All right. Okay, great. Thank you. I'm Yigal Nochomovitz, biotech analyst here at Citi in New York. This is the second day of our virtual Oncology Summit. It's my pleasure to have with me from Zai Lab, Rafael Amado, who's the Head of Research and Development at the company. Welcome, Rafael. Thank you for doing this. For, for those listening, if you have questions for the company, just email me, and then I can relay those over to to Rafael. Maybe, you know, just to start out, if you could kind of just give a bit of a high-level overview of the, you know, Zai Lab, and how you're, how you're transitioning from a, from a local China business to more of a, more of a global enterprise as you build out, build out your pipeline?
Yeah. Thank you for the opportunity to chat with you. The company was founded in 2014 to bring medicines to patients in China, and that, that engine continues and is commercially profitable. More and more, we are focused on bringing in global products. We have our own engine to discover either protein therapeutics, translational medicine and everything that's required to to to drug discovery, as well as business development. In the recent past, we've actually moved a global pipeline together with the local regional, very effectively. Our lead product is Zoci, which is a DLL3 ADC, which we can talk about. It is in phase III right now.
We've had INDs that have moved really fast to the clinic, like ZL-1503 in atopic dermatitis, LRRC15, which is an ADC, which is in phase I. Immunocytokines, PD-1, IL-12, T cell engagers. What we're doing is take advantage a bit of our global capabilities that we have had to build, but on the back of a very efficient engine in China that was delivering products for the local regional approvals, and they're now a strong component of a way for us to screen these global products. If we see that there's activity for China to participate and gives us access to patients. The local regional business continues and this guard, you know, it's a long-term opportunity with multiple indication.
We're launching COBENFY this year, TIVDAK as well, and we are filing TTF in or tumor treating fields in pancreatic cancer. You know, it is really a dual engine. The last one has built, has been built, you know, more recently, but it's progressing quite fast, and much of it is at the expense of having formed a really strong team and also having the China capabilities for access to patients.
Okay, well, let's start with the lead asset with ZL-1310, the DLL3 ADC, which is getting a lot of attention, as you know. Maybe if you could just kind of characterize the activity that you've seen with this asset so far. You know, what is, what are the areas that you'd like to comment on in terms of where it's got the most potential in small cell lung cancer and perhaps in some other settings as well, where DLL3 is widely expressed?
Yeah. DLL3 antibody drug conjugate utilizes a cleavable linker. Of course, we started in the tumor, and then we end up in tumor where DLL3 is most expressed, which is small cell lung cancer, and we have a very ambitious program there. We started our phase III study, and that was on the heels of a very large phase I and II study that now has over 150 patients. That showed us that the response rate at the dose that we chose for development is in the order of 68%, with a durability across all the doses and including doses above 2 mg/kg of over 6 months. This was in multiple lines of therapy, second, third line, et cetera.
We did a lot of careful dose finding under Project Optimus, comparing various doses, and we landed on 1.6 because it was the best balance of efficacy and safety. It's probably one of the safest ADCs, and there's about 13% Grade 3 toxicity. There's no drug discontinuation. Then some of the properties to highlight is that it's incredibly active in the brain. We are looking at this very carefully, but patients tend to respond after the first or second dose at an 80% rate, which is a big problem, brain metastasis in non-small, in small cell lung cancer.
In addition to that, and because of this, we want to move the molecule to first line and neuroendocrine carcinoma, where we're seeing encouraging data as well, and also to combine it with other products like T cell engagers, in addition to checkpoint inhibitors. These are some of the properties of this product, and we're already enrolling in second line after platinum and after tarlatamab, and we plan to start the frontline studies and the NEC study this year.
Okay. The first study would be for an accelerated approval? Is that in the second line? Is that how you're thinking about it?
The way it's designed is, it's, it's an overall survival study with an interim analysis for response, which could lead to an accelerated approval. All patients need to be approved before we do that analysis, and we think that they will be approved by March or so, about a year from now. And then we will do the response comparison. It's not just response, it's also durability. And then if the accelerated approval occurs, then it will continue on for overall survival for confirmation. If the interim analysis is positive, we'll, we'll file in 2027 with a PDUFA timeline somewhere in 2028.
You said this, you got about a 68% overall response rate in the data you've seen so far. This would be an accelerated approval based on ORR response rate? Is that how you're thinking about it?
