What's your valuation in Hong Kong? And maybe we start there.
Sure. Our market cap in.
Super excited to have the management team and an old friend from prior to Akeso, Bing, join us. Looking forward to this fireside, looking forward to seeing you tonight at the game. I saw your hat, so all of that is lined up. For those of you who don't know, Akeso is a Hong Kong-listed company, but more importantly, one of their key programs is now licensed in by Summit Therapeutics and Summit traded at a valuation which we've all seen. I think peak was $25 billion. Remind me, Bing, because this is very important, people get confused. How much economics do you guys still have on ivo versus Summit? And what's your valuation in Hong Kong? And maybe we start there.
Sure. Our market cap in Hong Kong is in the zip code about $8 billion USD.
Okay, let me clarify.
Yes, $8 billion USD. Yes. We still retain, I would say, all of Asia with the exception of Japan. So Summit has Japan, U.S., Europe, LATAM, and Africa.
Sorry, Summit has—t hey have U.S.?
Summit basically have everywhere in the world except Asia, but they also have Japan within Asia.
How much economics did you guys keep on the U.S. and some of those territories?
We mentioned low double-digit royalties and a few billion dollars in buybacks.
Got it. And from your understanding of the current $8 billion in market cap, how much is attributed to this program by your investors?
To be honest, it depends on the investors you talk to. For the U.S. and European investors, they attribute a large portion of that value to the economics we get from Summit. However, for the investors in China, including Hong Kong, they're actually more focused on our P&L. And the recent driver for some of that is actually the inclusion of both ivonescimab and cadonilimab into the National Drug Reimbursement List in China, which just happened about two weeks ago. Domestically, that's a very big catalyst for us.
Got it. And maybe just expand on that a little more. So you guys got approved for ivonescimab in China recently based on the trial that we saw last summer, HARMONi‑2. That was not the basis of approval in China, was it?
That was exactly the basis of approval.
It wasn't?
That's a third-gen EGFR refractory patients in China.
EGFR refractory patients. Okay, got it. Maybe for folks who are perhaps less familiar, remind us, how is this approach different than what Roche studied in IMpower150 , which was take Avastin with a PD-L1? You have a PD-1 in VEGF, but it's a bispecific. How does having both of them on the same molecule change it versus taking Avastin and a PD-1 separately?
Sure. There's actually two layers to that question. I mean, the first obvious layer is the fact that when you put both the PD-1 and VEGF in the single antibody, you have co-localization. So you remove some of the side effect issues that bevacizumab, for example, I've seen with bleeding risk around squamous cell in particular. So that's just the first layer. But we're not the first company in the world to do bispecific. So it's really our proprietary tetravalent structure that actually allows us to do this better than everybody else. So I think yesterday, Allen at Summit did a good job of explaining the mechanism of action, but I'll just repeat it at a little bit lower level, which basically the VEGF molecule is a dimer. So in our tetravalent structure that we can actually combine two ivonescimab together by a single dimer structure.
Now, imagine multiple dimers and multiple VEGF dimers. You can actually daisy-chain these things into a multi-molecule structure. So the term for that in chemistry is avidity, which is a multi, I'll say, non-covalent bonding that increases the attraction of these multi-molecule structures. So this is something that is very unique to our tetravalent structure that a traditional bivalent structure for bispecific just could not achieve.
Got it. Maybe focusing on the data more specifically. So we have the EGFR mutant lung, which formed the basis of EGFR mutant indication in China, number one. We have the PD-L1 above 1%. That was the ASCO data, which caused Summit to go to $25 billion and all the move here in the U.S. But what's coming next is, and I'd be curious if you can expand on it, and I want to get it to the rest of the pipeline as well. A, the OS data, survival data from the PD-L1 above 1% trial, as well as a chemo combo trial. So could you remind us the timing on each of those?
Yeah. So we actually haven't provided guidance on the timing, so I think for HARMONi‑2, which is the data that we present that we're along around PFS, OS is probably going to take a while, and the fact of the matter is both ivonescimab and pembrolizumab are pretty good drugs, so a lot of the patients, frankly, are alive, so we're not hitting that OS endpoint.
Is this less than 20% survival events right now? Is it that low?
We're not commenting on that.
Okay.
So roughly, I think probably OS for that, we're thinking end of 2025, early 2026.
Is that right?
Yeah.
Oh, wow. I would have thought this is a 2Q event for your first 35% events.
No, so now for Summit, we'll have their own U.S. study. That readout is middle of next year, but that's EGFR refractory.
Summit will have its own U.S. study in EGFR refractory. So that's akin to your China approval.
Exactly.
EGFR mutant. And the primary endpoint is PFS in that?
I believe it's aiming for OS.
Primary is OS, and okay, so let's start to go down.
But I don't want to cross-signal with Summit on that one.
