Hello everyone, good evening, good afternoon, and good morning. Welcome to HUTCHMED R&D Day. Today we are very happy to have our CEO and CSO, Dr. Weiguo Su, on the line, as well as Dr. Mike Shi, our Head of R&D, as well as our CMO, in here with us. Today we are going to share with some exciting prospects of some of our key products with you. And you know, right now everyone on the line is in a muted mode. But you know, at the end of the presentation, when you have questions, you can raise your hand or type your question in the chat box. Now, without further delay, let me hand over the time to Dr. Su. Dr. Su. Thank you, David. Good morning, good evening. Welcome again to HUTCHMED R&D Day. We hope to periodically share with you the progress of our programs. Today's session is designed to give you an update on our late-stage programs. Michael Shi will do most of the talking. Before we get there, though, I just want to give you a quick overview on our late-stage programs. Fruquintinib, as you know, our flagship product, it's now approved in China, obviously, for third line and above colorectal cancer. It's been on the market in China for almost six years now, with over $100 million in sales last year. Late last year, fruquintinib was approved in the US for late-stage colorectal cancer and launched immediately after the approval in November last year. Recently, in June, EMA approved fruquintinib in European countries. So we are working together with our partner Takeda to prepare for the launch in European countries. The NDA is still under review in Japan and many other countries around the world. Savolitinib, our selective MET inhibitor, it's approved now in China for MET exon 14 skipping non-small cell lung cancer. We just submitted an NDA in China, based on the confirmatory study, again, in MET exon 14 skipping non-small cell lung cancer, including treatment-naive patients. And it is also in several other studies in lung cancer, as well as gastric cancer, intended for registration in China. It's most exciting. We expect NDA filing in the U.S. based on the SAVANNAH registration or pivotal study, later this year. It would be our second product for registration outside China. Through surufatinib, we'll provide you an update on clinical development in first line pancreatic duct adenocarcinoma. Recently we shared some data; we published some data at ASCO and also ASCO GI. And based on the encouraging study, surufatinib now entered into a phase II/III study for this very difficult to treat disease. Obviously, surufatinib is on China market for a few years now for neuroendocrine tumors. And it is now pretty much the prescription lead for in this category for this particular disease, with over 20% market share. Very exciting, savolitinib. You're gonna hear more about from Mike. NDA is under review with priority review status granted. We expect, hopefully, approval before end of the year for immune thrombocytopenia, which is actually an autoimmune disease, our first product for autoimmune disease. savolitinib is also in a registration phase III study for a related disease called wAIHA or warm autoimmune hemolytic anemia. And you're gonna hear a little more about it as well. Also exciting, we just kicked off our international clinical development of savolitinib for autoimmune disease, specifically ITP and wAIHA, as the initial indications. And in China, obviously, as we anticipate the approval later on this year, we are preparing for the launch of this product. HMPL-306, our IDH 1 and 2 dual inhibitor, entered into phase III registration studies in China for recurrent and refractory AML. And obviously, as you know, it's a very exciting product with high potency and selectivity, as well as excellent brain penetration. So it could be suitable for glioma, for instance. So more to come, obviously, for this compound, particularly in solid tumors. Now, not on this slide, but also now, in the registration stage are our in-license EZH2 inhibitor, tazemetostat. NDA was accepted in China with, again, priority review granted. The first indication is a late-stage follicular lymphoma. And this product, together with our partner Ipsen, is also in a global phase III, including China, in second-line follicular lymphoma. And also, obviously, it is also approved in the U.S. for epithelioid sarcoma, and other, and with potential for other solid tumors. We are quite excited about the potential in solid tumor area. Another product, HMPL-689, our selective VGF, I mean, FGFR inhibitor, is also now in pivotal phase II, in cholangiocarcinoma with FGFR2 mutations and rearrangement. So, we also look to complete enrollment and hopefully file for approval soon, maybe next year. So all in all, we have seven late-stage products, and these, and for almost every one of these products, we are looking to develop for new indications and to maximize the clinical as well as commercial value of these products. And these products together will drive HUTCHMED growth for years to come, certainly for the next three to five years and beyond. So today, Mike will give you an update on surufatinib, savolitinib, as well as HMPL-306. And you know, we also look to give you an update on our early programs in due course. So with that, I'll now invite Mike to give you an update for the three products I just mentioned. Mike, please. Yeah, thank you, Dr. Su. It's a great pleasure to hear, be here to update your key programs. Yeah, so as Dr. Su said, right, so we are gonna highlight some of the key program, you know, for our first wave product. So, surufatinib, we are, you know, expanding this, into the clinical development for pancreatic cancer. And, this is a, you know, in the big market and, for the incidence in China, about 100,000 cases. And, with the estimated market size, CNY 300 million-CNY 1 billion. And as the main, clinical therapy at this point moment is really the chemotherapy as a strain. And globally also has a, incidence of 500,000 cases. And the representing is a high unmet medical need and this, so this is a, one of the area I'm gonna update you about a, indication expansion development for our first wave product surufatinib. Also very exciting is the second wave product, savolitinib, a highly specific SYK inhibitor we develop in-house. The initial indication is targeting immune thrombocytopenia. In China, there are about 100,000-250,000 actively treated cases, with a market potential of $100-$700 million. Globally, it also has an incidence of some 57,000 cases with a prevalence of 500,000 cases. And with the current market for the product globally, you know, around $5 billion range. And on the new product front, third wave compound, the first dual inhibitor, IDH1 and IDH2 dual inhibitor, our initial clinical development also have updated the presentation for AML at the EHA. And with the incidence of about 20,000 cases and the China market $100-$200 million. And also there has other potential in other disease indication. Also globally there are about 190,000 cases in AML. So first I'm gonna update you about savolitinib. We presented the key data last month in Europe at the European