Great. Good morning, global investors. Thank you for joining CStone Pharmaceuticals' ESMO Data Review Conference Call. The call is going to be mainly focused on the CS2009 data readouts at our recent medical conference ESMO. Today, joining our call, including Jason Yang, CEO of the company, and also Nicky Ni, CFO of the company. This is Ziyi Chen, China Healthcare Analyst at Goldman Sachs. I am going to be moderating this call. Before we kick off the session, I would like to highlight that this call is strictly for clients of Goldman Sachs and CStone only, and this conversation is not intended for the media and is off the record. Participants will be removed from the call if they cannot be properly identified, and this call is not for the purpose of sharing or receiving non-public, otherwise confidential information.
Attendees are public and market participants who may not receive and should not request non-public and otherwise confidential information about issuers or securities or about market securities. We already see the data coming out, abstract and also earlier today there has been a presentation. Now I am going to hand over the call to the management team to get started on the introduction of the data. Then we are going to potentially open the line for potential Q&As if you have any questions. Jason, please.
Yeah, that is great. Good morning. Thank you guys for calling the data interpretation, also a little bit of update and a little bit perspective. We have been truthfully very happy with the data. I think for phase I, we just want to look at four aspects. I think typically PK, PD, safety, and the preliminary anti-tumor activity in the phase I background, and also in reference to similar drugs, right? I think we see many of this data meet our expectation and quite a few actually exceed my expectation based on the design. So I am happy to share with you what I think of this data and what is the next step. Yep. Next slide, please. This just show you that today we talk about tri-specific, but we do have quite a few on the right sides that will go into clinical next year.
We probably have three or four INDs next year. We can talk to you guys later. Next slide. Next slide. Yeah. Just to remind you that why we are here today, right? We designed this molecule four years ago, and really the driving force is that we need to have a second generation IO backbone that not only have PFS but really, really has OS that can beat the current standard of care, right? PD-1, PD-L1 plus chemo, or maybe plus some CARs. But the bottom line is the IO backbone has to be improved. We have tried all kind of things, right? Recently we. I mean Tivicay is recent example, and they also tried 4-1BB.
In the early days, people tried TIM-3, [INDX 3], and all kind of stuff, but that really did not improve upon PD-1, so it's not yet systematically beat PD-1 plus chemo, right? In the end, we realized that CTLA-4 really, really is the only molecule that add to PD-1 can improve OS further, right, anywhere from 5%-12% over a year of 10 years. In all those trial, CTLA-4 only dosed two to three cycles because of toxicity. Now if I can make a molecule that can contain CTLA-4 antibody and that can be dosed together with PD-1 continuously for one or two years, I would expect a lot more improvement of OS upon PD-1, right? This is because we know PD-1 does improve OS over standard care. Now we want to improve OS upon PD-1 by adding CTLA-4.
Now, the VEGF, it's very important. It's not only important because it has the angiogenesis function, but more importantly, as I will explain further, in the tumor microenvironment, it can create a framework that actually trapping PD-1, CTLA-4 in the system. So make it work much, much harder. Okay? Now, the problem, of course, has been how do you make the CTLA-4 tolerable, right? Safe and tolerable. So that this actually bring us back to the two Nobel Prize in the past several years. The first one, of course, is the function of CTLA-4, discovery of CTLA-4, as a brake immune checkpoint, right? That actually block CD28 from over-activation because that is so-called immune second signal to stimulate by binding, CTLA-4 binding to CD80, right? That's the first Nobel Prize. The second one is this year's peripheral immune tolerance.
Really just to say why we can-- the normal human body does not attack our own tissue. So that's the peripheral immune tolerance, and that's Treg. Now, the Treg, the whole Treg function is the same because CTLA-4 is blocking CD80 binding to CD28, so there's no over-activation either. Okay. Now the toxicity associated with CTLA-4 is actually coming from this tube. So on the right side, this tube, right? So your CTLA-4 antibody is so potent, it pulls CTLA-4 from CD80 so that CD28 can get activated. Okay, so how can we generate or create a molecule that does not actually pull CTLA-4 from T or regulatory T cell or Treg cell? Now, if you look at the CTLA-4, it's actually a dimer, right? And the CD80 is a dimer. So essentially, their binding is like a monoclonal antibody, so that's a bivalent binding, very tight. Okay.
