Ep. 362 - AACR: Data and de-risking

Bispecific antibodies and dual-payload antibody-drug conjugates were in the spotlight at this year’s American Association for Cancer Research meeting in San Diego as biotechs unveiled their latest preclinical and first-in-human oncology data. On a special edition of the BioCentury This Week podcast, IQVIA Biotech CMO James Kyle Bryan joins BioCentury’s analysts to discuss what AACR revealed about modalities gaining traction, plus shares his perspective on de-risking clinical development and eliminating the “white space” that delays biotechs’ timelines in the clinic. This episode of the BioCentury This Week podcast was brought to you by IQVIA Biotech.

View full story: https://www.biocentury.com/article/659235

#AACR #BispecificAntibodies #ADC #OncologyData #ClinicalDevelopment 

00:01 - Sponsor Message: IQVIA Biotech
01:43 – AACR Early Signals
05:17 – Antibody Innovation
09:22 – Dual Payload ADCs
13:48 – De-Risking Drug Development
19:16 – Looking Ahead to ASCO

To submit a question to BioCentury’s editors, email the BioCentury This Week team at podcasts@biocentury.com.

Transcript

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[AI-generated transcript.]

Voice Talent: 0:02

BioCentury This Week is brought to you by IQVIA Biotech. A full-service CRO right sized for biotech. Dedicated to helping biotech leaders close unproductive gaps in clinical development so they can protect timelines, preserve capital and stay ahead of risk.

Jeff Cranmer: 0:23

Welcome to a special edition of the BioCentury This week podcast. With AACR here and ASCO on the horizon. We have the good fortune to be joined by the CMO of this month's BioCentury This Week podcast sponsor. He's Dr. James Kyle Bryan, he is the CMO of IQVIA biotech. Kyle also serves as global head of the IQVIA Hematology Oncology Center of Excellence. Now at IQVIA, Kyle's focused on drug discovery and development in the biopharma industry with an eye on helping his clients' de-risk their clinical programs. That, plus his oncology focus comes in handy for us as like some of our listeners out there. We are knee deep in the stream of readouts from the American Association for Cancer Research Meeting in San Diego. Joining me today are my BioCentury colleagues Selina Koch my fellow Executive Editor and Lauren Martz, Executive Director of Biopharma Intelligence here at BioCentury. I am Jeff Cranmer, your host, and I'd like to bring Kyle right on in and, and say, Kyle, welcome to the program. It's great to have you on first time.

James Kyle Bryan: 1:46

Thank you. I appreciate the welcome and I appreciate the opportunity to talk with you guys and talk with your listeners. I find that I'm very much of a uh a little bit of a geek when it comes to biotech and biopharm and drug development. You know, my, my pedigree goes back to very small biotechs that got bigger and then got smaller. Worked in the CRO world for a while. I just find the whole experience is just endlessly fascinating.

Jeff Cranmer: 2:15

Well, welcome to the Geek Club Kyle. You are in very good company with my colleagues Lauren and Selina. We like to get deep into the weeds on topics such as AACR, and I'd like to caution our listeners not to be too fooled by Kyle's Louisiana accent. He's actually a doctor up in the PNW, where our production engineer Cole Travis hangs out. Now, Kyle, I know you've got a man on the ground at AACR down in sunny, hopefully sunny SoCal. and you've been uh riffing with him on topics of interest. I, I wonder what most immediately has caught your attention from what you're hearing.

