All right. Hello, everyone. Thanks for joining us. My name is Jonathan Chang. I'm part of the Leerink Partners Equity Research Team. It's my pleasure to host the management team of MacroGenics, and we have with us today CEO Scott Koenig. And for the clients that are sitting in the audience, if you have any questions today, feel free to raise your hand, and we'll certainly try to get to you. And with that, let's get started. Thank you for joining us.
Oh, always a pleasure, Jonathan.
Would you like to take a few minutes to introduce the company?
Sure. I mean, I think, most people know the company pretty well. We've been in operation, now 24 years. The company's been focused on developing immune-based therapeutics. In the history of the company, we've actually, contributed to the, approval of three drugs that, came from our portfolio. We, focus on, three different platform technologies, one around Fc engineering antibodies, second around bispecifics, multi-specifics called our DART platform, and as you know, our, extended efforts now in, developing antibody drug conjugates. Company is probably in, the best shape it's ever been in the history of the company. We're... You know, and, and this is, really due to a fantastic team that, we have working at the company. We're executing on preclinical and clinical, opportunities now.
I'm sure we'll be talking about some of the phase 2 opportunities that we're working on right now, but I'm as optimistic also about many of the things that are now moving into phase 1 development and our preclinical portfolio. I think the prospects of the company look very good, and as you know, we've been very disciplined in terms of making sure our balance sheet is in order and having enough capital to support these programs.
Great, thank you for the introduction. Let's start off with vobra duo, your B7-H3 ADC program. How do you see the B7-H3 landscape, and how is vobra duo positioned in that landscape?
Well, as you know, this has been a target of ours that we've been working on for now over 15 years. We've had multiple molecules targeting B7-H3 in the clinic. In fact, right now, we have two distinct molecules, actually, now three distinct molecules in the clinic targeting B7-H3, and continue to work on preclinical molecules targeting B7-H3. This has been a darling of ours since our initial work, where we showed overexpression on most solid tumors, identifying variable domains that are targeting different epitopes, showing a very high binding to tumors versus normal tissues.
Obviously, the expression of B7-H3 in the tumor microenvironment was particularly attractive to us, with regard to expression on dividing tumor cells, the endothelium of the vasculature, as well as T-regulatory cells and the association with tumor progression and overexpression of B7-H3. So we are, you know, all in on going after this target and from various vantage points. With regard to the landscape, as you alluded to, being the first one out there with molecules to B7-H3 and now validation from a number of both pharmaceutical as well as smaller companies pursuing these targets with different modalities only increases our enthusiasm that we made the right choice very early, and to continue to pursue different modalities against this target makes a lot of sense.
So I think that we're in a wonderful position now with vobra duo, having shown significant activity in phase one development, that now as we are going to read out on our TAMARACK study in phase two, we hope to identify the appropriate dose to move forward, not only in the prostate cancer indication, but as we recently announced, expanding into five additional tumor types, with an alternative dosing regimen, will obviously build on the opportunity and the prospects for success.
Great. So can you help set expectations for the Vobra Duo update expected at ASCO?
Yeah. So, as we have articulated previously, it was clear to us that while we had very significant activity across multiple different tumors, but particularly highlighted with our effects in prostate cancer, we were having the majority of the patients that had either dose discontinuation, dose interruption, or dose reduction. And literally, the majority of the patients fell into that group, and this typically occurred on a mean or average basis about a month and a half into dosing.
So, by taking a very holistic approach, in the patients we treated at the 3 mg/kg Q3W, and understanding their response rates and dose reduction as it correlated with side effect profile and clinical activity as well as PK, we came to the conclusion that by reducing the dose and increasing the time interval for dosing, we had the opportunity to achieve a better clinical outcome and a reduced side effect profile. And so with that, that's what we are testing right now. As we had announced on our earnings call, the initial cut of the data from the first patients were evaluated by a data safety monitoring board for the two doses. They recommended continuing the dosing going forward.
So I would say in the next few months, we'll have a really good sense, have we achieved what we were setting out to do, of having a safer drug and as good or more active drug than we previously put out? Now, with regard to the particular parameters that we're evaluating this, as you know, there are a lot of different ways we can look at control of prostate cancer. We took a holistic view of looking at not only our own experiences, but what had previously been reported by Daiichi with their 7300 molecule at the ESMO presentation this past fall.
What we have said is that with the doses that we are pursuing right now, there is no reason we shouldn't achieve comparable PSA 50 reduction compared to baseline about half the patients. So we've set a parameter. We expect that to be in the 40%-60% PSA 50 reduction range. Again, based on what Daiichi reported on the overall response rate of about 25%, we similarly were reporting around that number. Again, that should be achieved and hopefully higher. That will be somewhat dependent on the mix and the severity of the disease in the patients. As you know, that can vary quite greatly depending on the amount of visceral disease versus non-visceral disease.