Now, then we make an antibody that are monovalent, only one arm of CTLA-4. So the affinity will be much weaker at around 20-30 nanomolar instead of a single or subnanomolar, right? So in this case, it will now be able to pull CTLA-4 from CD80 in the peripheral. Okay. Now, in the tumor microenvironment, that's different because tumor microenvironment has T cells that get exhausted as they all express PD-1, right? And then tumor express PD-L1. So interact with PD-1, that actually suppress effective T cell. Now, we have the trispecific antibody that also contains PD-1 antibody. So in this case, PD-1 and the CTLA-4 will bind to both PD-1 and CTLA-4. So in this case, it could have affinity-driven enhancement of affinity, restore the binding affinity of PD-1, monoclonal PD-1 antibody, and also monoclonal CTLA-4 antibody.
So this kind of synergy make antibody works to block PD-1 and the CTLA-4 actions in the tumor microenvironment. This actually is further enhanced by the VEGF NWO. So the VEGF bind to VEGF-A, which is a dimer. So it causing cross-linking, forming a network, and that will further enhance PD-1 and CTLA-4 affinity by 10 to the fourth to 340. So in a sense, the trispecific antibody work on three targets synergistically within the tumor microenvironment, working very hard. But in the peripheral tissue, they are actually pretty flat, so not working so hard. So there we expect a lot of efficacy, but relatively low safety issues in there. So let's go to see whether that we actually are meeting this goal. All right. We started phase I trial March this year, and we finished enrollment of 72 patients really, really fast.
It's because this is dose escalation with spec failures, so it's, you've probably just seen a lot of trials. This is an unbelievable speed. Actually, we also started phase II, because with the data we have, we started phase II already, and we expect to enroll treatment-naive non-small cell lung cancer by end of this month. We should have enough data by middle of next year to start phase III trial. So our plan is to engage U.S. FDA pretty soon for the phase II expansion, and then by the middle of next year or Q3, we engage with FDA for the end of phase II and the pre-phase III negotiations so that we will have a dose HR design and agree with U.S. FDA. Indication-wise, the most important is the chemo combo in first-line squamous, non-squamous, non-small cell lung cancer.
The other two, one is in the second-line setting, combined with docetaxel or something else against docetaxel. That should be a very easy win, the trial. That post-IO, of course, because you will see post-IO, the drug's working. So this will be a good indication to win. Of course, there's always the monotherapy in the first-line setting. Whether we are going to do that or not, I think we will together, make that decision with our partner. Because that's going to be a pretty challenging trial because enrollment, right, is not going to be easy. Okay, so this is our plan. So now let me just show you the data from the dose escalation. Next slide. As I just mentioned, 72 patients. The median age is a typical phase I patient, so it's pretty old patients. The trial enrolled more than 55% of non-Asian, right?
Non-Chinese, let's say. Mostly, it's all actually from Australia, so 54% are white. On the prior therapy, also typical phase I, so almost 40% of patients have three and above three prior therapy. Prior IO, so 51% of patients have prior IO therapy. Some of those has multiple round of IO, including bispecific. So essentially, every patient that should be treated with IO has been treated with IO, and there's also off-label treatment with IO. Angiogenesis, same situation. So everyone that should be treated with VEGF has been treated, and there's also off-label treatment. So the tumor type, non-small cell lung cancer is the most numerical patients because we focus on that. Even though a lot of those patients has not yet had a first tumor assessment. We only have 17, as you will see. But we enrolled 33 already. Next slide.
The first important readout for us is the safety, and that is also what our multinational company has been telling us. They always say, "If you can make it safe, it might work. We do not worry about efficacy, we worry about safety." If you look at the safety of the grade three and above TRAE, right now it is only 30.9%, and the grade three immune-related TAE, it is about 4.2%. We know this is relatively short follow-up, but you also can tell that 20 mg actually has been followed up. 21 patients have been followed up for quite a while, I think three to four months. 20 mg per kg is not a low dose. It is pretty high dose. Those 1 mg to 10 mg have quite a lot of those patients escalated to, from 1 mg to 3 mg, from 3 mg to 10 mg, and 10 mg to 20 mg.
There has been quite a bit of up intro dose escalation to 20 mg. You can see this. Those data are much more mature. As you know, that irAE typically occur in week four to week eight, right? I think for the dose one to dose four, I think we pretty much all passed the week eight at least, right? I think this safety looks, even though it is immature, looks very attractive. Next slide. This is just an easy way to visualize the safety, the most frequent AE. On the right side, you can see very few grade three TRAE. Next slide. Obviously we want to look at relevant comparators, right? In our case, we have tri-specifics.