James Kyle Bryan: 2:57

Thank you. Yeah, we do Have one of my colleagues from the Center of Excellence down in San Diego at AACR, and I'll just say he is definitely getting his steps in. He's visiting posters all over the place and tracking people down and listening to conversations. I talked with him a little bit last night and said, you know, Jeff, what's, what's at the top of your mind? What, what's your impression at the end of a long day when you're relaxing and. Thinking about a beer or something like that. And he was sharing with me that, you know both the targets and the, the agents that we're accustomed to seeing the immune checkpoint inhibitors, you know, that era of the checkpoint inhibitors is far from being over. There's tons of abstracts that are focused on both the familiar targets, you know, pembrolizumab and the PD-1s. But also some targets that we sort of in the past had maybe underperformed in some late phase studies, but are now resurrecting either in combinations or in niche indications, things like LAG3 and TIGIT. There's been a lot of talk about CTLA-4 kind of new generation CTLA-4 agents with maybe novel mechanisms or different ways of trying to attenuate that toxicity profile, that sort of dampened what we were able to do therapeutically with those guys. You know, novel linkers, novel payloads, novel strategies for getting our drugs where they need to be, releasing them at the right time, in the right concentration, and, and getting a really kind of a controlled payload release in the ADCs. Obviously bispecific antibodies and both single target and bispecific ADCs. And then the dual payload ADCs are very big and all over the place.

Jeff Cranmer: 4:50

Kyle, let me jump in here. I, we, we are gonna dig deep into the ADC dual payloads. Lauren just did a big piece on that for us in BioCentury, but I'm intrigued about what you're saying about TIGIT. I, I, I had kinda left that by the road side a little while ago, so I'm. I know Lauren's written a lot about this. Lauren uh I'm curious uh are you surprised to hear what Kyle's saying there about LAG3 uh TIGIT and the like?

Lauren Martz: 5:16

So uh I'm not surprised. And I think the thread that's underlying a lot of what you've picked out and what your colleague has picked out at AACR is, is antibody innovation. You know, the bispecifics and the ADCs. So. We're talking about giving new life to some targets like TIGIT that haven't necessarily seen a lot of clinical success, especially the, the high profile late stage failures that we've seen for TIGIT. I think that's where antibody innovation comes into play, and specifically for that target, I think there is, or at least a few abstracts and, and we've been seeing this ramp up over the years that are sort of dual checkpoint inhibitors, you know, bispecific antibodies, targeting maybe CTLA-4 and TIGIT. The idea there being that you could knock down two pathways, two pathways that are controlling the or restricting the anti-tumor immune response and, you know, potentially making that CTLA-4 side of the equation safer. So I think that's definitely something that we've seen cropping up and, and something that. We'll continue to see more of at meetings like this that are very focused on the innovative side of, the science.

Selina Koch: 6:26

On that safety side. CTLA-4 I think is, you know, known for having some, some tox. What's promising to make a difference there? Is it masking pH sensitivity? Either of you have thoughts on that.

Lauren Martz: 6:39

I think all of the above. we're seeing some masking technologies to improve safety. And there's also Fc engineering, Fc tuning to, to try to control the ADCC and enhance the Treg depletion. So I think there are several different strategies in development to improve the safety of the CTLA-4 mabs.

James Kyle Bryan: 7:02

You know, speaking of, of safety, the, the other thing that is showing up are other modifications to make our ADC safer. novel linkers trying to look at how to do the structure so that you get better stability of the ADC, you get a more controlled payload release. I think the tandem-cleave linkers are a really interesting part there, where you've got, it takes two steps to release the payload. So you need a, a cleaving that takes place at the tumor with the internalization, but this extra stabilization as the drug is circulating it really, I, think the greatest benefit there. I, I won't say greatest. You're, you're letting me get too excited there, but a solid benefit there. You have to remember, I'm a hematologist and oncologist, so blood always gets me in a positive mindset, but it's reducing the hematologic toxicity because it's not. having that risk of payload loss in the wrong place, the payload uncoupling is happening where it should be, and that gets you a better therapeutic index and improves your overall window.

Selina Koch: 8:12

What controls the two phases of the cleavage, is there like a kind of a finite number of different ways that's accomplished?

James Kyle Bryan: 8:20

I hesitate to say finite just because I feel like you know, the only thing we're limited by is our imagination. But some of the same techniques that are being used in masking where they take advantage of the fact that you know, there are differing enzyme levels at the tumor microenvironment compared to what you're experiencing in the circulation and utilizing that as that initial cleave taking place when you're entering in the tumor microenvironment. And then whether it's the target or the payload being freed up, then to go through that second cleaving after it gets internalized.