Hematology Association meeting. And this could potentially be the best-in-class SYK inhibitor and also the first-in-class compound in China. And also we developed in-house is our first innovative product. We already submit the NDA accepted by NMPA with the priority review with the hope to get the approval later this year. And so there are several fronts. We're gonna update you about the savolitinib. The NDA already under priority review and also we kicked off the registration portion of the clinical development for phase III portion of the trial for wAIHA in China in May this year. And also overseas developments already started, you know, in US, EU, and Australia. And also we have preclinical data and evidence there are more autoimmune disease indications we can pursue. First, I'm gonna give you an update about the ITP, and immune thrombocytopenia is with very limited treatment options. With the first line, pretty much the glucocorticoid treatment and second line with the TPO-RA agent, and fostamatinib, which is first inhibitor approved by FDA, but have a limited the durable response, with the durable response rate only 18%. And overall the patients have a high unmet medical need, have a poor quality of life and due to the fatigue, activity restriction, anxiety and the impact their life and the work. So, on the right-hand side is the recent report by IQVIA about the assessment of the China market for autoimmune thrombocytopenia. And there are 41,000 newly diagnosed cases and also 215,000 patients under active treatment. Equally important as about half of the patients; 215,000 patients actually lost follow-up, primary reason due to non-effective treatment or, you know, the cost associated with, you know, for treatment. So this is a highly untapped market. Globally, there are 50,000 cases and 520,000 prevalence. And also there's multi-billion dollar products currently on the market. First, I'll give you a very short update about the autoimmune thrombocytopenia. The ITP is an autoimmune disease. The body generates immune antibody attack to its own platelet in the blood. And as a result, it, you know, is lower the platelet and increase the bleeding. And so most of the patient when they first diagnosis, there are initial symptoms, right, like a bruising and the bleeding and also bleeding in the nose or the mucosa. And also, there could be a long-term effect, right, for the patient have internal bleeding. Also, as some of the critical cases have intracranial bleeding can lead to actually incapacity and also even death for the patient. So there's a huge unmet need for the patient with ITP. So the initial diagnosis, the patient with clinical criteria less than 30,000 platelet level and they could be asymptomatic or with minor bleeding. The standard treatment is a high dose glucocorticoid treatment less than six weeks. But most of the patient, over 50%, yeah, 50%-70% of patient who have do not have a long-lasting response, a risk, relapse. And they could the persistent or the refractory ITP. Subsequent treatment, which is the second and third line treatment, primarily based on the patient preference and also the development, like I mentioned before, the TPO, TPO-RA is the widely used second line treatment like our eltrombopag, romiplostim. And also, the anti-CD20 antibody rituximab for patients, some of the patients treated with splenectomy. Even though there are some newer versions of TPO-RA treatment and fostamatinib as a first SYK inhibitor approved in the ITP, there are still, you know, after second line treatment is very limited option, because, the, the traditional way is recycling for all these, agents, but not have a very durable response rate. So savolitinib, we think with the first line, our phase III trial, conducted in China, based on the clinical, endpoint, right, the primary and all the key secondary endpoint were met. And the NDA is already accepted by the NMPA, in China, in January. So, just a few words about mechanism of action for spleen tyrosine kinase or SYK. This is a key signaling pathway. It primarily works in the Fcγ receptor, BCR or B cell receptor and interacting all these immune cells and leading to all the downstream effect, autoimmune disease, inflammatory disease or even hematologic malignancy. And clinically there is strong evidence that clinical proof of study and also fostamatinib was the first approved SYK inhibitor. There are also potential other autoimmune indications, for example, rheumatoid arthritis, systemic lupus erythematosus, SLE, or could also be malignant lymphoma like the lymphoma. And the lymphoma. And the major treatment, right, I mentioned about the glucocorticoid, corticosteroid and rituximab and splenectomy is really targeting the blocking the cells, Treg and the B cell to produce autoantibody. And the other class of drug, TPO-RA is really stimulating the bone marrow megakaryocyte to produce more platelet. So, the primary mechanism for these existing therapies, what is different for the savolitinib, the SYK inhibitor, is that it has a dual mechanism. Not only can they block the autoimmune B cells to produce autoantibody, it also works on the macrophage, blocking the macrophage to engulf and degrade the antibody-coated platelets. So they have the dual mechanism, really have a potential to really treat the root cause for autoimmune disease. So, one difference for savolitinib compared with the first generation of SYK inhibitor fostamatinib, it has a highly specific target on SYK. Not only had a higher potency compared with the R406, which is the active metabolite for fostamatinib, it also a highly specific inhibitor, only the SYK pathway. For fostamatinib, not only they hit the SYK pathway, but also in inhibit about 20 other kinases. So, undoubtedly, causing the off-target toxicity. So a lot of undesired effects, for example, the GI toxicity, this inhibiting effect on the VEGFR inhibitor also leading to hypertension really have a narrow therapeutic window for fostamatinib. And so for the next generation savolitinib, actually we have a higher potency on the target of SYK inhibition, but also they have less off-target effect, with reduced off-target toxicity in the preclinical model, in the anti-CD40, CD41 treated mice. This just mimicking the human autoimmune ITP. And you can see on the left hand side there is a very rapid depletion of platelet level and treated with savolitinib and can sustain the platelet at a higher level. And the gray bar with the IVIG, which is another commonly used ITP therapy. So preclinical is good evidence inhibiting SYK pathway while maintain the platelet level. So, last month we presented our pivotal trial ESLIM-1 study and the EHA study as our presentation. So I'm gonna briefly update you about the key top line results for ESLIM-1 in the EHA. So this is a phase III randomized multicenter double-blind placebo control trial conducted in 30-34 centers in China. And patient population is chronic ITP with patient with a diagnosis of over 12 months and also receive a one prior line therapy. And patient could allow to have a common ITP therapy, one ITP therapy when they