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- [00:00]
A
You're listening to Biotech Hangout, a live and unedited weekly discussion of the latest news in our industry with a group of biotech leaders and experts. I'm Jeroen Werber along with my co hosts today, Tess Cameron, Sam Facelli and Brian Scorney. For more information about our guests and speakers and to listen to the most recent episodes, please go to biotechhangout.com so Sam, as you were just saying, we're coming off of Asco, which you know, ASCO is always, even when you think is not going to be super busy, inevitably turns into a very busy meeting. There was really a lot to discuss. There's a lot of fireworks. So we'll, we'll get to it in a second. But maybe first, what's going on in biotech? AI is hot and biotech almost by derivative is not. We're all seeing on our screens the upcoming SpaceX IPO at a 1.8 trillion valuation, about 25% looks like of the stock is going to go to retail. And so the question is, is that going to lead to sort of a market sell off or is this going to lead to sort of more momentum at that kind of valuation? Well, let's look at some of the parameters. So we kind of pulled it earlier today and this is kind of staggering numbers year to date, the NASDAQ is up 13% to stand that theme, the QS, the QQQ are up 18 and SMH, which we all know is a semiconductor index. Shaking my head, SMH is up 66% S&P as I mentioned or I haven't mentioned, is up 10. How is biotech doing? Large cap biotech where the IBB is up 1, XBI is up 8. And then if we just look at the last month, XPI is down 4, Nasdaq is down 2, Q's are down 2 and SMH is flat. So it looks like we're definitely seeing a little bit of migration. So maybe, Tess, do you want to maybe kick us off? Is biotech not hot because AI is hot or what's going on out there?
- [02:16]
B
Well, yeah, it's a really good question. I mean I think we have to remember the huge Q4 run up that we had in biotech, right, which was a lot of recovery after really being beaten down earlier in 2025. So I think that's, I think that's kind of important to remember. It's like, yeah, things don't look so great if we look at things on a year to date basis, certainly not on a Month to date basis. But gee, when we look at like a year, right, like past 12 months, it's like, well, that performance has actually been very strong, you know, driven by, you know, market recovery and a lot of the M and A that we've seen. Right. So I think that's, that's important to kind of keep that, you know, to keep that longer view in context. And you know, it's hard not to wonder if, you know, some of that is just coming from you know, demand for some of these, you know, big, you know, big AI companies and you know, also I think uncertainty around rates. Right. And wondering, you know, wondering if we're actually going to be in like a, you know, more of like a rate, you know, a rate increase environment instead of, you know, what, what I think everyone was expecting a couple months ago which was, you know, headed into, headed into rate decreases. So I think those are, those are a couple of the macro things that are likely having an impact. But you know, big picture, you know, looking at the past 12 months, you know, we've definitely seen, you know, big, big kind of, you know, big kind, big sector recovery.
- [03:50]
A
Yeah, great, great points and good, good tip about looking at the last 12 months that makes biotech look a little bit.
- [03:55]
B
I know it's hard, I know it's hard. We all remember yesterday and the past week, but true, biotech looks pretty good when we compare it to like April of last year.
- [04:05]
A
Yeah, absolutely. Brian, what do you say?
- [04:09]
C
Yeah. So you know, I think it's funny if you look at kind of the year to date chart. Yeah. You could bring up the point that S and P is now outperforming xbi, nbi. But you actually look at our indexes, they're not that volatile. It's actually the volatility of the S and P that's really kind of driven relative outperformance which we saw, you know, like a month and a half ago, we were really outperformed the S and P and that's just come back and we really haven't moved anywhere. And certainly like that, you know, you have to attribute a big part of that move just to the AI trade. The S and P and I think had like 10 straight up days. And you know, today you're seeing a bit of an unwind on the S and P with jobs report out and concerns about escalating interest rates. But it's not really, you know, I mean XBI is moderately underperforming but you know, I'm not hearing like big freak outs about interest rates. Although it's certainly on people's radar. So look, I mean, I think it's just interesting that the xpi, which we kind of think of as one of the most volatile indexes, just given how these companies can report and be up 150% or down 80% on clinical trial data, it's been kind of remarkably stable and is up and I think that's the best we can hope for. That sort of fundamentally you're just seeing more green days than red days and I kind of like where we are.
- [05:37]
A
Yeah, absolutely. Sam, what, what's the sentiment in Europe? You know, we were getting sort of a lot of generalist call from calls from Europe. They, I don't, I, I don't want to say they've quieted down, but they've quieted down a little bit. It doesn't mean much to me, but kind of what's the sentiment in the sector there?
- [05:53]
D
Well, I mean, to be honest with you, your own I've literally just come back so I haven't quite felt it. But look, we've had this setback. We're going to talk about a little bit in the share price of Abivax. I mean I want to qualify it that way rather than necessarily the trial. And that's one of the biggest European names at the minute. There's GenMap there too. And we're going to talk about a little bit of their competitive landscape with petrocentamab at some point. So I think in general investors, the biotech investors are reflecting exactly what you guys have just been talking about. They're, they're being whipsawed around by whatever happens in the AI space in that if money needs to flow there comes out of healthcare and pharma and biotech. If money comes out of there, it comes back into these sectors. But I think it's important to also remember that the old industries, anything outside of the Mag 7 or Mag 8, I don't know if I include Micron. It depends. Whatever companies you want to put in there have picked up a bit and I think there's a lot of people who believe there's value in those non tech sectors, which of course will be the next game to play. So how do we perform relative to the standard S&P 500 in terms of the general older industries, so. But not much different. Jerome.