There's a few things I want to sort of clarify on some of the prior data sets. So I'm going to focus on the PD-L1 above 1%. PFS hazard ratio is profound, 0.51. There's no arguing there. So it's almost a 50% improvement over Keytruda. However, there's several layers to it. First, the entire separation happens at the first time point and never expands from there. So how do you think about that? Why so much separation? I realize Keytruda does dip. You have a 30% progression on the first scan, and that's fine. But one of the things I think about is when you have chemo on board and you're follow-on trial, you're not going to get that early separation. So will you still have a real PFS hazard ratio?
We believe so. We believe, well, and expect that a chemo combo will just right-shift both curves. You should still see that separation is our view. Now, how far did that actually shift it? Obviously, we're going to have to publish that data when it's available.
But do you guys expect hazard ratio deterioration from that to the next trial, or you guys still think a pretty strong hazard ratio shows up on PFS regardless?
We think a strong hazard ratio on PFS.
Got it. OS on the existing trial? I'm not talking chemo combo. On the existing trial, OS? I think there was this thing I was sharing on some of my prior ESMO work as well that in your EGFR mutant study, PFS from 0.49 went to an OS of 0.82. There was deterioration. My sense is it's almost like an expectation now that there should be a meaningful— OS is in the 0.7 somewhere. We don't know where. I'd be curious, what your understanding is where the expectations are, but also, is that a realistic base case?
We're not providing guidance on that right now. We just have to comment on the data. As you're probably seeing, we're pretty conservative on disclosing these data. For example, nobody got a heads-up on, for example, our World Lung data. So we'd like to have the data speak for themselves.
No one got a heads-up on the World Lung data. Well, we had Summit talking about it at ASCO broadly, though, right? We don't have the data.
No, no. There's no way they would have seen that.
Oh, the curves. Okay, got it.
That is highly confidential. So we like the data to speak for themselves.
Got it. So the next meaningful update, 4Q next year.
Potentially towards the end of next year or early 2026 for HARMONi‑2.
Got it, and then the chemo combo trial?
We're not providing guidance on that.
But is it reasonable to assume that's a 2025 event or probably not, more like a 2026 event?
I would say closer to the latter.
The chemo combo trial, is China-based as well?
It will include the China arm.
It's all China. Okay.
No, no, no. It would include the China arm. So Summit is also doing their chemo combo, right?
So there's two chemo combo trials?
Right. So first of all, in the China one, we have ivonescimab plus chemo compared to tislelizumab plus chemo. So that's the China only. Summit is also doing ivonescimab plus chemo plus pembrolizumab plus chemo. That would include the China arm.
That Summit data timing would be what?
I'm not sure if they provided guidance on that yet. We don't provide guidance on that.
Got it. One of the other considerations also is with VEGF, the PFS to OS, there's always a fade. I guess, how do you guys think about that? As well as does VEGF do better in Chinese patients and not as well on the U.S. patients?
So again, we'll let the data speak for themselves on that front. But we've heard that commentary predominantly from, I would say, from Merck on the different response rate of VEGF between, I would say, East Asian population, non-East Asian population. We heard, I would say, anecdotal comments around that, but our view is it's not necessarily better response. We have seen that Chinese population tolerate higher dose of VEGF than non-Chinese populations. So that we've seen, that they have a higher tolerance for dosing. As opposed to response, I don't think we're ready to comment on.
Chinese patients also don't report neurotox in cell therapy trials.
In cell therapy. We're not cell therapy.
Yeah. I know. I know. I'm just saying the tox control is very high there.
Yeah. We report all of our data with brain metastasis in these studies as far as I see.
I mean, I guess my last one would be, if I were to be a super skeptic, I could say I was just a high-dose PD-1. How do you think about that? Because sure, Merck did a lot of dose optimization, but there is a scenario to be had where you just run a double-dose Keytruda trial. That could look very different potentially. How do you think about that?
First of all, there's a safety issue that we clearly addressed. You don't want that to float around in an area that you don't want to go around. That's where the bleeding risk comes in. So if you go back to World Lung, and some of the comment by the oncologists is that they were actually pleasantly surprised at the lack of major safety signal for squamous, in particular, major cavitations in some of these tumors, which poses significant bleeding risk, and that you don't see from our molecule, so that is an inherent benefit of our particular tetravalent structure bispecific over two separate monoclonals.
Got it. Now, I don't want to spend the entire time on this, and I want to note I'm keeping at least half the time on the rest of the pipeline.
Thank you.
Can you talk to me about, because I feel like there's less of a focus there? Just as a company, are you guys, since there's so much U.S. exposure and U.S. interest in Akeso broadly right now, in part through Summit, but broadly, is the aspiration to remain a company primarily predominant in China, or would you guys want to have more U.S. presence as well?
