Great! Welcome back. My name is Silvan Tuerkcan. I'm a Senior Analyst with Citizens JMP. I cover Precision Medicines. It's my pleasure to host Scott Koenig, President and CEO of MacroGenics. Thanks so much for joining us.
Well, Silvan, thank you so much. I appreciate the opportunity. Now, obviously, I wasn't doing such a great job last week communicating our excitement around vobra duo, and I think this is a great opportunity to be able to, you know, discuss this and why we're so enthusiastic about the prospects of that molecule and obviously our entire portfolio.
Great. Well, thanks, thanks for, for coming and joining us. Obviously, yeah, we, we've talked about the data, and obviously, that's what we're gonna focus on today. Before we dive into details, I just wanted to. Maybe if you could set up the TAMARACK trial, what you're trying to do, and and what kind of setting you're studying this ADC in.
Yes. And so, as you know, the use of this drug goes back a few years, where we saw very encouraging data in prostate cancer and actually in other tumors as well, where we had shown very good PSA reduction responses, objective ORRs in the castration-resistant prostate population. But we had observed side effect profiles that we believe were not sufficiently low to be able to continue to develop that at the dose we were using, which was at 3 mg per kg on a three-weekly basis.
In fact, the mean number of doses that we achieved in that phase I study in castration-resistant prostate cancer expansion cohort of 41 patients was only three doses, where we were seeing these side effect events at a meantime after about a month and a half.
We embarked and did a very thorough analysis to understand what were leading to these side effect conditions, and came up with the conclusion and the hypothesis that by both reducing the dose to 2 mg per kg now on a Q4 weekly basis, or 2.7 mg per kg on a Q4 weekly basis, we would be able to book in doses that we thought would both reduce the side effect profile, as well as potentially improve the efficacy because the overall exposure would be now increased quite dramatically. And what, you know, what we feel we have achieved, which we will talk about, obviously a little more detail now, is both parameters: a better activity against tumors, better safety profile.
Great. So maybe starting with the safety profile, could you walk us through the maybe improvements in the safety profile going from, you know, the prior regimen to this now TAMARACK Q4 dosing regimen at these two doses?
Yeah. So let me and let me sort of bring this up because I know that investors reacted to a series of data that we put out approximately a month ago, which was based on data that we had incorporated in an abstract presentation that we intended to be presented at ASCO. All that data from that in that press release we put out a month ago was data that was accumulated through the 6th of January of this year. As you know, 60% of the patients enrolled in this study came in the fourth quarter of last year. And so that data, which we put out, you know, was very encouraging.
So, number one is many of the most notable AEs that we wanted to reduce, such as palmar-plantar erythrodysesthesia, effusion, did not even appear on the most frequent AE table that we incorporated in that press release. And as we pointed out, the discontinuation rate, the 2 mg dose was 4.4%, and on the 2.7 was 2.3%, and the Grade 3s were 25% and 31%. So now, what we put out last week was an update of the safety profile, now with the efficacy that people were awaiting. And again, the situation is that we were now taking accumulation of all the patients that were dosed throughout the course of the study.
That added three, at least 3.5 months more of data of the patients treated. Remember, we're treating 176 patients in this trial. So we clearly expected increased AE events and side effects going forward. But I think what happened was, is that because that data that we put out last week was only four weeks data, people couldn't understand why it was so proximate. The reason why is, is that the original data only dated back to January, and this data was all the accumulated data through April. So, that was where there was a disconnect there.
So to be able to look at an apples-to-apples comparison, which I did note on, on the, on the earnings call last week, I asked our data safety group to do a comparison of all patients that were treated or discontinued on the TAMARACK study through 16 weeks, because I knew that every single patient had achieved, that timeframe. So we're talking about a full look at the 176 patients in that study. And then I said, "Compare that to the side effect profile of patients who were on the 41 patients in the Phase I study, who had completed 16 weeks of the data." Now, we have not published the results of the Phase I study. That's being put together for publications we hope to go out later this year. But, as I had noted on the, earnings call
Every single one of the parameters we looked at, Grade 3s, discontinuation rates, drug interruptions, drug reductions, were reduced by 50% or more in the current TAMARACK data on a percentage basis as compared to that in the Phase I study. So again, what we did is we achieved what we had set out to do, was improve the safety profile in addition to improving the efficacy there.