- [07:16]
A
Okay, well one of the things that, you know, we're going to get to B1 shortly, that a pretty good Asco. But one of the things that's been going on, I know it was discussed recently is the recent Binza bipartisan legislation, Biotech Investment National Security act, which explicitly adds to the COINS coverage. Of course, coins, as we remember, the COINS act was. Has to do with US Outbound investment screeching, screening sort of regime, including countries of concerns like China in terms of prohibiting or requiring notification of US Capital flows. That was sort of started to. This framework came up sort of in December of last year. And now, of course, there's a, A joint sort of Binza is expected to. Well, we'll have to see if it's actually going to go through. Tess, do you want to comment on this? I know there was discussed last year and you. You definitely have an opinion?
- [08:16]
B
Yes, absolutely. Happy to. So I think, you know, first, just in terms of, in terms of what's happened, you know, I think your own. As you, as you shared this, you know, kind of Binza proposal. And then we also had a letter from John Moulinar, who's the chairman of the select Committee on the, on the ccp and maybe just stepping back and like, talking about coins, right? And like, what was the purpose of COINS in the first place? Um, you know, the, A lot of the motivation behind coins and this, you know, coins is really focused on technology, semiconductors, AI. And a lot of the focus around coins was around not transferring like, expertise. Right? It was like, oh, like, you know, we don't want. It's kind of like capital flows, but like, even more than capital flows, it's like, you know, expertise and, you know, things that like, you know, American investors may have like, learned from all of their work on, like, AI in the US like not wanting that to, to, you know, benefit and go to, you know, go to China. And the letter that Mulliner, you know, put forward actually went, you know, quite a bit further than coins because under coins, licensing is allowable. Right. But what Molina is actually calling for is, you know, he's really drawing attention to like, licensing deals as well and, you know, calling for, you know, calling for making, you know, such licensing deals more difficult. So he's actually, you know, calling for something that would be a significant expansion of coins. And when we saw the letter come out and Peter and I and some other members of our team really thought through, like, well, let's start with what our North Star is, which is what is best for American patients. Right? Let's start there. And let's think about this legislation and what impact this legislation would have. And ultimately what it would do is it would slow down access to new medicines. Right. And you know what the legislation, you know, would also do because, you know, essentially it would make it very difficult for US Funds to do anything. It would make it very difficult for, like, US Pharma to do anything. But, like, hey, you know, if I'm a European investor, I'm like, absolutely, like, put that, you know, coins act in. That's great. Because guess what? Like, you know, if I'm a European investor, my deals with, like, China biotech are going to become that much cheaper, right? Or if I'm a European pharma, it's like, well, you know, awesome. Like now, you know, maybe my US peers can't get these, you know, China licensing deals, but, like, game on for me, right? So it's interesting because it's actually kind of this, like, you know, gift to, you know, European funds, you know, European pharmas that could essentially, you know, put them in a really strong leadership position to continue working with, you know, China innovators and bring those, you know, medicines to, you know, bring those medicines globally, right? Including. Including to the U.S. there's nothing in coins that said, you know, that says, you know, oh, like, you know, a China, you know, a drug discovered in China can't make it to the U.S. right? It's just saying, like, U.S. funds can't go there. You know, U.S. biotechs can't go there. And, you know, based on what Moulinar was kind of suggesting at his letter, you know, could potentially just make straight, like, you know, licensing deals beyond, you know, equity investments more challenging. So, you know, there's really a lot of unintended consequences associated with, you know, associated with the legislation that's being proposed posed. And Peter and I and our colleagues were really heartened to know that we are certainly not the only people in the sector who see this as really against American interests and against U.S. patient interests. Bruce Booth also had a great article where he talked about Patient First, America first, the case for global collaboration and arguing that, again, we really have to look at everything with the North Star of what is, what is best for patients. And there were a number of other investors, Rod Wang, you know, chen from, from TCGX, you know, on, you know, on X and on LinkedIn, really describing the importance of kind of staying grounded in what our sector does, which is bring medicines to patients and doing that in, you know, a way where we're bringing the best medicines and we're doing that in an efficient way where we can, you know, high efficacy and safety. That's really what we're looking for. You know, Peter And I also addressed in our article, like there are actual like valid security concerns, right? Like manufacturing. That is an absolutely valid concern that we should be, you know, looking to resolve. If we look at like, you know, we kind of separate out physical supply chains for manufacturing of drug product versus like, you know, the innovator supply chain which is more around like ideas and molecules and like, you know, where we should be, you know, really thinking about, you know, security, national security and taking more action is on the manufacturing side where we should be thinking about like, how do we, you know, ensure supply of, you know, not just like end product, you know, the kind of finished drug product, but also drug substance and some of the inputs to drug substance. You know, these are supply chains where we are heavily dependent on, you know, on China and some other countries and is something that we should really be looking to resolve. But the conversation hasn't, you know, hasn't, you know, gone that way. Instead it's, you know, being more focused on like, you know, kind of money going to, you know, money going to China and you know, how does that threaten US biotech? And it's like we've got to let money go where money will go and you know, the US should compete on having a more, you know, efficient system where, you know, innovators can just spend more money in the US to develop their drugs.