What's most important for this disease, when no drug is shown to cure this disease, is how long are the patients staying on drug? What is the duration of response? What is the radiographic or progression-free survival, which is believed to be the best correlate for overall survival going forward? And so, again, what Daiichi reported with their DS-7300 of 5.3 months, we said, "Look, we got to do better than that." As I've spoken to investigators, baseline, depending on which population it is, of at least six months of our PFS. But clearly based on the data that's come out of a VISION study, CARD study, and others, we'd like to see it higher.
Whether it's 8 months or 10 months or longer, that will be dependent, you know, on the results and which population we're treating.
Got it. Can you discuss how you're thinking about the dose optimization efforts with vobra duo and your comfort level on the potential improvement on safety and tolerability?
Well, again, to reiterate, when we looked at the results of the phase 1 data with regard to side effect profile, dose interruption, what dose was reduced to, we looked on an individual basis, what was the total accumulated dose that any given patient had seen, and then integrated that on a going from a Q3 to Q4 weekly basis, especially looking at the patients who had their doses held or interrupted. Could we come up with a... And looking at the PK, could we come up with a scenario where we would see a better benefit? And that's how we ended up with a 2.7 Q4 and 2 Q4 that would bookend what we thought would be optimal doses.
I could—as I've shared with you previously, we had this discussion with the FDA when we did the original design for TAMARACK, and they were very comfortable. In fact, they said, "Scott, you know, going to Q4 makes a lot of sense to us. We don't think you need to reduce the 3 mg down to 2.7, but that's up to you." We felt that tweaking that down, and as I've pointed out, if you look at the ultimate exposure of somebody that's on 3 Q3 and compare it to somebody that's 2.7 Q4, that's a 28% reduction, assuming that they get equal complete doses. But as I pointed out to you and others, that the majority of the patients at 3 Q3 had their doses reduced.
So if we're getting that improved tolerability by that reduction and increased dosing interval, they will ultimately get exposed to as much or more drug than we saw at 3Q3. And so, then when we looked at Cmax and trough levels, again, not great changes in that. So I think we're in the right Goldilocks range to achieve what we want. The data will tell us if we made the right decision.
Understood. And how should we be thinking about what we could see in the abstract versus in the full ASCO presentation?
Well, again, as I pointed out on our earnings call last week, to give clarity to everyone on what was possible, the over two-thirds of the patients that enrolled in the TAMARACK study occurred in the H2 of the Q3 to the H1 of the fourth quarter. And so, given so late in the year when the two-thirds of the patients came into the study, we had to submit the abstract in early February, which meant we had to analyze the data, cut that data. So we decided to use the data that was presented to the DSMB, where they did their analysis, included that data in the abstract. That is primarily safety data because that's where we had the most aggregate data going forward.
Given that ASCO abstracts data is coming out, I think, the twenty-third of May, and the meeting is a little, just, about a week later, it's not a long time to wait to see both the additional data on safety, but also, obviously, the activity efficacy profile that we will present.
Understood. And how should we be thinking about the over-enrollment of that study? You guys over-enrolled that by a considerable margin. How should we be thinking about that, and what do you think was the driving force behind that?
So, when we did the amendment to remove the control group, which, where we were getting the greatest pushback, patients did not want to be on a control on a second androgen receptor-targeting agent. We made that decision very early. The initial amendments occurred in the U.S. sites, which are very few compared to Europe. Europe is the dominant enroller in this study. So we were able to get a couple of patients in on this amended protocol, you know, starting in the late Q2. But it wasn't till later in the year when the amendments went through in the European sites and obviously occurred at different times. What we were quite surprised at is all of a sudden we were seeing an enrollment, a rapid enrollment in as we were opening these European sites.
In fact, we never got to do site initiations on a significant number of sites because we were approaching the 100 patients planned. And so we felt that when we got to that point, there were a lot of patients that were in screening, and we did not feel that ethically that it was the right thing to do for a patient to go through that process to not give them the opportunity to participate in the study if they wanted to, if they met the entry criteria. So we said at that time, "We're cutting off future screening.
We're not opening up any more sites, but if you, if your patient meets the criteria and wants to be in the study, we'll put them in." That's how we got, as we announced last week, 177 patients that were dosed in the study.
Understood. So on the TAMARACK study, can you discuss what kind of patients were enrolled? I guess how many were pre-taxane versus post-taxane, and you also mentioned earlier, that how you're thinking about the benchmarks there, that there could change depending on the.
