Morning, everybody. Welcome to Day 2, HealthCONx in sunny Miami. Thank you, Scott, for joining us. We've got Scott from MacroGenics here with us. Excited to have you.
Thank you. Thanks so much, John. It's always a pleasure.
All right, so let's start from the top. The programs that have been getting the most attention at MacroGenics for the past couple of years are B7-H3.
Correct.
You've got a number of these in development, most notably recently Vobra duo, the MMAE-bearing ADC, which has had some safety tolerability challenges.
Let me just make one correction. It's duocarmazine, not an MMAE.
It's a duocarmazine.
It's a DNA alkylating agent.
Sure.
Yeah.
Notably, not a topoisomerase.
It's not a topo1 inhibitor, right?
Can you, let's start with just the update of where these programs are currently. There's multiple ADCs, a monoclonal antibody. Where are they, and where are the company's priorities for developing B7-H3 further?
As you know, we have had, we were actually the first company that had to develop molecules targeting B7-H3. We recognized very early that this was a very unique opportunity, given its expression broadly across multiple tumors with low expression on normal tissues. So we ventured out to develop multiple technologies using our antibody platform, but was agnostic with regard to effector mechanisms. So obviously, as you know, we started out with an Fc-engineered molecule called enoblituzumab. This is using our same Fc technology that was in margetuximab, which was approved for HER2-positive late-line breast cancer, where we can enhance binding to the activating receptor.
That study currently for enoblituzumab is in a neoadjuvant prostate setting based on some very exciting data that was published last year, showing that treatment prior to a prostatectomy in patients with newly diagnosed disease would have beneficial effects, as evidenced by infiltration of their prostate and inflammation there, and reduction of and maintenance of PSA values, which were negative after prostatectomy. That was done in 35 patients. There's currently a 219-patient study that's enrolling phase 2. It's a controlled study that's an IST being led by a group at Hopkins, so that'll take a couple of years, and in fact, if that shows a promise there, that will be a complete transformation for the prostate world.
Most of the attention, as you know, for the past year was on Vobra duo, which is an ADC molecule that, again, we had developed over a number of years, demonstrating activity in multiple tumors. We highlighted our focus on prostate cancer. As you know, we were very excited about our initial data when we were treating a 3 mg per kg every three weeks, where we were seeing about half those patients were developing PSA 50 reductions and objective responses. We had observed that we were seeing a certain pattern of side effect profile and determined that, or hypothesized that if we reduce the dose, we could get both better efficacy as well as better safety profile. That led to the TAMARACK study, which was a 181-patient study that we recently showed the data at ESMO this year with the six-month landmark endpoints.
In fact, the way that study was designed, where we were treating at 2.7 or 2 mg every four weeks, so reducing the dose and increasing the dosing interval, we achieved what we had said we were out to accomplish, which was we were able to increase the number of doses given to patients from the 3 mg, which was a median of four to up to six. We had a very good both ORR and PSA responses, and we were able to reduce the major side effects going forward.
As you know, we have indicated that we will have final data coming up very soon in the next couple of months. What we have said that we will wait for that data in terms of the overall activity, the safety profile, to determine what are next steps for that program and look at it in light of all the other prostate therapies going forward.
Scott, I got to say at this point, investor expectation is that the Vobra duo program is absolutely dead.
Right.
But like you say, you did manage to mitigate the tolerability issues at least somewhat. What are the bars for actually taking the program forward at this point when you see final data for TAMARACK? What would you have to see in order to feel like this was a developable agent?
Yeah. So just let me put it in context. On the landmark six-month endpoint, where only 36% of the events had been achieved, the endpoint events had been achieved for both those doses, so really a small percentage. We were already seeing, for instance, at the 2 mg Q4, an rPFS value of eight and a half months. So this is quite favorable to the historical data. If you look at all the patients, this is both in the pre-taxane setting and post-taxane setting. If you look at the comparative data from KEYNOTE-921, PRESIDE, even VISION, you're talking about eight months of activity. So with a result that's exactly in that vein and with confidence intervals that run between seven and 11, the expectation is that we'll actually see even better rPFS. Obviously, we'll have to wait for the data.