- [14:31]
A
It's a good point maybe. Sam, to you. Do you agree? I mean, to put you on the spot, you know, some people will say a lot of what China does well is copycat. We see an antibody in the US we see another targeted antibody, we'll put them together into bispecific and they do this in industrial strength. It makes things kind of uninvestable a little bit because do you really need 10 best in class sort of bispecifics or antibodies? So do you agree? Kind of. What's your view and what do you think is going to be the European response? Are they going to try on the national level, are they going to try to protect their own farmers?
- [15:11]
D
So on the first point I would say we're going to come and talk about PD1VEGF in a minute. I remember Chris Bardon at the AACR pre event conference saying that nobody would have invested in a PD1 VEGF bispecific. Now we're going to discuss whether there's real data here or whether we have an issue with regards to this PD1VEGF in the west versus China. But the reality is they did it. And that's where I think China can, can currently do things that we don't have the appetite for. On the other hand, the hardcore innovation where let's take for example DirectXon, Raci again they all fit in this conversation, right? And that came out of two companies in the US thinking through, matching their, their effort together at least revolution buying, the circling a mechanism in. So I want to see more evidence of really completely new ideas and technologies coming out of China and I have to say I doubt that that will not happen in the next year or two. These big deals that you see that are happening with Hungary, with Innovant within those there will be molecules that will come out which will be new science and new biology. So I don't think this is a train or whatever you want to call it that's going to be stoppable. There's no reason why Chinese innovation is going to be any worse. They lead already in material science and chemistry by far in terms of share of new ideas and new ideas generation. It's going to happen. So we have to make a decision Tesla's talking about is whether we want access to that innovation or do we want to stifle the access that our companies have to that. From the European perspective, I don't think AstraZeneca, GSK, Roche, Sanofi are going to be able to escape any major changes to rules that happen in the US at the end of the day, that is the country that currently where they make most of their profits. And that I think will cause a very interesting conversation at the board level. If they're able to get away with it, then I think it gives them an advantage versus us large pharmacists because let's face it, that's. Those are the groups we're talking about, the large farmer. Right. So I don't know if they'll be able to get away with it if this becomes legislation, which I hope it doesn't, but so they're over.
- [17:48]
A
Brian?
- [17:49]
C
Yeah.
- [17:49]
A
What about you? I don't know if you're seeing a lot of competition as it's coming from China in your coverage.
- [17:55]
C
Yeah, look, I mean I think it's always been a competitive area, whether it started with just kind of like the just attack on IP and kind of bringing similar molecules to things that are patented in the US quicker to. Now what we're seeing, Chris's point on PD L1VEGF, there's a novelty there. It's not totally too novel targets but the concept of doing a bispecific is novel and I'm sure We'll just continue to see more innovation there. So look, I mean, I think it's ridiculous. We don't go around saying like, oh, you know, we're all going to make just our own PD1 antibody and like, if you can't make it in your house, like you shouldn't have access to it or like you shouldn't be able to provide it to other people. But you know, I mean that's, that's the political climate that we deal with right now, right? It's sort of like this attack on globalization versus, you know, the need to sort of retain jobs, retain scientific ip. And look, you know, I don't know that there's like a, a great answer. I'm probably more in favor of global collaboration than not. But you know, there's a lot of ins and outs and nuances in that argument. But you know, I think eventually it's, it's just inevitable, right? So you just kind of have to deal with that inevitability and I think you got to kind of embrace it to some extent.
- [19:18]
B
Maybe I'll just make one quick other comment because I know, I know we have a ton of ASCO stuff to cover, but you know, for the, for the kind of fast follower argument, you know, that you made your own like, you know, in the copying argument. Well, like for that we have ip, right? Like if someone makes like an actual copy, like guess what, they're not going to be able to commercialize that in the US So it's not very valuable. But like, hey, is China really good at like getting around patents and you know, figuring out like, you know, here's something that like, you know, is interesting and like potentially better, that like, you know, builds off of like, you know, a patent from a, you know, what may be like a US Biotech. Absolutely right. But like, I also view that as like fair game, right? Like there's a lot of, you know, that, that is maybe something that a lot of U.S. biotechs, you know, could play that, you know, five years ago, right. Like now it's kind of, you know, that's kind of a hard pitch for like a US Biotech to really sell because, you know, I think everyone knows, like, well, there's probably some like more efficient, fast followers that are going to come out of China. So it does raise the bar on like, you know what, you know what I think US biotechs need to, need to work on to get funded in terms of like, you know, making that fast follower approach, like more challenging. But you know, under the patent system that we have, like that's, that's a totally, you know, totally fair game to kind of come up with something that's new and maybe potentially better. You know, that builds off of, you know, that builds off of, you know, existing IP that a company has put out.
- [20:53]
A
Yeah, I mean, I guess the question, look, I mean, the other side of the argument, maybe I'll take that for a second. At the end of the day, we're talking about a global industry that is very US centric, where we're losing our edge. You can argue China historically has protected the biotech industry. They've subsidized it. Many of the scientists were trained here. And if you look at the end of the day, whether it's semiconductors, whether it's shipping, increasingly now, frankly, E vehicles, obviously on the tech side and the AI side, there is a global competition going on. And one can hear about the argument about patience. You can also argue some of the E cars out of China are incredible. US consumers would probably love to buy them. But you do need to have a certain degree of protectionism when it comes down to equal trade and equal competition. And I think that kind of factors into the argument as well. And I guess the question is enough innovation in China that we don't have here.