enter the study if they're under stable condition. It's a 2-1 randomization trial of savolitinib 300 mg QD doses with a placebo in the pretreated patient population. There's a 24-week double-blind per treatment period for patients who did not respond. After 12 weeks treatment will allow to enter the open-label study. The primary endpoint is the durable response rate, which is defined by the platelet count over 50,000 at four of the six visits in the 14-24 weeks. And not counting at the rescue therapy. The secondary endpoint is overall response rate, time to respond, and the reduction of rescue therapy and concomitant ITP at a baseline and the WHO bleeding score and quality of life. There are three stratification factors, baseline platelet counts less than 15,000 or higher than 15,000, concomitant ITP therapy, yes or no, prior splenectomy, yes or no. So these are the basic demographics for this ESLIM-1 trial. The highlights, the three red boxes here are the three stratification patterns. You can see this as is very balanced between the treatment on the placebo arm with the baseline ITP count less than 15,000, the 60%-60%, and splenectomy and also the concomitant ITP treatment, about 33% or 32% of treatment. So it's highly balanced. And the other parameter, as you can see, is underlined here is the baseline ECOG score, 21 with 13, which is slightly imbalanced. And also the prior ITP treatment in the treated arm is 75% patient who previously treated the TPO-RA versus 65% of the placebo arm. And also the bleeding score, which is also higher, 69% versus 53%. So in general, as you can see, in the non-stratified patient population, overall the treated arm has actually more severe patients with ITP. Here is the primary endpoint in the ITT sets. savolitinib significantly improved the durable response rate compared with the placebo. What I really wanna point out here, you can see it because this is heavily pretreated patient. There are four lines of, average four lines of treatment for, either placebo or savolitinib group. And the placebo is really, there's just no, no durable response, 0% versus savolitinib group, we have 48.4%. This is really exciting because, so far counting the durable response rate, this is the highest, for all the product approved or in the experimental condition. So far we have observed that the highest durable response rate and highly statistically significant with p-value 0.0001. And also some other key clinical parameters, at least one platelet count over 50,000, which is the overall response rate is 71, 71% versus 16%. And also patient with two consecutive, platelet counts over 30. Also, increased double from the baseline level in the 0 to 24 weeks. Also is very high in the treatment arm is 73% with the 6% in the placebo. And also the other clinical, key endpoint is, platelet count over 30,000 and increased with 20,000 baseline and, 75% versus 22%. So, all these, high, you know, robust clinical, criteria for platelet increase, has been demonstrated in the savolitinib treatment group. And also looking at the subgroup analysis and highly consistent among all the different subgroup, regardless gender, baseline platelet, and TPO, TPO-RA treatment, concomitant medicine treatment, all these, right? and, and also the anti-CD20 antibody treatment is highly consistent. There's a, a wider boundary for the prior splenectomy, is, it's also favorable for the savolitinib group, although the interval is, wider. This is probably because it's a small number of patients, only eight patients, in this splenectomy group, which is also reflecting the clinical treatment paradigm practice in China. Also, we can see the platelet increase is very rapid. So the top purple line is the patient with the durable response. The middle line is the total patient with the savolitinib treatment. The lower line is a placebo arm. As you can see, after seven days, in one week, so the platelet already increased over 50%, 50,000 and sustained at a high level. So the onset is very rapid. The overall duration of response in the responder is 18 weeks in savolitinib versus 2.6 weeks in the placebo group. Another area is very interesting as we're looking, the savolitinib treatment is highly consistent in the prior ITP therapy. As you can, you know, this is a heavily pretreated patient, average line prior therapy is four line therapy. So in patients, with the prior therapy less or equal to three line, and the four line or higher than five line, all the durable response rate, overall response rate and the proportion of patient with a consecutive platelet count over 30,000, and double from the baseline, all consistently favor savolitinib group. Even though in the placebo group, in the less treated, heavily pretreated patient, you see some, overall response. But, as the patient, on the right hand side, you can see when they reach the five line, over five line, literally zero response. And the savolitinib group, which is, still a large portion of the patient, have a favorable, robust and highly consistent durable response rate or response rate. So, it's really from all these clinical parameters demonstrate that clinical response data is highly reproducible regardless prior line of therapy. And other endpoints, we also see savolitinib reduced the rescue therapy. And in patients, you know, if there's a condition by judgment of investigator, they can use rescue therapy, either IVIG or platelet infusion. These are significantly reduced in the savolitinib treatment group compared with the placebo group. Only 22% of patients during the treatment received the rescue therapy, which is over 10% less patients as a rescue therapy compared with placebo arm. And also another very important parameter, as you recall, about 33% of patients when I entered the trial, they have concomitant ITP therapy, most of them are corticosteroid. For the savolitinib treated patient, there's a significantly higher portion of patients, 27% versus 10%, have patients with the reduced dose reduction or even discontinuation of the baseline concomitant medical treatment, medicine treatment. Because if the platelet level reaches over 100,000 and, you know, over four weeks, by the criteria, by judgment for the investigator, they could potentially reduce or discontinue the concomitant treatment, but keep the savolitinib. And that also the WHO bleeding score also significantly decreased in the savolitinib treatment arm. In terms of quality of life, it has been measured by SF36. All the eight domains look favorable to the savolitinib treatment. What I highlight here as the key function, physical functioning, energy and fatigue level, and general health, these are very important quality of life measurement for ITP patients. The savolitinib treatment has reached a statistically significant improvement in these domains. So, generally, the patient quality of life improved in the ESLIM trial. Also, I wanna show you here because, you know, traditionally, if you look at the, the ITP field, when fostamatinib was launched, there were, you know, generally in the medical community, they think the SYK inhibition might not