We definitely look at both PD-1, CTLA-4 specific, PD-1, PD-L1 plus CTLA-4 combo, CTLA-4 alone, and then PD-1, PD-L1, VEGF bispecific, and the PD-1 monoclonal antibody. If you just look at the grade three TRAE and the TRAE leading to treatment discontinuation, against all these classes, you can see right now it is very, very favorable. We do expect it will go up, but we think that it will be similar. At the worst, it will be similar as the PD-1, VEGF bispecific. Next slide. We also look at the irAE. In this case, we look at any grade irAE as well as the grade three irAE versus the same classes of molecules. Again, the frequency right now of irAE and the grade three irAE are very low. Again, I think even if the data mature, we will still be in pretty safe places. Next slide.
We are looking into the detail of frequent irAE. Those typically is skin rash and the thyroid disorders and then SGLT, right? There are rare ones, but we are not seeing many rare ones yet because the sample size is still small. But even if you look at the more frequent ones, right now it is much lower than the PD-1, PD-L1, CTLA-4 bispecific or PD-1 plus CTLA-4 monoclonal combination. Right now it is very well-tolerated. Next slide. This is actually interesting, is look at the VEGF related tox, because we have the same VEGF that is from Ivonescimab, right, sugemalimab as AK112. Also the molar ratio is the same, right, as AK112. Both molecule are 200 kilodalton. We have the same molar ratio. Meaning that our 200 mg contains 15 mg of ivonescimab as AK112 does.
But right now, of course, with the shorter follow-up, if you look at the four type of VEGF related tox, the hypertension, protein urine hemorrhage, and the simple embolism. Right now it is very low, so we have two cases of hypertension, one case of protein urine, and one case of hemorrhage for a patient who have duodenal ulcer, so that patient should not be enrolled, but he signed the consent into the 3 mg per kg. So in general, right now, the VEGF related tox is really low. So this is very, we are very happy. So OIM escalator is also very happy because they think that hypertension, they typically can manage it, but sometimes protein urine is a problem, especially in grade three, right? It is recurring because you are losing essentially nutrition. So, so far so good for the VEGF related tox. Next slide.
So PK, so typical, a textbook like linear PK. So that means we do not have a lot of ADA, neutralizing ADA antibody interfering with PK, or there is no target-mediated drug disposition. So it still looks good. Half-life, 6-8 days. Similar to AK112, probably one day longer than AK112. Next slide. The receptor occupancy in the peripheral T cells, so you can see that at 20 mg, the blue line, we saturated the receptor occupancy. And that saturation also can be observed even before the second dose, so-called the dose interval, right? So it is a cross-dose interval. We still have more samples coming, so the 30 mgs will have more longer follow-up. But overall, you can see from the blue line, which is 20 mg, it is actually the receptor occupancy is constant. So that helps us determine those going forward.
But this certainly is an underestimate of the receptor occupancy within the tumor microenvironment because this is a peripheral. Because in the peripheral, there is no synergy, and in the tumor microenvironment, there is a lot of synergy, so that binding will be much tighter. Next slide. The pharmacodynamic biomarkers. So the T cell proliferation, as indicated by upregulation of KI67 and also the CTLA-4 specific activation as a suppression, as indicated by ICOS. If you look at the top, the proliferation on CD4 proliferation essentially is driven by CTLA-4 blockade. So you can see a plateau at 10 mg per kg, okay, this again is in the peripheral. And for KI67 in CD8, that is contributed by both CD4 blockade and the PD-1 blockade, and you see also a plateau around 10 mg going forward. ICOS also behave similar at 10 mg.
So essentially, 10 mg should work, and we see it works, right? But going forward, you always want to have a little bit of margin going forward at 20 mg or 30 mg probably will be the right dose taking into Phase II. So next slide. Now, this is interesting. So this is the serum free VEGF-A. You can see that even at 1 mg per kg, immediately post-dose, the serum free VEGF dropped from about 500 to undetectable level, below 10 picogram per ml. Okay, and it stayed that way. And that is true for 3 mg per kg, 10 mg per kg, 20, 30 mg per kg. So this is actually very different from either AK112 or bevacizumab. In those case, the serum free level can jump up and down after dosing. Right?
A lot of people asking why this one behave differently or why the suppression is so much tighter. I think it's hard to explain. The only way that I can explain this is because we got three targets in the tumor microenvironment that cross-linking causes the VEGF actually trapped inside the tumor microenvironment so it does not come up that much. That would be a reasonable explanation, but of course, there's no evidence to say that's true, but right now there's no need to really know the mechanism. As long as know that we know the cross-sensitivity definitely neutralize VEGF-A, that's, again, it's another way of proof of mechanism. Next slide. The efficacy data, this is the cut for the ESMO poster, and just one week later. Next slide. Just one patient converted from SD at third tumor assessment to PR.