- [21:54]
D
Can I just add one quick thing here, One thing that I would really hope we don't see because I think it actually increases the risk in my view, is companies remaining in stealth and not filing ip. I think that's quite risky because that assumes that China or anywhere else in the world will not be on the same track of trying to get intellectual property in a new area.
- [22:21]
A
Right.
- [22:22]
D
So if you play that game and test would be probably perfect to deal with this because you were also involved very much in the early stage companies, private VC type companies. If you hold your cards too close to your chest and someone else plays their card on the IP front, you've lost, you've lost that initiative. Right. Because you're no longer the innovator. And that's going to be a very interesting game to play. So whoever does that needs to be very careful and very sure that they are absolutely at the leading edge of this and everyone else is eons away. So just one last thing, because I hear that too, a lot.
- [23:00]
A
Okay, perfect. So let's move on. We have a lot to get through and I think we're going to have to do a little bit of rapid fire because we do have some other non asco topics as well. And so we started talking about VEGF by specific. So Sam, it's a great segue. This was one of those situations. There was. There's kind of two things to talk back to back. We're in the same sessions, the PD1 VEGF by specifics and then it's going to carry US right into RAS essentially. Same session at ASCO1 data got a clapping ovation. Totally appropriate. Absolutely expected the PDAC innovation. This is going to be one of those ascos. We'll all remember the other one. Amazing data and a very critical reviewer on the value of the translatability of Harmony 6 from China to the global patient population. Do you want to. Do you want to take that on?
- [23:53]
D
Sure. I know we were both there. So even is a map. It's a drug that Summit licensed from a Kiso China company and is developing in the US. Harmony 6 is the one that we've all been waiting for to tell us whether there is a chance that Summit can succeed also in the West. So Harmony 6 was a phase 3 trial of PD1VEGF in squamous non small cell lung cancer. And this is important because VEGF antibodies usually had a bit of an issue actually quite most of lung cancer, but specifically in squamous in that the risks outweighed the benefits of using them. But here the idea has always been that if you're going with a bispecific you might be able to make the. The drug more conditional in terms of its if its activity and therefore it should get better side effect profile. And we're seeing that in most of the cases. I can't say that every single bispecific is doing this but here Harmony Six worked. I know the discussant was very her job, Dr. Julie Bramer, was to discuss the data. It worked in the population, it was tested. We have a meaningful increase in overall survival. We have a meaningful reduction of 34% in the risk of death in the trial. And this was a pretty well followed trial, although there's quite a long way to go still. This is an interim OS and so and the data has been published in the Lancet, it worked in the various subgroups. So that's another good signal. Two particular things were which one we knew about which was the imbalance of women in the trial and we also knew that there was a obviously a data set for the over 65s and under 65s and we saw some of that split at ESMO last year for the PFS data here in the OS trial. When you look at the data, the trial Pretty much benefited the folks under the age of 65 in this trial. And then so the question now is, okay, this is great as it is for the China trial and the population in China, I'm pretty sure the drug will be, it's already approved in China so I'm assuming that it will be approved on the back of this data because it's a successful phase three. The question which I think is what everybody was in the room to try and second guess is whether it's translatable to the US. So your own I pass on to you to tell me what you think about that.
- [26:37]
A
Well, I mean it was, it was fascinating because if you look in general there's a growing body of evidence suggests that this combo really is doing something both whether it's response rates or a little bit on durability. And you know, we've always known there was biological differences for whatever reason in EGFR populations between China and ex China. And it's probably smoking squamous, which is this study also has a very high component of as, as the presenter said, the male smok heavy smoker in China. In that population it looks like it's probably potentially a little different than the western population, certainly by age. Potentially non squames are the ones that are hopefully going to be fairly predictable. And we would argue that based on our analysis, when you looked historically at data from Tavimbra, let's say from B1 in China to western population, the data is essentially identical. So we might just end up having some differences for nuanced reasons. It might ultimately be mutational based and related to smoking for whatever reason. But the totality of the data is increasingly suggesting that this bispecific really is doing something and it could be conditionally within the tumor. So Biontech with Bristol had data as well. This is from the leading part of their phase three, their global phase three. This was sort of from the part A of the study. They showed slightly better response rates, about 63% overall, 64% in non squames. To give you this is with chemo, to give you a sense, Ivo from Akiso and Summit does about 50 to 54. By the way, the Pfizer PD1 VEGF does 68%. So there's subtle differences. Now these are kind of smaller cohorts but ultimately our KOLs are increasingly beginning to kind of believe that there will ultimately be a difference and they kind of want to see a, you know, about a 25% reduction in a hazard ratio in survival in frontline non small cell for that to really be the new standard. And they're continuing to get a little bit more excited frankly and triple negative. And now actually there was data on colon cancer too from Summit that really looked interesting too on Frontline with chemo. And when you compare that data to Avastin chemo in the past, again Ivo looked better. So we're beginning to see that all across the board. Remember of course, PD1, as we all know this has no activity really in colon. Well, we got our fingers crossed and we're obviously following closely. So let's talk about the other one which was really memorable and incredible. And that was the data form on PDAC from, from Revmed. That got a standing ovation. Sam, go for it.