Great. So maybe if I may summarize that, and you can tell me if I'm wrong or right here. So you, obviously, the safety profile in TAMARACK worsened versus the January update, obviously, because we accumulate many more patients. Obviously, some of them for longer, and a lot of them, the bolus we saw for the first time, right? But then if you compare the updated TAMARACK data, which was objectively worse than the previous data cut, to the earlier study where you had a prostate cancer patient and non-small cell lung cancer patients, you see a roughly twofold improvement, across the board.
Just a little correction is, because I wanted an apples-to-apples comparison, we only looked at the prostate patients.
Mm-hmm.
I would just point out that prostate patients, in general here are 70-80-year-olds who have severe androgen suppression and have many comorbidities, and tend actually to be a much frailer population, with this disease, as compared to those with other cancers, including the lung cancer patients. So I didn't want any confusion there, that we're mixing and matching different tumor types.
Mm-hmm
So that would be as clear. I should also point out, some of the more notable side effects that we wanted to reduce were also dramatically reduced in this later data set, which was the palmar-plantar erythrodysesthesia. Remember, the fact is that with Grade 1 disease, they only have swelling and redness in their hands. It's when they have Grade 2 disease, where they start having pain, which again, becomes the discomfort, not a worsening in terms of their outcome, but becomes a discomfort. It is unfortunate that we don't have a drug, no drug in castration-resistant prostate cancer that will cure these patients. In reality, all drugs being used in this setting are palliative, and their lifespan is approximately two years.
So they're looking for better comfort and in their remaining years, and therefore, reducing some of these side effects to, you know, give them more comfort is better. I would also remark is that the pleural effusions also went down as well. Again, Grade 1, Grade 2, almost entirely. And the fact is Grade 1, Grade 2 pleural effusions are asymptomatic. And so because we're scanning these patients for their disease progression, not for safety reasons, on an every week basis, we will often pick up the evidence of pleural effusions here. So again, we report this out, but again, this is better than we had seen previously.
I would say, in general view, obviously, I haven't spoken to every investigator. They feel we have accomplished our goals of having a drug that has manageable toxicity. In fact, as I pointed out in our earnings call, if you actually which are on our website if you look at all the side effect profiles and look at the butterfly part, they're virtually Grade 1 and Grade 2 across the board in terms of the side effects. You have a smattering of Grade 3s here, but again, by having these as manageable side effects, I think we have a drug, at least on this interim basis. Obviously, we'll have to follow these patients further along.
If this holds up with time, we have something that can be clearly developed further.
Great. So maybe talk about the Grade 3 incidence of Grade 3 events here. So apples to apples, we had 53% in TAMARACK, I believe, and then what was it in. You said it was a two times improvement versus
Right. So, here was the issue, is that the numbers that we had previously published was at an ESMO cut or on various other meetings. That was not the completion of the data. So those side effects continued to go up, both on specific AEs, as well as the aggregate AEs. So what we will be doing is ultimately be publishing these things going forward. Sorry.
No problem.
But the point is that 50% reduction in that 16-week side-by-side comparison
Mm-hmm
In that regard, in terms of Grade 3s, overall AEs, and again, the interruptions, the reductions, and, and
Yeah
et cetera.
Yeah. Great, and so now we're in agreement here. And how does that compare to some of the other assets? So talking about, you know, that are in development, B7-H3 ADCs. You know, we don't know if they're not immediately going into prostate cancer, but, like, in general. And then within prostate cancer, how does that compare to some of the newer bispecifics that are coming?
Well, I'll give you two examples. The most notable one that gets attention is, appropriately so, the Daiichi compound now, the 7300 compound that's now partnered with Merck. The data that they presented at ESMO showed Grade 3s of 47%. Again, right in the range that we just talked about. In fact, overall, if you look across the board in the various doses they used and also the different tumors, they were seeing interstitial lung disease in the 5.7% range. You asked about bispecifics. I again, a very notable bispecific that got a lot of attention at ESMO was the STEAP1 x CD3 bispecific that's being developed by Amgen.
