think our approach, which is the tetravalent format, enables co-engagement of these double- positive TILs. You really localize the effect, potentially have a better overall safety profile. We think that could be a real differentiator.
We also know that ovarian cancer in these later- line settings, chemotherapy is only driving 10%-15% response rates. The hope is we can show meaningful activity both in terms of the response rate, but also durability. That again is an opportunity to really differentiate, really driving much more extended efficacy benefits for patients. It is also one of the shortcomings with some of the ADC approaches in this area. There has obviously been a big surge of interest across lots of different targets. You have seen the folate receptors. You have seen the B7-H4. You have seen cadherin-6. A lot of ADCs are targeting ovarian cancer, many of which are relying on topo I-based payloads. The mirvetuximab asset was based on a maytansinoid-based platform. They do have pretty good potential to induce rapid tumor reduction.
The PFS in those studies in that late line population has only been five months or so in terms of median PFS. That is also an opportunity longer term to see where the monotherapy signal pans out, but opportunities longer term to think about a whole life cycle strategy that could be both monotherapy, but also combination.
Okay. That makes sense. But for now, your study, the LINNET, should have plenty of failures of these ADCs enrolling, right?
It could be. I mean, the only one that is approved right now is mirvetuximab. There may be some of those. This will be primarily patients with one to three prior lines of therapy. It actually is two populations that are embedded in this study, which is about a 60-patient study overall. One is the platinum-resistant ovarian cancer patients, which is the population where mirvetuximab is approved, although they are only approved for a subset that have high folate receptor expression. The other part of the study is actually looking at clear cell gynecologic malignancies. That is a subset that historically has not been very chemosensitive. Actually, the checkpoint therapies, although not approved, have seen a little bit more encouraging activity. It is a smaller disease, but potentially an opportunity to really show an outsized signal with a novel immune checkpoint approach.
Nice. Maybe moving on to B7-H3, obviously you're still very excited about that target and you're a leader in that space having pioneered already an ADC here. You now have MGC026, which uses a topo I payload. Can you just talk about that? It's called the next generation ADC for B7-H3 and how that fits in.
Yeah. So that molecule, which is called MGC026 for MacroGenics conjugate MGC026, as well as actually the two succeeding molecules MGC028 and MGC030, all leverage the Synaffix-based platform. We were an early adopter of that platform. We're really excited about the potential, the promises, and also the potential to differentiate from other topo I's. I think it's fair to say that not all topo I ADCs are the same. You can think about both the payload where we are relying on an exatecan-based approach. Daiichi Sankyo, which is probably the furthest along with topo I-based ADCs, theirs is predicated on deruxtecan. Again, there's been a lot of work published suggesting that exatecan is two- to five-fold more potent than deruxtecan. It supports better cell permeability and better bystander killing versus deruxtecan. It's actually less susceptible to multi-drug resistance and efflux pump escape mechanisms.
A lot of points of differentiation on the payload. They've been able to use one of their proprietary polar spacers to enable conjugation to exatecan. This payload tends to be a little bit more hydrophobic. That's really the challenge in terms of how do you enable conjugation. We believe we've kind of addressed that concern. The other differentiating feature with our approach is we do actually rely on a site-specific conjugation approach. This is called the GlycoConnect, where we can actually engage the native glycan. The benefits there are you do get a much more homogenous material. It's really DAR4 specific, potentially improves the therapeutic window and overall tolerability of the agent. By virtue of binding to the native glycan, you've essentially knocked out FC receptor function and potential liabilities of ADCC.
What has also been reported and published is that these FC gamma receptors can in some cases enable nonspecific uptake of these alveolar macrophages, which in some cases could also contribute to lung toxicity, which is something that everyone is always watching with regard to topo I. We will have to see how this all plays out in the clinical setting. I think there is a lot of reason for optimism in terms of where this agent will play. Obviously, the other point beyond the technology advantage is what is the development strategy. Where do we want to position. We will have some additional updates on that later in the year. We have not yet disclosed which specific expansion cohorts we are going to be pursuing. The hope is that would start panning out later part of this year.