- [29:27]
D
Yeah, so I mean, you know, I think that particular comment you just made kind of sums it up. Pancreatic ductal adenocarcinoma. The, you know, everybody knows about pancreatic cancer being an awful thing to get because pretty much there's been no improvement in standard of care. And now we have it, we have Diraxone, Rasib, which works by that mechanism I talked to you, I mentioned earlier, by bringing another molecule into the vicinity of the RAS molecule and then leading to inactivation. So I mean there's very little to. People try to draw cars between the lines as they separate in terms of overall survival or trucks or whatever way you want to call it. It is a significant advance for this disease. Overall survival jumped to 13 months, 0.2 months versus 6.7 median progression free survival was better, overall response rate was better and disease control rate was better. And frankly a lot of people focused on the side effect profile, which is absolutely right to do because there's no point getting a six month or seven months or eight months, whatever it is. Remember we're talking medians here. And there are people in this room, sub patient group that would have lived a lot longer and of course the opposite too. But the control arm is chemo. I mean that's not a walk in the park either. It's just that people have got, for want of a better phrase used to dealing with chemo side effects. Whereas here you've got something rash. Maybe you could say, well from the EGFR world in lung cancer we've got used to, but this is slightly different types of rash and it is problematic. Stomatitis, mucositis, diarrhea. So this is not, not a drug that is without side effects. But I think people would take the risk and take the drug because you can also dose down you can do. There isn't many. I mean the discontinuations were not as much of an issue as far as we are concerned. But there was obviously dose reductions and dose interruptions, which is one way of dealing with the side effect profile. So now what's left is what is the group here that benefits most? Well, the trial is tough to do that because over 90% of the patients, patients in the trial where the, sorry, over 70, about 80% of the patients in the trial were the G12DV and about another 30% were the G12 mutations in this RAS molecule. So what you've got is a very concentrated more than you would see in the standard real world distribution of mutations. So the question now ends up being, okay, so if I come with A more directed G12B D or A V inhibitor, will I be able to compete and do better than directxonrecid? Or if I come with a Kras pan KRAS versus a pan ras, can I manage the side effect profile? Well, all that has to be proven. But you cannot take it away from Revolution Medicine that they have set the bar now and they have opened the door for all of these things to be tested with patients having an option better than just chemotherapy. So I'm really excited by it and I think their standing ovation clearly showed that over.
- [32:48]
A
Okay, amazing. All right, so there's so much to talk about. Let's move to breast cancer. In the one area that I always struggle to keep my thumb and the pulse is the third area. And so there was more data from Par severa from Roche, which actually failed. But we had an update on it and there was a slew of other updates. Do you want to. Let's talk about Sird and then we'll move on to the Pi3 area as well.
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B
Yeah, sure.
- [33:14]
D
So Girodeserant is the drug here which was being tested in first line HR positive HER2 negative breast cancer. So. And it didn't meet statistical significance. So there was a numerical improvement in progression free survival, but it didn't quite make it. Now why is that? Well, it could be that it's the size of the trial, that it wasn't sufficiently powered. I mean when you look at the differences, overall survival was slightly different. Different. I mean obviously all of this can. Overall survival is a tough one because you get post progression therapy, median progression free survival 33 months versus 28 months and unfortunately the hazard ratio crossed one. So you think maybe if you had 1500 patients and the reason I say that number, or 1400 patients, it could have done better, but there was. Everything was numerically in favor of the drug. But you know, obviously you set your parameters for these trials. You set the number of patients with what you think is going to be the success criteria and it didn't work out. So that's where that is. But what does this mean for others? The other one that most people are focused on is camyzestran from AstraZeneca and that's reading out in the second half. Serena 4 trial is a similar trial to the persevera trial. And AstraZeneca talked about this at their analyst meeting and we're going to have to wait and see how that pans out. Obviously people are going to now worry about that readout. One thing here, the reason I mentioned the 1400 patient number is they have a larger trial. They're running a 1392 patient trial versus 992 patient trial. So a good 400 patients more that might help them just squeeze the stats in just the right side of the OF one. And of course it's a different molecule and the design, maybe there's some differences, but we also have to remember that some of these patients are coming from different. There were subgroups that seem to do better in the first EVERA trial. So it all waits, we wait and see. And last one here I want to touch on is Olema. We liked what Olema showed and frankly the, the data is, is looking pretty positive here. So we, we think Olema has, has shown. Sorry. Olema has time to potentially adjust its trial to try and deal with these things with this knowledge in hand. So that's going to be quite interesting to see what they do with regards to going forward with regards to what they've learned from Persevera and obviously what they will learn from AstraZeneca in the second half over.
- [36:03]
A
I mean, so does that, does that mean that surge should be ESR1 mutant drugs or. Because the second line data actually looked good in combination with the CDK4.
- [36:13]
D
That's right. That's right. But I'm not convinced that it's as straightforward as that in the first line setting. So I think it's for more than a conversation we're going to be having today. But the data did suggest that the ESR1 wild type metastatic disease, maybe additional mechanisms may be driving that. But it's really, I think we need the detailed data from more than one trial to try and figure that out because I don't know how different these molecules are with regards to that particular population.