They had a 50 not even a TEAE, it was the treatment-related emergent adverse events, was 55%, and they saw a 14% adverse event of musculoskeletal disease that they can't understand what the cause of is, and a discontinuation rate of 19%. So again, you know, every one of these drugs has their challenges, and obviously, hopefully, some of those will get worked out to provide better drugs for patients. We, you know, we're looking forward that we want these patients do better, irrespective of what the drug is, the mechanism of action. We do believe, obviously, targeting B7-H3 is has a very high probability for successes with both our vobra duo, as well as our O26 molecule.
Right. Thank you. And, obviously, there was a lot of volatility after we also learned about these five deaths on TAMARACK, you know, after the preliminary safety update. Could you please talk us through the five cases?
Well, you know, it's as I pointed out, again, so that there's pure clarity is that all these cases occurred after our January 6th cutoff, and we had no knowledge about the safety profile, at least myself, senior management, that was reviewing this data until very recently, and certainly after we put out the press release on the initial safety data. So it wasn't that we had knowledge about this in terms of the specific deaths or obviously deterioration on the safety profile. With regard, as I said on the call, many of these are getting adjudicated. We had two cardiac-related deaths and three others, two that was ascribed to pneumonitis and one ascribed to pleural effusion.
These are very complicated cases for many of them, where these patients have other comorbidities and other active diseases that are occurring besides the one that were defined here as a sort of an admitting diagnosis. And in many cases, the treatment that was instituted for these patients may have not been optimal, and in fact, many in certain cases, treatments for some of these conditions may have been the ones that caused the patient's demise. So I, You know, until we have this information, and we're reaching out to the various sites, these five deaths occurred in four different countries, and all but one of them were in countries where English is not the native language. And so obviously, it's been in some difficulty of getting the proper information.
But we hope that over the course of the next month or two, to be able to resolve that. It's unfortunate we're not gonna be able to bring these patients back to life, but as it stands right now, as I understand, many of these cases, there will be certainly questions of whether the relatedness for the, the drug will stand in that case.
So if you run the numbers, the TAMARACK death rate as it stands, so this is not treatment-related, but treatment emergent death rate is 2.8%, so five out of 176 patients. How does that compare to some of the other more recent trials that we've seen? Think about PSMAfore, CONTACT-02, or even your previous trial with the, you know, three Q3 dosing.
Well, I thank you for bringing that up and putting it in that perspective, which is, you know, to understand, and with the caveats that cross-trial evaluations are, you know, not optimal, but just to understand for instance, of the experimental drugs you're raising, as well as approved drugs. So let's go through enzalutamide, abiraterone, go through Pluvicto. You include cabazitaxel. If you look at all the trials that were done to get these drugs approved on the market, from PREVAIL and AFFIRM for enzalutamide, to COUGAR studies 301 and 302, for abiraterone, for the CARD study for cabazitaxel, and for VISION for Pluvicto, the AEs that led to death were between 2.9%-12%.
And so, again, with the caveats, these are cross-comparison trials, and we still need to complete the study, but we're approaching the end of the study. I think that, with now a mean exposure of greater than five and greater, in this trial, we've gotten that exposure now to a couple of hundred patients. And so, I think that, we're right in a similar range that approved drugs, their AEs convert to death, and similar here. And so back to the point I made earlier, I'm ascribing all five to associated with drug. They may not be all associated with the drug.
Great. Yeah, maybe a lightning round on these cases here. The patient, did they have a cardio- history of heart cardiovascular disease or maybe infarctions?
Yeah, so there were two, there were two patients in regard to that. Again, before I give any more depths, I'll just give you the flavor for these particular patients. One was a 70-year-old with a strong history of cardiovascular disease, had a history of ischemia, hypertension, hypercholesterolemia. That patient, in the middle of the night, had sudden death. The 81-year-old patient, who had a myocardial infarction, had severe aortic stenosis, had a permanent pacemaker, had cardiac problems before, and had an MI. Again, the patient with the MI, who was 81, had received multiple doses, and it was 69 days since the last dose of drug. For the 70-year-old, it was 34 days since the last dose of drug.
