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AstraZeneca’s ASCO Readout on Oncology’s Next Wave · Vanguards of Healthcare by Bloomberg Intelligence

0:27
Speaker 1: Welcome to another episode of Bloomberg Intelligences Vanguards of Healthcare
0:30
Speaker 1: podcast where we speak with the leaders at the forefront
0:33
Speaker 1: of change in the healthcare industry. My name is Sam
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Speaker 1: Fazili and one of the farmer analysts of Bloomberg Intelligence,
0:39
Speaker 1: the in house research arm of Bloomberg. I am thrilled
0:43
Speaker 1: to welcome Susan cold Brave again. Always a pleasure executive
0:48
Speaker 1: by President of Oncology R and D at Astrosenika. Of
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Speaker 1: course you don't need any introduction, Susan, so I don't
0:54
Speaker 1: know if we want to do that, but I'm ready
0:56
Speaker 1: to go straight into the conversation. We've both come back
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Speaker 1: from ASCO. I'm pretty sure you've had a much more
1:02
Speaker 1: interesting and amazing time than I have. But so, Susan,
1:06
Speaker 1: I thought that's not quite high level oncology and drug
1:09
Speaker 1: development in general. Is that an amazing place with the
1:12
Speaker 1: pace of understanding of the biology that underlies disease now
1:17
Speaker 1: sped up at quite a bit, I'm sure with AI,
1:20
Speaker 1: and it's providing a plethora of opportunities in developing new
1:24
Speaker 1: effective drugs, which we've seen some of at ASCODE just passed.
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Speaker 1: So what we wanted to What we're going to do
1:30
Speaker 1: here is to dig into some of this bit more,
1:33
Speaker 1: and especially given that we just had, as I said,
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Speaker 1: the largest doncology conference of the Yeah, so if I may,
1:39
Speaker 1: I'm going to test this statement with you. There are
1:43
Speaker 1: three or four key trends in oncology. One is go earlier.
1:49
Speaker 1: Two is diagnostics really coming in like ctDNA in terms
1:53
Speaker 1: of prognostic factors or checking whether somebody needs to continue therapy,
1:57
Speaker 1: and we've seen an approval there. Three is cracking tougher
2:01
Speaker 1: cancers and maybe tougher targets so pancreatic CLO to come
2:06
Speaker 1: immune desert diseases for want of a better phrase. And
2:09
Speaker 1: the last one or maybe they're related, is improving the tail.
2:13
Speaker 1: And here I'm talking about for those who don't know
2:15
Speaker 1: what this is all about, is the kablin My curve
2:18
Speaker 1: where you see the deterioriation or the patients that could
2:23
Speaker 1: start to either progress that's for a progression free survival
2:27
Speaker 1: or overall survival. We want to raise the number of
2:30
Speaker 1: patients that live longer. Of course, do you agree with
2:33
Speaker 1: those four? Would you add any and do you want
2:37
Speaker 1: to comment on those in general? Where you think that's
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Speaker 1: going Okay.
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Speaker 2: First of all, Sam, thanks very much for having makes
2:43
Speaker 2: great to be back. So in terms of the trends,
2:46
Speaker 2: I think the way I've described it is slightly different,
2:51
Speaker 2: but I think they're overlapping with many of the topics
2:54
Speaker 2: that you've identified. So the first trend that we've identifies, look,
3:00
Speaker 2: I think there's opportunity with the design of antibody drug
3:04
Speaker 2: conjugates and radioconjugates to improve on the current backbone of
3:08
Speaker 2: chemotherapy and radiation therapy in many settings, and you're seeing
3:12
Speaker 2: that come through in multiple different CANTA types now. So
3:16
Speaker 2: the second thing I've said is that what we currently
3:18
Speaker 2: classify as immune checkpoints inhibitors sensitive tumors, I think those
3:24
Speaker 2: are going to see some segmentation with the advent of
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Speaker 2: the next wave of medicines in that space, which include
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Speaker 2: the bispecific molecules, and that's going to segment that space
3:32
Speaker 2: a little bit because the different bispecifics are kind of
3:35
Speaker 2: different places within the treatment landscape that they may be
3:39
Speaker 2: differentially benefiting. The third is that I think there is
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Speaker 2: an opportunity to expand the number of tumors that we
3:46
Speaker 2: think of as iosensitive and the number of patients that
3:49
Speaker 2: we think of as iosensitive through the introduction of technologies
3:53
Speaker 2: like T cell engagers and the protein engineering around that
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Speaker 2: and the cell therapies, and that's going to expand what
4:00
Speaker 2: we think of in that space. The fourth, as you
4:02
Speaker 2: rightly said, is that we're going to actually put some
4:05
Speaker 2: of these together, and I think those are driving some
4:08
Speaker 2: exciting opportunities. By putting different combinations together, we're definitely going
4:12
Speaker 2: to move them earlier. And so to address your comment
4:15
Speaker 2: about the tail of the survival curve, if you really
4:18
Speaker 2: think about what's needed to improve long term outcomes in cancer,
4:23
Speaker 2: one of the fundamental pieces is about treating people at
4:26
Speaker 2: the earlier stages of disease, and so these technologies that
4:29
Speaker 2: you've referred to, like circulating tumor DNA, are a key
4:32
Speaker 2: part of enabling that trend. Beyond what we're currently doing
4:36
Speaker 2: in the coring, screening programs and adoption, which are largely
4:40
Speaker 2: based on not solely, but largely based on imaging tools,
4:46
Speaker 2: I think we can supplement those with some of the
4:47
Speaker 2: circulating tumid DNA tools, and I absolutely agree that we
4:52
Speaker 2: can also use that technology circulating tumid DNA to monitor
4:57
Speaker 2: patients during the course of treatment. And adapt their treatment
5:02
Speaker 2: according to what we're seeing with that kind of information,
5:05
Speaker 2: and that is a paradigm change in how patients are treated.
5:08
Speaker 2: So I think by treating earlier, by introducing these better medicines,
5:12
Speaker 2: and by monitoring more effectively with better technology, all of
5:15
Speaker 2: those things can contribute to this raising the tail on
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Speaker 2: the curve and actually improving the long term survival. And
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Speaker 2: I actually think we are at a point where you
5:23
Speaker 2: can start to think about what's required ultimately to deliver
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Speaker 2: a functional cure for patients, even patients in the metastatic disease.
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Speaker 1: What would be required.
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Speaker 2: I'm not suggesting it's possible currently for the majority, but
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Speaker 2: I do think it is possible in a minority, and
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Speaker 2: that we can work on how do we increase that
5:42
Speaker 2: proportion of patients for whom it might be possible.
5:45
Speaker 1: I'm going to define what we mean by it first
5:47
Speaker 1: in order to do that. Yeah. Yeah, so that segmentation
5:50
Speaker 1: is quite interesting. Let me ask you a question about access.
5:55
Speaker 1: I think I remember you on a panel at AACR
5:59
Speaker 1: saying that you'll be shure stocked even this most standard
6:03
Speaker 1: EGFR testing, for example, how there are so still many
6:09
Speaker 1: patients who don't actually get it when they should be
6:11
Speaker 1: getting it, and now we're going into a world of ctDNA.
6:15
Speaker 1: Talk us about how you think the reality of this
6:18
Speaker 1: will be. I mean, we've had one of the first
6:20
Speaker 1: approvals for bloody cancer in terms of CDYDNA, But think
6:25
Speaker 1: talk us through where is this going to continue to
6:28
Speaker 1: be an area where the United States is going to
6:32
Speaker 1: lead again and then all the other countries are going
6:35
Speaker 1: to take forever to reach or how does that shape
6:38
Speaker 1: up in terms of going forward? How do you feel
6:40
Speaker 1: about knowing that you're going to be able to do
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Speaker 1: something that's prognostic and you can follow these patients and
6:46
Speaker 1: not actually being able to develop deliver it.
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Speaker 2: So let me just step back a little bit, all right,
6:50
Speaker 2: What we call CITDNA is not just one thing. So
6:53
Speaker 2: we already have CITDNA based diagnostic tests. Many patients are
6:57
Speaker 2: identified today across the globe as being suitable for an
7:01
Speaker 2: EGIFI inhibitor based on the presence of a circulating tumid
7:05
Speaker 2: DNA by a marker. It's the relatively simple end of
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Speaker 2: that circulating tube DNA biomarker simple specific test for an
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Speaker 2: EGIFI mutation. So those are available. What I think you're
7:16
Speaker 2: referring to with the bladder cancer study that you were
7:20
Speaker 2: talking about is something that's called a tumor informed test,
7:24
Speaker 2: and in that version of it, you actually have to
7:27
Speaker 2: have some of the patient's tumor tissue that that gets
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Speaker 2: sent off and creates a personalized panel of specific genomic
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Speaker 2: markers that then increase the sensitivity of that test so
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Speaker 2: that you can reduce the level of circulating tumidare that's
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Speaker 2: actually detectable what we call the lower limit of quantitation.