- [36:51]
A
Okay, incredible. So let's actually, before we jump to pi3, since we started talking about CDK4.6s, let's talk about the CDK4, which is a new area, and recall CDK4.6s. There's three drugs right now on the market from Pfizer, Lilly and Novartis. They're dominant. It's really Lilly and Novartis game. The Pfizer compound is kind of palbo fallen by the wayside over the years because it did not show survival benefit. But increasingly, these drugs do cause neutropenia. And the thought increasingly in some emerging data suggests that the CDK6 modulation potentially does not really confer much benefit and might be the detrimental part that causes neutropenia. So naturally, companies have now developed what's known as CDK2.4 and 6s. CDK2 as a single agent also has become a little bit less promising because it hasn't shown dramatic clinical activity as a single agent. It's thought that maybe it can reduce resistance to the CDK4.6s. But increasingly the evidence suggests that CDK4 modulation is really the sweet spot. And there's two companies now working in phase three. The first one is Pfizer with a tirmocyclib, and the Second one is B1, which is now in phase three. So we saw updated data from essentially both of them, and the data looks really good. So B1 really did the full unveil and they went right into a phase three. They started the program, just to give you a sense, about three years behind Pfizer, and they're probably year behind now. That's how fast they're able to move on a global basis. Their compound showed pretty impressive 63% confirmed response rate, 74% unconfirmed. This is in combination with endocrine therapy. Letrozole. They did not have any neutropenia, which is critical, so they can ultimately combine with other mechanisms down. They did have some GI toxicity, which is really mostly grade one and two. Once they give the drug with food, the Tirmo has a response rate that's up to the 60s. So it looks like potentially onk is getting a little bit more response rate. And now B1 has started enrollment. In the meantime, Pfizer's now completed enrollment. So this is an area that's super interesting to watch. They're both actually going to go now head to head against the CDK4.6s in combination with endocrine therapy. Historically, CDK46 with endocrine therapy does like, let's say 50 to 55% response rate and two year progression free survival. And as we just mentioned, Pfizer compound gives you about 10 points higher and B1 potentially even gives you sort of 15, maybe even 20 point higher. The question becomes is that going to be enough to actually beat it head to head? And those studies are ongoing. These are 10, you know, these are 1,1100 patient studies that take about three years to read out. So these things are ongoing. What's really interesting is now to shift over to the pi3k axis. About 15% of patients develop pi3, what's known as pik3amutations in breast cancer. So now relay incumbent along with Pfizer are going to go and specifically focus on that cohort in the frontline setting and they'll take that CDK4 from Pfizer along with their PI3K inhibitor and come with endocrine therapy next year. And that's going to go head to head against CDK4. 6. That strategy is fairly compelling because you're doing three drugs versus two in patients who have mutations and you're giving them a peak 3amutant inhibitor which is very effective and is frankly in phase three on its own in second line. So that regimen is going to start phase three next year.
- [41:05]
D
We lost you, euron.
- [41:11]
B
I see him coming back on.
- [41:14]
D
He was doing so well. Okay, let's maybe just as we wait for Jeroen to get back on the usual Twitter spaces hiccups continue to happen. Johan can hear me. Brian, can you hear me?
- [41:34]
B
We sure can hear you.
- [41:36]
D
Okay, cool. I'll take the next topic that we were going to talk about. And that was, I think maybe just to give people a break from my voice and your own voice, we should move to Tess to talk about grail at asco.
- [41:51]
B
Yeah, absolutely. So happy to talk about grail. I think this was a you know, probably, you know, probably pretty, you know, disappointing, you know, disappointing readout for a kind of pan tumor, you know, multicancer early detection. But a lot of, you know, a lot of kind of interesting points here. So first just, you know, let's start with what they showed which is, you know, they had a study where they were looking at reduction in stage three and four deadly cancers at three year follow up and they missed this in a pretty big way. So that was the, that was the, you know, the primary endpoint. And you know, I think the, you know, IRR was a little over one and they had about 706 patient interventions versus 700 controls. So pretty well balanced there. And there was a 14% reduction in risk for the stage fours, but interestingly, an increase in the stage 3s. So this is a pretty challenging thing to read just in terms of understanding if there's a real signal associated with, with these multi cancer early detection tests and question of, hey, these may be helpful from the standpoint of understanding your cancer, but are they really going to change mortality and outcomes? Which I think remains a question. You know, maybe on the, you know, on the positive side, you know, they did show, you know, you know, it was a well run, well balanced, you know, well balanced trial and they did have a reduction in emergency presentations. Right. So, you know, again, maybe that points to, hey, well, you know, people at least know what they have, right. And can, you know, maybe that helps in emergency situations, but maybe it's not, you know, really changing, you know, mortality outcomes. And then the test performance, you know, actually looked pretty good. Right. So again, this is, you know, these, these multicancer early detection tests. I think the, you know, the positive predictive, you know, value was about 52%. You know, really high, you know, really high specificity. So, you know, very helpful in terms of knowing and helping screen for cancer. But question on what that actually means for outcomes and mortality. And some of that may be a question of just what the associated interventions can be when you learn about cancer at an early stage in this pan tumor way. I think that grail is taking an approach of looking at, at, you know, pan tumors if they're looking across a lot of different cancers. You know, I think that a lot of the, you know, a lot of the, you know, in this trial, there was, there was more of an impact in crc. Right. And so this may be something where, you know, we have to kind of look at a cancer by cancer basis and understand how does, you know, knowing about, you know, cancer early change how you were treated and how, you know, what patient care looks like so that it can result in, you know, an improvement in mortality and mortality and outcomes. So, you know, more to. More to do in the, you know, msaid. More to do in the MSAID space. But, you know, important to at least see that the test data is looking good. And now, you know, we have a lot more work to do on interventions.