Selina Koch: 8:58

I mean, ADCs are so interesting and their complexity, you know, the modularity of it you can do all kinds of uh antibody engineering as Lauren was talking about, on the antibody end multiple specificities, whatever. Then there's the linker, which sounds like those are getting more complex as well. And then there's the payload. There's a, like any number of cytotoxins, but there's radioisotopes on and on. Now there's also this dual payload approach, right. Maybe we should talk a little bit about the increase in abstracts this year and what we're seeing for, for dual payloads at AACR.

Jeff Cranmer: 9:30

Yeah, that's a, that's a good call there. Lauren just wrote about that. Lauren, why don't you jump in here?

Lauren Martz: 9:35

Sure. Thanks Jeff. So the dual payload ADCs is one thing that we've picked out as a trend in the abstracts from this year. There were, I think, more than 40 abstracts that discussed this idea which is something that we've heard a bit about. But again, really taking off in this crop of abstract. These were broken down by uh or we broke these down by dual payload ADCs that are delivering two cytotoxic chemotherapy payloads. and some that are delivering, you know, one of the standard cytotoxics plus a targeted therapy or something else like a degrader. I think both of those were, were really interesting approaches because the two cytotoxic chemotherapies, a lot of times it's combining the standard therapies that ADCs deliver. And the idea is that you could overcome resistance that that ultimately develops with most of the ADC treatment, even though these are really potent therapies. It's still a chemotherapy and tumors can still sort of evolve resistance to, to get around them. And then I thought the chemo targeted therapy combinations were really interesting because, it just offers one more way to, first of all to combine two things and, and avoid resistance, but also to localize. The effects of the targeted therapy. In the news last week, we saw the Re volution Medicine data for their pan-RAS inhibitor, that was just phenomenal data. But we do know that there are some side effects. So, you know, one of the abstracts that we saw in this crop this year um from Affinity Biopharma, delivers a pan-RAS inhibitor and you think, well, maybe this is a way to sort of better localize that pan-RAS e ffect and, and avoid some of the side effects We don't know yet. This is all preclinical but just a really interesting crop of abstracts.

James Kyle Bryan: 11:20

Yeah. those are really good points. I mean, one of the things I think that's really interesting about the dual payload ADCs is. Sort of the steps that you have to take through in the development as you look at this, because again, the, the concept is really strong. I love the concept behind, for example, if you're using a DNA damaging agent along with a DNA repair inhibitor and that gets to the whole idea that the reason the ADC fails or the treatment fails is payload resistance. It isn't actually loss of target, which all of us that have worked in the antibody world are always, you know, what happens to the expression of my target over time? Is that changing? Is this why my agent isn't becoming as effective? But when you're looking at two payloads, you, you've got to think about the individual toxicities of the agents and the risk of overlapping toxicity of the agents. But then the, the extra wrinkle is, well, what if there's a new synergistic toxicity that I don't see with A, and I don't see with B, but when I put A and B together, I now get C, which I wasn't expecting. So as I work through, you know, the dose escalation and the dose finding and dose optimization aspect of it, it just becomes one of those things where we need to keep our eyes wide open looking for those safety signals.

Lauren Martz: 12:45

that brings up another point that I heard in the reporting for this story, which is, yes, the combinations we have to assess the safety. But even once you figure out the right combinations and the right doses, actually creating an ADC that is able to deliver the right ratio of these payloads is really challenging. You know, depending on which type of linker you use, whether both payloads are on the same linker, you know, it, it's a, it's a heavy lift and, and a really interesting challenge.

Selina Koch: 13:11

more of these? Um. Abstracts that you're seeing at AACR have branched linkers or do they connecting them up separately,

Lauren Martz: 13:19

That ha that's not disclosed in all of these.

Selina Koch: 13:21

Often not disclosed? Yeah.

Lauren Martz: 13:23

I hear that a lot of them are separate linkers, but I can't confirm that.

Selina Koch: 13:27

Yeah.