7:47
Speaker 2: At the moment, most of the solid tumor tests that
7:50
Speaker 2: are currently available there are limits of quantitation. Is you know,
7:54
Speaker 2: to be able to detect one in ten thousand ten
7:58
Speaker 2: to the minus four censervity.
8:00
Speaker 1: But actually probably.
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Speaker 2: What we need to be really improve the prognostic ability
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Speaker 2: of the presence of circulating tumor DNA after say surgery,
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Speaker 2: is to get to one part per million.
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Speaker 1: And I think there are.
8:14
Speaker 2: Some tests that are currently available that can get to
8:16
Speaker 2: that level of sensitivity. And let's just take a moment
8:19
Speaker 2: to understand why that would be important. If you see
8:22
Speaker 2: a patient who's diagnosed with cancer in the metastatic setting,
8:26
Speaker 2: with extensive metastatic disease, you see these scans of patients
8:30
Speaker 2: with prostate cancer with multiple bony metastases, probably you're looking
8:36
Speaker 2: at somewhere between ten and one hundred billion cells that
8:39
Speaker 2: are cancer cells in that patient. So you think about
8:42
Speaker 2: that and you start to realize that when we get
8:44
Speaker 2: a partial response what we see on a CT scan
8:48
Speaker 2: with a reduction, you're probably less than one log cell kill.
8:52
Speaker 2: So you might have gone from ten billion to one billion,
8:56
Speaker 2: but you've still got one billion cancer cells present. That's
9:00
Speaker 2: why you start to understand that you need something that
9:02
Speaker 2: can go down many orders of magnitude to have the
9:06
Speaker 2: sensitivity to really detect a level of disease that then
9:10
Speaker 2: is more likely to be ultimately survivable. And the reason
9:14
Speaker 2: why I'm talking about this is you see this in
9:16
Speaker 2: the hematology space already. We have what's called minimal residual disease,
9:23
Speaker 2: a test accepted from a regulatory perspective as an intermediate
9:26
Speaker 2: clinical endpoint in the setting of multiple myeloma first line,
9:31
Speaker 2: and there's a specified level of sensitivity associated with that.
9:35
Speaker 2: Of course, in the blood, with the blood based cancer,
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Speaker 2: it's easier to measure this disease. But I think this
9:41
Speaker 2: is going to come into the solid space, and I
9:43
Speaker 2: think we are getting to the point of sensitivity that
9:45
Speaker 2: we need. And so when you see that, I mean,
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Speaker 2: there are some data that've been published over the last
9:50
Speaker 2: year or so that show when you get to these
9:52
Speaker 2: very sensitive tests in the setting of somebody that's had
9:56
Speaker 2: surgery for breast cancer and the associated humoteray, if they
10:00
Speaker 2: have clearance on the sensitive on the very sensitive tests,
10:05
Speaker 2: it's more predictive of long term outcome than pathologic complete responses,
10:08
Speaker 2: which is currently used at the end of that new
10:11
Speaker 2: adjuvant period. So it starts to be more discriminatory and
10:16
Speaker 2: really helpful. And I think we've got to sort of
10:18
Speaker 2: a start building those data sets and b show the
10:20
Speaker 2: clinical relevance and clinical utility of those data sets as
10:24
Speaker 2: we're developing our plans for our new molecules that will
10:28
Speaker 2: come into this space.
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Speaker 1: Okay, now, just one thing more about this high level
10:32
Speaker 1: conversation we're having going earlier, How should we think about
10:36
Speaker 1: the optimal strategy for bringing therapies into earlier stages is
10:39
Speaker 1: particularly in tumor types where how should I put it,
10:43
Speaker 1: treatment options are limited even in limited static stage. Is
10:48
Speaker 1: the future going to continue to forever be You're going
10:51
Speaker 1: to have to start late and then come up earlier
10:53
Speaker 1: or do you think there are chances where you can
10:55
Speaker 1: just cut that circumvent that need well, I think.
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Speaker 2: I think it is established a paradigm. I feel like
11:02
Speaker 2: that you need to establish safety typically and that's typically
11:05
Speaker 2: in a later line disease. But what you can do
11:08
Speaker 2: is move the development plan so that you can move
11:10
Speaker 2: into the earlier stage at an earlier point in the
11:12
Speaker 2: development plan. And in fact, we've already got examples of
11:16
Speaker 2: how we've done that. So we did that honestly with
11:19
Speaker 2: the cameras estrument program, our next generation third which in
11:24
Speaker 2: the Phase one period of time. Along with establishing the
11:28
Speaker 2: safety profile in second line plus homone sensitive hommone receptive
11:33
Speaker 2: positive breast cancer as well as that, we also did
11:37
Speaker 2: a window of opportunity study, the Serena three study in
11:40
Speaker 2: the curative intense setting to show the impact of this
11:45
Speaker 2: molecule on both signaling but also the proliferative marker, which
11:52
Speaker 2: is Q sixty seven in that setting, because we know
11:54
Speaker 2: that that is the most predictive outcome for activity in
11:59
Speaker 2: the adjubant setting. And it was the combination of the
12:01
Speaker 2: Serena two data, which was a randomized data set from
12:05
Speaker 2: the second line breast cancer, plus that wind of opportunity
12:08
Speaker 2: which led us to have the confidence to enter into
12:11
Speaker 2: the two adjuvant studies for Chemisestra and the Cambria one
12:14
Speaker 2: and Cambria two studies. So we have already done that.
12:17
Speaker 2: We've done that at pace. Similarly for the Enhertu development program,
12:22
Speaker 2: you know, as well as moving at pace into the
12:25
Speaker 2: metastatic setting and the hur too high, we also planned
12:28
Speaker 2: early for the neoaguvant study the Destiny brest eleven and
12:32
Speaker 2: the post neoaguvant study the Destiny BREASTO of five, both
12:35
Speaker 2: of which and polices say, we've just got FDA approval,
12:39
Speaker 2: but we had to plan for those before we had
12:42
Speaker 2: the actual outcomes of the late stage metastatics. You can
12:45
Speaker 2: see that compared with the historical view of development, we
12:49
Speaker 2: have taken at risk investments into that early stage setting
12:53
Speaker 2: at an earlier point in the development plan.
12:56
Speaker 1: So I just want to pick on that last phrase.
12:58
Speaker 1: It is more a pharmaceutical company a farmer company's decision
13:04
Speaker 1: versus what is required by the FDA, because I've seen
13:08
Speaker 1: some of the new molecules where I mean the two
13:10
Speaker 1: that you mentioned in her Too and chemistis strand are
13:12
Speaker 1: relatively well established targets relatively what I said, But the
13:16
Speaker 1: molecules are obviously new and different, so you would maybe
13:20
Speaker 1: worry about the side offf profile if you went into
13:22
Speaker 1: an any patient, But the trials are designed in such
13:24
Speaker 1: way if you do see a side effect issue, you
13:26
Speaker 1: can end quickly, right, So this is more a risk
13:30
Speaker 1: taking issue by the industry as opposed to a some
13:34
Speaker 1: dogma that's been said that they have to early has
13:37
Speaker 1: to be after you've proven yourself in late. Is that right?
13:40
Speaker 2: Yeah? I mean, I think the key thing is that
13:42
Speaker 2: we I mean, we did go and discuss obviously the
13:45
Speaker 2: trials that were that we have, both with the investigators
13:48
Speaker 2: that might be interested in recruiting their patients, and so
13:51
Speaker 2: they will require a certain level of safety before they
13:53
Speaker 2: would be willing to put a patient that's potentially in
13:55
Speaker 2: a hare's got other options in the in a curative
13:58
Speaker 2: intent setting onto with new medicine. And in addition, of course,
14:02
Speaker 2: the regulatory authorities want to also be convinced that you've
14:05
Speaker 2: got a reasonable safety database in order to do that.
14:08
Speaker 2: My point is though, that you can choose to do
14:11
Speaker 2: that and build those data sets at the pace and
14:15
Speaker 2: move at an earlier point when you've still got you
14:17
Speaker 2: haven't fully de risked the likelihood of success in the
14:20
Speaker 2: later later line at the time that you make that investment.
14:24
Speaker 2: And I think it speaks to an understanding of the
14:27
Speaker 2: investment versus the innovation curve here. I mean those two
14:30
Speaker 2: Cambria studies that I've talked about, they are there are
14:34
Speaker 2: over five thousand patients in each study.
14:37
Speaker 1: What they were about we can all multiply with whatever
14:40
Speaker 1: they say the number of the cost is for patient
14:43
Speaker 1: and the number of years because their longer trials.