Yeah, so, one of the major differences between what we did in the phase 1 study versus what's in TAMARACK is in the phase 1 study, all the patients were required to have progressed or have experienced a treatment with a taxane, particularly docetaxel, and had progressed on at least one androgen receptor-targeting agent. When we moved to TAMARACK and made the amendment, we opened this up to a larger population. They could not be on more than one taxane, more than one, or meaning docetaxel. And for the androgen receptor-targeting agent, while that was in the original TAMARACK trial, but was not a phase 1 requirement, originally, we required the patient to have sustained at least 12 months of exposure to an androgen receptor-targeting agent.
We took out that requirement to be on at least 12 months. So with that liberalization of the protocol, it opened up the patients that previously had no opportunity to be on this trial, or in fact, being on other experimental agents to this study. And so I have to say, I was surprised. I expected the majority of the patients to have been taxane, docetaxel experienced, but now only requiring up to one, allowed patients who had not seen a taxane on this study, and obviously, a number of patients who had not been on a androgen receptor-targeting agent for 12 months. So what that turned out to be is approximately, it's not exactly, but approximately half the patients are chemotherapy naive, and half the patients are chemotherapy experienced.
So, you know, it was serendipitous that we had this over-enrollment of patients, and in the end, this is obviously benefiting the trial and the decision-making with regard to what is the appropriate patient population to pursue if we meet the activity and safety criteria that we set up for the study.
Understood. You also recently disclosed, on your earnings call, the decision to expand the TAMARACK study to include other tumor types. Can you discuss the rationale there, and what are the reasons for this?
... So again, taking advantage of the experiences we've had in a number of different tumors in the phase I study of vobra duo, looking at the landscape of other molecules targeting B7-H3 and the activity they have seen, we selected tumors that we think have. And looking at obviously the IHC criteria in terms of expression pattern of B7-H3 on these tumors, we picked five to move forward with, that we think would have a good likelihood to have responses. And assuming that we've made the right choice with regard to dosing, we think that these patients with other tumors would benefit from vobra duo. So I think we're in, we're in a pretty good situation, having both our own personal experiences and seeing what's out there.
So, for example, what's, you know, it's very clear to folks with both data produced by Daiichi and Hansoh with regard to small cell, we have not had the small cell cancer experience that others have had. We had one patient in dose escalation that actually had activity with Vobra Duo at a lower dosing regimen. That patient stayed on with small cell over six months with tumor reduction, but that was the only patient we had in the study. So it was clear that that was one that we should go after, given the activity of the topo s there, and see what a DNA alkylating agent would do. With regard to activity, we've seen in our own experiences responses in melanoma and lung cancer.
So those are clearly ones we should continue to include. In fact, historically, we had originally planned to do an expansion in melanoma and didn't come back to it, and so we added other opportunities that we think are promising as well.
Understood. Let me check, see if there are any questions from the audience at this point. All right, it's been crystal clear. So how should we be thinking about the strategy behind the second-gen B7-H3 ADC program, and then how that could be positioned versus, vobra duo?
So I will take exception, not in a pejorative way. People always talk about next gen when you do another thing. We actually see this as an opportunity that you have two molecules that could be as good. The way we have looked at this, and if you go back two years ago, we made the decision that we wanted to expand our footprint in ADCs. We did a very comprehensive look at what we thought were good linker toxins, and particular with the success of Trodelvy and HER2 and others using a topo one, we asked the question: Could we find a platform that had a topo one inhibitor, that could meet or actually beat that of those two molecules?
So we were convinced, based on the data that was presented to us, the very promising prospects of the Synaffix platform, where they're using what they call SYNtecan, which becomes exatecan as the active agent. By conjugating that molecule to the glycan in the Fc domain, they have indicated that they can get more potency than both SN-38, which is in Trodelvy, and the deruxtecan, which is in Enhertu and DS-7300, that they can get better activity in terms of reducing efflux and MDR. And then, what Daiichi has indicated, and more, and higher potency when they've, in fact, look at molecules that have deruxtecan at a DAR of 8, compared to their SYNtecan, exatecan of DAR 4, the DAR 4 performs better than that of the deruxtecan DAR of 8.
So from all these parameters, in addition to what Daiichi has said with regard to the basis of the mechanism for interstitial lung disease, ILD, which they obviously see with deruxtecan, they ascribe it to the fact that alveolar macrophages take up their toxin, and this is likely through Fc engagement or through the mannose receptor. By the fact that SYNtecan and exatecan binds more to the glycan site, that destroys the binding to these macrophages. So the potential of now giving a more potent drug that could actually prevent or reduce the incidence of ILD is also another advantage. Now, getting back to the question, how do you prove this? And so, from our vantage point, you don't wanna have too many variables when you're doing that test.