James Kyle Bryan: 13:28

Yeah, there's not a lot that they've talked about yet, about for example, the DAR on these agents and, you know, what's the DAR of this payload and what's the DAR of that one? It is one impacting the other. So there's a lot for us still to learn. And again, the, the engineers are kept very busy.

Selina Koch: 13:47

I think the segue is really nice into a, a topic that I know is um on your mind lately de-risking. So we have like like I was saying, this complex modular modality where all, you can tweak any piece of it in lots of different ways. Like yeah, the human imagination can do almost anything there, right. The combinations are staggering, the possibilities. Um, but how do you think about smart de-risking?

James Kyle Bryan: 14:13

The way I tend to think about it is, is like this, I think when it comes to drug development, and particularly my, my pedigree is in the biotech world and sometimes in the very small biotech world. Where when it comes to evaluating a an agent or an antibody or a compound or any investigational product, you have to be a little bit careful of being more paternal than professional in your evaluation of it. You do get this feeling it's your baby, but, just recognizing that, you know. It may be a, a smarter thing to think of it like um when you're making breakfast, you know how the first pancake never turns out all that great and you may need to toss that one away and, and focus on the rest of the batch, that's kind of the thing. So I would say that one of the bits of advice that we give our biotech clients is, again, look at it professionally. Consider like a stage gate analysis where you're really looking at, at every step in this development. And setting parameters for what you're going to do if you see this, or what you're going to do if you see that. As opposed to well, let me see what happens, and then I'll think about what my decisions want to be. Because you, you've gotta be looking at is the science credible? So what's the science and the tech readiness of this is one point. Is the risk acceptable? Company wide, the risk to a patient, the risk benefit aspect of it. And to do a, a real risk assessment that you're then going to apply to your decision making at each stage as you go along here. What's the investment? Is the value there, do the economics work for me? And then finally, you, you can't forget, is this a strategic fit for my company, for my group that are developing it? You may see something really interesting that can carry a, an exciting new direction, but if the strengths of your team aren't in that kind of development, then you're either gonna need to bring in new team members, or you're gonna need to think about, well, maybe this is something that I hand over to someone else to develop at this point. Or I look for a different kind of partner, a different kind of engagement. To take it to the next phase. I think that too often, especially in our, smaller biotechs, that you can get in a more of a state that where your, your overview of the program, it looks more like a project review or an operational review where you're tracking progress as opposed to having a real decision driving mindset at these strategic discussions of shall we continue or not continue. As opposed to making the little tweaks around the edge. So that, I guess would be my, my broad approach to how you de-risk and think about this. Ultimately, you know, we, we want people to focus on trying to eliminate the white space. A lot of the unproductive part of drug development comes from not the time to get to a milestone, but getting to a milestone and then the delay in coming to a decision or deciding what you're gonna do with the information that you've received. And I think that again, it's a place where it's important to look at your team, look at your advisory persons, whether it's your board or your scientific advisory board, and kind of build in that sort of upfront planning smart decisions about your protocol to keep it in scope with what you can accomplish and really use the data and, and kind of cross-functional alignment to get to a good decision point.

Jeff Cranmer: 17:59

Some good practical advice there from Kyle. We're gonna take a quick break and then we're gonna come back and look ahead to ASCO.

Voice Talent: 18:07

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Jeff Cranmer: 19:14

Okay. We are back on the BioCentury This Week podcast, it's a Special Edition. And we are joined by Dr. James Kyle Bryan, who is the CMO of our sponsor, IQVIA Biotech. we're gonna get Kyle's thoughts in a moment on how he's getting ready or thinking about ASCO which is, you know, it's next month, so it's not too far away. You know, AACR just runs into ASCO, though you do get that little uh digestive disease week apéritif in between. Lauren uh before we get there, do you want to um just give us a few takeaways just wrapping up the ADC thoughts.