be as potent or effective because fostamatinib, for there were two phase III trials, they only reached durable response rate about 18%. But from our analysis, really, it's not the SYK pathway is not critical or important for the entire ITP, but it's actually is the drug itself for fostamatinib because not only as you recall about, fostamatinib, it's a prodrug, it needs to be converted to a metabolized into the active component, R406. But also, from the, because the off-target effect, side effect, have a higher toxicity and limited the, dose level it could be reached. So from our analysis, you need to have a sustained target inhibition for SYK inhibition with the EC50, about a C12 of 47 ng to inhibit this exposure. So fostamatinib only hit less than 12%, reached the target inhibition level. But savolitinib, what we show here is the light blue color line here is the 300 mg QD dose we used in the phase III trial had the sustained 24 hours target inhibition. So this really demonstrates savolitinib has the best in class potential, have a sustained target inhibition and also this clean profile and limited off-target effect and have a better wider therapeutic window. And here also update you about the drug exposure and safety summary. And the median exposure for the savolitinib group is 24 weeks and versus placebo is 12 weeks, as you call. If the patient don't have a response, with a platelet increase over 50,000, they can actually, you know, withdraw from the, the double-blind period and open-label, enter the open-label stage. So we have, savolitinib have a longer, exposure duration. And, also the compliance for the two group, placebo and savolitinib is very similar. Also important on the, treatment-emergent adverse event, particularly the high-grade, TEAE, the savolitinib treatment arm, with a greater than three, TEAE, the placebo and the savolitinib treatment group are very similar. And serious AE also very similar. And there's a very low, discontinuation rate, about 3% of the patient for savolitinib treatment. And also the patient with the, dose interruption or reduction is about 12%. So in general, the savolitinib is well tolerated, in this second-line trial. And also here's the most common TEAE by P term. The top one is the upper respiratory tract infection, COVID-19 infection, the LDH increase. So as you see, the study enrollment period for the phase III trial, ESLIM-1, is September 2021 to the end of 2022, which is the later part of the enrollment is really the pandemic exposure for COVID-19 in China. So the upper respiratory infection and COVID infection is really reflecting that. And also, I wanna mention here the exposure time for savolitinib on the left panel here, which has a longer duration of exposure, the treatment duration is 24 months, 24 weeks versus 12 weeks in the placebo. So highlight the EHA results for ESLIM-1. And they met all the primary and secondary key endpoints in this very heavily pretreated patient population. We are very pleased to have seen highly robust, durable response rates, 48% savolitinib versus zero in the placebo group. Also, in patients which are also heavily pretreated with the TPO, TPO-RA, 75% have been exposed and refractory to the TPO-RA treatment. There are equally very consistent efficacy results observed. And the fast onset after a week of treatment, the platelet increase already very obvious. And also, it improved the bleeding score and quality of life, including fatigue. So, in general, also I wanna mention, compared with fostamatinib, it has low GI toxicity observed in the ESLIM-1 trial and less hypertension. And also importantly, I wanna mention here, there's just no thromboembolic event that has been observed in the ESLIM-1 study, because TPO-RA agents are stimulating the platelet production. Sometimes they can have an overshoot of the platelet, leading to a higher incidence of thromboembolic event. This SYK inhibition pathway has another advantage with no thromboembolic event. Salvaleplanib is an efficacious and tolerable option for chronic ITP. Also, compared with the emerging therapies in development, the FcRn receptor agonist, and also the BTK inhibitor, rilzabrutinib, the other SYK inhibitor, cevidoplenib, and also the BAFF inhibitor monoclonal antibody, ianalumab, all these have been reported. If we look at the durable response rate, it is all, you know, very, range from a lower end for the fostamatinib, 18%, to 20% to a lower 30% for the other new agents. We are very excited about the data, the 48% durable response rate in the ESLIM-1 trial. Also looking at the primary ITP landscape, I mentioned that TPO-RA, TPO-RA agonists are predominant as prescribed market share, you know, both globally and also in China. And globally they reach, you know, Promacta have a over $2 billion treatment, sales and, and Nplate also over a $1 billion status. The, the two agent, TPO-RA and, hetrombopag is only available in China. And Tavalisse, which is the fostamatinib, also approved in the U.S., U.S., Japan, and Europe, reached at $94 million, sales in 2023, pretty much limited by their, less durable response rate, in the late line therapy. This is the treatment landscape. We think, savolitinib has a very unique position, which is gonna be an added MR in, in this, ITP treatment. And also mentioned some of the undesired effects for the existing therapy, for example, of eltrombopag, the hepatic decompensation, liver toxicity, the black box warning, and also have a drug-drug interaction, some other effects like cataracts, transaminitis, and side effects. Avatrombopag, which is a newer TPO agent, and also have a risk of blood clotting, it could be as high as 7% reported. Romiplostim also have a marrow reticular fiber formation, highly variable platelet count, and the pain at administration site. Fostamatinib, as I mentioned before, the GI toxicity and the hypertension, which has a limited effect for this prescription. So, here's the review article by Dr. Nicola Cooper and University of London. They really mentioned, right, because the feature of the SYK inhibition without overproducing the platelet overshoot can have maybe a good option for drug to consider for patient with increased thromboembolic risk and, for example, coronary heart disease, diabetes, and advanced age or obesity. So this is also from the ESLIM-1 trial. We also observed the SYK inhibitor savolitinib has no reported thromboembolic event. So this could be an advantage compared to TPO-RA. And also, I already mentioned here, this is not a direct head-to-head comparison, it's a cross trial comparison. I wanna mention here, so at least that we look at the data apparent result, the diarrhea, nausea, hypertension are lower in the savolitinib treatment group. And so this is also could be a, you know, an effect and also have a lower discontinuation, 3% versus 10% for fostamatinib and the dose reduction. Also, I mentioned all the other TPO, TPO-RA treatments. They're all reported thromboembolic events and some could be fatal. And we don't see. We have very low incidence of platelet counts increase over upper limit normal reported in the ESLIM-1 