14:45
Speaker 2: Yeah, so you know, and the lever at the time
14:47
Speaker 2: that you have you have to make that investment, you
14:50
Speaker 2: have to do that on a basis of less information
14:53
Speaker 2: than everybody would ideally like to have in order to
14:56
Speaker 2: So that's I think this is this comes back to,
15:00
Speaker 2: you know, the reward for innovation, and the element of
15:03
Speaker 2: that is that those a significant rest that we're taken
15:06
Speaker 2: in the with the purpose of really transforming the outcomes
15:11
Speaker 2: for patients, and we think that going into these early
15:14
Speaker 2: stage settings are a critical component of transforming the long
15:18
Speaker 2: term outcomes for patients.
15:20
Speaker 1: Now we're going to get into some of the more
15:22
Speaker 1: specific topics that relate more to ASCO in a minute.
15:26
Speaker 1: But we just published before ASCO a report looking at
15:29
Speaker 1: the amount of look at about one hundred and twenty
15:31
Speaker 1: six companies. So I mean every year, every time, I'm
15:34
Speaker 1: going to be able to add that a bit more,
15:36
Speaker 1: every time I can identify companies fairly and correctly as
15:39
Speaker 1: oncology companies. You know, a significant increase in revenue from
15:45
Speaker 1: you know, obviously a lot of it comes from Johnson
15:46
Speaker 1: and Johnson, Astroseneka, et cetera, the large companies, but a
15:51
Speaker 1: significant increase in revenue, A significant still proportion of licensing
15:55
Speaker 1: deals are for oncology, about half of the lunches indeals rough.
16:00
Speaker 1: But I've seen a very interesting trend I V see
16:03
Speaker 1: investment in oncology seems to have, I don't want to
16:06
Speaker 1: say collapsed, but seems to have fallen completely in the
16:09
Speaker 1: opposite direction to what it was before two thousand and
16:12
Speaker 1: one or two. Before two thousand and one or two,
16:14
Speaker 1: VC investment in oncology, whether it's seed or series A,
16:17
Speaker 1: et cetera, was much higher than other indication other areas.
16:22
Speaker 1: Now it's flipped. So and we had a dinner just
16:26
Speaker 1: before ASCO asked this question to everybody at some companies,
16:29
Speaker 1: some groups said it's too complicated. Now it's become the
16:32
Speaker 1: arena of farmer companies. And maybe this relates to what
16:36
Speaker 1: you just told me that you can have, you should
16:38
Speaker 1: be doing. You do trials even at an earlier decision
16:42
Speaker 1: process where it only works if you're a large farmer.
16:45
Speaker 1: Do you have any do you have a view on that?
16:47
Speaker 1: Is that other reasons that you think vcs are not
16:50
Speaker 1: maybe that that excited by oncology versus but because you
16:54
Speaker 1: go to ask or you think phenomenal so much new
16:58
Speaker 1: stuff is going on.
16:59
Speaker 2: Well, I don't think it's phenomenal. I think it's the
17:01
Speaker 2: most exciting period in cancer discovery and development that I've
17:05
Speaker 2: experienced over the last twenty five years, because we are
17:08
Speaker 2: seeing the possibility of making things that were sought to
17:12
Speaker 2: be undu druggable. The technology with protein engineering of what's
17:16
Speaker 2: possible for this next wave of t SELL engages, for example,
17:21
Speaker 2: is truly exciting and I think can help address some
17:23
Speaker 2: of the challenges that we're seen with previous versions of
17:26
Speaker 2: that technology. I think the technological advances in the cell
17:30
Speaker 2: therapy space are really exciting, and the opportunities there are
17:34
Speaker 2: great and we're starting to see with this whole molecular
17:38
Speaker 2: glue the opportunities for a new wave of small molecules
17:43
Speaker 2: that can address a lot of the important intracellular targets
17:46
Speaker 2: that have proved difficult in the past. So I think,
17:49
Speaker 2: you know again, and that's together with the AI efforts
17:53
Speaker 2: and the technological advances in diagnostics that have also referred to.
17:58
Speaker 2: So what I see is a huge opportunity to make
18:02
Speaker 2: those change now to the point about it being complicated.
18:07
Speaker 2: I think one advantage that we have at Astroseneca, if
18:10
Speaker 2: you look at our clinical trial portfolio, for example in
18:14
Speaker 2: breast cancer and lung cancer, when we go and we're
18:17
Speaker 2: thinking about doing trials, we can offer to sites a
18:22
Speaker 2: certain scale where you know there are multiple trial opportunities
18:26
Speaker 2: that can address a significant proportion of the patient population
18:29
Speaker 2: that they see coming through their door, and that makes us,
18:33
Speaker 2: I hope, a more attractive partner for those clinical sites
18:37
Speaker 2: and investigators. I also think if we are have access
18:41
Speaker 2: to many of the current standard of care medicines because
18:44
Speaker 2: they have been medicines that we've helped to develop, it
18:47
Speaker 2: helps provide, you know, opportunities for running phase three trials
18:51
Speaker 2: that are a little bit less expensive than when you
18:53
Speaker 2: have to go in because the compared to drug costs
18:58
Speaker 2: in phase three trials or considerable proportion of the total.
19:02
Speaker 2: So I think they will start to be a place
19:04
Speaker 2: where scale matters, and that is something that I think
19:07
Speaker 2: is important. I also think that partnership matters. I mean,
19:10
Speaker 2: one of the reasons why we have been successful in
19:13
Speaker 2: China is because we've been in China for three decades.
19:17
Speaker 2: We have a large R and D capability in China ourselves,
19:21
Speaker 2: and that helps us with the partnership that we've been
19:23
Speaker 2: able to do with a number of the companies within
19:26
Speaker 2: the China ecosystem. So I think you have to have
19:29
Speaker 2: a longer term view, not just a near term return.
19:33
Speaker 2: You have to have a view about how you get
19:34
Speaker 2: to scale, and you have to have a view about
19:37
Speaker 2: the global capability that you need so that you can
19:40
Speaker 2: partner effectively and compete effectively across the.
19:44
Speaker 1: Spectrum you mentioned from molecular clues. I look at your
19:48
Speaker 1: portfolio and I see quite a lot of activity in
19:50
Speaker 1: ADC's by specifics. Glues and all of these degraders aren't
19:56
Speaker 1: necessarily right up there in terms of the number of
19:59
Speaker 1: assets you have. Focus areas is that something that might
20:02
Speaker 1: change going forward.
20:03
Speaker 2: Yeah, So watch the space so you know, it's fascinating.
20:09
Speaker 2: The part of the iceberg that you see is Astrosenica
20:12
Speaker 2: is the bit that's in the clinic and beyond. I
20:15
Speaker 2: have the privilege of seeing the things that are coming
20:17
Speaker 2: through and we're working on, and I will tell you
20:20
Speaker 2: that there's lots of exciting opportunities within the discovery space
20:23
Speaker 2: that you'll see coming through over the next couple of
20:25
Speaker 2: years or so. So absolutely, I think that this is
20:28
Speaker 2: something that we've been looking at. And actually, you know,
20:30
Speaker 2: when you invest in a new technology and new modality
20:33
Speaker 2: if you like, like the radioconjugates, like the ADCs, it
20:36
Speaker 2: really is important that we played to win one of
20:38
Speaker 2: the Astrozenica core value is around this, which means that
20:43
Speaker 2: you're you're not just investing for a couple of years,
20:47
Speaker 2: but you're building a base. You understand the context of
20:50
Speaker 2: you know what it takes to make a great ADC,
20:53
Speaker 2: What are the elements of the system design? What can
20:55
Speaker 2: we continue to learn so that we can improve on
20:57
Speaker 2: that and then plug into the next way the radioconjugates,
21:01
Speaker 2: the same with the cell therapies, the same with the
21:03
Speaker 2: T sell engages and the same with the molecular globes.
21:05
Speaker 2: So we have been working on understanding if you like
21:09
Speaker 2: some of the rule books about you know, what it
21:11
Speaker 2: takes to do this and build that capability across our
21:14
Speaker 2: discovery groups.
21:16
Speaker 1: So we see we've seen quite a lot of deals recently.
21:18
Speaker 1: I think fires did to deal with it was innovant
21:21
Speaker 1: if I'm not wrong, for portfolio of ADCs. Now there's
21:24
Speaker 1: a lot going on in the ADEC world. I think
21:26
Speaker 1: finally people are getting more comfortable with ADEC is not
21:31
Speaker 1: an ADC each one, but it's a combination of three
21:33
Speaker 1: elements they get together and define. So tell us what
21:37
Speaker 1: do you think about the new payloads that people are
21:39
Speaker 1: talking about zest, the small molecules, the graders, double payloads.
21:45
Speaker 1: Where do you think the most promising future is in
21:47
Speaker 1: the next wave of ADCs.