At 20 mg per kg, then dose-wise, it looks better. Essentially, every dose you got some response, right? Because the denominator is different, the response rate actually as you go up the dose, it looks like there will be more response rate. That we'll wait to see, right? Data will mature further. I think important to see is that the disease control rate. Remember, all these patients are coming with tumor progression. If the drug has no effect, the tumor will keep growing, so you will not see a lot of stable disease. That's reflected in disease control rate. We have a 71.4% of disease control rate in this phase I patient population. That means the drug is actually working. Next slide. Right. Then we look into which tumors actually have reached a partial response level.
We have 17 patients from post-IO non-small cell lung cancer. Everyone has IO treatment, and 41% has anti-VEGF treatment. The response rate is 17.6, and the disease control rate is 42.4. Within the 17 patients, there are five patients who are EGFR or something else mutation. As you know, EGFR mutant non-small cell lung cancer does not respond to monotherapy of IO. If we remove those five patients, and they're all actually three out of 12, 25%, and DCR reached 83.3%. This is a pure post-IO AGA active, AGA negative non-small cell lung cancer. This really support this drug will probably works better in both front-line and the second line, right? Because you are overcoming IO resistancy.
If you remember EGFR TKI, the third-generation EGFR TKI are much better than first-generation because it can overcome some of the resistant mechanism of first-generation EGFR TKI. This is important. You need to have this type of data to be confident you will be able to beat KEYTRUDA, for example, right? Because those are PD-1. Right now we know that our drug works post-PD-1 like KEYTRUDA, and we actually have a lot of patients who have KEYTRUDA from Australia. Then you look at ovarian cancer, relatively cold cancer, TNBC, relatively cold, and nccRCC, non- clear cell or renal cell carcinoma, relatively cold, and then a soft tissue sarcoma, very cold. The drug is working across these type of tumors, looking at disease control rate as well as response rate. Next slide.
For the 17 non-small cell lung cancer, we look at the duration of treatment and also the timing of response. If you look at the left side, the green one is 10 mg. 10 mg, you have two patients that still are on treatment, and one SD, another one is PR on the third tumor assessment, right? It is coming a little bit slow, but it is still coming. That is also typical of later stage clinical trial. You do not see all the response in the first tumor assessment, right? In first line, you see probably 75% of response in the first tumor assessment. The remaining typically in the second tumor assessment. But in later line, the sensitivity is lower, so you see quite a few response coming later. Okay. Also, 10 mg apparently not enough, so you have three patients progressed at 10 mg.
For 20 mg, more patients stay on treatment right now, and also you have one patient becoming a partial response at second tumor assessment. For 30 mg, right now we have four patients. One patient progressed. Three patients, one of those patients had the tumor response at first tumor assessment. Again, we have a lot of other patients at 30 mg that have not had tumor assessment. When those happens, we expect a tumor response rate where it goes up more than probably 25%. Okay. On the right side, we are also showing you the, each one has IO and then tumor type, squamous, non-squamous, both response, right? Because there is quite a few non-squamous, so the safety is not an issue. Then the VEGF treatment, prior treatment, and also the AGA mutation.
Look, the AGA positive ones do not have partial response, so they do have some SD and also PDs for this patient. So drug is still working in this population, just not as sensitive as-
Next slide. We look at all the 49 patients who have had at least one tumor assessment and looking for duration of disease control. The first patient is a soft tissue sarcoma patient. The patient has a partial response at second CT scan. The first CT scan has a 24% of tumor reduction. Those escalate patients from 1 mg to 3 mg, and the patient has been on 3 mg per kg as of today. The patient is still receiving treatment with a tumor reduction of more than 40%. This patient has failed three lines of chemo before coming to the clinical trial. I think this is really lucky for this patient because otherwise, there is really no treatment, right? The soft tissue sarcoma. In the early doses is longer follow-up. You can see the disease control rate is pretty good.
We are talking about seven, eight months already for lower dose patients. For higher dose patients, there is a lot of patients still on treatment. The follow-up time is still short. I think it is very promising for us to expect to see a pretty long PFS for this phase I cohort patients and when the data mature. Next slide. Correct. We put all these data in perspective of relevant drugs with their phase I trial data. You can see you are all familiar with this phase I molecules. They are all relevant, bispecific molecules, either bispecific VEGF or bispecific CTLA-4. Immediately you can see that our trial has much higher prior IO therapy, and we have much shorter follow-up because we need to report data early for a lot of other purpose. The disease control rate is much higher.
