Thank you so much for joining me, Scott. We're here with CEO of MacroGenics, and hopefully we're gonna get into all of the nitty-gritty. So Scott, why don't we start off with just a brief intro to your current programs and the state of play, and what are you excited about going into 2024?
Well, first of all, Jon, thank you so much for allowing us to kick off this great meeting here in Miami. We are in a, I think, a wonderful position, a great setup, for investors and obviously for the company. If you think back over our 23-year history, everything we have now in terms of the pipeline, in clinical development, in preclinical development, our balance sheet, our opportunities for bringing a lot of non-dilutive capital into the company, is at the height. And I think this is a wonderful setup for investors, because it really is an opportunity to get in when, frankly, the market has been pressured, you know, biotech stocks in general, us as well, and we're at a great valuation.
You have a nice setup in 2024 with multiple clinical readouts in phase II, additional phase I studies, new clinical assets coming into view. Just to give you a little bit of, again, platform history, the company has three well-developed mature platforms, one around Fc engineering of antibodies, one around bispecific or multi-specific molecules called DARTs. And as we have indicated over the last two years, we have upped our game in our antibody drug conjugate efforts, not only having 2 clinical assets that are ADCs, but we've added on 7 slots for development of preclinical molecules that we will roll out most likely on an annual basis into the clinic.
So, that on top of the fact that our balance sheet is nicely secured with guidance right now into mid-2026, with lots of opportunities from two of the three approved products that we helped to develop, providing potential future milestones and royalties, I think it's a great situation for the company, for investors, and most important, for patients.
Let's start with Vobra Duo , with some of that near-term, late-stage readout that you were highlighting there. TAMARACK, initial data phase II in mCRPC, expected first half next year, which was actually accelerated. Can you start there and tell us what are you expecting to present in that initial data readout, and how should we position that in the changing mCRPC landscape?
Absolutely. As you know, we have been actually the leader in the development of molecules targeted B7-H3. This is a ligand that is highly overexpressed in most solid tumors. We have developed a number of different molecules to this target. Vobra Duo is vobramitamab duocarmazine. It is an antibody-drug conjugate with a cleavable linker, with a toxin that alkylates DNA. So, you're binding to tumor cells as well as the vasculature in the tumor and other B7-H3 cells that contribute to tumor growth. And this allows for the alkylation of DNA and the induction of apoptotic cell death subsequently.
As you know quite well, Jon, we had presented very exciting data over the last couple of years, demonstrating that this molecule in a number of different tumors has had significant anti-tumor effects. And we highlighted initially the effect in castration-resistant prostate cancer, highlighting the value of reducing PSA50s, as well as RECIST-evaluable responses in these late-stage populations. As you noted, we are conducting a study called TAMARACK. We went about doing this to try to identify the optimal dose to move forward into a registration study, where we observed in our earlier phase I B studies some side effect profiles that we thought we could improve. In particular, PPE, or palmar-plantar erythrodysesthesia, which is known as hand-foot syndrome.
Our goal here was to reduce grade 2s, where patients would get perceived pain, and reduce that to grade 1 or reduce the incidence of this. We had some other side effects we also wanted to address, and by looking at a stringent evaluation of patients treated with their various objective responses, anti-tumor responses, their side effects, we came up with two doses that we felt would bookend ones where we would achieve reduction in these side effects, yet ultimately get even better potential efficacy, because these patients would remain on drug longer, where before they were coming off, despite the fact their tumors hadn't progressed. And so we went forward with two doses of 2.7 mg per kg every four weeks, or 2 mg per kg every four weeks. The goal was to enroll 50 patients per arm.
As we announced on our earnings call, we essentially blew through those numbers very quickly, that the study was enrolled in U.S. and Europe, exceeding the 100 patients we intended. So we're in wonderful shape now that this study is fully enrolled. This accelerated the potential readout of this trial by at least 6 months. And so, you know, we're nicely set up in the Q1 to provide some data. What is the data? Well, obviously, it'll come in different waves. We'll look at the safety parameters that I alluded to. We will look at PSA 50 responses, and then ultimately, our PFS going forward.
Doc, if I may just jump in with two quick ones there. One, I know there's a little bit of confusion after the recent Merck Daiichi deal, whether it's the same target or not, so could you clarify three and four?
Absolutely. So-
I was with them, too, by the way, as everyone knows.
