Good morning, everyone. Thank you for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the senior analysts here. In this session, please join me and welcome Mr. Kevin Xie, CFO from Gracell Biotechnologies. Welcome, Kevin. Thank you, Kelly. Thanks, Jeffrey, for inviting Gracell to present at this conference. Great. Maybe to start off from the two platforms, Gracell has been focused on FasTCAR and the TruUCAR, allogeneic approach. Could you lay out the progress has been made from the last 12 months from both platforms? Sure. We have made a lot of progress over the last four months in our program development, specifically our lead asset, GC012F. We have had the U.S. IND cleared earlier this year, and now is actively enrolling patients for our phase Ib study. We also have a newly diagnosed multiple myeloma study, IIT study, ongoing in China. Most recently, we presented the 19 patient data with a median follow-up time of 15 months at the IMS conference in Greece in September. We will be doing an updated presentation at ASH in December. In addition, this program also have treated 9 NHL patients. All 9 of them are DLBCL patients. We presented those data at ASCO EHA in June as well. And, most recently, we have announced that we are expanding this program, which is the dual CAR. I should have clarified first, this is the dual CAR BCMA CD19 dual CAR, expanding to autoimmune and the first indication being SLE. Currently, we already enrolled more than a handful of patients in the China IIT study for refractory SLE patients. At this point, we presented some data on Monday in our Q3 conference call. And also, we are planning to file the U.S. IND for SLE before end of 2023. Terrific. Maybe let's first focus on multiple myeloma program. You have started a U.S. phase I trial in the late-line patients. Can you tell us about the progress in patient enrollment and study sites activation? Sure. The phase I b program, basically FDA's focus is on safety, so the design is two dose, six patient per dose, so it'll be 12 patient total. The enrollment will need to be staggered by the requirement of the FDA. So we have started dosing patients, and, we anticipate the total enrollment of these 12 patients will be probably, complete by mid-2024. Okay, great. And have you had a discussion with FDA on the potential pivotal trial beyond the phase I? Do you think the phase I will be actually converted to pivotal? Well, you know, in the filing, certainly we have included our phase II design proposal. In terms of process, once we finish the phase I b study, we will be having a meeting with the FDA. I think that will be the time to finalize the phase II slash pivotal trial design. So, we're going to have to wait until we finish the phase I b to get the final clarity. Okay, terrific. And, two very important features for the, your dual CAR, in multiple myeloma is... And besides the really, like, active efficacy, you also show differentiate the safety profile. I want to highlight no ICANS, no neurotoxicity, is a big differentiation from any other, CAR-T therapies in the market, and also the short, vein-to-vein time. What is your expectation to the, U.S. phase I data? Do you think you need to actually, replicate this safety profile to be competitive, given the multiple agents now in the multiple myeloma market? Yeah, it's. There's a lot of contents embedded in that long question. So basically, there are already two commercially available single BCMA drug on the market. One of them is doing very well. So for us, we understand that this program needs to be extremely differentiated, competitive to drive adoption by the time we launch our program. So how are we going to be differentiated? You know, the efficacy and durability obviously is very important. Besides that, as Kelly mentioned, safety and fast delivery are, you know, equally important in terms of making an impact on the clinical outcome and meet the patient needs. So over there, on the safety side, collectively, we have treated about 60 oncology patients. I mentioned the 29 r/r MM-... and we're gonna present 22 NDMM patients in December, and plus the 9 patients in NHL. So far, we have not seen any ICANS or neurotoxicity of any grade from the entire study, the 60 patients. The CRSs are mostly low-grade CRSs. So far, the safety profile arguably is the cleanest among the programs that we have seen in compared to single BCMA, although we're a dual CAR. So the question is that, what are we expecting for the U.S. phase I b trial? I guess the short answer is that the process has been proved very robust. So we believe that we should see consistent safety profile from the U.S. study as we have seen from the China study. But we're in the middle of that, so on the- What about a vein-to-vein time, do you think you can see further optimization? What we have. So first of all, for those of you who's not familiar with our process, the GC012F is under our FasTCAR platform. It's autologous FasTCAR manufacturing process, which basically shorten the manufacture time from multiple weeks to two days. But in terms of vein-to-vein time, there are other components. The most biggest time-consuming step for us is QA/QC, and so which takes about seven days for us. So collectively, our guidance for what we call the manufacture turnaround time is 12-14 days. That's including that seven-day QC time. We do believe that we can shorten that seven-day even further. But you know, it's more of a regulatory requirement question. I think that if you ask the KOLs who's treating patients, I think, you know, having a consistent two to three weeks delivery time to them is already a huge leap forward versus the current treatment paradigm from conventional CAR T. Yeah. Terrific. And