To all, it is very similar. It is hard to compare because each trial enrolled different patients. AK112 phase 1 enrolled quite a bit of ovarian cancers, so you got a 25.5 in that trial results. For others, it is enrolled different patients, so it is hard to compare. The DCR, it tells you it is a lot, okay? Meaning that our drug is working across different tumor type. Next slide. We are trying to do apple-to-apple comparison. We pick up all the non-small cell lung cancer plus IO patients from various trials from this molecule. The old case, we already show you that out of 17, we have three partial response. If we get rid of AGA negative positives, the response is 25%. On the second column, that is a relatively new trial for [AD04] plus VEGF, both similar.
It is a relevant trial because that is on a second line, pure second line setting, 47 patients, and then they are all AGA negative. I think this is good trial design. They definitely want to focus on AGA negative second line and trying to generate data, like potentially trying to head-to-head against those Taxotere, right? Because you cannot add to docetaxel, you already have two drugs and that is going to have a lot of toxicity problem. I think with this 12.8% response, I think trying to head-to-head against docetaxel has some challenge there. Whereas in our case, we can add it to docetaxel, right? Because we have a single drug that is much more and also much safer. Just talking about going forward. You look at some other trials, so for example, the AK104 phase Ib/II trial that has 23 patients.
Those again are AGA negative or unknown, and in this case it's line two and above. In this case, 23 patients have no response. The PM8002 trial has eight patients. Those eight patients, they're all AGA negative and at second line post-IO, they have one response, so 62.5% disease control rate. If you look at across this, you can probably appreciate that the trispecific antibody is probably going to do better in post IO non-small cell lung cancer with or without AGA mutation. This is actually good for us because we want this drug to work in first-line non-small cell lung cancer and also second-line non-small cell lung cancer in combo with chemo and to beat KEYTRUDA with chemo.
Certainly we can also do a monotherapy, but I've said that before, that's going to be a tough decision to make. Next slide. We see the phase I data from our development molecule. When the phase I data was wrong, people are probably not impressed with that first phase I data, right? But when those molecule come into phase II treatment-naive, either as monotherapy or combo with chemo, the response rate suddenly jumped, right? It's getting much higher than a typical PD-1 or PD-1 plus chemo. Each one is slightly different because sample size, and also baseline. Bottom line is, the bispecific plus chemo or bispecific alone has a better response, better PFS than PD-1 plus chemo or PD-1 alone. That's a given, that's a fact. Just like HARMONi-6 reported yesterday.
Of course, the problem is that whether you will have OS, right? We here, we fully expect that we will see similar or slightly higher response rate, longer PFS, and much, much longer OS. We truly expect that the CD4 will add 10% of OS on top of PD-1, right? With the bispecific PD-1 VEGF that adds roughly 20%, together you can add about 30% of OS on top of PD-1, current PD-1. Then you will be pretty safe to run phase III trial. That's the expectation going forward. Next slide. This is a summary of what I just said. I think the safety tolerability, with immature data, it's very encouraging. We also have very low infusion reaction, so that's really a good thing to have.
The fact that with dose to 45 mg per kg, a continued dose at multiple cycles already, the highest cycle we have is probably 12 cycles already, really saying that we manage CD4 toxicity really well and also VEGF toxicity. The PK/PD, really showing the drug is behaving well inside the body, and the PD showing that the drug has bonded to its target and it's doing what it's supposed to do on PD-1, CD4, and the VEGF. Under tumor activity, you definitely see good response in post IO, post-standard cares tumor in a phase I setting. You see very encouraged efficacy in post IO non-small cell lung cancer that support our phase II focus on non-small cell lung cancer. Certainly, we have 15 cohorts. There's a lot of other cohort variety.
But because non-small cell lung cancer is the most compatible one market-wise, we want to get into that, start a phase III before we get a box start. That is the future development. I think that is it. I will be happy to discuss further if you have any questions.
Sure. Thank you, Jason. This is very comprehensive and really congrats on the data. I think safety data looks pretty promising for us to moving forward. Since we talked about safety, there is a couple of questions so we try to understand a bit more. Number one is that when we look at the AE, across different doses, right? How should we understand the reverse dose dependency? Grade three plus TRAE actually is 24%, 9.5%, 7.4% when the dose goes up, and particularly grade three plus irAE only observed in the lower dosage, right? While in the DL5 and DL6, we did not see any of the irAE. How should we understand that?