21:49
Speaker 2: So I think, just to step back a second, I
21:52
Speaker 2: think one of the things we need to understand is
21:55
Speaker 2: from the current wave of ADCs, what are the principles
21:58
Speaker 2: where things are working well and therefore what do we
22:00
Speaker 2: need to improve on. So, for example, one of the
22:05
Speaker 2: things we've focused on is understanding the appropriate linker payload
22:11
Speaker 2: balance and technology and this is really important. Just the
22:13
Speaker 2: thing and antibody drug conjuge has three key components. You've
22:16
Speaker 2: got the antibody that's driving to the target, and you've
22:20
Speaker 2: got to choose that target effectively. You've got the linker,
22:23
Speaker 2: and then you've got the payload. And I think it's
22:24
Speaker 2: possible to optimize all three pieces separately and then optimize
22:29
Speaker 2: the system together. So I think it is true to
22:33
Speaker 2: say that you're going to see some dual payload technologies
22:37
Speaker 2: coming through. Actually we have our first version of this
22:39
Speaker 2: already in the clinic, but it's also some novel payloads
22:44
Speaker 2: that will come through as well, and you know, I
22:47
Speaker 2: think we still have to understand and optimize how those
22:49
Speaker 2: might be. Just because it is a small molecule that
22:52
Speaker 2: works doesn't necessarily mean that when it's a small molecule
22:55
Speaker 2: and you put it onto an antibody for a conjugate,
22:57
Speaker 2: you're actually going to improve the therapeutic index. So that's
23:00
Speaker 2: the key question that I think is important to ask
23:03
Speaker 2: an answer and to understand that PKPD element of that
23:07
Speaker 2: really thoroughly. So one opportunity with the degrader technology is
23:12
Speaker 2: can you get the enzymatic activation so that you are
23:17
Speaker 2: leveraging the amount of drug that can be delivered, because
23:20
Speaker 2: you know, compared to just administering if you could an
23:24
Speaker 2: oral version of a degrader putting it onto an antibody,
23:27
Speaker 2: you know, how much are you relatively delivering to the
23:30
Speaker 2: tumor versus what you would give orally and are you
23:34
Speaker 2: really widening the therapeutic index? So it's not just one
23:37
Speaker 2: element of it. I think you have to view it
23:39
Speaker 2: as a system design and understand what are the criteria
23:42
Speaker 2: you're going to use about when you think you've got
23:44
Speaker 2: something that has improved on that system design. So you
23:48
Speaker 2: see a lot of things being done because they're possible
23:52
Speaker 2: to be done, but I think we need to make
23:53
Speaker 2: sure that we're doing those things that make sense because
23:57
Speaker 2: they can deliver that improved therapeutic index, and there's different
24:00
Speaker 2: evidence of that. So I think that's that those are
24:02
Speaker 2: the things that we're thinking about with an Askrosenica.
24:06
Speaker 1: Okay, so if it's okay with you, let's jump to
24:08
Speaker 1: ask go a little bit. So liver cancer is an
24:11
Speaker 1: interesting one. It's one of those areas which fits what
24:13
Speaker 1: we just talked about starting later and then moving earlier.
24:17
Speaker 1: So now we have the Emerald three data. I think
24:20
Speaker 1: I asked a question at the Endless meeting about whether
24:23
Speaker 1: you think you can you can get the dual stride
24:28
Speaker 1: the regime. I'm sure you tell us a little bit
24:29
Speaker 1: about what this is about plus hate approved as it
24:32
Speaker 1: is given that the trial was to two different approaches,
24:37
Speaker 1: with the triple and a double, so that my question
24:40
Speaker 1: of is if OS doesn't reach statistical significance with the triple,
24:44
Speaker 1: can you still file the double, et cetera. So just
24:47
Speaker 1: took us through that first, the progression of your presence
24:50
Speaker 1: in liver cancer, which is significant. You know, you made
24:53
Speaker 1: you made big strike, sorry, big strides. That wasn't that
24:59
Speaker 1: wasn't pretty desire. It just came out. So okay, enough
25:02
Speaker 1: talking yours.
25:03
Speaker 2: Okay, So let me just again this is an example
25:07
Speaker 2: of changing a paradigm in cancer treatment. We've started, first
25:12
Speaker 2: of all by taking the learnings from CTLO four inhibition,
25:17
Speaker 2: you know, and liver cancer is one of those tumors
25:19
Speaker 2: that is sensitive to CTLA four inhibition. The challenge has
25:23
Speaker 2: been with the single CLA four inhibitor antibodies, you know,
25:28
Speaker 2: liking judo is you know, can you get a balance
25:31
Speaker 2: of the toxicity and the efficacy and so what the
25:34
Speaker 2: original STRIDE regimen was was was a single tremuliminum ab
25:38
Speaker 2: high dose which is the st part if you like,
25:40
Speaker 2: of the the acronym stride together with you know, longer
25:45
Speaker 2: duration treatment with the PDE l one infhimsy and put
25:49
Speaker 2: that together into liver cancer and we did that in
25:52
Speaker 2: the advanced liver cancer setting in the Himalaya study. What
25:55
Speaker 2: we've seen is those data have matured is that you
25:58
Speaker 2: really do get this as you describe it, tail on
26:01
Speaker 2: the curve, which is due to this priming effect that
26:05
Speaker 2: you get with the anti cto for antibody, and that
26:08
Speaker 2: has delivered really long term improved efficacy for that tail
26:12
Speaker 2: of the curve and Himalaya with durable overall survival benefit.
26:17
Speaker 2: What we've now done is take that STRIDE regimen, put
26:19
Speaker 2: it together with transarterial chemombolization or TASTE as it's called,
26:24
Speaker 2: into an earlier stage of liver canc those patients that
26:27
Speaker 2: have got lower bulk of disease hasn't spread outside of
26:30
Speaker 2: the liver and are eligible for embolization, which is a
26:34
Speaker 2: commonly used technique. The challenge with embolization, whilst it works well,
26:38
Speaker 2: is that the medium progression free survival is still within
26:42
Speaker 2: six to ten months, so people will progress and then
26:45
Speaker 2: require another embolization episode. So the other drug that is
26:50
Speaker 2: commonly used in the setting is levatine, which is a
26:54
Speaker 2: VEGGEF tarising kind as inhibitor that has been used here
26:57
Speaker 2: and again has shown efficacy, but with an increase in
27:01
Speaker 2: some of the toxicities that were associated. So we had
27:04
Speaker 2: a three arm trial design taste alone, taste plus the
27:07
Speaker 2: Stride regimen, and Taste plus the Stride regimen plus Lenver.
27:11
Speaker 2: So that was the design of the study and what
27:12
Speaker 2: we've seen is the primary end point was combining the
27:15
Speaker 2: Lemver plus Stride plus taste arm with the taste only
27:19
Speaker 2: arm and showed an improvement in progression free survival with
27:22
Speaker 2: the hazard ratio of point seven and a trend to
27:25
Speaker 2: overall survival that has a ratio of point eight four.
27:28
Speaker 2: What we also saw, which was which is very encouraging,
27:31
Speaker 2: is that if you just look at the arm B
27:33
Speaker 2: versus arms C, the Stride plus taste versus taste, we
27:36
Speaker 2: also see an improvement in progression free survival with a
27:38
Speaker 2: hazard ratio of point seventy to one and an os
27:42
Speaker 2: trend with a hazard ratio of point seven. But those
27:46
Speaker 2: numbers that have just quoted, those weren't formally statistically tested
27:49
Speaker 2: because they fall below the OS in the Lemba arm
27:53
Speaker 2: in our multiple testing procedure. So I think it's very
27:57
Speaker 2: encouraging to see these data. You heard the presentation and
28:01
Speaker 2: the discussion at ASCO, and you know, one of the
28:04
Speaker 2: conclusions is much of this benefit is driven just by
28:07
Speaker 2: the STRIDE regimen. However, there is some subtlety on that
28:11
Speaker 2: because there was a subgroup in Japan that seemed to
28:13
Speaker 2: do particularly well on the Lemba plus Stride plus taste
28:18
Speaker 2: and so you might ask, well why is that? And interestingly,
28:22
Speaker 2: the prevalence in Japan of the etiology that drives at
28:25
Speaker 2: HCC has shifted. It's shifted because hepatitis C, which used
28:28
Speaker 2: to be the key driver of majority, is now a
28:30
Speaker 2: curable disease. And it's also shifted because you know that
28:34
Speaker 2: with hepatitis B vaccination there's a reduction in the burden there.