That's correct. It would be based on an ORR response rate compared to the standards that are available worldwide. This is a global study, just like the initial phase I study was a global study. We will include chemotherapy, anthracycline, because that's something that's used in Japan, lurbinectedin and topotecan. We're including, again, patients that have failed tarlatamab, so that's why we're not including tarlatamab in the control arm. It's a comparison to second line, and the patients I'm sorry, to chemotherapy, and the patients could be second line or may have received tarlatamab as well.
What would you be expecting for the control arm, blending all the topotecan and lurbinectedin, and amrubicin? What, what would be expected there from response?
Response rate, you know, in the mid-twenties or so.
Okay. sounds like you have a pretty good delta already built in, if you, if you reproduce what you've seen in the, in the dose escalation part.
Yeah, as a matter of fact, we wouldn't need that many patients. It's just that, we have to have all the patients approved, otherwise there will be no equipoise after, after the approval and to continue the study. Also, we need to build a sufficiently large database to be able to file. The study is, is, as you, as you allude to, over power.
Okay. Assuming you get the accelerated approval, then it would be fully approved on OS?
Yeah, the study will continue blinded, and we will follow patients for overall survival. Of course, you know, we don't control post-progression therapy, so patients that have not received tarlatamab could receive tarlatamab or, you know, lurbinectedin or any, any other therapy. We think that it would be distributed randomly. The only thing we're doing is stratifying for tarlatamab or no tarlatamab in the patients that are enrolled, so that we have an even number in both arms.
Okay. Are there other considerations, for example, to have a, a, another endpoint that would look at just the brain mets? Because you mentioned that the response there was also very, very high. Is that something that you would-- that has, has that been built into the study?
Yeah, it's been built into the study. It is, it's not a specific endpoint because the response rate in the brain is difficult to categorize as a regulatory endpoint. I must say that, you know, it's something that investigators really have really capitalized on. Unlike other studies, you know, we decided to enroll patients that had brain metastases that were untreated, because a lot of these patients present with very bulky disease, and they progress very fast. If they have to stop for brachytherapy or some other Gamma Knife or something else, their systemic disease would just move quite fast, and the patient would be debilitated to receive chemotherapy. We actually have a higher response rates in patients that have untreated brain mets.
Now, we will look at that in the statistical analysis plan, and we will report on that. You know, there is a lot of interest in this, but it won't be, you know, quote-unquote, an approvable endpoint. The endpoint will be overall response by RECIST.
Okay. Then you mentioned-- So then the frontline study, how would that work? You're gonna go up against, like, a tarlatamab, or how would you do that? What would be the plan?
Tarlatamab has some studies in first-line, in combination with chemotherapy, also, study in so-called maintenance. There's some examples of ADCs that, combined with checkpoint inhibitors, have been able to supplant chemotherapy, and we hope that this is one of those examples. To that end, in the Phase I/II study that we started, and we've added several cohorts, one of the cohorts that we added was first-line patients treated with ZL-1310 plus atezolizumab, or that doublet plus carboplatin. Then we yet need to analyze that data for durability and then make a decision as to what the regimen will be. The control will be very obvious. It will be the current standard, which is platinum etoposide and a checkpoint inhibitor.
We don't think that, you know, by the time that we start this field, the, this study, the field would have changed so dramatically. At the moment, our goal is to see enough durability and high enough response rate to be able to supplant chemotherapy in the front line.
That you said you would combine with, like, did you say tislelizumab, a PD-1?
A PD-1. It will probably be the durvalumab or, or, or atezolizumab. You know, they, they're both used, you know, at the preference of the investigators.
Okay, when could you foresee that one, that first-line study starting?
You know, thankfully, we, we don't have good durability yet because, you know, patients are staying on study. That data is gonna come, you know, mature data is gonna come sometime in the second half of the year. We plan to present other data along, along the year, but this will come later on. We obviously will know what the data tells us in, in the beginning of the second half, and then make a decision then as to whether to proceed. You know, there are other possibilities, which is, you know, combinations with T cell engagers and so on, but there is insufficient data to really be able to launch a phase III study at the moment.
If we do more than 1, our first 1 would be chemo sparing, starting in the 2nd half of the year.
Okay. These studies, the second-line study, as well as the contemplated first-line trial, these are, global studies, right? Where are they, where are they enrolling, in which geographies?
We, we decided to do global studies even from the inception, because we think that that represents real-world data. I mean, we, we're seeing other products do trials in China, and we know by experience that there are differences between regions. The study will take place in Japan, in Korea, in China, in Europe, and obviously in the United States, in Turkey and some other countries. It will be a truly global trial.