Right. The number one is that the early dose, it is not just lower dose, the early dose has been followed up much longer, right? So we first take the dose in March, so we are talking about seven, eight months. As well then the 45 mg, those has been followed probably one to two months. So it is much shorter. So even though the irAE typically come out four to eight weeks, right? So there is not much come out yet. As I said, the AE rate will goes up, but even if the AE rate goes up by 50%, it will be very much within the acceptable range for a trispecific antibody, right? So that is one obvious explanation. The second is 1 mg to 10 mg is not really just 1 mg to 10 mg. There is quite a few patients escalated already to 20 mg per kg, right?
But it still belong to the initial 110 cohort. Okay.
Got it. Is it fair to say that we should be taking, let's say, the dosage cohort one to three safety profile, given you mentioned that for those lower doses, has been followed for a longer time. Meaning grade three plus TEAE is 38%, TRAE about 24%, irAE about 10%. This is kind of like baseline when we are looking forward for a potential that the safety profile going to be showing in this study.
I think it's a reasonable assumption. Except that in early days, when we enroll patients, right, there are some enrolling is probably not appropriate. For example, we enrolled one patient with Duodenal ulcer, right? Cells of the pancreas. Those actually not supposed to be enrolled because those patients have a strong bleeding tendency. But we do have one patient at 3 mg. That patient does have grade three hemorrhage, right? That's actually increased the hemorrhage case. I think a small sample size, sometimes one or two events, they can tear the scale higher disproportionately, right? Disproportionately.
Again, I think the frequency is one thing. Secondly, is the type of AE, whether it's relatively easy to manage it. For example, grade three hypertension is probably easier to manage it than grade three protein urine, right? Also, like in this case, we have grade three AST/ALT without a symptom. That's also considered as a grade three in this counting of five, right? I can tell you all the five. The AST/ALT is one of that. Then in the grade three neutropenia, that's also grade three. Essentially, when you look at all these five grade three, you're not concerned. We're not concerned.
Got it. Also how should we be looking at the potential RP2D?
Yep.
Probably 20 mg or 30 mg. Also, if you look at the data, right? Well, of course it's all small sample, but 20 mg looks the ORR a bit lower, right?
Yeah.
But I think your PK chart already showing that it's pretty dose-dependent, linear, kind of perfect chart for that. So when the sample starts getting bigger, we should be expecting higher dose going to give us better response, right?
Correct. So we will really be making decision based on data. You can see that in the dose escalation, 20 mg, we have 21 patients, 30 mg we have 27. So those data is going to mature eventually. Also in the phase II, we are going to enroll homogeneous patients, like non-small cell lung cancer, then comparing 20 versus 30, right? For example, each arm has 20 patients, for example. That will be giving a pretty good assessment as to efficacy and safety. Based on that, we will make a decision which dose to take forward.
Got it. Thank you. This is a question actually, today we got from investors, is that because from when you're explaining the design and the mechanism that you mentioned about the PD-L1 is a single valent design, CS2009, right? Versus a lot of bispecific antibodies is actually bivalent. So is it fair to expect lower efficacy for your asset at a 20 mg per kilogram compared to a bispecific bivalent design at the same dose level? Or is it actually relevant because you have the synergistic effects and also the affinity might be also different through different design.
Yeah. I think the biggest misconception for IO is that you want to have very, very high affinity molecule. Right? Now look at the PD-1. So who has the highest affinity for PD-1? Who has that? Tislelizumab, right?
Right .
Libtayo actually has higher KD, higher affinity than KEYTRUDA, right?
That's right.
So, if you look at literature right now, people realize that for blocking antibody, you do not want to have super high affinity. Because in a tumor microenvironment, when you have a super high affinity, which has higher Kon but low Koff, its binding will not come down. So it is actually forming a protective shield around the tumor, and then more drug cannot pass through that shield. So the activity, the antitumor activity actually get decreased. Okay. So you really want to have a moderate Antibody that it goes on, it goes off, right?
Yeah.
And then once this gets on, there is all kind of a synergy. The synergy actually solidifies this network bonding. Because our antibody, remember, we have a lower affinity, but we got much higher dose. So it is really saturating the environment, right? So it is just like, you attack a city. You do not have very strong giant, or 10 or 20 giants, but I could have 100 just immediate sized soldier, right? So they probably will not do the same job or do better. That would be the idea.
Got it. Well, also you mentioned about you are going to run a randomized control trial there between the 20 mg versus 30 mg to determine the RP2D, right, for the phase III.
Yes.
Could you elaborate a little bit more about the potential design when you are going to start to do that and sample size, all what kind of indication you will be targeting?
Yes.