We're definitely expecting us to be a global biotech. ivonescimab is a fantastic drug, but we actually have another one that we think is just as good. Cadonilimab is a bispecific PD-1/CTLA-4. It was approved in China two and a half years ago for second and third line cervical cancer. Just got approval for first- line gastric. And unlike pembrolizumab, nivolumab, and tislelizumab, we've shown in gastric cancer that we can have a significant OS hazard ratio benefit across all levels of PD-L1 expression. So that is one where, in particular, I think the September 25th ODAC meeting on gastric cancer really gave us an opportunity to think about that opportunity in U.S. and Europe. And gastric cancer is not huge in the U.S. It's talking about 25,000, 30,000 incidence rate a year with about 80% HER2.
So this is the September 20 that happened already, right?
Yeah.
You guys present some of that.
But significant market in Europe, significant market in Japan. So within gastric, potentially could be a $5+ billion peak sales opportunity for cadonilimab globally. Not to mention that we're also in, again, proven cervical, which is not huge in the U.S., about 10,000 incidence rate a year. But we are in phase III for liver cancer in China. That is about a 30,000 patient opportunity in the U.S. alone, probably more in Europe. And lastly, we're in the early part of a phase III in China for non-small cell lung cancer that's PD-L1 negative. So again, just I think yesterday we mentioned there's an IIT study initiated study in China, a phase Ib, phase II study.
But the 5 billion you mentioned is mainly just gastric and cervical?
No, just gastric.
Just gastric is five, and presumably PD-L1 negative lung would be additional upside.
Yeah, because that's 30%.
That's 30 billion.
That's 30% of non-small cell lung cancers is PD-L1 negative. So if you think about our portfolio for PD-L1 low to high, we have ivonescimab. For negative, we have cadonilimab. And then not to mention that we have five other bispecific in phase I right now that we can combo with these two primary cornerstone bispecific that's approved.
What are those programs?
Sure. We have just LAG-3 PD-1, LAG-3/ CD73, PD-1/ CD73, TIGIT, TGF-beta, and then claudin 18.2 and CD47 all in phase III. So again, they're in phase I. All five in phase I. So we've got five shots on goal. But if you look at our track record, for our first two, we're two out of two. So hopefully out of the five, we get a few more winners in there. And we've seen some of the failures from the big pharma for TIGIT, for LAG-3, but those are monoclonals. And as we demonstrated with CTLA-4 and VEGF, when you actually put them in combination in our tetravalent format, actually that's not the case with claudin 18, CD47 actually. But the other ones are tetravalent format that we actually are able to see new biology that you cannot see by just having two monoclonals.
Got it. And since you mentioned VEGF, I didn't mention VEGF. I will ask you two follow-ups now. One being scope of indications beyond lung. How do you think about that for IVO?
Sure. So we initiated a global phase III for head and neck cancer.
That's you guys.
That's us and Summit.
Okay.
So because it includes ivonescimab, it also includes adding ligufalimab, which is our CD47 molecule into the combination. So we've shown good data at ESMO where ivonescimab has about a 30% ORR on itself, but when we add ligufalimab, that it goes to 60% ORR. So that's a global study that's both us and Summit will work on it together.
Okay. So head and neck is the first indication beyond lung.
Yeah, that's the one that we're doing phase III right now. And then there's a bunch of other ones. Triple-negative breast cancer is one where it could be very interesting. Again, we published data around this at ESMO. Colorectal is another data we published at ESMO. We haven't publicly disclosed plans to do that, but I'll just highlight, again, if you look at the ESMO data, those are the ones where we have pretty promising phase II results.
Got it. And given the newfound valuation of Keytruda, are you guys looking to be opportunistic to significantly expand the scope of some of these other programs, CTLA-4 and well beyond, or was that always the plan anyways?
That was always the plan. I mean, we just did a raise about a month ago, $250 million, and 70% of the use of proceeds is to do global expansion of our study.
Did you bring in mostly U.S. investors into this now?
There's some European ones as well.
Okay. But this was not a predominantly Chinese group?
No, no. We have more investors, more funds from London than from Hong Kong this time.
Okay.
Yeah. So a lot of investors from London plus Europe, U.S., so that's New York, Boston, San Francisco, and Singapore. Some investors from Hong Kong as well.
Got it. Thoughts on the Merck in licensing and how that structure is different? I know there's a lot to talk about the VHH domain, but we don't know a lot of the details. Also, the PD-1 to VEGF bispecific for that molecule versus yours?
Yeah. That's a good question. What is the difference in the molecule? I don't know. Oh, yeah, I know. So we have ivonescimab is like a 4x4 pickup. I guess they take out one of the wheels. So you have three wheels on that truck. I guess that's their molecule.
That's right.
With all respect to Merck.
Okay, great. Excellent. And the PD-1 to VEGF bispecific, that's one-to-one for you guys, right?
Yeah.
Okay, because there's also, I think, a difference there as well on the Merck side.
They have two VEGF and one PD-1. Yeah. But again, if you look at the molecule licensed from BioNTech, licensed from Merck, they all follow the tetravalent structure. They may call it something else, but it's pretty much that structure.
Okay. Excellent. Anything last minute in the audience? Anything we missed? Okay, excellent. I want to be respectful of your time as well.
Thank you so much.