trial and no thromboembolic events observed in the ESLIM-1 trial. So other could be a, you know, another key differentiation for this savolitinib versus other agent. And also at the EHA on the same day, the oral presentation, the manuscript is published online in The Lancet Hematology. So from marketing perspective, really we wanna look in the key differentiation for savolitinib. We wanna capture the previously treated patient with TPO, TPO-RA, you know, with the even patient with heavily pretreated patient population, 75% prior refractory to the TPO, TPO-RA treatment. We have seen the similar durable response rate. This is one of the important strategy for us to consider. For patients, as I mentioned, there's a significant portion of the patient have increased thromboembolic event and being targeted inhibition for SYK without overshooting the platelet and thromboembolism AE. So this is another key advantage for the patient, for the ITP patient. And also, you know, because the high durable response rate and improved quality of life, we can target a patient in the second line treatment market after glucocorticoid for the patients seeking those improvement. About 33% of patient with the concomitant medication, we can see the dose reduction and the interaction for the concomitant ITP treatment. So this is also demonstrated the good safety and the efficacy with the potential combination of a glucocorticoid could potentially move it even to earlier line there. Also, internationally, we have initiated the phase I trial and open to enrollment. From a clinical development perspective, there are a few other areas we could consider additional phase I trial in the global setting or a combination with a glucocorticoid, and or even combination with standard care. Also, for autoimmune disease, a significant portion of patients have developed a secondary ITP and could potentially be other indications could be developed. Here's, that's the highlight for ITP. Also, I wanna quickly update you. Also at the EHA we present our clinical proof-of-concept study for phase II trial of savolitinib in the warm autoimmune hemolytic anemia, wAIHA. And a few words about the epidemiology and disease. wAIHA occurs about 0.8%-3% of three per 100,000 patients with a prevalence of about 10-20 per 100,000. It is a predominant form of the AIHA and also it's a high unmet need because the death rate also could be up to 10%. China incidence about 20,000, 26,000, global 150,000. Similar, mechanistically is very similar to the ITP, is the autoimmune antibody attack the red blood cell and engulfed by the macrophage. So traditional therapy, this is even in the higher unmet need because there are just traditional treatment is the glucocorticoid to treatment anemia. And there is no FDA approved as target therapy. Rituxan is commonly used as off-label use, but patient can progress rapidly and also have a very limited treatment option. So similar to ITP, we think that durable inhibition of B cell producing antibody and also blood macrophage eating up the antibody-coated red blood cell will have a very effective treatment for wAIHA. This has been shown previously in our preclinical animal model study, but now we are very pleased to see our clinical study. These are the, you know, primary and secondary wAIHA patients previously treated corticosteroid and is a placebo-controlled study, three to one randomization, double-blind phase at 0 - 8 weeks. After eight weeks, it can go to the open-label stage, up to 24 weeks. So from clinical overall response rate, we can see, you know, the first eight weeks we have 43% of patient have a response, which defined a 100 g per liter increase of hemoglobin and also the 20 g increase of 20 g per about the baseline level. The durable response rate is a three consecutive treatment, you know, meeting that criteria is about 18.8% patient. When they finished the open label 8- 24 week, there are additional patients have a clinical response. The overall response rate is 66.7% overall response rate, combined for the 24 weeks treatment period and the durable response rate of 47.6%. And here's the hemoglobin increase. I can see about 4- 5 weeks after treatment, it reached over 100 g level and sustained a high level. So this is a little bit slower, as you recall for the ITP, you can see the platelet increase of, you know, to the normal range, after one week. So, for the wAIHA, the hemoglobin increase take a little bit of a long time, but it's highly sustained for this savolitinib treatment group is about the 71% overall response rate and it's highly durable. Also, in terms of patient who previously treated, or without, anti-CD20 Rituxan, the response rate also similar, the savolitinib is efficacious in both on Rituxan treated or untreated patient population. So here's the takeaway highlight for the POC trial, overall response rate is 67.7% durable response rate, the overall response rate and the 47.6% durable response rate in the 24 weeks treatment period. And even patient crossover from placebo achieved a similar high response rate and very rapid, sustained improvement hemoglobin level and stable response over 24 weeks treatment period and 71% durable response for the responder, durable response for the responder. And so based on this encouraging data, we initiated a phase portion of the ESLIM-2 trial. And just a few words in another preclinical model we have seen, on the left hand panel here is the rat model for collagen induced arthritic model. We can see savolitinib actually, which is the red line here compared with the R406. There's a decrease in the arthritis paw swelling as the measurement. And also in the lupus model, we can see savolitinib treated compared with dexamethasone and the vehicle has a sustained overall survival. You know, 100% of the NZW model actually lived to the 24 weeks. To highlight, you know, the savolitinib data, there's once daily oral dosing, you know, no drug not affected by the food. And in multiple preclinical model, we showed the efficacy really indicating target inhibition for SYK, which has a potential for multiple autoimmune indication or malignant heme. And also in combination, not only with the experimental medicine like a BTK in that clinical model, we can see the added benefit. And also in the clinical trial setting, we can see in the combination with the other ITP treatment, also see the benefit. So it's because of the low target, off target, toxicity can combine with the other agent and also targeting the root cause of the autoimmune disease. And so overall globally we already have over 700 patients already treated with the SYK inhibitor and this have been demonstrated a highly specific and efficacious agent. We are very pleased for the development for savolitinib, our new agent. So I think we can probably skip the break since it's an online event. Maybe I can continue to give you update about the other program. One is the surufatinib in the pancreatic ductal adenocarcinoma PDAC development. And it's the goal is really for our approved and approved the product to expand the indication. So the Sulanda Dr. Su as already