And so the fact that we know we have an active drug against B7-H3 with vobra duo, we're using the exact same variable domain, so we're taking that as a variable in the equation. We're then able to ask the question: Is the toxin gonna do better in this setting? We'll have the control. It's basically the control experiment. If that turns out to be true, what this opens up is enormous. Number one, for the patients who, for instance, are getting vobra duo, the opportunity of sequencing the drugs or giving in combination... or going into tumors because mechanistically, certain tumors will respond to topo ones, some will respond to DNA alkylating agents. There's evidence, obviously, in the treatment, for instance, with cervical cancer, topotecan is combined with cisplatin, an alkylating agent and a topo one. That's an FDA-approved combination.
There are other uses of combining these things. So if we are able to meet that hurdle, we can now expand into all these other targets that we have variable domains on. We've announced that we're doing it also with ADAM9 later this year, and then we're working on, you know, targets 3, 4, 5, as we move forward. So in less than a year or about a year, by the time we get this additional data, we will know whether we have something very significant here that is for benefit of patients and then obviously for, ultimately for development.
Understood. We will try to remember not to call it.
Well, that wasn't-
What could a development path for Vobra Duo look like in prostate cancer?
So again, it all depends on the activity profile that we see in the non-chemo versus non-chemo-experienced versus chemo-experienced population. So, ultimately, we are in discussions with a lot of the KOLs of what their advice is, depending on response rate and activity. But one could envision if the chemo-naive population, the data looks good, you could, you know, go after standard of care, which is would be docetaxel. You know, others have also, as you know, continued to use a second ARAT. It's under consideration, but it's, again, a conversation we would have with additional investigators as well as regulatory agencies. In the post-chemo experienced population, again, that could be against chemo or physician's choice, where they would be able to have another ARAT or other agents included.
So likely a 2-to-1 randomized study, but still have to determine based on the results.
Got it. Maybe with the time remaining, I'll try to touch on your other programs. So with lorigerlimab, your PD-1 CTLA-4, what is the latest status of that program, and, and how might that also be positioned in prostate cancer?
So, as you know, we're doing a study called LORIKEET. This is based on very promising data we presented last year at ASCO GU, looking at late-stage patients where we were seeing PSA 50s in a 29% range, and objective responses in a 26% range. In fact, all the patients that responded objectively had PSA 90s or greater. We moved into an early-line therapy of chemo-naive patients. This is a 150-patient study, 2-to-1 randomized, to see a combination of docetaxel plus lorigerlimab versus a control of docetaxel alone. Study is enrolling. As I've indicated before, we expected this study to completely enroll this year.
The timing of that will be determined in the next couple of months, what the speed of enrollment in which will then determine when we'll have first cut of data. We certainly will provide update of where the study is in the H2 of this year, and hopefully, if it enrolls faster than you know we had planned out, then we'll be able to provide some data later this year, more likely in the first part of 2025.
Got it. Maybe just in our remaining minutes, can you discuss how you guys are thinking about business development opportunities and your cash balance and runway?
On the latter, we had approximately $230 million in cash and cash equivalents. We have not changed our guidance with regard to that cash supporting the studies that we've discussed that are ongoing into 2026. With regard to business development activity, as you know, we've been very successful in the history of the company. We've brought in over $1 billion of non-dilutive capital since our IPO a little over 10 years ago, and probably approximately $1.4 billion, if you include money we brought in prior to our IPO. Constant discussions with regard to platform opportunities, molecules preclinically and clinically, always ongoing. We expect to have more deals done on an annual basis.
So, you know, nothing should be no surprises there in that regard, given the breadth and depth of our program. I should also point out, with two of our approved products, there are some key metrics coming out. There's about a little over $1 billion of milestones still that are potential for ZYNYZ and TZIELD. As you know, on the TZIELD story, Sanofi has said that they are looking for regulatory approval in diabetes on that. So, if that occurs, that should obviously increase the probability of the potential $380 million of the milestones from that asset.
And then, as you know, Incyte has 2 phase 3 registration studies that will be completed and announced at some time in anal cancer and lung cancer. So if one or the other becomes successful, that obviously increases the probability of seeing some of those milestones as well as royalties from them as well.
Got it. That's all the time we have. Thank you, Scott, for being here and joining us, and thank you for people in the audience.
Well, thank you, Jonathan. Appreciate it.