28:37
Speaker 2: So now actually the majority of patients in Japan have
28:40
Speaker 2: non viral etiology, mainly through the metabolic syndrome or you know,
28:45
Speaker 2: alcohol related liver disease. So those two are now driving
28:49
Speaker 2: the majority, and that may be the patient population where
28:52
Speaker 2: there may be a particular benefit from adding LEMBA. So
28:55
Speaker 2: that's the data that we've seen. Your specific question is
28:58
Speaker 2: given that we don't yet have overall survival in the
29:02
Speaker 2: primary comparison of a versus see what's the regulatory position,
29:05
Speaker 2: and I think what what you would expect to see
29:08
Speaker 2: is that, Look, the contribution of components is going to
29:10
Speaker 2: be important. Overall survival is also important. You know, we'll
29:14
Speaker 2: have ongoing dialogue with regulatory authorities around the world, but
29:17
Speaker 2: I would expect that there will be an expectation and
29:20
Speaker 2: an update for overall survival to see if that trend
29:23
Speaker 2: that we've currently got is continued. Now, based on what
29:26
Speaker 2: we saw with the Himalaya data, we're optimistic that with
29:29
Speaker 2: long a time, we will continue to see a benefit
29:31
Speaker 2: based on that stride regimen that will improve over time. So,
29:35
Speaker 2: you know, I think the again, the dialogue with regulatory
29:38
Speaker 2: authorities will be ongoing around that, and we need to
29:41
Speaker 2: wait and see what the feedback will be. But I'm
29:44
Speaker 2: optimistic that this is a regimen that people see to
29:48
Speaker 2: be important. And what you heard as well from dr
29:51
Speaker 2: Abbert Alpha at the News asked the specific question is
29:54
Speaker 2: from his perspective, it's something that since the Stride regiment
29:58
Speaker 2: is already available in the US, some people will choose
30:01
Speaker 2: to use. You know, obviously that isn't the same as
30:04
Speaker 2: being available following a regulatory approval. I just want to
30:08
Speaker 2: be clear on that. But I think what people are
30:11
Speaker 2: seeing is that the Stride regiment is the key driver
30:15
Speaker 2: of efficacy in this.
30:17
Speaker 1: In this setting, Okay, I'm going to give you you
30:19
Speaker 1: don't have astros because R and D budget anymore. You
30:22
Speaker 1: have to make a choice just between these two. Just
30:26
Speaker 1: just let's play this game to do a trial of
30:28
Speaker 1: a PD ONEF by a specific plus in judo in
30:32
Speaker 1: this setting right plus taste or for Rostomik plus Lenva
30:36
Speaker 1: plus taste or neither.
30:40
Speaker 2: Well, I think one of the things we've got to
30:41
Speaker 2: do is especially digest that. I mean, we do have
30:45
Speaker 2: a phase two platform study ongoing in in China called
30:49
Speaker 2: the Gemini Study, and we've published some data actually for
30:53
Speaker 2: real the customer from the habitabilitary part of that study,
30:57
Speaker 2: the Gemini Study at this ASCO, so we are testing
31:01
Speaker 2: for US to MEG and Jeff based regimen within that
31:05
Speaker 2: Gemini Phase two study. We've also clearly tested RELDEGOSTOMIG and
31:10
Speaker 2: a ve JEFF based regimen in that study as well.
31:14
Speaker 2: So the ideal next step based on the Emerald three
31:17
Speaker 2: data and the decisions around that will be based on
31:21
Speaker 2: the you know, what we see in the Phase two
31:23
Speaker 2: and which patient populations we think are particularly suitable for
31:26
Speaker 2: one versus the other. I think there's always a balance
31:29
Speaker 2: of the efficas you can possibly achieve with the overall
31:32
Speaker 2: tolerability balance. And again, if you look at the the
31:35
Speaker 2: Lemba arm from the Emerald three that was published, you
31:39
Speaker 2: can see that, you know, there's some initial crossing of
31:42
Speaker 2: the survival curve, and I think there's undoubtedly a higher
31:46
Speaker 2: toxicity burden that's associated with that. So in an ideal world,
31:49
Speaker 2: if we can get to the level of efficacy that
31:52
Speaker 2: we want to see without having the added toxicity, that's
31:55
Speaker 2: what we're aiming at. And so I'm not doing it
31:57
Speaker 2: directly answer your Actually what I was, I be based
32:00
Speaker 2: on Phase two and with that goal of I think
32:03
Speaker 2: it is showing that this potential to improve the efficacy,
32:06
Speaker 2: but you're going to be able to do it without
32:07
Speaker 2: the added burden of the ToxS.
32:08
Speaker 1: I'm going to use AI to see whether it can
32:10
Speaker 1: di sake something you said in there to take some
32:12
Speaker 1: Now I want, okay, let's talk about breast cancer if
32:15
Speaker 1: you go as well. No doubt breast cancer is an
32:19
Speaker 1: area that as Desak has been in for the breast
32:22
Speaker 1: cancer for a long time, right, and you've got this
32:26
Speaker 1: new approach that you're trying and others are trying, which
32:28
Speaker 1: is the oral surds. Now, we did see some data
32:33
Speaker 1: from a competitor. I'm not going to ask you to
32:34
Speaker 1: comment on that data obviously for the obvious reasons yesterday
32:39
Speaker 1: from Russia's trial called Persevera. Having had some time to
32:42
Speaker 1: digest that data, do you think this affects the probability
32:46
Speaker 1: of success of fair enough for in any direction? And
32:49
Speaker 1: if you don't want to comment, I'm happy to move
32:50
Speaker 1: on to the next question.
32:52
Speaker 2: Well, I mean, I do want to take the opportunity
32:54
Speaker 2: to talk a little bit about the Serena sex study,
32:56
Speaker 2: because again I think this is about this is a
32:58
Speaker 2: paradigm changing study, and you know, we just want to
33:02
Speaker 2: acknowledge that this continues to be debate about this switch
33:06
Speaker 2: strategy on the basis of this, so you know, when
33:10
Speaker 2: you change paradigms, not everybody agrees to start with. That's
33:14
Speaker 2: been my experience, and I think it is still important
33:16
Speaker 2: to have the debate though. So what we're trying to
33:20
Speaker 2: do here is identify at the earliest possible opportunity the
33:25
Speaker 2: emergence of a sign that the patient's tumor has got
33:30
Speaker 2: a resistant clone that is emerging, that will grow, and
33:33
Speaker 2: that will lead to progression. And I think what we've
33:35
Speaker 2: seen is that when you at that earliest point when
33:39
Speaker 2: you can detect the emergence of the es R one
33:42
Speaker 2: mutation in circulating tumor DNA, if you then switch, we
33:46
Speaker 2: showed that that improved the progression free survival. We also
33:48
Speaker 2: showed the presentation yesterday that that improves the that what's
33:53
Speaker 2: called the PFS two and point the time to the
33:57
Speaker 2: second progression. It also delayed the times of deterioration in
34:01
Speaker 2: quality of life, importantly, because when many of these women progress,
34:05
Speaker 2: they progress with bone metastities that are painful, and a
34:08
Speaker 2: lot of that improvement was associated with that delay in
34:11
Speaker 2: onset of pain, but also shortness of breath and some
34:13
Speaker 2: other quality of life endpoints which are really quite important.
34:17
Speaker 2: In addition, what we showed is that when you switch
34:20
Speaker 2: to chemisestrant, you can clear completely the total CDDNA, not
34:24
Speaker 2: just the ESR one mutant, but the total ctDNA in
34:27
Speaker 2: the majority of patients on the chemisestrant arm, whereas on
34:31
Speaker 2: the control arm you continue to see elevation of the
34:34
Speaker 2: total ctDNA, which is a kind of measure of the
34:36
Speaker 2: tumor burden. So it's clear you're having direct anti tumor
34:40
Speaker 2: efficacy during the period following that emergence of ctDNA and
34:44
Speaker 2: before actual clinical progression. And I think that's an important point.
34:49
Speaker 2: So the question is what does that mean in terms
34:52
Speaker 2: of the clinical relevance of that switch strategy. If you
34:56
Speaker 2: look at the efficacy that we're seen with chemisestrin in
34:59
Speaker 2: this setting, compare it with the efficacy that's been seen
35:02
Speaker 2: when you dose with an oral third in the second
35:04
Speaker 2: line setting after a clinical progression. The improvement of PFS
35:08
Speaker 2: was seven and a half months in serena six. The
35:10
Speaker 2: improvement in PFS in the second line setting it has
35:13
Speaker 2: been seen, including in serena two, is typically much shorter,
35:17
Speaker 2: two to three months across the range of pieces. And
35:20
Speaker 2: you know, I think this, you know, it just reinforces
35:23
Speaker 2: the basic principle that treating as an earlier points of
35:26
Speaker 2: the disease is likely to be more efficacious than treating
35:29
Speaker 2: at a later point if you wait to that clinical
35:32
Speaker 2: progression point. At that point, you've had more tumor doublings,
35:36
Speaker 2: you've got more time for the genomic instability to generate
35:40
Speaker 2: more diversity of resistance mechanisms, and you're less likely to
35:43
Speaker 2: be a suitable for a single agent oral SERD and
35:47
Speaker 2: be likely to respond to that. And that is clearly
35:50
Speaker 2: seen in the totality of the data there. So you know,
35:53
Speaker 2: the skeptics are still saying, okay, but you haven't shown
35:56
Speaker 2: the overall survival of the switch strategy. What we have
35:59
Speaker 2: shown is that the overall survival in the camerasistant SORE
36:03
Speaker 2: in a sixth study showed no detriment with a hazard
36:06
Speaker 2: ratio point eighty seven. And you've seen these series of
36:08
Speaker 2: endpoints pfs PFS two, quality of life time to first
36:13
Speaker 2: subsequent treatment, time, second subsequent treatment, and ctDNA clearance with
36:18
Speaker 2: an associated trend to overall survival. So I think when
36:21
Speaker 2: you put the totality of that together from our perspective, obviously,
36:25
Speaker 2: we think that is indicative of the probability of that
36:28
Speaker 2: long term survival benefit. And you know, first time necessitic
36:33
Speaker 2: breast cancer has been already established and accepted as a
36:37
Speaker 2: place where waiting for overall survival you're waiting too long.