Yeah. So, as many of you know, there was an announcement, actually during the ESMO meeting recently, that Merck and Daiichi entered into a partnership around 3 molecules. One of these molecules, which actually garnered the greatest portion of that deal with that about $2 billion upfront, was allocated to their B7-H3 ADC molecule. We are going after the exact same target, B7-H3. We've been working on this target for over 15 years now, and the difference between our molecules and their molecules are distinctly two different things. They're hitting the same protein, but we're hitting different epitopes of that molecule. And I can tell you, we spent a lot of time identifying a particular epitope that we incorporated in Vobra Duo that has superior properties in our hands compared to the Daiichi's I-DXd molecule.
It has better incorporation into cells. Our preclinical data suggests that we have better activity in various model systems. We also differ between the two different toxins. Their toxin is a topoisomerase inhibitor, not different than what had been used-
Right
... in their ENHERTU molecule. We have been working on, as I said, a DNA-alkylating agent called the duocarmycin.
Right. And just to clarify also, in the prior data, just the way I understand it, 39 patients had a PSA evaluation, 16 had a RECIST evaluation. You were 4 out of 16. But could you also remind us what doses were in those prior trials? And I think there was 1 DLT, so how you stepped down the dose?
Yeah. So, again, you've characterized it quite correctly, with about half the patients having PSA 50s or greater, which, if you look at the historical data Daiichi had discussed, they were seeing 22%-23% in the doses that they were moving forward. So we were seeing about twice improvement in terms of PSA 50s. They have recently updated their data at the ESMO meeting, showing 25% objective response rates, rPFS of a little over 5 months, and OS of about 13 months. With regard to our goals here on reducing the side effect profile, as I said, what we're trying to do is reduce that PPE grade from Grade 2 to Grade 3.
We were seeing about a third of the patients reported with that side effect, so we'd like to both decrease the incidence and obviously the severity of the-
The dose in this 25-
Oh, and the dose in that was... So every patient was started at 3 mg per kg every three weeks. As I said, we are now testing 2.7 every four weeks, or 2 every four weeks. What happened in the way the setup of the original study was, is that patients were allowed to get their doses held or reduced or stopped, and ultimately, the majority of the patients had one of those things happen to them, which prompted our change in the way we wanted to dose these patients. By looking at the PK, looking at obviously the responses, we were able to come up with a 2.7 Q4 or the 2 Q4.
So, you don't think you're underdosing at the 2 per-
Absolutely not. Just to put this in perspective, Byondis , from whom we had licensed the duocarmycin linker toxin, which they used in their phase III successful study with HER2 as the target, they were using 1.2 mg per kg on a Q3 weekly basis. So here we're going 2 Q4 or 2.7 Q4. We feel very comfortable.
Did you consider doing every two weeks? 'Cause there's often this perception that Cmax correlates with efficacy in ADC setting.
No, a-
Not necessarily, but there's always, like, this question that comes up.
No. There is, there's no evidence that that is of benefit, and in fact, there is no, you know, the toxin itself, the free toxin, has a very short half-life. The antibody obviously can circulate with the conjugated toxin for a couple of weeks. But the bottom line is that what we have observed is by increasing or decreasing the frequency of dosing, you're giving a little bit more time for recovery of some of the that side effect profile here.
I see.
That is a better rationale than just keep hitting, hitting, hitting them every two weeks, as you propose.
Maybe moving on to one of your other prostate programs, we're also expecting data from LORI, a CTLA-4 PD-1 bispecific program next year. So remind us exactly what we should be expecting from that, from the monotherapy expansion cohorts. I know you, you presented initial activity this year, it looked very promising, although obviously still early, but it's an indication where traditional checkpoints have struggled. So how, how are you positioning that update this year?
We are in a fantastic position with lorigerlimab. This is a bispecific DART molecule, which contains specificities for PD-1 and CTLA-4. We spent a lot of time trying to maximize the T cell activating properties, but mitigate the toxicity, which was observed when ipilimumab and nivolumab were put together. As one might remember historically, ipilimumab was originally started at 10 mg per kg. Bristol had to bring it down to 1 mg per kg, with 3 mg of nivo, and only limit to four doses of ipi. They could not give continued doses in that combination. The major toxicities were several, but most prominently were that of colitis, immune-mediated.