Okay. That makes sense. Okay. How did... In terms of the competitive landscape, because there are a few other DLL3 ADCs out there, as you know, and there's some that are not ADCs, but they're, you know, different, like T-cell engagers. How do you, how do you see your asset in this, in this competitive landscape? You mentioned-
Yeah.
You have a good dose. You know, you picked the 1.6, which you felt was a good, a good mix of balance, safety, and tolerability with FPC.
Yeah, exactly. I mean, we've seen other payload linkers that are similar to this one that we are employing, and the doses are slightly higher. Of course, you know, it has to do also with the affinity of the antibody, whether it's internalized or not, depending on the target, the half-life, et cetera. 1.6 is a relatively modest dose, as opposed to 2, 2.4, et cetera. As a consequence, we don't have a lot of myelosuppression. We don't have, you know, Grade 3 or above ILD, and the combinability should be easier. I don't see these products competing with T cell engagers.
T cell engagers tend to require higher target expression, and the ADCs tend to work really well in bulky disease, in spite of low expression, because the payload and the linker gets cleaved in the tumor microenvironment. Even cells that are bystander can be killed by the payload, which in our case is a Topo1 inhibitor. Doing that will expose immunogenic death and new epitopes that, having been attracted, the T cells to the tumor bed, they could potentially react to. We view this as orthogonal mechanisms of action.
With regards to other ADCs, there are, there are some that, you know, are more advanced, perhaps, the IDEAYA is the most advanced one, but we, we have at least a year ahead of them. You know, so far, their data comes from China. The follow-up is slightly lower. We'll just have to see how all these drugs play in the in the treatment of small cell lung cancer. A lot of it is gonna have to do with how they're developed, how they're combined, and how they're positioned, what line of therapy. You know, we are very focused on our, on our product and moving it as fast as possible.
Right. Let me, let me see. There are a few other assets that are worth discussing. I'm not sure which one you want to mention next, but sticking with the ADCs, you have the LRRC15 ADC. This is the 6201. What tell us more about that target, and what, where you would go with that molecule?
This is a leucine containing molecule that is expressing in tumors that have mesenchymal origin, namely sarcomas, some neuroblastomas, some melanomas, and it's highly expressed in osteosarcoma as well. It so happened that it's also expressed in fibrous tumors that contain fibroblasts. We have preclinical data with several models that have no expression of the target in the tumor cells, but it's expressed in the CAFs, or cancer-associated fibroblasts. Because the payload and linker get cleaved, that tumor microenvironment, there can be influx and efflux of the payload into cancer cells that don't have the target. In PDX models, we see activity not only in tumor positive marker, marker-positive tumor, but also in marker-negative tumors.
Of those, breast cancer, pancreatic cancer, head and neck, lung cancer, those are the ones that tend to have the highest expression in fibroblasts. Our study is dividing the cohorts into patients that are tumor negative but CAF positive, and also a group of sarcoma patients. I think it's a pretty exciting drug. This target has already been used. There was another company that developed that discover an ADC, and there was some activity, but it was, it was just too toxic, and the development of it was abandoned. There is a chance that it may work on taxane-resistant failures in sarcoma and ifosfamide.
If it, if it works in tumor negative, I think it would prove a very sort of pioneering event in the field of ADC, which is that you don't actually need to have the target in the tumor for these drugs to actually have activity.
Okay. That one, I understand that just started or is starting this quarter.
Well, it just started. Yeah, we, we got in January the Study May Proceed letter from FDA. We're opening sites and, you know, recruiting patients. You know, we, we file in China, the CDE, and once, once we, we get sites open there, we obviously limit the number of patients. We, we start getting accrual relatively fast. I must say, there's been a great interest in the sarcoma community, both from Europe and the United States, on this asset, so I, you know, I'm, I'm looking forward to seeing the results.
The other oncology assets that are coming up that are going to enter the clinic this year are the ZL-1222. This is the PD-1/IL-12, and then the ZL-1311, which is the MUC17/CD3. Which one of those would you like to highlight as, you know, most, you're most excited about?
Yeah. It's-- so in oncology, we're working on ADCs and innovation of ADCs, so we will, we will, you know, proceed with dual payloads, biparatopics, and, you know, some other modalities. We also want to enrich for tumor for T-cell engagers as well. We started with MUC17. That's, that's a pretty exciting molecule, at least preclinically. It targets two epitopes. It also has silencing of not complete silencing, but attenuation of the CD3 moiety, so that perhaps CRS is not as as pronounced as it can be with the typical bispecifics. This is for gastric and gastroesophageal junction and other GI tumors. That, that will be an IND this year. Then we have this immuno cytokines like PD-1/IL-12.