mentioned, is, you know, ranked the second brand in the market in the NET in China. And also, we have reported, actually the investigator-initiated trial, reported at the ASCO last year about the first-line combination with PD-1 and chemotherapy. And, I'm gonna highlight some of the data, top-line data and also our clinical development in the first line, PDAC. So pancreatic cancer is, you know, a represent a huge unmet need. It's a China market of about 100,000 incidence with, you know, about a $1 billion range of the market potential. And globally, the incidence really reaching over half a million patients. And this very hard to treat because, is, you know, immunologically cold the tumor and this, what we call the immune desert because it's highly fibrotic and very limited treatment option. Also, because the diagnosis onset is very late usually and very few, small percent of patients actually can go through their surgery. The overall compare with the breast cancer, prostate cancer or the other cancer type with a high over a five-year survival rate. Unfortunately, pancreatic cancer patients is less than 13% of the five-year survival rate. The treatment option is primarily chemotherapy dominated. The first line is either FOLFIRINOX or gemcitabine with nab-paclitaxel, Abraxane. And the overall, the lifespan for these patients is less than a year. First-line treatment with the response rate about 20%-30% PFS 5-6 months. If they progress, it can go to the second-line treatment. But in general, the patient actually have a very short survival rate, because it's really complex and challenging by the disease etiology, with the late presentation of the disease, fibrotic and immunosuppressive stroma and resistant, relatively resistant to immunotherapy. Here is the FOLFIRINOX and the gemcitabine and Abraxane. So GA or AG is what we call it, which is the standard of frontline therapy, I mentioned about, with, you know, in their clinical trial over existing therapy before, the pivotal trial with the median PFS only 5-6 months and overall survival 8-11 months. So that's kind of the treatment landscape for the first-line therapy. So why we think surufatinib could potentially be important addressing the pancreatic cancer because the mechanism of action is, you know, surufatinib is not only inhibit VEGF, but also has other targeting agent, for example, CSF1R, you know, attacking the tumor-associated macrophage, you know, enhance the T cell, you know, activity against tumor. Here's the preclinical data. It's a little bit more. If you're on the right hand side, you can see the plot here is the mouse xenograft had fast growth when they used the AG gemcitabine Abraxane. It have reduced the tumor growth and the AG plus surufatinib also reduced the tumor growth and the AG plus surufatinib the PD1 have the best tumor inhibition. The primary reason we have done further analysis in the AG pretreated patient or the chemotherapy treated patient, there's increased, you know, macrophage, M2 macrophage and CSF1R in tumor cells, which will further develop a resistance and also in lead to the higher PD1 immune checkpoint inhibitor, immune checkpoint, PD1, you know, had overexpression. So targeting all these features in combination with PD1 and surufatinib plus chemo is really have a, you know, good preclinical evidence to block the tumor growth. So, in this, this is one of the IIT studies by Professor Guanghai Dai, it's a dose escalation and expansion study. The primary endpoint is the dose, that means the toxicity for the dose escalation stage. And then in the randomized phase, surufatinib plus camrelizumab plus S-1 versus AG. So I wanna mention here is there's a slight difference in the chemotherapy backbone, you know, even with the compared to the chemo arm, the first line is a standard care, Abraxane plus gemcitabine. For the, for the treatment group, the chemo is Abraxane plus S1. So it's a little bit different backbone treatment. In the preliminary data reported at the ASCO GI early this year, the, the combo arm, the NASCA have a 50% overall response rate versus AG about 27% overall response rate. So the AG is a standard of care. The, the data for AG is highly consistent with the report of first line data. And what we really impress is the NASCA overall response rate, which is 50%. And also, the median PFS in the NASCA arm also reached nine months and OS is now mature, but is reported about 13 months at that time data cutoff. So, versus the standard of care in the first line setting, PFS 3-6 months, overall survival 7-11 months, the IIT in first line pancreatic cancer, the NASCA trial, the NASCA treatment regimen also have a significant improvement, the PFS and OS, which is highly encouraging. So based on the data, the IIT results, we are, you know, initiate the phase 2/3 trial, camrelizumab and the AG, and surufatinib, followed by the sur and camrelizumab maintenance therapy. So the phase II portion, the primary endpoint is overall response rate and the secondary endpoint is PFS because, as I mentioned, there is a, for the IIT data because they use S1, we wanna use the AG as a, compare with the standard of care. So we just really wanna have a quick, you know, phase II portion to verify the IIT data in this combination setting. And then the phase III, with the primary endpoint of overall survival. And the trial is really initiated in China. And with the next program, I wanna also update you a new program, which is our third wave product, HMPL-306 is the dual inhibitor for IDH1 and IDH2, mutated relapsed refractory acute myeloid leukemia. And so this is based on the data we published in EHA last month, we also entered a phase III trial. So here's the overall AML demographic, the patient demographic and also the market potential. In China, about 20,000 incidence and about $100-$200 million dollar market potential. Globally, we see the incidence exceeding 200,000 cases. So among these leukemia patients, AML patients, IDH1 or IDH2 mutations account for 15%-25% of AML patients. Also we know, just based on the current treatment standard landscape, nearly 25% of AML patients fail to achieve remission of the treatment. So far there's really no dual inhibitor for both IDH1 and IDH2 approved globally. So one IDH1 approved, TIBSOVO, is approved in China, two IDH1 inhibitors and one IDH2 inhibitor approved in the United States. So a few words on the AML, is really where the myeloid cell cannot differentiate to normal blood cells and turn into the cancer. And so this is a highly deadly disease and symptomatic weakness, fever, infection. So this patient is really in a very dire stage and there the treatment, so the isocitrate dehydrogenase IDH1 and IDH2 is a key enzyme in the Krebs cycle. And so it, the IDH1 is located predominantly in the cytoplasm and the IDH2 and IDH3 located in the mitochondria. And so IDH catalyzes the oxidative decarboxylation to form alpha-ketoglutarate and during the metabolism and the mutant IDH can lead to the highly carcinogenic 2-HG, 2-hydroxyglutaric acid. It plays an important role in the etiology of solid tumor and hematologic malignancy, and