MacroGenics, Inc. (MGNX) Earnings Call Transcript & Summary

Perfect. So good morning. My name is Peter Lawson. I'm one of the biotech analysts at Barclays. Welcome to Miami Barclays Global Healthcare Conference and really pleased to have up on stage with us management from MacroGenics. We've got Scott Koenig, President and CEO.

And your first questions are going to clearly be dominated by B7-H3. So I wonder if you can talk through what we should expect to see in the full data set versus abstracts and kind of what you can potentially squeeze into that abstract in which...

So I mean just sort of set up the situation, which I know a lot of people are quite aware of. We're moving forward in finishing up a Phase II study called for vobra duo. This is our ADC molecule targeting B7-H3 with a DNA alkylating agent called duocarmycin. This study is looking to compare 2 different lower doses than what we used previously in a chemo experience population in the -- or metastatic castration-resistant prostate setting. We're looking in this study of comparing dosing at 2.7 mg every 4 weeks compared to 2 mg every 4 weeks. Historically, we were testing this later line population at 3 mg per kg q.3 weeks. As we have said is this study got accelerated because we had a very vigorous enrollment trajectory, particularly in the last half of the year, 2/3 of the patients came in between the time period of the second half of the third quarter and the first half of the fourth quarter. And we ultimately dosed 177 patients in the study despite the fact that originally we were planning on 100 patients in the study. As we announced on our earnings call, we had a DSMB look at the study futility analysis, obviously, looking at safety and the activity that was available at the time and the recommendation for the DSMB was to continue the study going forward. So back to your question with regard to disclosure of information, an abstract was put together, which was due early in February. It took the data that was evaluated by the DSMB to put in the abstract. As we announced on our earnings call, this is safety data, which obviously was one of the primary objectives of the study is to improve upon the historical safety profile we had seen in the higher dose regimen. We believe that, as we announced also is that the presentation if accepted, will be at ASCO. And again, we don't know the nature of that. Our expectation is probably [indiscernible] because we -- the abstract was safety, but we don't know that at this point. But we'll have to make obviously a cutoff date prior to when that presentation is due, which is probably sometime early mid-May. We'll have to do a cutoff date ahead of that time to be able to do as much cleanup of the data and to obviously incorporate it in the study, whatever we have to present. So given that, what we have said is we'll provide data on all the patients that are dosed, we look at, obviously, everything from who's still on drugs, any discontinuation rates, any changes in dosing. We'll look at PSA 50 reduction or PSA reductions in the whole population as well as percentages that ultimately achieved PSA 50 and overall response rates. But it is unlikely that we'll have a sufficient number of patients that have been dosed long enough to get a mean -- median rPFS value that is noteworthy. So what we indicated on our earnings call is that likely that we would update data in a scientific meeting later in the year. And as you know, there are a number of different cancer conferences later in the year. So I just wanted to set up expectations about that. We'll be obviously transparent about the data and to see what it is. As you know, I've kind of put out for the various metrics before we even had that study enrolled, I put on, based on our own experiences, what Daiichi has put out on their 7300 at ESMO last year, what I think would be fair ranges for given responses across the board there. And we're not changing it vis-a-vis the data as it goes along. We'll see what it is and what ultimately the study turns out. But if we obviously clearly meet the objectives of the study, which is improved safety, tolerability and activity that meets our goals then -- we would then plan a Phase III study and likely to do that sort of in the midyear time. Obviously, we'd have to wait probably to later summer to get the rPFS, but ultimately be in a position so that we could start a Phase III controlled study sometime in the first half of '25.

Okay. Perfect, for safety in the abstract, we would get discontinuation rate?

Yes. You should be able to see all that as of that particular cutoff obviously, yes.

And then hand foot syndrome, pleural effusion, kind of the...

You'll see, I -- to be frank I don't remember what was ultimately in the detail in the abstract, but there was certainly a lot of detail there, but you'll get the quality and quantitation on a lot of these side effects that were being particularly looked at in that study of concern.

Okay. How long would the median follow-up be, I guess, when we think about the second half data for those 177 patients?

I don't know the actual number there, but I would say that it depends on the exact time of the cutoff. Is it going to be sometime in March? Is it going to be sometime in April. And as I said, 2/3 of the patients came in the latter part of the year. So somewhere between 4 and 6 months would be my guess at this point. But I don't want to give you a number now and just say that's what you said. I want to see what the data looks at that particular time.

But if that second half data said, you're going to...

Yes, we're talking basically of the final data to make a decision whether we want to pursue a prostate indication, whether it be in the chemo-naive or the chemo experience. But as we did indicate on our earnings call is that with obviously, the DSMB is to move forward, there was some -- certain degree of confidence that the dose either one of those doses could be used to look at other indications going forward. And as we said that we are going to advance into 5 new additional indications like prostate cancer probably starting midyear.