Okay. Yeah. Maybe I'm going to try to poke around that a little bit. Obviously, Daiichi , I think, correct me if I'm wrong, was still very focused on small cell lung cancer. You obviously have experience with Vobra d uo with a different payload in prostate cancer. What other tissues make sense for topo I B7-H3?
B7-H3 is a target. This is why there is such broad interest in this target. It has a very broad expression pattern across a number of different solid tumors. The ones that have really advanced now to pivotal studies, Daiichi Sankyo and others have targeted small cell lung cancer as a priority indication. That is both in late line settings, but also starting to move into earlier lines of therapy, also combinations with standard of care. Esophageal cancer has been a tumor where there has been pretty interesting data published and some late-stage studies ramping up. Actually, prostate cancer, Daiichi Sankyo recently announced that they are standing up a large, I think a 1,400-patient phase III study in that indication. There is actually a number of others. There is probably a dozen or so tumor types spanning GI cancers, gynecologic cancers, thoracic cancers. It is still, I think, a wide open arena.
Obviously, a lot of competition. I think this is an area you're going to have not just winner take all, but there'll be a few groups that will be able to carve out a meaningful market opportunity for themselves.
Yeah. I was trying to, I remember Daiichi making several comments about how big they view B7-H3 as an opportunity for themselves.
Exactly. That was obviously reflected with the collaboration they did with Merck. That was a major partnership, $2 billion in upfront capital committed. They are obviously looking to extend this across many different tumor types. I think we are just getting started in terms of where the field is going and where the different development opportunities are for that program.
Great. Maybe talking a little bit high level about MacroGenics on the operational side. At year 2024, you had $200 million in cash. And the runway was into the second half of 2026. Just how we think about extending the runway and what BD options do you have? You've done already a lot. And what kind of, what are the key catalysts that you could use maybe to get more diluted funding perhaps or something like that? So what do you think will be the highlights until your cash runs out?
Yeah. We'll obviously have data coming out over the course of this year. We've also had, I'd say, a pretty impressive track record in terms of our corporate deal-making prowess. Over the last three years, we've actually brought in about $475 million in non-dilutive capital. We have not done a formal marketed offering since 2019. We've been able to, obviously, public markets are probably not going to be a primary option at this point. Non-dilutive sources of capital is something we're always thinking about. Again, we've had a strong track record in executing in those areas. We're always exploring options for the future. The expectation is we'll continue to extend that runway to enable us to support these programs and carry them to important inflection points.
Great. Maybe talk about MGD024. Gilead has an exclusive option here to license the CD123 x CD3 DART. What are some of the factors getting that option? What are you in your phase I trial?
Yeah. So the molecule that's MGD024 targeting CD123 and CD3, it's actually a follow-on molecule or a second-gen molecule that came in the wake of flotetuzumab, which was also CD123 directed. Here we've actually tailored the CD3 binding domain. We've in some ways detuned the affinities, but also changed the whole kinetics of the binding properties. What that has enabled us to do is reduce some of the cytokine release that we've seen with that earlier stage molecule. That's all based on some of the early preclinical work that we have done and published. It also is an FC bearing construct, whereas the first-generation molecule did require continuous infusion. The benefit of that first-generation molecule is we have a lot of data and empiric evidence that we can start baselining against to figure out how do we further improve the features of this molecule.
That is not a dose escalation. It is part of an option-based agreement with Gilead. They are really driving the timetable in terms of data disclosure and dissemination. It is going through dose escalation, which has been a fairly prolonged effort. That is partially for these class of molecules and based on the direction of the FDA. They have taken a little bit more measured approach in terms of how we are going through dose escalation and also the requirement to start at this MABEL dose level, which is very, very low doses. It continues. We are excited about the prospects of the molecule. Actually, about a year after that first collaboration was announced, Gilead expanded the relationship with MacroGenics with a second bispecific molecule. That is also now progressing. That is still preclinical stage. We are very excited about that relationship.