36:40
Speaker 2: Actually in this hormone receptive positive breast cancer setting the
36:45
Speaker 2: median overall survival expectation. The good news is that it
36:48
Speaker 2: is longer than five years. Bad news is if you
36:51
Speaker 2: have to wait for that in order to introduce a
36:52
Speaker 2: new drug, you know, the pace of innovation in that
36:55
Speaker 2: space is going to slow down, not accelerate, and that
36:58
Speaker 2: would be a step backward in my view for for
37:02
Speaker 2: breast cancer. And I think the final point is that
37:05
Speaker 2: it's really important in terms of the collaboration that we
37:09
Speaker 2: that we have with investigators and with regulatory authorities that
37:13
Speaker 2: this consistency in approach, right. You know, I'll just remind
37:17
Speaker 2: you that we had agreed the end points for Serena
37:19
Speaker 2: six with the FDA. We got breaks through therapy designation
37:23
Speaker 2: when we got the initial results through. That's really important
37:27
Speaker 2: in terms of planning and making investment decisions that we
37:30
Speaker 2: can rely on the guidance that we're getting as being
37:33
Speaker 2: consistent when the when the trials then subsequently read out
37:36
Speaker 2: so I think there are various principles that are involved
37:38
Speaker 2: in the in the in the debate here that are
37:40
Speaker 2: really important for people to understand.
37:42
Speaker 1: Okay, thank you for that. And then if you wanted
37:44
Speaker 1: to go earlier again on the same theme with CAMI,
37:47
Speaker 1: do you think the side effect profile warrants or is
37:50
Speaker 1: good enough to go earlier.
37:52
Speaker 2: Yeah, the side effact profile that we've seen with cameras
37:54
Speaker 2: Estron is really very encouraging. Actually, if you look at
37:57
Speaker 2: the Serena six data and you compare across all the
38:02
Speaker 2: cross trial comparison caveats warning here, you know, you've actually
38:07
Speaker 2: got really good discontinuation rates, very low, very similar to what'
38:10
Speaker 2: seen with the rometoes inhibitom, the direct randomize comparison that
38:14
Speaker 2: we had within Serena six, And in terms of cross
38:17
Speaker 2: trial comparisons, we've also got a low rate of GI
38:20
Speaker 2: side effects, these niggerly side effects that can often cause
38:23
Speaker 2: patients to not want to continue. In the adjuvant setting,
38:27
Speaker 2: we've got, you know, again the maintenance of improvement of
38:31
Speaker 2: quality of life, and we've treated over ten thousand patients
38:34
Speaker 2: now on the Cameossterron program with these two large adjuvant
38:37
Speaker 2: studies that we've got. The safety profile that we're seeing
38:40
Speaker 2: across all of that is excellent. In the specific you know,
38:44
Speaker 2: cardiac safety that was raised. We don't have a QTc
38:48
Speaker 2: direct effect from cames esterant. We do have a body
38:53
Speaker 2: cardia effect. This is a class effect. It's seen across
38:55
Speaker 2: It's seen in the Juridesterent data sets as well as
38:57
Speaker 2: the Camesstern data sets. Me it's seven percent of the
39:00
Speaker 2: of the patients that have an AA associated with with
39:04
Speaker 2: brady cardia. So overall, the safety profile is extremely good
39:08
Speaker 2: and well managed.
39:08
Speaker 1: Okay, Now, Susan, I'm going to jump to the day
39:11
Speaker 1: after tomorrow, sure, or maybe two days after tomorrow. I
39:14
Speaker 1: don't know how you would classify these various drugs. I'm
39:16
Speaker 1: talking about the phrase that you guys use today, tomorrow,
39:20
Speaker 1: et cetera. So, pancreatic cancer. You have a pan care
39:24
Speaker 1: as that you've licensed in from a Chinese biotech company
39:27
Speaker 1: called Jacobio JAB twenty three E seventy three. Wonderful name
39:33
Speaker 1: and so, and I want to roll two other questions
39:36
Speaker 1: in here. We've seen, you know, the standing ovation of
39:39
Speaker 1: this year was for diraxon racib in second line pancreatic cancer.
39:43
Speaker 1: Overall survival benefit almost doubled for a company called Revolution Medicines.
39:48
Speaker 1: So that company is one of the few biotexs that's
39:51
Speaker 1: really well funded, and they have a whole host of
39:53
Speaker 1: other molecules that are in development. Talk to us about
39:56
Speaker 1: where you think pancreatic cancer will be in five years
39:59
Speaker 1: or however, how long you want to go. You have
40:01
Speaker 1: a claudin eighteen point two. You have a P fifty
40:03
Speaker 1: three approach that's quite interesting, especially in the context of
40:07
Speaker 1: RAZ and RAS resistance, et cetera. And you have your
40:10
Speaker 1: RAS rock. Tell us how you feel, at least on
40:13
Speaker 1: the pancreatic side, what the market would look like in
40:17
Speaker 1: your view in five year star.
40:19
Speaker 2: Okay, well, let me just first of all acknowledge and
40:21
Speaker 2: congratulate the team that's involved in the you know, the
40:25
Speaker 2: breakthrough that we've seen at OSCO. It is truly exciting
40:29
Speaker 2: to see that kind of breaks through for this kind
40:31
Speaker 2: of disease where it's been so hard to see progress
40:33
Speaker 2: over the last few decades. And I think what it does,
40:36
Speaker 2: it's kind of like a starting point. It kind of
40:38
Speaker 2: opens the door on the opportunity for really transforming this
40:42
Speaker 2: particular disease, And I have to say that, you know,
40:45
Speaker 2: whenever I sit in one of the ASCO planary sessions
40:48
Speaker 2: and I look at KAPLA myercoves, I always think about
40:50
Speaker 2: some of the individual patients that are on those curves
40:54
Speaker 2: or on another trial. And my own uncle fortunately died
40:58
Speaker 2: of pancreatic answer a couple of years ago.
41:01
Speaker 1: Sorry to hear that.
41:02
Speaker 2: And it's you know, you just look and think it was,
41:05
Speaker 2: you know, just a little bit too late. What else
41:08
Speaker 2: can we do for the patients for whom we don't
41:10
Speaker 2: want to be too late? So I am excited about
41:13
Speaker 2: the overall prospects in the RAS field, and I'm excited
41:16
Speaker 2: that we can further improve on the current profile of
41:19
Speaker 2: pan RAS inhibitors. And that's why we're invested in the
41:22
Speaker 2: pan k ras because by not hitting n RAS and
41:26
Speaker 2: h RS, I think there's an opportunity to have a
41:29
Speaker 2: wider therapeutic index. But perhaps you know, similar levels of
41:32
Speaker 2: efficacy with lower rates of RASH and GI side effects,
41:37
Speaker 2: and also better combinability, because what you're currently seeing is
41:41
Speaker 2: it's probably not possible to combine with the current standard
41:44
Speaker 2: care chemotherapy at the normal doses, and that it requires
41:48
Speaker 2: modification of the of the doses, of the of the
41:51
Speaker 2: pan RAS and the chemo component. So if you're going
41:55
Speaker 2: to get really effective combinations into the first line, having
41:59
Speaker 2: something that's a better combinable profile, I think is going
42:03
Speaker 2: to be important. So I also think that it's not
42:06
Speaker 2: going to be just about RAS. I think RAS is
42:09
Speaker 2: going to be a key backbone, but you're actually going
42:11
Speaker 2: to need these combinations in order to really advance the
42:15
Speaker 2: disease in the oly stage setting. So we're excited about
42:18
Speaker 2: our Chlordin eighteen point two antibody drug conjugate sunny V
42:22
Speaker 2: as we call it, which is coordin eighteen point two
42:25
Speaker 2: with an MME based payload. We've obviously started important phase
42:30
Speaker 2: three trials in the gastric cancer setting, which is also
42:32
Speaker 2: a tumor type that has a high level of chlordin
42:34
Speaker 2: eighteen point two expression. We had the Claritic gastric one,
42:39
Speaker 2: which is monotherapy sonny V versus standard of care chemotherapy
42:43
Speaker 2: in the later line setting, but we've also started Clarity
42:47
Speaker 2: gastric two in combination with IO in the first line setting,
42:51
Speaker 2: and we've seen some really encouraging not just the original
42:55
Speaker 2: the overall response rate, but the durability of efficacy, particularly
42:59
Speaker 2: in combination, which we're excited about there. So I think
43:02
Speaker 2: this asset is also setting activity in pancreatic cancer, and
43:06
Speaker 2: it's something that would be interested in looking at combinations
43:09
Speaker 2: with in that setting. The other drug AD draw your
43:13
Speaker 2: attention to is we have a peer empty five inhibitor
43:17
Speaker 2: is AD four to three seven zero, which we presented
43:20
Speaker 2: some data on in the Primavera study. This is in
43:23
Speaker 2: a different setting now in Hodgkins disease, and I only
43:27
Speaker 2: draw attention to that because I think it gives proof
43:29
Speaker 2: of principle that this is a good peer empty five inhibitor.