- [45:53]
A
Amazing. That was great test. So I clearly got cut off and I don't know where I was when I got cut off. Any hints.
- [46:04]
B
You were talking about, you were talking about? I think you were getting onto the CDK4.
- [46:12]
A
Okay. All right, so I'll keep it brief, because I know we have a lot to get through. So the CDK4 area is super interesting. There's CDK4.6s are the dominant drug. They sell about 15 billion. But it's thought that CDK6 modulation probably does not do a ton on efficacy and adds to the neutropenia. So there's two companies now with CDK4 data in phase three. First one is a Tirmo cyclib from Pfizer, and the second one is a drug that's now in Phase 3 from B1 called 395. A tirmocyclib from Pfizer is in a frontline study. Fully enrolled, gives you about 60% response rates. The big Achilles heel is it does cause neutropenia. And neutropenia is a little bit of an issue when you're trying to combine this class with other classes. B1 has managed to move very quickly. They're now showing you between 63 and 74% response rates. They don't have neutropenia. They do have some grade 12 GI nausea and a little bit of diarrhea, which is just frequency. That's been much better now that they're taking the drug in the Fed state, Pfizer is fully enrolled. B1 was about three years behind. They're probably only about a year, year and a half behind now because they move really quickly. And so they started enrolling their phase three. The big question is, can these drugs actually be the CDK4.6s? Head to head in frontline? They do give you between 10% higher response rates on the Pfizer side to maybe 15, 20% higher on the B1 side. Just to give you a sense, the CDK4.6s give you about two years of PFS. Those studies are ongoing now, and it will take about another two to three years to get the data. In the meantime relay, which has a PI3K inhibitor, they're moving to a Phase 3 next year with Pfizer, with the tiramocyclib in front line. So this is going to be in patients that have a PI3K mutations. It's about 15% of patients. And there they're going to test the CDK4 with their PI3K inhibitor in that setting, head to head against the CDK4.6S. So that's probably a more elegant way to de risk a phase 3 study because you really should be able to beat stdk46 alone with a pi3k, given that relay showed really good data. They're Actually running a separate phase three in second line with their drug in these mutants. Patients with these mutations. We're expecting positive data probably sometime in early 28 for that regimen. So lots going on in that space. The other big data at ASCO is Victoria 1 from Sulcuity, when they have a PIK3AMTOR inhibitor that showed very good data, doubling the PFS rate. This was in the first in a pi3k mutant population and in the second line setting, so they went to 11 months from about 5 1/2 with a triplet against the doublet. The physician feedback is this is going to become standard of the care. The only Achilles heel is you have to take an IV infusion three out of four weeks and it does cause some mucositis and some, some inflammation of the stomach lining. And so physicians are fairly optimistic and hopeful that once Relay has data from their oral inhibitor which is better tolerated, that gonna provide another really good option for patients. And that's probably again another year and a half, two years away. So really lots going on in breast cancer, maybe. Sam, over to you on in vivo CAR T. Huge, hugely important area with data from in myeloma that led Lilly to buy colonia for up to about seven, seven and a half billion, three billion upfront. Can you maybe address that? And then Legend's about to have data next weekend in lymphoma with their in vivo cartoon.
- [50:25]
D
Yeah, sure. I'll do the myeloma and I'll pass on to you for lymphoma. So the trial, the data, it was exactly the sort of thing that we love digging into. The abstract had six patients. The actual presentation had 18 patients. This colonia, lini colonia, I mean, whatever we want to call it now, relapse, refractory multiple myeloma patients, in vivo CAR T, bcma. So we're all going to compare to everything else that's going on. Cartitude 1, which was obviously an autologous, that's Carvicti Autologous Car T. And AstraZeneca's got the IsoBiotech Car T that they've sort of ESO T1 is the name of the molecule. So the colonia, the data, 100% ORR, 100% MRD negativity in the data. But then there were a couple of things that of course you want to not see necessarily with CAR T, but the devil will be in the detail when we see all this. So all patients achieved residual, minimal residual disease negativity. And then 4 out of 6 patients with follow up over 4 months reached complete response, which is the direction you want to see data go. But at month three, one patient relapsed and another patient turned MRD positive. Now these early signals are kind of a little shadow on durability but you want to know the details in those patients. Remember these are range of three to five lines of therapy and of course it's a bit dangerous to compare to say cartitude 1 where the range was 3 to 16. So let's just, I just want to temper excitement there a little bit. Bit. So we need to see what was the characteristics of these patients. Were they triple hit cytogenetics, really high risk, had they had whatever every line after the five that they had, were they in that group? Did they have proper plasma extramedullary disease, for example plasmacytomas. Those are the questions that I think need to be addressed because, because even the autologous CAR ts are not one and done. So all that needs to be something to look at. Very promising. Still the number of patients have gone up. I'm really excited about that. And of course on the side effect profile you still see some immune effector cell associated neurotoxicity syndrome icans and of course a grade three which was a grade three event, one of them, but no delayed neurotoxicity. This is 2.8 months. Right. So in terms of media and follow up, but I'm excited by, I think we're going to see more evidence that this is a real future thing that could be competing with the autologous which of course the autologous companies are all working on. I'll pass it on to you.