And then the patient mix that we're seeing for the Phase II kind of, if you can talk through anything about, who've seen prior dosing, who haven't, who are naive.

Yes. So again, when we loosened up the entry criteria, and allowed for patients up to 1 docetaxel, taxane exposure that gave patients who either were not eligible for chemo or do not want to be on chemo to enter to this study. And so while I don't have the exact numbers among the 177 patients as I recall, approximately half were chemo-naive and half were chemo experienced. So there will be sizable numbers in those groups to independently analyze them for both -- same activity to see if there's any differences there. And that will obviously guide us, ultimately, if successful, which population to pursue for a Phase III study.

And then for ARAT exposure, kind of how should we be thinking about that enrollment criteria? How many...

Yes. So again, that was another criteria we modified in the amendment originally, as we were thinking about a [indiscernible] controlled registration study, there was a request from the regulators to only enroll patients who had experienced successful treatment within ARAT of at least 12 months when we took off the control arm of the study and didn't make it registrational, we then loosened up that criteria and only required beyond an ARAT [ and put this every quarter ] full 12 month of exposure. So clearly, there will be patients that couldn't continue for varying reasons, progression of the disease or side effects or whatever. But as long as they've been on it for some period of time, they were allowed in the study as well.

What caused that change was slow enrollment?

I think the original change on amendment was when we saw pushback on using a second ARAT as control from particular investigators, we were fearful that the time to enroll in the study would take too long and it was more important to us to get an answer. Do we -- can we identify a dose that was acceptable to move forward, not only for prostate cancer but for other indications. And so looking where we are right now, that clearly was the right decision for us because of, obviously, the speed of enrollment and the enthusiasm to participate in the study.

Should we think about most of these patients have been on an ARAT for less than 1...

I would assume though I don't know the answer to that. So I have no idea exactly what the mean or median or how many fell into the greater. But I would presume [indiscernible] but we'll have to update you on the future...

And there is a [ watch out ] period.

Well, there is a [ watch out ] for all drugs. So they -- and again, each one of them have some requirement that they watched out on drug. For instance, a radiopharmaceutical or an ARAT or whatever.

Yes. I guess, at onetime point you're going to show us kind of an immature rPFS. Will it be kind of landmark PFS data that we should be thinking about seeing?

Well, I think ultimately, it will be a landmark rPFS data whether ASCO or after ASCO. Again, when the cutoff is and how much mature data, I won't comment on exactly when that happens.

Okay. And then how low do you think the hand foot syndrome? And is there any feedback from physicians about whether that's manageable?

Well, I'm not commenting on the conduct of the study. Clearly, a situation where we want the incidence to reduce. And then in note that do ultimately kinds of symptoms of hand foot syndrome, reducing grade, as I pointed out, the majority of the patients were Grade 1, 2. But once they get Grade 2, they experienced the pain in the extremities, particularly in the feet, which is most problematic. I want to sort of set the setting for these type of patients being in that age group, elderly men, although I'm not androgen suppressed, but androgen suppressed elderly men actually are more feeble elder population. And so having the discomfort of pains in the feet to do walking and daily living can be quite problematic. So if we can reduce grade as well as incident for that, that would be the objective.

Got you. Is pleural effusion I guess that was the...

That was another side effect. Again, looking to see a reduction in incidents there.

Is that more serious for at least the treatment position?

No, the fact if it's in a situation where you have effusion that is not creating any issues with respiratory functions, perception of shortness of breath, et cetera, and it turns out to be incidental finding that's not a problem. Obviously, if it gets to the point when it impacts their ability to exchange oxygen that you would have to do a procedure to eliminate that fluid. That's where it only becomes problematic. So it's -- you want to minimize the number of patients that have to get thoracentesis to get the fluid removed.

Got you. And the registration trial, if you -- what would that look like?

Again, it will be dependent on the effect size and the population. So we'll have to see what the data is in the chemo-naive versus a chemo experience population. Presumably, it will be a controlled trial, either 2:1 or 1:1 randomization. Again, we'll have to see the effect size is from the current study and then determine the size of the study, the control groups. And there are a lot of options here. We are engaging KOLs around the world for their advice. As you know, if you look at the control groups that are still used despite the fact there has been some pushback often using second antigen receptor targeting agents as a control, it may not be the most optimal one, but it's always still acceptable at least to some of the regulators at this point. We'll see how the [indiscernible] sort of evolves over time, likely a key as a control line of therapy to determine which one and whether we control drug or a physician's choice among the couple still get...

Is there anything that we should be watching that could hoping for what a trial would look like based on other readouts. It seems to be this pushback for this and ARAT is becoming more prominent...