43:32
Speaker 2: In the Hodgkins disease setting, we actually achieved really good
43:36
Speaker 2: complete response rates at the high stote of six hundred milligrams.
43:39
Speaker 2: The complete response rate was forty four percent and the
43:42
Speaker 2: overall response rates was around eighty percent, which I think
43:45
Speaker 2: is impressive in that disease. In that disease, you've got
43:49
Speaker 2: an epigenetic change which causes loss of the empty up
43:53
Speaker 2: protein and about eighty percent of those cancers which is
43:55
Speaker 2: why it's particularly sensitive to this mechanism. But we also
43:59
Speaker 2: have MP TAP deletion genomically in about a quarter of
44:04
Speaker 2: pancreatic cancers. So I think this is going to be
44:06
Speaker 2: an important opportunity for combination with the RAS inhibitors in
44:11
Speaker 2: that subgroup of pancreatic cancer that has that sometimes. So
44:14
Speaker 2: that's another combination that I think will be important. And
44:18
Speaker 2: so we're excited about the portfolio that we can bring.
44:21
Speaker 2: You know, a pan ka ast chlaudin eighteen point two antibody,
44:25
Speaker 2: a peer empty five inhibitor, you know, and there are
44:28
Speaker 2: other drugs that we've got in an earlier stage that
44:30
Speaker 2: may also be of interest in this disease. So you
44:33
Speaker 2: start to see the opportunity to build what I call
44:36
Speaker 2: the transformative regimens of the future for this disease.
44:40
Speaker 1: So we are with you and all your wonderful explanation
44:43
Speaker 1: about the next generation of peer at five inhibitors. So
44:47
Speaker 1: looking very much forward to that. You actually mentioned Hodgkins.
44:51
Speaker 1: Let me just move to sort of atomic very quick question.
44:55
Speaker 1: So in one area of non Hodgkins, do you see
44:58
Speaker 1: ser of atomic making the impact.
45:01
Speaker 2: Oh, we're excited about this asset, so thanks for raising it.
45:04
Speaker 2: Just as a reminder, it's this is a CD nineteen
45:07
Speaker 2: CD three bispecific T cell engager with a modified CD
45:11
Speaker 2: three effinity, and we think that first of all, CD
45:14
Speaker 2: nineteen can be a better target than the CD twenty
45:18
Speaker 2: by specifics because it is expressed in a broader range
45:22
Speaker 2: of the B cell lineage, and you still see it's
45:25
Speaker 2: expressed even when you've got some CD twenty loss, for example,
45:28
Speaker 2: after a prior car T or T cell engager. So
45:31
Speaker 2: I think that's that's important now in terms of the
45:34
Speaker 2: data that we have seen and we have shared, and
45:36
Speaker 2: we shared quite a lot of data at the ASCO
45:38
Speaker 2: meeting as cheer, and we'll have some more data coming
45:40
Speaker 2: out at the EHAR meeting which is coming up in
45:43
Speaker 2: the next week or so. We've seen activity in relapsed
45:46
Speaker 2: refractory forllicular lymphoma, in acute lymp for plastic leukemia, and
45:52
Speaker 2: in diffuse large B cell lymphoma. So all of the
45:56
Speaker 2: B cell driven malignances are basically a place where I
46:00
Speaker 2: think the servetomy can have activity. And what we're seeing
46:03
Speaker 2: is with this modified CD three affinity and together with
46:07
Speaker 2: the step up regimen that we've got very low rates
46:10
Speaker 2: of saturcan release syndrome and icons compared to what we
46:13
Speaker 2: would expect to see from some others. And that's enabling
46:16
Speaker 2: us to deliver levels of efficacy that are really encouraging
46:19
Speaker 2: with high cr rates across those diseases. Actually, when we
46:23
Speaker 2: look at it in the follicular and FOMA setting, I
46:27
Speaker 2: think we can achieve efficacy that is comparable with some
46:30
Speaker 2: of the cartes, similarly in DLBCL for instance. So I think,
46:38
Speaker 2: you know, obviously what people are wanting to see is
46:40
Speaker 2: the durability of those of efficacy, and so you know
46:44
Speaker 2: that will come naturally with time. But we're very encouraged
46:48
Speaker 2: with the profile that we've seen so far.
46:50
Speaker 1: We receive very good durability with these city three engages
46:53
Speaker 1: in my loma. So I don't know if it's exactly
46:55
Speaker 1: the same, but I don't see why there should be
46:59
Speaker 1: an issue with there's but we'll see. And then talking
47:01
Speaker 1: about buy specific borostomic obviously you had some data and
47:05
Speaker 1: I'm going to make a statement and you tell me
47:07
Speaker 1: why I'm wrong. The vorosomic first line data in the
47:11
Speaker 1: evolved two sub study two versus Jim Pearley was presented,
47:16
Speaker 1: which was presented at ASCO. Given both of enrolled what
47:20
Speaker 1: seems to ours and they're similarly designed people locally advanced
47:24
Speaker 1: trials where would I be looking for a deferentiation in
47:28
Speaker 1: terms of the outcome of vorosomic versus jimp earle and
47:34
Speaker 1: what would favor the BISPEC over what probably will be
47:37
Speaker 1: cheaper pd ones in the not so distant future.
47:40
Speaker 2: Yeah, So I think for me, I think you need
47:42
Speaker 2: to put the totality of data that we've got with
47:43
Speaker 2: Ubusto MAK together to really understand the differentiation. So the
47:47
Speaker 2: first thing I would say is that compared with PD
47:50
Speaker 2: one PDL one agents, I think CTLA four can really
47:54
Speaker 2: add benefit at the lower end of the PDO one
47:56
Speaker 2: expression range. So we have the evolved along O two
48:00
Speaker 2: phase three study ongoing in the PDL one less than
48:03
Speaker 2: fifty percent, with the primary end points in the PDL
48:06
Speaker 2: one less than one percent. For that study, it's focused
48:09
Speaker 2: on where that's the segment of lung cancer where we
48:12
Speaker 2: already know that the PD one PDL ones aren't working
48:15
Speaker 2: as well. They don't really add a huge amount of
48:17
Speaker 2: benefit over chemotherapy alone in that particular less than one
48:21
Speaker 2: percent subgroup. And we've seen that already with the POSEIDON data.
48:25
Speaker 2: That gives us further confidence that that's not just an
48:28
Speaker 2: observation here. With this this Wanderer Similarly, I think there
48:33
Speaker 2: are other CLA force sensitive diseases where you can have
48:37
Speaker 2: the differentiation. So are other Phase three trials are ongoing
48:41
Speaker 2: in mesothelioma and cervical cancer, and then we also have
48:45
Speaker 2: a head leg tumer Phase three that is ongoing. So
48:50
Speaker 2: when you look at the totality of that, really it's
48:52
Speaker 2: around the durability of response. And this is one of
48:55
Speaker 2: the challenging things to see from early phase two data
48:57
Speaker 2: sets because what you're typically looking at is a waterfall
49:00
Speaker 2: plot with a response rate. That isn't the place where
49:03
Speaker 2: you're going to typically see the added benefit of a
49:06
Speaker 2: CLO for as I've said with the Himalaya data, you
49:10
Speaker 2: see it on the tail of the curve and that
49:12
Speaker 2: raised up. So you really need some landmark analyses to
49:16
Speaker 2: really see the differentiation. And that's what we tried to
49:19
Speaker 2: build over the time period where we've been examining old
49:22
Speaker 2: Rustomik in the phase two studies is understand that both
49:26
Speaker 2: the durability of response and if you look at the
49:29
Speaker 2: poster that we had in the head and neck, there
49:31
Speaker 2: were some patients that had really good durability of response.
49:34
Speaker 2: It is a subset that's always been the case with
49:36
Speaker 2: the CTO for programs, but I think there really is
49:40
Speaker 2: evidence that you can that you can see that, particularly
49:43
Speaker 2: when you look across the totality of the program.
