Good afternoon, everyone. Tara Bancroft here. I'm one of the senior biotech analysts at Cowen. T hank you very much for joining us for our fifth Annual Oncology Innovation Summit. So for this session, we have a fireside chat with MacroGenics, and it's my pleasure to introduce Scott Koenig, the CEO. So we're very happy to have you here, Scott, and thank you so much for joining me. So before I get started, to those of you who are listening in the audience, please feel free to email me, any questions you might have or use the link that was provided. So Scott, first to kick it off, why don't you start with a general overview, any updates you wanna highlight for us before we dive in deeper into the program, specifically vobra duo?
Well, first, thank you, Tara. As you know, MacroGenics is an established, fully integrated immune therapeutics company, which includes a commercial manufacturing unit producing two commercial products. We're 24 years in operation. Three molecules that emerged from our pipeline have received FDA approval. We have multiple molecules in clinical development derived from our proprietary ADC, bispecific DART, and Fc engineering technologies, with near-term readouts in 2024 and 2025, and a deep preclinical pipeline advancing to the clinic annually that provides opportunities to obtain non-dilutive capital and organic growth for the company. We are confident in our ability to execute on our plan and to advance the clinical and preclinical programs in our pipeline. As you mentioned, vobra duo has been in much of attention. It's an ADC molecule targeting B7-H3.
It's an ideal cancer target, enabling us to capitalize on the broad expression across multiple tumor types. The interim data on vobra duo demonstrated encouraging antitumor activity and improved manageable safety compared to our phase I study. With these safety results, which are not unlike other commercially approved products for patients with mCRPC, we're very optimistic about the this program. We're on track for full TAMARACK results in the second half of 2024, and plan to launch a phase III development in 2025. It's a very compelling time to invest in MacroGenics.
Okay, great. So I think, we can jump right into the TAMARACK trial. So you, as you said, stated, you recently provided a pretty comprehensive update. And so first for some context, could you discuss the baseline characteristics of the patients that you enrolled in the trial? Remind us of median prior lines of therapy, how the median number of cycles that they received, and those types of details.
Sure. So just first, TAMARACK was designed to test 2 lower doses of vobra duo compared to the doses we used in the phase I dosing study. We did this to ultimately choose one to advance for our phase III studies. The patients in this trial had to have advanced on at least 1 androgen receptor targeting agent and could have up to been treated with 1 taxane, namely docetaxel, and no more than 3 lines of prior therapies. Up to 60% of the patients were RECIST-eligible, with a median of 70. A subset of these 77 had measurable disease. I don't have exactly the number right now of their previous lines of therapy, but as I said, no more than 3 lines of therapy were included.
Okay, great. Can you disclose what proportion of patients were naive to chemo?
Yeah. Of the, intent-to-treat population, there were 181 patients, 43% were chemo naive.
Okay, great. So let's, let's move on to efficacy first before we get to safety. So can you highlight first what, what you view as the key strengths of, of the efficacy data specifically, maybe starting with PSA50, then ORR?
Yes. As you know, I put out the sort of milestones that we were intending to achieve or beat back last November, so this is even before the study was fully enrolled. With regard to PSA50, we've noted that 50% of the patients, both at the 2.0 and 2.7 doses, confirmed and unconfirmed, were achieved. 44% were confirmed in the 2.0, 37% on the 2.7. In the April data cut, that interim cut we just provided data on, the majority of the patients were still on therapy, so the chances to increase the confirmed rate are certainly there. In terms of the overall response rate, again, we achieved what we had put out intended, with 25% confirmed ORR in the 2.7 dose.
So far, 18% confirmed in the 2.0 dose on the interim data. Now, if you look at both confirmed and unconfirmed, 44% at the 2.7 dose, 24% on the 2.0 dose. Again, confirmed ORR rates will increase with time, as the majority of the patients were still on study as of the April cut. So again, we have met and exceeded what we had anticipated, both in terms of our own data sets that have been observed for competing molecules, such as the DS-7300 Daiichi Sankyo molecule. I think also I would like to note in terms of RECIST-evaluable patients with measurable disease, the disease control rates were 91% and 88% for the 2.0 and 2.7 doses respectively.
Okay, great. And so I've been getting this clarification question from investors. So if you could confirm how you defined what a confirmed and unconfirmed PSA50 response is?
You know, we're comparing this to their baseline PSA levels. Obviously, if they've achieved 50% reduction on the first one, that gives the so-called unconfirmed group that achieved the 50%, which they already stated. They need a second measurement, which is four weeks or later, that also shows a 50% reduction compared to baseline.
Okay, thanks. And so I know that you already talked about how many patients at each dose are remaining on therapy, but considering that data point, to what extent do you believe that either or ORR and PSA 50 could improve with longer follow-up?
Oh, as I pointed out, there's no doubt both of these could potentially improve, given the large number of patients that were still on therapy as of the April cutoff, more than half in that regard. So there's no reason to not expect that one or either of the doses would have improvements, both in terms of ORR and PSAs.