Lauren Martz: 19:57

Sure. Yeah. Just to, to wrap up what we talked about, we've, we've gone through the, the dual payload ADCs is, actually the bispecific dual payload ADCs are sort of the tip of innovation right now at AACR. Uh we found 44 abstracts that cover dual payload ADCs. A lot of them are bispecifics. and just looking more broadly, because Kyle has a focus on antibody innovation in his past. There's a lot more in those abstracts. There are trispecific specific ADCs and masked biologics and, and all kinds of really interesting ways to innovate and take different approaches to risk as Kyle has talked about. You know, with, with these dual payload ADCs. It's a lot of the same targets that we've seen for the approved ADCs when you're talking about the tumor antigen. It's a lot of the same payloads, but just combinations of payloads. So you can see companies and institutions, although most of these are from companies thinking about where they're going to apply that risk um which is it really the technology.

Selina Koch: 20:58

um, is anyone going out on a limb there and kind of stacking up a little bit of risk? Say putting a new target on with a dual payload or...

Lauren Martz: 21:06

That's a great question. There, there are quite a few new targets and by new. Not new to us as people who are looking at the innovative edge of everything, but new as in no ADCs approved against this target. Certainly a lot of new tumor antigens that are in the list, really a lot of the same cytotoxic payloads that we've seen, but there is some innovation. For example, a company called Baylink has a dual payload ADC targeting GPC3. And one of the payloads is a protein degrader. So lots of risk in that one, but huge potential reward, I guess, if it works well.

Jeff Cranmer: 21:44

And you can check out Lauren's article on BioCentury.com. I'll drop a link in the show notes. Wanna bring Kyle back in here. Kyle uh how are you thinking about ASCO from where you sit at this time of year?

James Kyle Bryan: 21:57

Well, you can't really be at AACR without thinking about ASCO. In my mind, the way I think about is that AACR is, has always been about the strategic direction of cancer research, where are we going strategically? ASCO has traditionally been about clinical practice. What are we doing directly for patients? You know, is this going to change clinical practice? Not that we don't see preclinical data at ASCO because we do, but that sort of what I call the pull through the AACR to ASCO pull through and what likely to happen. So I, I really think for this year's ASCO, we're gonna see more about the dual payload ADCs some of the early clinical proofs or at least early discussion on this. I think again, this narrative of where the ADC resistance originates that narrative, I think is gonna be picked up. And we may see some additional interesting discussion around that. Ultimately, you know, we're, we need to see the Phase I expansion data. And it's possible we'll have some of that more likely, we're talking about pull through for 2027 ASCO. But it's a, just a, a really interesting period there. I think looking at other combinations whether it's with checkpoint inhibitors or whether it's with chemotherapy, I think those are gonna be there. You know, there's a couple of things that we didn't really even touch on today, that will probably be featured when we're looking at the data at ASCO. We didn't even get a chance to talk about the mRNA cancer vaccines or talking about maybe the AI derived biomarkers and what's happening in that space. We'll have an exciting ASCO, the amount of data there is way more than you can consume in four or five days, so that's why we all end up reviewing the abstracts and watching the virtual meeting for months to come. But it's really been an exciting AACR so far, and it's not over yet.

Jeff Cranmer: 24:04

Excellent, Kyle. Well, thank you for sharing your thoughts. would love to reconnect with you after ASCO just to see what the big takeaways were for you uh there. And, Always grateful to IQVIA Biotech for sponsoring the BioCentury This Week podcast. Kyle and Lauren and Selina's, thanks so much for sharing your thoughts on AACR and Kyle. Looking ahead for us to ASCO.

James Kyle Bryan: 24:30

it was wonderful, Jeff. I really enjoyed talking with you and with Selina and Lauren, I'll look forward to connecting with you again soon.

Jeff Cranmer: 24:38

Okay, you've been listening to the BioCentury This Week Podcast Special Edition here with Dr. James Kyle Bryan, CMO of IQVIA Biotech.

Voice Talent: 24:52

BioCentury would like to thank IQVIA Biotech for supporting the BioCentury This Week podcast. To learn more about how IQVIA Biotech’s dedicated teams deliver support from innovation to impact, visit IQVIABiotech.com