But getting back to your question is, we'd like to see obviously increasing rPFS values that exceed eight, probably close to the double digits or double digits. We obviously like to continue to maintain a reasonable safety profile that then could be addressed with additional study designs. So the answer right now is we'll look at the totality of that data in the context of what's going on in the prostate space and make our decision going forward.
Of course, there's also a topo payload, B7-H3, coming secondary to that.
Correct.
I know when you started that program, you were talking about the potential to do combinations or to address different patient populations. Given the tolerability challenges that vobramitamab duocarmazine has, should we be thinking of the topo payload as more of a replacement, or are you still thinking about the potential to use both agents?
Again, we'll look at these independently, and we are developing these as parallel track events. Obviously, as you know, not all tumors respond to the same cytotoxic agents, and so you'll see some tumors respond better to one versus others. As you know, the field has gravitated to a lot of topo1 inhibitors, and as you know from the data that, for instance, in the HER2 space, that coming back with a second agent with the same linker toxin or the same toxin ends up not giving any additional benefit to the first treatment,
so having a second ADC mechanism could bode very well to complement topo1, even if it's in the same tumor environment, and then obviously, different combinations based on the safety and the activity profile could be quite different depending on the linker and the toxin. So right now, until we make the decision on Vobra duo, we see this as separate independent tracks.
Makes sense. Now, for B7-H3, you mentioned you see utility across a wide variety of tumor types. Obviously, some other folks developing B7-H3 programs have been prioritizing other indications, while you have focused primarily on the prostate space. At this stage, looking forward to the topo payload version of the molecule, considering where else B7-H3s have shown utility, where are you focused today? Are you still doubled down on prostate, where the current data is developing, or do you think there are more efficient paths to value in other indications?
I think you raise a very important question. It is, how do we use the capital that's at hand to get the most bang for the buck going after indications? And given the broad expression of B7-H3, both in terms of common tumor types as well as the more rarer tumor types, we actually have a large opportunity to make that decision to go after several of these. So what we are doing right now, for instance, in the topo1, we're in the middle of dose escalation there. We have the ability to pick based on positive responses in any given tumor to expand and add additional patients for those indications. Our expectation is for this phase 1 study for the topo1 B7-H3 molecule called MGC026 that we will complete phase 1 in 2025.
We will select the particular tumors based on the competitive landscape out there, as well as our own activity that we observe. We think this particular topo1 inhibitor linker payload, which we licensed in from Synaffix, has attributes that other topo1s don't have. It seems to be more potent, for instance, based on comparison to deruxtecan, which is in the Daiichi Merck molecule. It seems more potent than SN-38. It has also likely better safety profile, less efflux, and multi-drug resistance. We actually have made molecules with our variable domain targeting B7-H3, for instance, with deruxtecan and with the topo1 inhibitor from Synaffix, and actually see, at least in preclinical models, enhanced activity of the Synaffix technology. We are looking quite favorably that as that data emerges, we'll have very clear signs of which particular tumor types to expand in going forward.
All right. Well, maybe let's switch gears a little bit and discuss the other major clinical program that I think people are interested in. That's lorigerlimab, your PD-1 CTLA-4 bispecific, tetraspecific, I suppose, but bispecific, and the LORIKEET study coming first half next year. So could you remind us why you're focused here also in prostate? We've seen other PD-1 CTLA-4 bispecific programs with a very broad set of tumor potential tumor activities. What's focusing you here? And again, where else do you see the potential for lorigerlimab?