- [53:22]
A
Yeah. So on legend they're going to have data at EHA, which is next weekend, not this weekend. This is in 12 patients. So this is in vivo again. So as you know you just give the patient an IV infusion that's got lipid nanoparticles and essentially a whole construct inside to then go into the blood and actually transfect T cells to make car T in the blood. So there's no conditioning, you know, there's no waiting from long vein to vein time to make the cells and enrich them outside the body. The data looked really good. Two dose levels. The higher dose levels had essentially 100% response rate, 83% complete responses. Durability at this point of follow up is only 2.2 months and there's no real ICANS or you know, major toxicity other sort of than grade 1 2. The bar in general is sort of in the 70s, 80% based on ex vivo response rate. So 100% and this is in six patients at the second dose level is promising. Of course what we need to ultimately see is to make sure this is going to be sustainable and so we'll wait for that. I'm going to just to flag there is a lot going on in head and neck these days between genmab, Bicara and J and J on the EGFR side, super promising programs. JNJ now filed and biotech investors were really kind of looking at Miris which got acquired by genmab and then by Cara and were discounting JJ and JJ came from essentially nowhere to filing robberant ahead of everybody else. So lots going on by the end of the year and then we'll continue to talk about that over time but we want to leave time. Abivax had their long awaited maintenance data in ulcerative colitis. The efficacy looked very good but there was essentially seven cases of cancer versus one at the high dose versus one on placebo. The stock was down 45% and then I think recovered sort of 30% of that loss so far. Far. Sam, what do you think? Should, should the stock have been down this much or not?
- [55:29]
D
I mean look on the efficacy side I think it outperformed what most people were looking for. Right. It was bigger than the see the best hoped for which is 30% placebo interest that I don't know what you guys are looking for but it did better than that. So efficacy side looks good. 50 milligram dose in terms of the concentration of malignancies that they reported. It just optically scares you, you. Right. The company has detailed it. The, they had Kols on the call who or they have conversations with Kol seems to suggest that maybe it's not related to the, to the disease, to the drug and we know that this patient population has the higher risk and we know that other drugs in the space such as the JAK inhibitors do carry a black box for malignancies and but it still scares you when you see it concentrated in the higher dose versus one signal in the lower 25 milligram dose. So I think it's going to be an overhang on the worries about this. I mean the stock has recovered. It hit 70%. I mean it looked pretty bad on the day that the data came out and it's recovered. Some people have come out in supporting it. So we'll see it will come to the FDA probably we'll get a,
- [56:52]
B
an
- [56:52]
D
adcom and a lot of this I'm pretty Sure will be discussed there. So we'll see. And I don't know if there is an obvious mechanism, stick explanation for this, but we'll, we'll wait and see. That's where I can, that's, that's as far as I can go.
- [57:09]
A
Yeah. Fantastic. So, Brian, over to you. We had like three, three topics, but we, we've kind of three minutes left maybe. Let's take on the FDA Rare disease roundtable meeting that was held on Wednesday with a new act commissioner. What, what did you, what were your takeaways from that?
- [57:26]
C
Yeah, so, yeah, there was a, there's this roundtable, as you said, include a number of senior leadership at fda. And we talked a little about this last week and some of the feedback that's come in on, on Kyle Diamantes, who is the acting commissioner right now after Marty Macri's departure. And you know, I mean, I, I think this is a continuation of what I commented on last week that, that it, you know, know, the feedback on him, even though kind of looking at the cv, you wouldn't be like, oh, this guy is like a clear great acting director background. He seems to be saying and doing the right things. He seems to be willing to be deferent to sort of a little bit of the voice of industry, a little bit of the voice of the patient. He had this roundtable and look, as we've discussed, you know, throughout the last year or so of Macri's tenure, there's sort of been this like lip service to flexibility, particularly in orphan disease, but sort of these actions that have not reflected what he's been. He was saying in meetings, what Prasad was saying in meetings. And now with that sort of leadership gone, you know, diamante sounds, you know, he's saying many of the same things, but it does seem like he's less likely to interfere directly. Comments from the meeting that I think are particularly important and positive for the orphan side of things is, you know, just kind of talking about the importance of regulatory flexibility, the importance of patient voice. You know, personally, one of the things that I like the most that he said about it is he intends on bringing back much more adcom. So he wants to really rely on sort of career staff as well as external experts more so than the, you know, the prior leadership did. And you know, one of my favorite parts of the job is, you know, historically going to the ADCOMs. More lately listening to the Zoom ADCOMs that the FDA holds. But, you know, I kind of love bringing everything to light and you know, seeing, seeing people debate it out. So look, I mean I think, I think it's definitely at least an incremental positive, especially for sort of these orphan areas that I know a number of us cover where, you know, you can't really run full 500 patient dual clinical studies to show efficacy. So, so this flexibility is required. But again we'll see. I think there's this cautious optimism that the political interference that we saw in the last leadership will not be the case here. But I think a lot of people heard Macri's comments when he first came on and also said the same thing. Oh, this guy sounds really flexible. So we'll have to see. But from my perspective, I think this does look like at least an incremental change, change in a positive direction for these types of stories.
- [60:12]
A
All right, well, terrific. This was a little bit of a tour of the force, a lot to cover. We had a good, good amount of sort of discussion and debate in the beginning and then sort of like a rapid fire drill through. Thanks everybody for joining. To my co moderators.