So again, a nice long window in terms of when they were exposed to the drug and their outcome, but with a very strong personal history. Actually, the 81-year-old was also a very heavy smoker as well.
Great. Maybe about the causes of effusion-related deaths. Was it inflammatory, or was it cancer-related or, you know, infection-related, or maybe cardiovascular related? Do we know anything about that?
So this, this is, again, a very, confusing case in terms of ascribing what the cause of death was. This is a patient that I don't remember his age, it was in the 70s, who presented with a pleural effusion. It was this patient had been on the drug for over 200, 265 days, but the last dose was 106 days before they presented with a pleural effusion. So if you just I don't know the specific half-life of the drug in this patient, but if you go back to our Phase I data, the half-life of the drug was about a week and a half or a little longer, you know, obviously, depending on the subject.
If you just take that time of 106 days since the last drug, there should be no drug on board in this patient. I can tell you that this patient was treated for other problems. At least one of the drugs may have caused this problem, unrelated to, obviously, the vobramitamab here. But again, we need to query and get more information about that until we get more confidence with regard to what the cause was in that particular patient's demise.
Great. I want to save some time for to go through the efficacy here, but maybe a quick question at the end about, you know, the death. Are there any possible drug-drug interactions that we can think of that can cause deaths because these patients may be on other drugs? And then will that change or impact the enrollment criteria for any future trial in any way?
Again, we have a very comprehensive pharmacovigilance group that is monitoring this, all the drugs that they're on. And our sense is, right now, there clearly can be drug-drug interactions, but nothing has cropped up in that regard. I would like to also say it was very serendipitous. Our independent data safety monitoring board actually met yesterday. This was planned a long time ago. It's their just routine follow-up. They've reviewed all the safety, continue the study. So again, outsiders, independent, looking at the data, are confident that the study is being conducted properly. Now, I will be very clear, we are always looking for early signals for anything that is associated with a drug. Back to the point is manageable side effect profile. So is
If we can identify something very early that may tip us off that somebody might develop pneumonitis, we'll obviously implement a new screening procedures or monitoring procedures to prevent or treat as early as possible if those things crop up.
Great. And maybe talking about switching gears here to efficacy. Obviously, maybe you can characterize this at a high level in the last minute or so we have here. PSA50 responses and ORR radiographic responses that you presented, how do you view that fitting in with, you know, some of the more recent data sets we've seen, more recently? Obviously, it's hard because your trial enrolled pre- and post-taxane, and you know
Well, I have to say that we are very, very pleased with the data to date. It's interim data. Again, we'll see what the point. But again, if you go back to what I've put out as the targeting, we've already achieved these in one or both of the doses. And as I pointed out, the majority of the patients are still being treated. And so, for example, when I discussed, for instance, the PSA50 rate, if you remember, I said between 40%-60%.
Mm-hmm.
We have, in both doses, unconfirmed 50% responses for two and 2.7. In terms of the confirmed responses, we're seeing 44% in one and 37% in others, and the we still can increase those of the unconfirmed to become confirmed on the PSA50 side. So we have achieved that box. We've checked that box with regard to PSA50. With regard to ORR response, again, nice criteria to judge by. Remember, we said about a quarter of the patients from our earlier study, that cutoff we saw, confirmed and unconfirmed, around a quarter of the patients. Same story with the Daiichi molecule, 25%.
We've already achieved confirmed 25% responses, and if you now take the confirmed and unconfirmed responses, we're at 43% at the 2.7 mg Q4, and that doesn't even consider the patients with stable disease that still could become, develop a PR going forward. So I am very encouraged by the data we've seen so far.
Great. Well, thank you, Scott, and then the next update is the second half of the year, right?
It is. We obviously want to finish the study, get the RPFS, follow up on safety here. But, again, we're very excited about the prospects here and hope we'll be able to move forward into a Phase III development in prostate cancer and other indications.
Great. Well, thank you, Scott. Thanks for taking time, and yeah, thanks for the information.
Thank you. Thank you. Thank you.