Yeah. So we're very excited about the prospects for lorigerlimab, not only in prostate, but in other tumors as well. But focusing on the studies in prostate, let's sort of step back. We know that the combination targeting of PD-1 and CTLA-4 enhances anti-tumor activity in multiple tumor settings. The issue became for particularly ipilimumab is that the toxicity observed with that combination limits the dose you can give and the number of doses you can. So for instance, despite all the efforts that Bristol had entertained, they were limited to always giving one mg per kg for a maximum of four doses. And because when they went for further dosing, the increased toxicity, particularly GI toxicity, became limiting. And so as you know, Pam Sharma, many years ago, in a collaboration with Bristol, was exploring Ippi and Nevo in combination in prostate cancer.
While they did not achieve a successful outcome for their trial, they did see increased, improved responses in those patient population. It was our thesis that if we could design a molecule with better, at least as good, activity or potentially better activity, but a better safety profile, and be able to give this drug repeatedly, we may get a better result in prostate and other tumors as well. Sure enough, when we designed this molecule, as you alluded to, we made this as a tetravalent bispecific molecule. Two binding sites at PD-1, two binding sites at CTLA-4. You have increased avidity to cells that are co-expressing both those molecules that are enriched in the tumor microenvironment, which are exhausted cells. Therefore, you get a localization to the cells that are most effective in targeting the tumor.
The second way we improved that molecule is we made this on an IgG4 backbone because it was our hypothesis that T regulatory cells, which eliminated or mitigated many of the side effects including the GI toxicity, were being eliminated by having an IgG1 in the case of ipilimumab. And so sure enough, when we did the tox studies, when we did dose escalation studies, we had much lower side effects events and were able to give this drug repeatedly. So we additionally did dose escalation in multiple tumors. We did expansion in four tumor types. We saw a very nice signal in prostate cancer. Data that we presented two years ago at ASCO GU, we were seeing 29% PSA50 reductions in late line patients. Objective responses in 26% of these patients that were confirmed, and all the patients that were having confirmed responses had PSA90s or greater.
So with that, and some of these patients were being treated on a Q3 weekly basis for over two years. So with that basis, we said, let's go and move upline. And so we went into a study, which is called LORIKEET, where we're looking in patients who have progressed on antigen receptor targeting agents but have not seen chemotherapy. So it's a very early line castration resistant prostate population. That study is 150 patients, 100 patients getting a combination of standard of care docetaxel plus lorigerlimab on a Q3 weekly basis, six mg per kg, much higher obviously than ipilimumab would have been given, versus 50 patients with docetaxel. I'm happy to say we are just about finished enrolling the entire trial. We have a few patients just to add. We will have the data in 2025. And so we look forward to that.
I should also say that we are planning to move into other tumor types as well based on our safety activity profile and feel that this is a broadly usable molecule in a checkpoint space, either individually or in combination with other agents.
Let's dial in on the LORIKEET results that we're expecting. In the late line expansion cohorts, you mentioned some of the results you saw there. To my eye, thinking about late line prostate patients, that ORR number looks highly competitive, but the PSA50 number looks a little bit lower, where I might expect a 50% or mid-50s to a 60% number. This is sort of where you're at in the late line with Vobra duo, where Amgen is at with STEAP1, and where various other folks are at in that late line setting. So why the disconnect between PSA50 and ORR, or at least maybe more concordance for LORIKEET, where in other agents we see less?
Obviously, every mechanism is going to have some degree of differences. But just to put it in perspective, at the same meeting where we presented this data for ASCO GU, Bristol presented their data of Nevo 3, Ippi 1 on a Q3 weekly basis. Remember, we saw 29% PSA50s. They saw 13.8% PSA50s. We saw 26% ORR. They saw 9.3% ORR. So again, it fits the thesis that by giving a safer drug and more frequently, we can get a better response. Back to the question versus other mechanisms of action, the beauty here is that we're adding this on to docetaxel.
So we're looking for a very good response in the chemo-naive population, adding on further there that you have orthogonal mechanisms that could ultimately improve the response here. And so if you think about the fact that there's no checkpoint approved in prostate cancer, this makes a lot of sense. And if we can actually prove that in this setting, we can actually go into other tumor settings where combination therapy with a combination checkpoint like this might prove very valuable.