also for the U.S. phase I, regarding the enrollment criteria, do you allow patients who had a prior BCMA agent treatment, including both CAR T and the bispecific? And, in that case, do you worry about the efficacy impairment to your agent? Very good question. We do believe GC012F, given the clinical profile we have generated, should be an effective agent for all multiple myeloma patients. So we're not excluding the patients with prior BCMA or prior BCMA CD19. Although, there are specific requirement in terms of minimum wash-out time, for those patients to join the study, and that those will be evaluated on a case-by-case basis. I would just say that, for our phase I b, the 12 patients, our expectation is that, we would not have significant number, for those prior BCMA or prior BCMA CAR-T. And once again, it's focused on safety. It probably make more sense, to have a separate cohort when we move to the phase II and evaluate those type of patient profiles separately. Yeah. On the other side, you might be able to show activity in post the BCMA settings. That's definitely true because we believe our dual CAR BCMA CD19, the binding site is differentiated from a single BCMA. So just because it has relapsed other BCMA in the past, it doesn't mean our program will not be effective. But so, so one step at a time, and this is something that we definitely understand the opportunity. Yeah. Great. Let's talk about lupus program, and now it is a very hot topic in cell therapy space. What is the potential for CAR T in autoimmune beyond the oncology, which they already showed success? So first question is, there are multiple lupus program in CAR T, but they all target the CD19. Maybe first, help us to understand why targeting BCMA is important. Sure. The study from Dr. Georg Schett that published in Nature late last year, with the single CD19 treating refractory SLE patient very successfully, was really groundbreaking. And since then, we have seen the CAR T industry have moved very aggressively to autoimmune, and the SLE is being one of the big focus. And so far, most of the companies are going in there with a single CD19 with the MOA, such that the key to achieve immune system reset is to have a deep depletion of the B cell, which CD19 definitely is a very good target there. For us, our dual target, CD19 plus BCMA, we believe is going to add additional clinical benefit. Why? While the CD19 we talked, you know, just I said, that, has been proven to be effective target to depleting B cell. They are also autoantibody secreting cell that's in the plasma cell, that a good portion of them actually are CD19 negative.... that over time, could still trigger an autoimmune reaction. So, there has been academic research including UPenn study in 2016, to support that finding. And recently, we also have conducted our, preclinical study. We share some of that data on Monday's call to support the benefit of BCMA in eliminating, autoantibody secreting cell more effectively than just a single CD19. So we believe, once again, the Dual CAR program is going to be differentiated. Yeah. Okay, great. You just mentioned the U.S. phase 1 trial could start as early as next year? For- For lupus. That's, that makes sense given that, we're filing the IND before year end- Okay. this year. Yeah. Can I make assumption that for lupus indication, you don't need to do another round of technology transfer from China to U.S.? That is correct. So once again, for those of you who's not familiar with our process and, you know, our FasTCAR manufacture process, was first invented in China, and we have a GMP manufacturing facility that manufacture the whole entire A to Z, from plasmid, lentivirus, all the way to finished CAR. In the U.S., Lonza is supporting our phase Ib study for multiple myeloma. This was after a very successful tech transfer. So all the process is identical, our China versus Lonza in the U.S. Therefore, for SLE, the plan is to have identical process. Actually, the doses we're using even are identical to the multiple myeloma program. Mm-hmm. Have you started talking to hospitals? How many study centers are you targeted to bring in for the first wave for lupus program? We have started that process. Yeah. Okay, great. Maybe dig a little bit deeper into the data you presented on your earnings call. You showed elimination of antibody secreting cells. I mean, this is absolutely relevant to indicate efficacy. But also curious, have you measured the autoantibody itself to evaluate deep response? Yeah. So what we shown on Monday, the earnings call, was that I mentioned our program in China so far have enrolled more than handful of patients. And we've shown that the four of the first enrolled patients, these are the low dose, 1 × 10^5 per kilo. We've shown the depletion of the B cell, memory B cell. We've shown the recovery of naive B cell. In addition, we also shown that we have conducted study essentially to take the bone marrow sample, purify bone marrow sample from one of the IIT patients and perform ex vivo study with single CD19 and with our dual CAR CD19 BCMA, and comparing the elimination of ASC, autoantibody secreting cell. The result have supported very clearly that the dual CAR is much, much more effective in eliminating those ASCs. Yeah. And to your question, in terms of other antibody, yeah, we are tracking many other biomarkers. It's you know, we're going to wait until we have longer follow-up time and to share those data together and more patients. Yeah. So all this data, PK/PD data, will be presented, along with the phase 1 update from China trial? Yeah. So the plan is to present the data first half 2024. What you would like to see is at least double-digit patients enrolled with