Great. What kind of patient are you enrolling in that trial or who's getting dosed?
These are hematologic malignancies that are typically CD123 expressors, primarily AML. MDS would be really the prevailing tumor types.
How does it fit in AML? Would this be post-relapse or?
For this initial population, it'll be post-relapse or later line population. Again, based on the design goals of this molecule to create something that's a little bit more convenient in terms of administration, potentially a little bit more tolerable. The opportunities are also to go into earlier line and do combination-based approaches. Some of that work we've also published. There does seem to be nice complementarity of mechanisms when you add into other agents.
Yeah. Would it be combinable with venetoclax or some of the target therapies?
It could be. I mean, there's a lot of opportunities there. Azacitidine. There is a host of agents that we're looking at. Ultimately, Gilead will likely direct that strategy in terms of where they want to combine and how they want to prioritize.
Great. What are the next steps on Gilead on that particular molecule? Would it be an opt-in or in what mode could that happen?
Yeah. The way that the agreement was structured, there is an opt-in decision point. Actually, there are several decision points that are hardwired into the agreement. That would be in the context of the phase I study. Specific timing guidance we have not actually provided at this point.
Okay. Great. Maybe ask about your CEO search. How's that going? Can you give us some color around what kind of candidate you're looking for or when that could come to an end?
Yeah. Late last year, the board announced that we have a nationwide search that they kicked off. We do not have any specific timetable to really disclose at this point. There is a subset of the board, four members of a search committee. They are going through that process. Scott Koenig is continuing to function as the CEO and is committed to really supporting the company and making sure there is a good transition when that next candidate is.
All right. Welcome back. My name is Silvan Türkcan. I'm a Senior Analyst at Citizens. Thank you so much.
Great. Thank you. I appreciate the opportunity to present here today at the conference and talk about MacroGenics and all the milestones and upcoming events for the company over the course of this year.
Yeah. Great. No, looking forward. Maybe can you provide us some background of how you're redirecting MacroGenics now, after the R&D engine and specifically after the Vobra duo?
I think the operative word there is R&D engine. We've had a history of being a very prolific drug discoverer developer. We actually have four assets in the clinic, which were all homegrown assets, in some cases leveraging platform technology that we developed internally. We have also licensed in for our ADC portfolio some proprietary drug linker chemistry. Four assets in the clinic actually spanning three different mechanisms. We're very excited about the prospects of each of these. The lead asset in that portfolio is lorigerlimab, which is a bispecific molecule that blocks both PD-1 and CTLA-4. We actually fully enrolled a randomized phase II study. We'll have some data coming up latter part of this year on that program. We also have two ADC programs leveraging a topo I-based drug linker that we licensed from Synaffix.
Those are in the clinic in phase I going through dose escalation. Again, we're excited about prospects of where those studies might be later in the year. We also have a bispecific molecule, which is predicated on a T-cell engager mechanism. CD3 by CD123 that is part of an option-based deal with Gilead. That's also going through phase I dose escalation. In our earlier research labs, we continue to innovate and advance additional molecules, the first of which will be now in the clinic next year. That's another ADC program called MGC030. A lot of activity in the portfolio, multiple mechanisms, many of which are actually quite complementary with one another. We think we've never been really reliant on a one asset kind of investment thesis. It's really been a portfolio approach.
We think the portfolio will do very well over the course of this year.
Great. No, thanks for this overview. Obviously, maybe I'd like to start with the bispecifics because it is obviously a very growing or hot topic right now. We're waiting some very important readouts, I think, from summits and others this summer generally in that space. Can you just give us an overview of lorigerlimab and how you came up with what you designed the molecule for and how it fits, what data we've seen and how it fits in the prostate cancer?
Yeah. So we're very excited about that molecule. Obviously, the whole field of checkpoint inhibition has gone through a little bit of an evolution with the first introduction of pembro and evo about 11 years ago, a flurry of interest in alternate checkpoint molecules, which in some areas did disappoint.