So what we did is, we redesigned such a molecule that had all the PD-1 blockade activity, CTLA-4 activity, and what we observed is that within the tumor microenvironment, cells are enriched that have co-expression of both PD-1 and CTLA-4. So we designed a molecule that had two binding sites for PD-1, 2 for CTLA-4, so you had an avidity advantage to bind to those cells and reactivate these exhausted cells. To mitigate this, the toxicities, which I was alluding to, the colitis in particular, instead of using an IgG1, which is the subclass that ipilimumab uses, that actually the AZ molecule bispecific uses. Because if you have an IgG1 molecule, you can mediate ADCC or antibody-dependent cellular cytotoxicity, and it turns out the cells that mitigate this autoimmune colitis effect are so-called Treg cells.
And CTLA-4 is upregulated on most Treg cells. So if you have a molecule that can destroy these Treg cells, that causes an increase in rise of this colitis effect. By making our molecule an IgG4, which does not mediate ADCC, we, we prevent that effect and get all the salutary effects of T cell activation. And sure enough, we dosed up originally in, in monkeys up to 100 mg per kg, no colitis. We moved up dose escalation in humans, 10 mg per kg, no DLTs. We, we treated 127 patients across multiple tumor types, one grade 3 colitis in all those 127 patients. But what's most important is, is the clinical benefit, which nobody has seen with any of the other checkpoints.
Namely, we saw a 29% PSA50 or greater response, a 26% objective confirmed responses in castration-resistant prostate patients. Of the 35 patients that were evaluable for a peripheral disease, every single one with confirmed objective responses had PSA 90s to 100. And these patients that were having a clinical benefit were staying on drug for now, some of them now almost two years right now. So again, quite a different profile than, say, an Ipi-Nivo combination, or for that matter, some of the other competitive bispecific PD-1/CTLA-4s. So we are now started a study in chemotherapy-naive patients who have castration-resistant prostate cancer, who have progressed on androgen receptor targeting agents. This is a 150 patient study, 2-to-1 randomization.
They get docetaxel plus lorigerlimab for 100 patients, and for 50 patients will get the docetaxel control. The historical studies have shown with the docetaxel control, an rPFS of eight months, so we have to beat that number. We've begun enrolling patients, U.S., Europe. We expect that to enroll next year and hope to have the first set of data in the second half of next year.
Now, we are running out of time here. We didn't even get a chance to talk about the combination study that you're running, Vobra Duo and Lora. We haven't had a chance to talk about your CD123, CD3 bispecific, the follow-up to teplizumab that we were joking about before we started. Obviously, there's you were talking about advancing additional ADCs into the clinic in 2024. So, you know, in the last two minutes, what in the rest of the deeper pipeline are you most focused on for the coming year? What should people be focused on beyond Vobra and Lora?
Yeah, so in the quick two minutes, unless if you want to give me another 30 minutes to talk is the fact is, is that we're very excited about the relationship with Synaffix, where they have a very unique linker toxin technology. We think that based on our data and data that they presented the exatecan, the topo one inhibitors, will perform better than deruxtecan, which is in HER2 and the Daiichi molecules and a number of others. This molecule that we just announced in IND will start clinical studies in the Q1 next year. We have a second topo one molecule getting set up for an IND late in 2024 and have picked the subsequent target three, four.
So keep looking at this as an opportunity not only to build our platform organically, but also as opportunities for partnerships to bring in additional non-dilutive capital, extend our runway, for investors. Again, as you've alluded to, we're going into expansion studies with planned early 2024, with a combination of Vobra Duo as well as and lorigerlimab. We are also going to announce probably early 2024 the next studies of lorigerlimab apart from prostate cancer-
Prostate
... in other indications, and we're now also working on for Vobra Duo , beyond prostate cancer, additional indications that we're gonna go into. So there's a lot going on, coming in 2024.
Very exciting.
Just as we wrap up, can you remind us, based on this phase II data coming up in first half, is the next step potentially exploring a phase III plan? Could and/or would you need a partner? I just want to make sure I understand sort of strategically how you guys are thinking.
Yeah. So, again, we have been very open. Obviously, I can tell you that I have a lot of pharmaceutical and big biotech companies waiting for that data to look at that. We're obviously open to, entering into partnerships around-
Okay
... that molecule because of the broad number of indications one can pursue. So until we have that data, you know, that wouldn't happen. But in the meantime, we will go ahead, as we see the data unfold positively, to design an appropriate phase III study-
Right
... for castration-resistant prostate cancer.
This is not $100 million upfront, and they can take most of the drug kind of study?
Well, let's just, the starting number is the $2 billion upfront from
Okay
... from Merck.
$100 million for response.
So anyway-
Sounds good
... we're obviously excited about the prospects here.
Well, thank you so much for joining us, Scott.
Well, thank you very much.