This has been a long time coming, being able to give IL-12. IL-12 is a very potent CD8 T-cell stimulant. You know, we have data that PD-1-resistant tumors actually can recover sensitivity when exposed to IL-12. What we did is we have dual chain PD-1 in the N-terminus, and then we constructed IL-12 muting, which is obviously alter the amino acids to signal in an attenuated way. It doesn't signal in the periphery and doesn't cause all the toxicity of IL-12. It only signals in the tumor microenvironment in CD8 cells. We have done some elegant studies where, you know, tumors regress, but if we actually deplete of CD8, the tumors grow, and it seems to be mediated by CD8s as well as NK cells.
You know, it, it, it, it will be a product that we'll probably test in PD-1 failures, and then from there, it could move into other tumors where checkpoint inhibitors are the mainstay of therapy and see whether, you know, they're, they're better, just like the whole field of PD-1 better.
Okay, this one has both-- for both, 12.2 and 1311, you decided to do the Fc silencing. Is that right?
Yeah. This, this is, this is, we, we mutated Fc, to increase the half-life in, in this product. Yes.
Okay. What I'm not familiar with other assets that have these combos, like the PD-1/IL-12 and the MUC17/CD3. Are these unique, as far as you know, in the landscape?
At least they have innovative properties. I mean, the other, the other changes that are being done to bispecifics is introducing costimulatory molecules. They, they may stimulate CD8s with more potency and perhaps derive a more juvenile kind of population, because T cell exhaustion is one of the mechanisms of resistance of bispecifics. We, we perhaps may, you know, get into this area with either 4-1BB or CD28. There is a lot of innovation in this space. We can access companies not just in the U.S., but also in China, where there's a lot of know-how, technical know-how in both small molecules and protein sciences.
The same thing with ADCs, where, you know, now dual payloads are coming into play, biparatopics, you know, more than one epitope, and then payloads that are small molecules that are not even chemotherapy, that can be targeted to specific tumors. These are, these are some of the innovation in these fields that we, we would like to be a part of and at least be able to test them and, you know, see whether we have, vulnerable decisions, in patients, potentially in Asia, where, where we have, much more access than in the U.S.
I just remembered, though, there is a, there is another PD-1/IL-12 from Innovent, right? How is yours different, or is it, is it different?
Yeah, it's a larger molecule. The, the, as far as we have been able to tell, the IL-12 signaling is, is really, really attenuated. There's hardly any IL-12 stimulation. You know, time, time will tell how, in terms of how it behaves in the clinic. Dialing this requires very careful, you know, mutation of amino acids because you don't want it to be too promiscuous, but at the same time, it, it, it has to stimulate the CD8 cell. You know, my-- our impression is that the CD12 and the IL-12 stimulation of our product is more adequate than the Innovent one, but, you know, we will have to prove this in the clinic.
Okay. Moving away from oncology, you know, the, you have the IL-13, IL-31 receptor bispecific for atopic derm. I think you're going to have some data in the healthy volunteers coming up this year. What do you need to see on that, on that readout, to move forward and, and, prepare for a, for a phase II?
Yeah, we're very excited about this product. Um, in, in preclinical, uh, non-human primates, uh, we see inhibition of pruritus, uh, uh, immediately, and it tracks, uh, with a single dose, it tracks with the half-life. The same with [vorinostat], it gets, uh, abrogated, uh, for the duration of, of the, uh, PK of the product. Uh, so we're testing now the same thing, the PK and PD, in healthy volunteers in single doses. Uh, we, uh, we launched that IND last year, and we've already accrued, uh, two of the cohorts of the healthy volunteers, and then we're moving into multiple ascending doses in patients with atopic dermatitis.
In terms of what we need to see is, you know, the abrogation of scratching, which may lead to a faster healing of the lesions mediated by IL-13, because of mechanical damage of the skin. Also a half-life that allows extended dosing by patients. Of course, if we, if we can get lack of conjunctivitis or, you know, some of the side effects that are seen with Dupixent, that would obviously be a plus. We continue to generate preclinical data in other Th2-mediated diseases like asthma, rhinitis, prurigo nodularis, and eosinophilic esophagitis, et cetera.
We will be publishing that, those data, but we're starting in, in, in atopic derm, and the patients, patient cohort, the multiple ascending dose, we should have actually efficacy data in addition to PK/PD in the second half of this year.