accumulation of 2-HG causes DNA hypermethylation and promotes tumorigenesis. Importantly, not only IDH1 and IDH2 is the target for cancer, a valid drug target, but also the IDH mutated one and two as well can actually switch and lead to the resistance. If you inhibit IDH1 mutant, mutant, the IDH2 could be activated. So during inhibition of both IDH1 and IDH2 are very important to prevent the isoform switching and leading to the drug resistance. And also the epidemiology, you can see the IDH1 or 2% of the patient mutation in a variety of the tumor, solid tumor and the hematologic malignancy is about 60%-80% at the glioma patients. And also, secondary glioblastoma, 75%, 70% of the patient, AML 15%, 25% and the MDS about 10%. The other, lymphoma, AITL, about 26%. So, in sarcoma, chondrosarcoma, osteosarcoma, cholangiocarcinoma and, and also giant cell tumor bone, so also have a kind of a high mutation rate for IDH1 or 2. So it's actually important target both solid and malignant heme. In the preclinical data, here's the HMPL-306, in vitro, target inhibition and, it can reduce the 2HG production. And, the EC50, IC50, it is, quite similar, you know, against the IDH1 mutated cell, versus the IDH1 inhibitor, ivosidenib, AG-120. You can see the potency reaching a ton, quite comparable nanomolar range. The, the IDH2 mutant, cell lines, also has a, HMPL-306 has a, very, potent target inhibition. And And in some of the IDH, mutation type also has more potent efficacy. Another feature of 306 is highly brain penetrant. On the left side is the AG-120 TIBSOVO, you know, the plasma and the brain concentration, drug concentration of the AG-120, you can see is predominantly still plasma level and, the brain concentration is very low. On the right hand side is the HMPL-306, 50 mg/kg. And the brain concentration has, with the increased exposure time, the brain concentration has really reached the higher level. So it is a, it has a potential for neuro tumor indication, for example, glioma. And here's the phase I dose escalation and dose optimization study for HMPL-306 in AML patient, starting for 25 mg QD all the way up to 250 mg QD. And we also chose two expansion dose level at 250 mg and 150 mg QD level. From the preclinical data, we know, I mean, from the clinical data, we know that 150 mg dose above is an efficacious dose, versus both IDH1 or IDH2 mutated patients. We have the, finally based on the clinical data, for the phase I, we, I'll explain a little, we chose the RP2D dose as a 250 mg QD dose for first cycle, followed by the 150 mg QD from cycle two up and beyond. This is really helping to reach the, you know, have a quick loading, to reach the homeostatic states, have a higher concentration, reach the higher constant stable concentration to allow the demonstrate the efficacy because the AML patient is a very aggressive type of form. So reaching that initial high concentration, high exposure is important to inhibit a tumor growth, cancer growth. The efficacy, we look at the CR and the CRh rate as an important clinical parameter because, this is widely, you know, the clinical progress has demonstrated, the complete response or CR with incomplete hematologic recovery has a good predictor for OS, right? So this is one chosen. And again, we look at the efficacy and also safety for the study. Here's the top line results, for both the efficacious dose during the dose escalation phase and the RP2D dose. Here's, we can see in, on the left hand side is IDH1 mutated patient, on the right hand side is IDH2 mutated patients. In the 150 mg and 250 mg group, we see about the CR CRh rate of about 27%. Then in the RP2D, because the quick loading and the quick time to reach the higher plasma exposure, we also see higher CRh rate for IDH1 reaching 45% and IDH2-mutated patients at 50%. Also, quite important because the AML patient could be a heterogeneous patient population. So we have observed some patients with a concurrent IDH1 or IDH2 mutation also with the other key driver mutation, for example, FLT3 or KRAS or NRAS mutation. So, if we exclude those patients with the co-mutation for FLT3 and the RAS, we observed the RP2D dose has an even higher response rate, right? With the IDH1 about the 50% CR rate and RP2D dose at for the IDH2-mutated patients at 62% of the CR rate. So this is highly, highly encouraging. and, you know, 'cause the dose escalation stage actually have an earlier treatment and the RP2D dose has a shorter exposure. But this trend very start to show here with the efficacious dose 100 mg, 250 mg with a longer follow-up. We already observed the 13-month median OS for both the IDH1 and IDH2 patients. And also the RP2D dose, you can see the trend is quite similar. This is highly encouraging because, as I mentioned, for the second line treated patient with IDH1 or IDH2 mutation, the standard efficacy, I mean that life expectancy overall survival is about 5-6 months. So this is highly encouraging. From the safety perspective, adverse event, the TEAE show on the left hand side, the TRAE show on the right hand side. The predominant AE reported as the hematology and related heme has event platelet count decrease, anemia, neutrophil count decrease, but the higher grade level is low. And so this is in general, the tolerability is very good for 306 as a good safety profile. And also I will show some of the, you know, comparisons for the other IDH1 or 2 inhibitor. So overall, here's the summary with the HMPL-306 phase I AML data, compared with enasidenib, the IDH2 inhibitor, ivosidenib IDH1, olutasidenib IDH1. And also on the right-hand side is the Lilly compound 738, which is also a reported IDH1 and 2 development inhibitor in development. If you look at the, you know, in the similar indication, if you look at the IDH1 or IDH2 mutation mutated patient in AML at the RP2D dose, the CR/CRh rate for the 306 already reached 60% or 62% of in the IDH1 or IDH2 mutated patient. And other, you know, other IDH1 or IDH2 inhibitor, for example, you can see the CR/CRh rate in general is about 20-30 range, either versus IDH1 or IDH2. And also from the reported data from Lilly compound, it really show they need a high dose to reach the target inhibition for IDH2, you know, as compared with the IDH1 inhibitor. So even though it's reported that the dual inhibitor is still predominantly at the IDH1 inhibitor because the in the IDH2 patient, a mutated patient needs a higher dose to reach that target inhibition. So from a safety perspective, we see the general profile for toxicity is actually quite manageable, compared with some of the other competitors either approved or in development. We can see enasidenib has a higher QT prolongation, and the other inhibitors also have some reported QT prolongation. We haven't observed it in the 306 study with a QT prolongation. And also in terms of differentiation syndrome, which is also a class effect. And some of these differentiation syndromes could be hard to treat and could lead to respiratory failure. Sometimes it could be fatal. In general for the 306, we see a relatively lower, you know, percentage of patients with the