49:45
Speaker 1: So I've got two more drugs to talk about, but
49:47
Speaker 1: let me just get this one. Is this the year
49:50
Speaker 1: we get phase three dator from Bogostomik over rostlingk Remind me,
49:54
Speaker 1: I don't remember what they think.
49:56
Speaker 2: We have said twenty seven and beyond.
49:58
Speaker 1: I think okay, So next year, I hope I'm still
50:02
Speaker 1: here when you get the data carti, is it the
50:09
Speaker 1: one twenty and is it the three or five? To
50:12
Speaker 1: help us understand how do you think they fit into
50:14
Speaker 1: the current miloma space? If that is just thinking about
50:19
Speaker 1: the cancer side, right, and what are you thinking about
50:23
Speaker 1: in vivo data? That's speaking to build which had a
50:26
Speaker 1: lily with some envva data that evolved quite nicely. Maybe
50:29
Speaker 1: one patient relapse but in your and maybe they were
50:33
Speaker 1: EMD patients or something particularly sick. And then you had
50:36
Speaker 1: just recently from Legend just reported some data on a
50:40
Speaker 1: C the nineteen CARTI in vivo for another indication. So
50:46
Speaker 1: just put those two things in perspective for release.
50:49
Speaker 2: Okay, So again just to put it into context. I
50:52
Speaker 2: think we've got the today, tomorrow and the day after
50:55
Speaker 2: tomorrow in the category that so autologous cartes are today
51:00
Speaker 2: right their technology that we currently have and has been
51:03
Speaker 2: shown to work across multiple different hematologic lignancies. What we
51:09
Speaker 2: have with A one two is a duel car which
51:12
Speaker 2: has got two targets CD nineteen and BCMA that's going
51:16
Speaker 2: into multiple myeloma. And the data that we presented at
51:20
Speaker 2: ASH last year is in both relapsed, refractory and multiple myeloma,
51:25
Speaker 2: but also from an investigative initiated study in China that
51:28
Speaker 2: our colleagues at Gray Cell ran in high risk newly
51:32
Speaker 2: diagnosed multiple myeloma. And what we saw there is, first
51:37
Speaker 2: of all, the things that I think are really competitive
51:39
Speaker 2: in terms of the complete response rate and the MRD
51:42
Speaker 2: negativity rate in that in those settings, particularly in the
51:46
Speaker 2: newly diagnosed multiple myeloma setting, and you're seeing those rates
51:52
Speaker 2: in a patient population for whom the current standard of
51:54
Speaker 2: care is a quadruple treats progression, and I think those rates,
52:00
Speaker 2: admittedly in smaller patient number samples, really compete well. I
52:05
Speaker 2: think with the outcomes that you would expect from a
52:08
Speaker 2: quad regiment. So just imagine if that's deliverable at scale
52:12
Speaker 2: for a patient, you have a potential once and done
52:14
Speaker 2: regimen and then you know, no treatment versus continued quadruple
52:20
Speaker 2: therapy with the associated adverse events that will continue for months,
52:25
Speaker 2: if not years, many years in the case of myeloma.
52:28
Speaker 2: Because we've been you know, the industry has been very
52:31
Speaker 2: successful and improving the benchmarks in that setting. So I
52:35
Speaker 2: think that's a really exciting, exciting profile, and I think
52:37
Speaker 2: the two targets makes a difference. I also think the
52:41
Speaker 2: manufacturing process using our fastcar also makes it makes a difference.
52:45
Speaker 2: And the good news about the profile that we've seen
52:47
Speaker 2: is we don't have any of the parkatanism that's been
52:50
Speaker 2: associated with at least one of the myelama directed cell therapies.
52:55
Speaker 2: That's really important, particularly when you're talking about that newly
52:57
Speaker 2: diagnosed patient population moving forward at pace with that program
53:02
Speaker 2: that is today and we'll deliver that, But we're also
53:05
Speaker 2: looking for how can we further scale cell therapy. So
53:09
Speaker 2: first of all, how do we scale autologous into solid tumors.
53:13
Speaker 2: And we're excited by the data that we've got with
53:15
Speaker 2: our GPC three car t that's autologous with the TGF
53:18
Speaker 2: beta dominant negative armoring that's AZD seven zero zero three.
53:22
Speaker 2: Where we have looked at those data, we're getting a
53:25
Speaker 2: roughly fifty percent response rate with good durability in late
53:29
Speaker 2: line hybertocellular cancer. So I think that's an exciting prospect.
53:32
Speaker 2: But scaling beyond just solid tumors in you know, with
53:37
Speaker 2: a single asset, and thinking about what we might do
53:40
Speaker 2: to enhance the patient population that can access this transformative technology.
53:45
Speaker 2: And to do that you need something that's more off
53:46
Speaker 2: the shelf. And there's two ways that we're addressing that. One,
53:50
Speaker 2: we have off the shelf technology that's called a universal
53:53
Speaker 2: effect to cell. We're just about to move into clinical
53:56
Speaker 2: trials with with that program. I think that's an exciting opportunity.
54:00
Speaker 2: And the second is through the ESO bi Tech acquisition
54:03
Speaker 2: that we've done, is that we have the opportunity for
54:07
Speaker 2: the in vivo. Now, the question really is can you
54:10
Speaker 2: recapitulate the efficacy data that we've seen with autologous cars
54:14
Speaker 2: and the safety profile that we've seen with autologous cars
54:17
Speaker 2: with in vivo, how can we improve on it. I
54:20
Speaker 2: think it's the early days yet of seeing the data emerge.
54:23
Speaker 2: But it is exciting, you know, when you think about
54:26
Speaker 2: the ultimate utility of cell therapy. Though for some settings
54:31
Speaker 2: like solid tumors, you are going to need the armoring
54:33
Speaker 2: to help overcome the immunosuppressive micro environment, and you might
54:37
Speaker 2: need more than one armoring technology in order to optimize that,
54:40
Speaker 2: and more than one the ability to fit all of
54:44
Speaker 2: that into an anteriviral vector or into an LMP. That
54:49
Speaker 2: will be one part of understanding whether off the shelf
54:53
Speaker 2: technologies that are based on alerghenetic or universal effect of
54:56
Speaker 2: cell base or the in vivo will be the most
55:00
Speaker 2: suitable way to go forward. So we are testing both
55:04
Speaker 2: of these with the with the you know, ambition to
55:08
Speaker 2: really scale and be a leader in the cell therapy
55:10
Speaker 2: space across both hematology and solid tudness.
55:12
Speaker 1: Susan, we've run out of time. I'm just going to
55:15
Speaker 1: put this question see as fast as we can answer it.
55:18
Speaker 1: Alpha emitting radio like and therapy. It's a new area
55:21
Speaker 1: of getting into prostate cancer. But you were one of
55:23
Speaker 1: the first to present data, one of the earliest movers
55:26
Speaker 1: AhR twenty four when we saw some data, and then
55:30
Speaker 1: of course a whole lot of other companies have got
55:31
Speaker 1: into this. Do you think you've kept that lead and
55:35
Speaker 1: when would we expect the next meeting for reader.
55:38
Speaker 2: Well, I'm delighted to say, first of all, we've got
55:40
Speaker 2: a name for our lead activity and based PSM A
55:44
Speaker 2: targeting and radioconjuga. It's called Zadago. And the second thing
55:50
Speaker 2: I would say is we have started our Phase three
55:52
Speaker 2: with this asset, so there was there was some data
55:55
Speaker 2: that were presented at ASCO for other alpha based agents
55:59
Speaker 2: TI getting prostate cancer. We're confident about the profile that
56:02
Speaker 2: we've got and post ASCAR, I think we're happy with
56:05
Speaker 2: where we're heading. We will share more data in the
56:08
Speaker 2: probably the next year or so on the profile that
56:12
Speaker 2: we have seen from the phase two expansion. But absolutely
56:15
Speaker 2: this is a place that we're committed to and I
56:16
Speaker 2: think we are aiming to be a really key player
56:19
Speaker 2: in the ready conjugate space. To watch this space.
56:22
Speaker 1: Brilliant one hour? How is it possible that it passes
56:25
Speaker 1: that fast? This is san Fazeli from the Angles of
56:28
Speaker 1: Healthcare podcast with Susan Cold Breath, which is always an
56:32
Speaker 1: amazing pleasure to spend time with you, So thank you
56:35
Speaker 1: for sparing the hour that you have and helping us
56:39
Speaker 1: enlighten us here. You know, we're very, very excited by
56:41
Speaker 1: the prospects of astro's growth profile and all these drugs
56:44
Speaker 1: that we've talked about. So thank you Susan for taking
56:47
Speaker 1: the time, and I'll look forward to seeing you at
56:50
Speaker 1: I don't know WCLC or ESMO or maybe ASH we'll
56:55
Speaker 1: see or maybe all of them all right, maybe all
56:57
Speaker 1: of them.
56:59
Speaker 2: Take care USUS uses
57:39
Speaker 1: MUSS bases