Right. Then, you know, just guys, I guess more generally, as you think about the global development pipeline across oncology, the assets we talked about, and then the autoimmune, you know, your-- what is Zai Lab's plans as far as development, and, and, and maybe even commercialization? You're going to do this as a, as a independent organization, or would you, you know, maybe think that you'd need partners in other territories to help market the products, or how, how do you think about that ?
's an excellent question. Obviously, you know, for Zoci, we want to have a very broad development plan. And, you know, we are pursuing this as I described before. Obviously, it will depend on what kind of activity we see with the other products. And we will file at least one IND every year, and perhaps bring, you know, one product from business development. I think in oncology, we can prosecute these programs. In non-oncology, it may be a little bit harder for us to do it alone, and we will be open to, you know, collaborate with companies that have been in this space and have done multiple indications in the past.
We think that, you know, before doing that, even though we, you know, we, we do have conversations, we ought to characterize the product better, not only just in terms of getting INDs, but also getting subcutaneous formulations that are going to allow for self-injection and as well as good PK, good PD, and efficacy. I think we will probably take this to phase IIB 1503 and then take it from there. Yeah, we see ourselves as a, you know, strong R&D engine that has a commercial branch in China, and eventually we'll launch products in the United States, and we'll be a global company with multiple assets, both in mostly in oncology and immunology.
If you launch... I mean, we're talking far in the future here, I guess, maybe not so far in the future, but if you launch DLL3 and you launch, you know, the PD-1/ IL-2 and these, the MUC17, if those all launch in the United States, and you get the, you get the atopic derm products to the market, would you still, you know, you'd have them in Europe and the United States, would they be in China, too, or you wouldn't, you wouldn't launch them in China, or you don't know, it depends?
I mean, it would be logical to retain rights in China, but I think every product will be treated on its own merits and depending on the resources that we have. I mean, they are finite, both in terms of, you know, people and personnel and, and our ability to fund all these programs. At the moment, every product that we are developing, we have a development plan for China and now Japan as well. There's a group in China that is taking care of Asia-Pacific. If a product gets out-licensed, then the, that, those would be discussions to be had, whether this is global rights or whether anything gets carved out. I mean, I think that that will be done on, you know, on a one-to-one basis.
Right. You mentioned. I just wanted to ask one specific question. On Optune, you said you're going to be filing in for, for the Tumor Treating Fields in pancreatic, yeah?
That's correct, yeah. I mean, the file is ready. We, we, we obtained innovative medical device, which allows us to have a 9-month review. As you know, Novocure obtained FDA approval, so we have the dossier ready, and we expect the approval to be happening this year.
You still are selling it for GBM, right?
Yes. Yes.
Mm-hmm. Okay.
Yes, the, the, we, we are selling it for GBM. That's correct.
As far as I understand, for non-small cell lung cancer, you, you decided to, to not pursue that, correct? Is that right?
Yeah, that's, that's correct. I think for non-small cell lung cancer, there was insufficient interest, you know, from the technical perspective, business perspective and opportunity cost that we didn't launch LUNAR-2. Lung cancer is a difficult and more difficult indication, and pancreatic cancer is a stronger unmet medical need. We also have constraints commercially, and we and development-wise, so we decided to wait for PANOVA-3. Likely, it was a positive trial, so we're pretty excited about this.
Right. We didn't talk about an important asset with in kidney disease. Let's, in the last few minutes, few minutes, I guess, pove, povetacicept. That's an important product. Can you briefly just describe the market for again, there in China? You know, how could, how could that asset be sold in China?
Yeah, so I, I, and what we does is have is BAFF APRIL targeting agents. So it, it essentially inhibits the secretion of antibodies, including IgA. The, the data, the phase II data is actually quite impressive. The market is, is pretty large. It's over 3 million patients with IgAN. You know, they, they get treated normally with blood pressure medication, like renin-angiotensin-aldosterone system, sort of in-inhibitors, diuretics. The problem is when they become nephrotic, and eventually 20%-30% or so patients with time develop a decrease in renal function to the point that they can end up in dialysis. It is an important medical problem.
You know, our, our, our partner has moved pretty fast to try to get approval based on an interim analysis, and we are having discussions with CDE to do likewise. You know, continue the to follow the patients for a longer time for a full approval. You know, the endpoints are proteinuria and maintenance of renal function. Those discussions are taking place now with, you know, our, our partner, Vertex and FDA and us and CDE.
Okay. Well, thanks, Rafael. Appreciate it. A lot of interesting assets, a lot of novel biology, and we're looking forward to seeing how it all, how it all shakes out. Thank you.
Thank you so much, Yigal.
Much appreciated.
Take care.
Thank you.