And when we are going to have the results for that?
Right. It is funny that you mention this. Look, if I want to make a drug, I do not want to make a shitty drug, right?
I would not try to deny a trial with 1,000 patients because I am not confident I will have OS. I put a very, very high OS hazard ratio, and that will necessitate a large sample size, just trying to get a statistically positive trial, maybe with a hazard ratio 0.8 or 0.82 or 0.78. I think we need to have a hazard ratio, OS hazard ratio, 0.75 or below in order to beat out in the market the current standard of care, right? To convince people that there is really better drugs around. For me, for the first-line squamous, non-squamous phase III trial, I think I will targeting a hazard ratio OS 0.75, right? I definitely do not want to go higher than that. Okay? If I have 0.75, my sample size is around 700, right?
Right.
700 deep. It cover both squamous, non-squamous. PFS is not even an issue because no matter what you put there, it is going to pass, as you would expect. Really, the sample size will be driven by your OS assumption. I do not want to do a shitty trial with 1,000 patients just in order to get a drug approved. Of course, I probably would not be the person making that decision because I think when we have this phase III started, I certainly hope that we have partner already joined us. For the second line, that actually is going to be relatively simple design. I think 300 patients might be good enough if we get rid of AGA positive patient population. You add on doses and they compete against docetaxel . OS only, OS, PFS.
You can do a due primary there. OS is definitely necessary for approval for the second line setting. I think that will be a fast-to-market trial. We are actually very excited about that trial.
Got it. Thank you. Well, of course, non-small cell lung cancer is going to be the key indication you will be targeting for sure, given it is very large. Of course, it is very competitive.
Sure.
But in this set of the data, we already see that there has been OR observed in several other indications, ovarian cancer, TNBC and RCC, STS. Among all those potential indications, what are could potentially be the ones you will be pursuing beyond small cell lung cancer?
Right. The most attractive one would be the first-line CRC, right? We have not enrolled those patient in dose escalation because if we open that indication, then majority of patient will be CRC because Australia has just way too many CRC. We specifically say, "I don't want to have CRC in my dose escalation." Phase Ib/II, we will have chemo combo, first-line chemo combo for first-line CRC, right? We fully expect that will be a very promising trial. Tri-specific plus CRC against a CRC plus maybe bevacizumab or something, right? I think just like AGo2 is doing, I think this is definitely the right thing to go. We have the advantage of CTLA-4 trying to convert a cold tumor like a CRC into relatively hot tumor. RCC and HNSCC, because those are the PD-1 chemo it did not do well, right? It's moderate, right?
Those are moderate efficacy. I think we go for that TNBC. PD-1 only, PD-1 10% and above has an indication, but that effect is very weak or very same deal, right? All this, I think the tri-specific has a lot of advantage to beat KEYTRUDA, all PD-1 containing standard care.
Got it. Also in the phase I study, this is still very small sample. We don't see you break down by Asian, Caucasian population, but it's roughly 50/50, right, based on your baseline. Have you observed any of the difference between Asian population, white population, any difference here in terms of response?
Absolutely not. Non-small cell lung cancer mostly come from China, so you see results there, but you look at ovarian, you look at TNBC, you look at soft tissue sarcoma, RCC, they're all coming from Australia.
Oh, got it.
Yeah.
You mentioned about phase II and that you are enrolling patients very fast. Could you elaborate a bit more? How many sites you have open and how many patients enrolled, what percentage, how you are going to be running that, and particularly when we should be expecting a data readout?
Yeah. The first question is easy to answer. We opened totally more than 30 sites in China and Australia right now. In Australia already started to enroll patients in one of the 15 cohort. In China right now we got CDE permission to enroll first line non-small cell lung cancer, so we are going through the EC process. Once that got approved, we should have a really quick enrollment for non-small cell lung cancer.
Our hope is that we will have some cohort that have enough patients to report at ASCO next year. Also ASCO, we will have phase I maturity, right? Data will be very mature at ASCO. I think, I also do not exclude that we might have some data disclosure in between, if we have some mature data readouts that are interesting enough for investors.
Got it. Thank you. I know you do not really provide a guidance on when you are going to be looking for a partner, a timeline. I think it is also not reasonable to provide any timeline. But just thinking about, you definitely need some partners to sponsor or co-sponsor some of the large future global trials, right? If you think about that, I bet that at ESMO, you already have been talking to some of the people on potential collaborations, potential future working together, either on trials or on more deeper collaborations. So when you are thinking about picking partners, what are the criteria? What type of partners you will be looking for?
Yes.