Well, I mean there's a lot of talk. But as we've seen just start of the study the second area of control in the new drug PSMA4 that as a control CONTACT-02 as a control. So the bottom line is despite that we've heard a lot of discomfort about using that it's still being used in trial. So we'll have to see how the feedback for both investigators, advice and regulators are. We'll have to see what the effect size is and determine what's the most appropriate for the study.

Were patients have been exposed or how many patients have been exposed to radiopharmaceutical?

I presume very small numbers there. And that -- clearly, there were approved on the market as [ Radian ] [indiscernible] with regard to the latter, the number of sites that we had in the U.S. was small compared to the number of sites in Europe. And at that time we enrolled the study, the availability of drug was very sparse in Europe. And the patients who -- there was also a limitation even in the U.S. But for those who are on drug, not enough time elapsed from discontinuation to be on the study. So my expectation is that there will be some, but probably very few.

Got you. Do you think you'll be first to market in prostate with B7-H3 or first to market generally for B7-H3?

Well, of course, we are hoping that where we'll be. We have no knowledge of other competitors' target B7-H3 that have advanced programs further than we have in that regard. So again, it's a lot dependent on the quality of the [ data ] that comes out will determine how quickly we're in a very good position to start a Phase III study, as I said, in the first half of '25. I don't know others. I mean, clearly, the 1 competitor that's most advanced has not announced an indication that they are starting a more advanced study in prostate cancer namely, Daiichi and Merck.

Got you. And you've got a broad development program recently the ADC -- first-generation ADC. Why do you think that approach was quite a broad one where they kind of pick 1 indication?

Well, I think that we are blessed with an opportunity now that we have been -- we were the first company to develop any molecule to B7-H3. This goes back now 16 years ago and we have now 3 molecules in the clinic targeting B7-H3. We had a fourth one, which we pulled out a clinic, even though there was activity that was one of our price specifics and we're looking at even other opportunity there. There are very few targets that have such a broad exposure across the board in solid tumors in terms of expression pattern and combined with a relatively low expression in normal tissues, especially if you are -- discriminate on which epitope and variable domain you go after having a large number of antibodies, B7-H3 we were able to select ones with different profiles that could take advantage of different mechanisms to limit tumor growth. So for instance, enoblituzumab, our Fc-engineered anti-B7-H3 molecule, was selected again for a good tumor to normal tissue ratio, but was able to sit on the surface of molecules much longer than the variable domain we selected for vobra duo, which gets to incorporate quicker. And so -- as a result, as you know, we are a study called HEAT just started as an IST led by Johns Hopkins and 3 other major institutions looking at the neo -- use of this as a neoadjuvant treatment for high-grade Gleason 8 to 10 local newly diagnosed patients who will ultimately develop metastatic disease based on the data that they had tested in the original 32 patients. So different mechanism of action, different profile of that drug, looks historically very safe. It's been in over 400 patients with evidence of antitumor activity, good T-cell activating properties. The vobra duo gives us opportunity, obviously, now in sort of mid-stage castration-resistant prostate cancer based on the activity and the safety profile. And as we just recently announced, and I hope folks get to see our AACR poster, we have just started clinical study with a variable domain that was identical to the one in vobra duo, but now has a linker toxin that inhibits Topo 1 -- it's a Topo 1 -- topoisomerase 1 inhibitor. But based on the preclinical data that Synaffix has presented to us in their studies, it could have a superior clinical profile to other Topo 1 inhibitors, particularly the Topo 1 inhibitor that's in Trodelvy SN38 and deruxtecan, which is obviously a 7,300 in HER2. So in fact, by being able to have a very good controlled experiment now where we have good targets, same antibody, but now a different toxin, we'll be able to look across different studies, our own experience, Daiichi's experience. And if that turns out to be a superior Topo 1 inhibitor, all of a sudden, that toxin can now be used in multiple other targets and other variable domains.

We've got 30 seconds on the clock. I guess, final question, just -- and as we think about the LORIKEET study, so your PD-1 bispecific CTLA-4, is that a similar population as TAMARACK?

So it's similar to the subpopulation that are chemo-naive. So from that vantage point, these patients have progressed on an antigen receptor targeting agent but have not seen chemotherapy. So as you know, that's a 150-patient study, 2:1 randomization. In this case, instead of single-agent therapy, we're looking at the combination of lorigerlimab, the PD-1 CTLA-4 bispecific with standard of care, which is docetaxel in 100 patients versus docetaxel alone. We expect that study to complete enrollment this year and then provide update on that data.

Perfect. We can talk whole day, but unfortunately. Okay. Thank you so much, Scott.

Thanks, Peter, as always.