Okay. So then, I guess, breaking it down by the different doses, what do you believe led to the higher unconfirmed PSA 50 at the low dose compared to the high dose? Like, what would explain that? Are you gonna be showing PK data at some point, relatively near term?
So, these are very small numbers, so I don't put much stock in terms of the higher confirmed PSAs at the lower dose versus the higher dose, because as I already pointed out, the ORR is better for the higher dose than the lower dose. So that doesn't necessarily coordinate exactly. I think these are just small numbers. I don't assign any particular significance to those differences on the PSA to point out at this point, especially when I said the confirmed and unconfirmed were identical.
Mm-hmm. Got it. Okay. And so I know you haven't released this quite yet, but when you do, do you plan to break out the data by those who are chemo naive and experienced? And you know, if so, what are your expectations for how it'll perform in each? Can you give us some context there?
Yeah. So, again, with the over-enrollment in this trial, we have a very unique opportunity to look at two distinct population with sizable numbers. And yes, we will update this data at a future scientific conference in the second half of this year. Our expectations is that, based on the data cut we saw in April, there is no reason to think that either one of these or both populations may be addressable in phase III studies and ultimately developed for both populations.
And the chemo naive, as is true in most of, if not all, of oncology, the chemo naive should do better than the experienced, right?
I would say that that's the expectations. Obviously, we'll have to see what the data pans out. The interim look at the data would suggest that there's no real unexpected results based on what we've seen so far.
Okay, great. And then, I guess, a general question about efficacy among the doses. Would you say at this point that the 2- and 2.7-milligram doses appear relatively similar in terms of overall efficacy?
I would say right now they're both in play as potential doses that could be used in a Phase 3 and then further development.
And so will you be disclosing PK data, like, on a patient-level basis or overall for the population, just to give us a better sense of what the difference between 2 and 2.7 milligrams is in terms of exposure and Cmax, et cetera?
Of course. As we had intended, those samples are being analyzed right now and completed. It just was not available at this April data cut. So, we will be able to provide an update on PK as related to both efficacy and side effects and predictability here at future meetings.
Okay, great. So then, let's move on to safety. So can you recap highlights of what you saw, and then any analyses that you've done? I know you mentioned on your earnings call a couple that you've performed for some context here, and what drives your confidence in safety looking improved over Phase 1?
Yeah, so, again, we're very encouraged what we've seen so far. We, as, I pointed out on the call, we did a head-to-head comparison of, at 16 weeks of treatment in the Tamarack study. So all patients, 176 patients that received a dose, if they hadn't, discontinued, during the course of therapy, had already achieved, 16 weeks of exposure. And so we felt that the best head-to-head comparison was 16 weeks from the 41 patients in the phase I study. And as I pointed out, on a percentage basis, there was 50% or greater reduction in AE profiles, Grade 3s, discontinuation rates, dose reductions, or dose interruptions.
In terms of looking at the butterfly plot, which we put out with regard to the specific AEs, in general, these were mostly Grade 1 and 2. There were smatterings of Grade 3s. And if you now look at the list, as I also pointed out, of the 5 most common AEs, say, for instance, at the 2.0 dose, it was asthenia, nausea, peripheral edema, decreased appetite, and fatigue. Just relatively constitutional symptoms, not really severe in that context. So, that was very encouraging to us. It turned out serendipitously, we had a planned DSMB meeting after we released the data on the call. They reviewed the safety, they reviewed the efficacy again, and told us to proceed with the study.
So again, confirming that outside independent groups are looking at the data. And then furthermore, we continue to get very strong positive feedback from our KOLs, as well as the actual clinical investigators who are treating these patients, and they see the value of vobra duo as potential, including the safety profile.
Okay. And for that analysis of the patients from phase I, are you gonna be sharing a slide or a table or anything with that? And also curious in terms of PK for the phase I, is there any particular reason why PK data weren't shared from those phase I patients?
So right now, the phase I data is being worked on to put a published publication together, to submit later in the year. So I think that will be the time when all this additional information should be available. I can't predict what the final content is gonna be exactly in terms of tabloid form, but we will share that data to give the picture of how we see the current study being so much more favorable and achieving our goals of improved activity, antitumor activity, as well as improved safety, using these lower doses and increased dosing intervals in these patients.
Okay, yes, I definitely understood, looking forward to that publication. and so it's understandable how it's improved from the phase I, but I guess it next begs the question of the comparison to the abstract. so with two more median cycles, what do you think happened here? Were the tox events that happened cumulative? Did they happen rapidly? Like, what do you think happened here?
Well, I can tell you what happened, which is, the original data was a cut in early January of the data. As I pointed out, 60% of the patients came in in the fourth quarter. That data was used to put into the abstract that was submitted in February. We were able to also do a side-by-side comparison of 12 weeks of 95 of the patients that achieved 12 weeks of exposure in Tamarack versus the historical data. But as I pointed out, that this data cut was 3.5 or greater time of exposure of additional doses, where now we have a median dose exposure of at least 5 doses, where the historical data was 3-3.5.