So basically, expanding access to IO to tumors where previously it hadn't been targeted.
You got it.
Effective, especially in combination.
You got it.
Makes sense. All right, so question from the audience. Yes, Amer.
What's your expectation on the second program on the same target into ASCO GU?
When you say the second program?
Oh, you're talking.
We talked a little bit about that before. So right now, we're in the middle of dose escalation. We expect to finish the phase one study this year. Prostate is one of the tumors that is incorporated here, but we're looking at a wide range of tumor types.
Prostate patients, will we have?
I can't say at this point for the topo1 inhibitor at this point. There'll be some, but clearly, there is interest, given the history where we work in prostate cancer, to incorporate those. But there are a lot of other tumor types as well.
Let's put it in perspective. As you know, the deruxtecan one from Merck, Daiichi was not very good, where they saw in those 50 or so patients an rPFS of only 5.3 months. The question then becomes, is our topo1 inhibitor, which I alluded to before, superior from a mechanistic standpoint that we could get an outsized response in prostate? It's back to the question, is the linker toxin effective in prostate for topo1 as much as the Vobra duo, which is a DNA alkylating agent? That is some of the reason why we're keeping parallel tracks going forward in this.
One thing.
Lung would be the preferred indication?
Lung would be an excellent indication going forward, absolutely, for the topo1s. It certainly is one. Certainly, as you know, a lot of companies are going after small cell lung cancer. But clearly, the opportunity for both adeno-and squamous is on the table for that.
My last one, sorry. ILD, have you seen anything of concern today? ILD, anything of concern today?
In the topo1?
Correct.
No.
Not at all.
We're not seeing today, there's no concerns so far on the safety profile, and nothing with regard to ILD.
You're in active dosing?
We're in the middle of the dosing range. I'm not going to comment further on the specific activity profile at this point. But as I say, we should have that study completed in 2025.
All right. Well, we're more or less out of time. But one last question before we go. I would love to ask about further BD. Historically, you've done a great job monetizing assets that weren't your core focus. I assume you're going to continue to do this into the future. Which of the assets that are in development or on your shelves do you think are the highest priority for you to monetize?
This is a big question. I'll try to do this briefly. As you know, as you alluded to, we've been very successful here. Just to put this in perspective, since the middle of 2022, we've brought in $475 million of non-dil utive capital. We have not gone to the equity markets with a formal raise since 2019. In that vein, as you know, we have a lot of on-the-come possibilities with regard to retifanlimab. As you know, the recent data in anal cancer, this is a partnership with Incyte, is going to go to the FDA for the anal cancer indication and first indication. They had a successful phase 3 also in lung cancer. Just to remind you, we have 15%-24% royalties on that. That's not incorporated in our budgeting process going forward, plus additional potential for milestones there.
We still also have potential milestones from the Sanofi deal with regard to teplizumab. They are obviously trying to get registration in new onset type 1 diabetes. With regard to additional BD activity, as you know, we have a lot of other active clinical programs, which include our relationship with Gilead on the CD123xCD3. We have a second target bispecific that is in research phase, which could potentially bring in additional milestones.
We have, I'm very happy to say, we filed the IND for MGC028, which is the ADC for ADAM9, which we'll start dosing early in 2025. Obviously, that's an opportunity either to take forward ourselves or potential partnerships around that. I could tell you there's a lot of other preclinical molecules that are very active. We have seven slots with Synaffix in total through our collaboration that we could use to develop new ADC molecules. And then some very exciting technology that we are going to talk about likely at a research conference in 2025, which we have not discussed at all.
Stop 30 seconds on flotetuzumab. Could it be active in some other indication?
The next generation, which is the MGC024, absolutely could be used in those indications as well. And as you know, we also have a CD19xCD3. That was CD123xCD3, the one you were referring to. But we also have CD19xCD3 using our next generation CD3 technology, where we substitute a single amino acid in the CD3 domain and dramatically reduce cytokine release, but maintain tumor activity.