multiple doses. I mentioned that so far, all the patients were dosed on the lowest dose. We have three doses. Those are exactly the same doses that we use for multiple myeloma, so we're in the process of dosing them up. You will see that, you know, hopefully, all the patients have had at least three months follow-up, maybe half of them have had six months, a few of them have even longer follow-up time by the time we present the first half of 2024. Great. And you also mentioned on the call that, you saw an early trend in B-cell aplasia in a recovery of naive B-cell phenotype. Can you talk about how we should think about this dynamic in timing, and how is it related to the balance of efficacy and the safety? If that makes sense to you. Yeah. Yeah. Basically, we're thinking about the durability of response. What's the impact on safety for autoimmune patient? Right, right, right, right. The MOA, once again, for CAR T treating autoimmune patient, is to achieve deep and durable immune system reset, right? So hopefully to achieve, quote, unquote, "functional cure." And so the depth of the depletion is important, the persistency is also important, but at the same time, you also want to balance the risk of infection. You don't want the B cell being depleted for too long.... Where is that balance being struck? I think the whole industry is still in the process of finding that. I believe it's also program-specific as well. Depends on the agents, depends on a lot of factors. So for us, what we have shown on Monday is those four patients are within three months the B cell, the memory B cell has been depleted very, very deep. At the same time, we saw the nice recovery of naive B cell from those patients. So those are exactly what you want to see. And you know, we have commented that so far the safety profile from those patients are very consistent in terms of a clean safety profile we've seen from oncology patients. Because if there's any safety issue, you would likely show up in the first few weeks. So that part we feel pretty confident making those comments. In terms of efficacy and other biomarkers, I think we need longer time to have more complete data before we can share with the public. Yeah. See, for the first data update in first half, do we expect the three-month remission rate? Um- Which has been shown in the Nature article for the German group's lupus- The- - study. Yeah, I mean, three months is not a high bar, right? And, You have longer? So we should have all of the patients have minimum three months. Okay. And, as you know, hopefully, half of them have longer than 6 months. And, you know, for the ones who dosed first, may have even nine months follow-up by then. Yeah. Okay. What would you call a success on the three months and the six months remission rate? Yeah. That's a good question. You know, Dr. Schett's data showing the 100% remission, it's difficult to improve from a 100%. You know, some people say it's not even possible. So, you know, there is a big gap in between the efficacy of the current treatment. There are two antibodies approved, and the efficacy is very marginal. I think everyone knows that, to that 100%. And, I think there's also an element of patient baseline from the German study that in terms of it's, it's relatively, you can call it, a healthy refractory SLE patients, much younger age. Our study, we are the patients we enroll so far in the much wider range in terms of, for example, the SLEDAI score and age group. So what is the definition of success? We believe, number one, safety is the number one gating factor. Needs to have a clean safety profile. What does that mean? Well, probably, you know, you don't want to see ICANS neurotoxicity for those patients. You probably, hopefully, you don't see grade 3 CRSs, at least not many, right? So from there, you know, the efficacy, whether it's 70%, whether it's 80%, whether 90%, I think we're going to have to wait until more data reported from different company to strike that balance. Yeah. Besides CRS and neurotoxicity, do you worry about the infection risks in the lupus patients? Because you target both CD19 and the BCMA, so it's a more profound impact on B cell. Yeah. It's a good question. It's a question that actually been asked, multiple times, even, in the multiple myeloma setting, because, for example, at the ASCO, when all the multiple myeloma program, all the other ones are single BCMA, a lot of questions on us, "Okay, you have CD19 as well. Will CD19 increase the rate of infection?" And then now it's the other side of the coin. Now, everyone said: "Well, CD19 looks safe, and would BCMA bring additional infection risk?" Well, luckily, we have the data. The 60-patient data I mentioned, that, the infection rate has been, in line with all the single CD19 and the single BCMA rate. So we feel comfortable in terms of our infection risk profile. Yeah. Terrific. I'm looking forward to it. And, outside of multiple myeloma and lupus program, any other pipeline candidates you would like to highlight? We also have two other platform. We have allogeneic platform called the TruUCAR, where we are working on some further optimization because we always believe for allogeneic program to be commercially successful, the efficacy and the safety needs to be at least close to autologous. You can't be just cheap and fast, right? That you're treating cancer patient. And then lastly, we also have a solid tumor program, we call SmartCAR, and we are going to present some preclinical data at the SITC very soon. And we have started enrolling patients in China IIT, so that's also a key focus of the company. Yeah. Terrific. We'll wrap up here, and thanks for a great discussion, and thanks everyone for attending.