So they have seen a lot more drug over many more months of period of time. What was observed between the original phase I, 12-week data and 16-week data, was a dramatic increase in the side effect profile. What people had anticipated is that the original ESMO data that we put out in 2021 was sort of the final safety data. It got a lot worse. That's why I knew that we would be improving this safety profile, and doing the 16-week cut was the appropriate thing to do as a side-by-side analysis.
but having said that we continue to look at ways to improve patient care, implement treatment and medical management education of the healthcare providers to prevent any exacerbation of any side effect we see. So that's always being implemented. And as was also pointed out, is that you know, the deaths that were observed, which were also noted, of the five deaths that we presented, that occurred after the original January cutoff over several different months period of time. These all occurred outside the U.S. As we've noted previously, two of those deaths were not deemed by the investigator to be associated with the drug exposure.
The three other patients, two pneumonitis patients, one patient with a pleural effusion, had very complicated cases with comorbidities and other active diseases. We're working, though, very closely with the patients' docs to identify the circumstances around those untimely deaths. But again, very complicated before we had the full adjudication of this. It'll take a little bit more time to put that out. But I should also point out two things. The two pneumonitis patients, pneumonitis is a known associated side effect for the whole class of DNA alkylating agents, so there is expectation that that may occur.
But ultimately, what we have observed is that by treating now 225 prostate patients and over 100 other indications, the rate of this pneumonitis is very much on the low side. And also, if you look on historical data for approved prostate products, our rate is on low or below the observed AE to death rates of 2.9%-12%. So again, we continue to try to maintain a good safety profile, but given the feedback that we're seeing from investigators, they're very encouraged about the prospects of this drug going forward.
Okay, great. So, how about these deaths that are under evaluation specifically? Do you have any more color on the timing of those in particular? Like, did they all occur much later, after several cycles? You know, and any more color you can give on that?
Yeah, well, again, I'm not gonna go into the specific details till we get all the facts back from the PV, but they occurred after several cycles in all cases.
Okay, great. And so what, what would your plans be if they do come back as related? What, like, what, what would be the path forward?
Well, as I've indicated, that is not surprising that there are certain side effects associated with classes of drug, pneumonitis being one of these. But again, getting better medical care implementation, making sure the docs are looking for such side effects, then, in terms of respiratory, symptoms that may lead to pneumonitis, intervention very early can prevent, more fatal outcomes, that were observed. So again, it is terrible when a patient dies, of any cause. We will do what is appropriate for, maintaining the best medical care, when administering a drug that is seemingly having beneficial effects, at least to date, on the interim analysis.
Okay. And then, so I guess we only have a few minutes left, but so I wanna get to expectations for the rPFS data in the second half of the year.
Yeah.
So I guess, could you discuss what your expectations are for that data, and if you're still using the 5.3 months for Daiichi as the bar for that?
Well, again, I put this out back in November. I pointed that out. As, as you note, I had indicated that, depending on which population we were ultimately looking at, the post-chemo or pre-chemo, we were looking north of 6 months at baseline. We had, had discussions with KOLs. They had indicated, if we achieve that, that is, addressable and, and developable. Clearly, now with a median of 5 doses being got, we're moving in a very nice direction. So clearly, the longer is better, 7, 8, or, or higher. And at this point, based on the interim data I'm optimistic that we should have exciting results, when we have the final data but w e'll have to wait and see what the effect rate is, subsequently.
W e're in the business of guessing and hypotheticals, so I have to. but I know that patients in TAMARACK, they're not necessarily more severe than a trial like VISION. So I guess, do you believe that rPFS could potentially be better than this or others in the space? Is that too high, in your opinion?
No, I think it's certainly possible. Now, there was nothing from the interim data that suggests that we may be able to achieve that or higher at this point. So we'll have to see as the data progresses.
And from your KOL feedback and market research, would an rPFS as low as 6 months be usable in the, at least in the post-chemo setting?
Well, again, it depends on obviously what the control group and how to design the study. That becomes a challenge in terms of what is viewed as addressable and helpful population, and then ultimately executing the study. So clearly, we would like to see north of six, and higher the better, and again, depending whether it's on the pre-chemo or the post-chemo population.
Understood. Okay, so unfortunately, we have run out of time, but I, I do want to take 20, 30 seconds to ask: What you believe is the most underappreciated aspect of the MacroGenics story by investors?
Well, thank you very much for that final question. so over the past several years, MacroGenics has made tremendous progress across our pipeline. We're well-positioned for growth and success as we advance this diverse portfolio of oncology candidates. We have a proven R&D track record with three approved products that are generated from our pipeline, fueling potential revenue as well. We're advancing multiple phase II programs in prostate cancer, building on the strong foundation of safety and efficacy we've established, with prostate cancer as the second leading cause of cancer death in the U.S., when we were actively pursuing multiple potential first-in-class programs. We're well-funded with a cash runway into 2026.
And, again, Jim and I are looking forward to providing updates later this year, and appreciate all the support we've had from the patients, partners, KOLs, and shareholders in making significant progress and exciting progress towards our mission of developing and commercializing innovative treatments for cancer. So thank you very much for the opportunity to present today.
Great. Thank you so much, Scott. Thanks for the time, and thanks everyone for listening.