Definitely top 20 pharma companies, or you are also going to be thinking about potentially selecting some smaller players, but who will be very committed to local trials.
Good question. The reason I come to ESMO is not because I want to stand in front of the poster, right? I do not need to do that. I have our CBO here, CSO here, and myself, and also a BD VP. So we have more than 10 high quality, multi iterate meetings with potential partner, right? Certainly I cannot say which one will submit a term sheet, but I can sense that the interest level is really high because most of those people already know the background. They talked to us more than one years ago before we actually have the drug in the clinic.
They also guide us what their interest is. Like I said, safety is their number one concern. Typically, they are not worried about efficacy. They think this is all validated targets. If your drug is doing what it is supposed to do in the PD-BD, you should be able to see efficacy at different stage of the trial. That is the situation. I certainly hope, and I am pretty confident that we should have a partner before we truly start phase III trial, right? We do not want to wait for partner to drive regulatory processes and also preparing data to support phase III trial, right? Because then you will be in trouble because they could delay your time significantly.
What is going to be the most important thing that you need to attract other partners? Yeah.
Right. I think we are talking about a drug that is going to revolutionize the IO field. I certainly do not want to pick a partner who just takes a drug and then do some small-scale trial or shitty trial. I want somebody who takes this drug and try and really wipe out the KEYTRUDA market. Again, the clinical capability and their track records and their business plan, I think it is more important than how much money to pay up front. Certainly, there will be a market price for this, right? We all know how much it should be worth. I know there will be competing processes.
Got it.
Yeah.
You mentioned about, I'm very interested about that, is that you mentioned about phase II, you are enrolling very fast, and particularly you now are talking non-small cell lung cancer indications. But for we are knowing that in China, there are so many different PD-1 plus, bispecific, trispecific, ADCs. They are pretty much competing for first line, squamous, non-squamous, second line, those EGFR wild type, non-EGFR or EGFR mutated population. I am kind of wondering why you still feel the patient enrollment is not an issue. Are you guys not competing with each other to getting the best quality of patients, getting the best quality of PIs?
Yes
for all those trials?
Yeah. Look, that is actually an interesting point. Even though you see so many noises from WeChat or from all kind of conference, right?
Right.
PIs do understand. You talk to them, they do understand which drug is going to be beneficial to their patients. But of course, they are also driven by some other things other than the patient's need. But bottom line, they are still a doctor. Okay.
Right.
You can probably tell why we are going 33 non-small cell lung cancer, right? So quick. So from 10 mg, 20 mg, 30 mg. So just very quickly in the last December month. So they understand that bispecific is going to have an uncertain OS issue, right? That is a fact now, right?
Right.
Like yesterday, look at the HARMONi-6. If you look at the second slide yesterday, their design, PFS 27 hazard ratio. I think that is actually conservative. OS assumption, it is 0.73 with 80% of the power. That is aggressive, right? So with that trial design, you think the OS will be able to succeed? Take a look. I will send you the folder. So pay attention to the chart design. So that is almost telling me that is going to fail OS, right? So really, for us, we have done quite a few pivotal trials. So H1, PFS, SOS, and the high quality, high publication. So PI know us. They want to work with us. Also, to some extent, they do not want to lose that partnership with us, right?
Because we, for example, a PD-L1 or a drug, in our hands, I can publish the JAMA with Zhang Yang, right? Publish in New England Journal of Medicine three times with [Su Sanhong] and others. Publish in Nature Medicine, publish in Cancer Cell. So this is the type of publication we get. Also the drug getting approved by EMA, the U.K., based on China owning trial. I think that also was mentioned yesterday but discussed right under sec TNT, right? Dimension of sugemalimab. So this type of quality help your trial progress because they know they are working with true professional. Okay? So that is also important.
Got it. Thank you so much. We have been running the call for about an hour. We still got a lot of questions. It is very interesting asset. It is the first time we see a new set of data by a trispecific, and definitely we are looking forward to more data in upcoming six months, 12 months. So hopefully next time when we discuss the data, there is more positive surprise to us, to investors. Thank you so much. Any wrap-up comments from you?
No. Thank you. I think, thanks all . After, I think we certainly appreciate your interest. I think that working together, we are pretty much all like it is, okay, raise a child, right? I always like to say that you can see the child grow and learn new skills and also becoming stronger. I think we expect to see that. I think in six months, we should have a lot of first-line patient data, so we do not have to explain why you do not see that today, right? That is good. So thank you so much. Yeah.
Yeah, no problem. Thank you so much. We are going to wrap up this call here. Thank you.
Yes.