differentiation syndrome, with the grade level also less than grade four.N o grade four patient has been observed. Also compared with other compounds, the bilirubin increases on the lower side; liver enzyme increases also on the lower side and no high-grade grade three has been observed, compared with some of the other agents that have reported liver toxicity and even late, fatal, drug-induced liver toxicity. So we believe HMPL-306 has a very competitive clinical profile, not only in terms of efficacy, but also the safety. So here's the summary for the phase I data, reported at EHA. We have this compound has a long half-life and also we reach sustained the target inhibition at both the 150 mg and 250 mg QD dose. We define the RP2D dose with a higher dose to start for the first cycle, 250 with the 150 mg maintenance. And this is, we show at this dose level has more robust the CRh rate. And also this compound has a potential to really inhibit both IDH1 or IDH2 mutation to overcome the resistance from isoform switching. And also, we think the CRh rate is highly robust and OS benefit we observed also seen, you know, quite long overall survival, compared with the standard, you know, treatment. Based on this encouraging result, we are launching the phase III study. The study is already initiated. This is a two-cohort design multicenter trial. With the HMPL-306 single agent versus control group, which is a solid therapy, investigator choice, either intense chemo regimen, labeled as a H here, or non-intensive chemotherapy labeled with a L here. So although it's treated as two cohorts, it's using the same center because we really wanna take advantage for screening the patient with IDH1 or IDH2 mutation; they can really put into this, this is this single trial instead of running two separate trial and using the same centers to screen the patient. So we are very excited. This is called a RAPHAEL trial. We are already enrolling, actively enrolling patients. Hopefully this is a, this is an important drug added to our, you know, portfolio, to have a registration trial started. Also a few words about the overall AML area. So in addition to IDH1 and IDH2 inhibitor 306, we also have other, you know, programs or developments in the AML space. One of our new compounds entered clinical development is the menin inhibitor HMPL-506 in NPM1 mutation or KMT2A rearranged AML. So they're in the clinical development stage. Also a few words because the for the 306, there are still other indications for example, glioma, cholangiocarcinoma, so could potentially be in the clinical development path, particularly for the glioma, we see high brain, you know, penetration, which has a potential to go to in the brain tumor development. So, to highlight our topic of today and for the surufatinib, you know, approved in China, we increase, expand our indication, into the first-line pancreatic cancer development, which is driving a sizable market to have a frontline product indication expansion. We are very excited. Our first innovative company in the immuno disease area, for the savolitinib, highly specific and potent SYK inhibitor, already have a successful positive Phase III trial, EST-101, in China. And we also have a global development program and in China alone is addressing a CNY 500 million-CNY 700 million market, with the patient population, ITP with a higher unmet need still existent. In 306, our dual inhibitor for IDH1 and IDH2, also had demonstrated best-in-class potential. Currently there's no globally approved dual inhibitor. In the AML, with the robust phase I data, you know, really addressing this, you know, deadly disease with a good, you know, market potential. So, addressing globally also has a high incidence, has a high unmet need. So with that, I'm gonna wrap up our R&D presentation for the three key program. And, you know, we are open for a discussion. Before I go there, just some of the key takeaways for the three programs I mentioned here. savolitinib is our first internally discovered best-in-class potential molecule, highly efficacious with a 48% durable response rate versus 0% in the placebo and improved the quality of life. And also, in the wAIHA top trial, also observed a highly robust overall response rate, 66.7% overall response rate and 47.6% durable response rate. Also in the surufatinib first-line NET trial, compared with the standard first-line treatment, the median PFS is nine months, the OS 13 months is highly competitive. So we are continuing the development in this deadly disease indication. And for the HMPL-306, the dual inhibitor, we have highly encouraging results with over 50% CR/CRh rate, which is really exciting data shown. And globally we have, we have not yet have any of the IDH1/2 dual inhibitor for AML approved. So this is really addressing the resistance at the front and also highly penetrable in the preclinical model could potentially lead to other neurotumor indication development. So with that, I think we can go to the Q&A stage. Yeah. Thank you for all your attention. Thank you very much, Dr. Shi and Dr. Su earlier. We are now going into the Q & A session, but before we begin, just what we'd like to remind everyone on the line that we are already in the blackout period towards our interim results announcement at the end of this month. So for all the materials which is deemed to be sensitive or, you know, financially, and, you know, please forgive us for not being able to share with you in much details. And then, you know, on the presentation which is already posted on our website, of course there is the safe harbor statement with the important messages. So please do refer to those important information. Now for the Q& A, there are basically two methods. You can type in the questions in our chat box or you can also raise your hand. You can press the raise hand button and then, you know, we can open up a mutual line so that you can ask the question directly. Either way, it is fine. Maybe I'll just first start off with a question that is already in our mailbox. Well, maybe this one is for Dr. Shi first. I think two specific questions. One is regarding and HMPL-689. You know, can the company explain whether it has stopped development when it was already in the registration studies and what are the prospects of this product for HUTCHMED? That's the first question. The second question is on surufatinib, that we haven't obtained a development partner yet. And can you elaborate a little bit, you know, whether this product is not as good as some of the other similar products available outside China? And, you know, is there any risk that, you know, similar products to surufatinib may come to China and impact the prospects of surufatinib in China? So, these two questions. Thank you, Dr. Shi. Yeah. So, first, as well as, as you recall, right, from our last earnings call, we have indicated, right, that development plans has been discussed and communicated 'cause our original plan was, you know, follicular lymphoma third line development with a single arm registration trial. We did, you know, observe very good clinical activity and safety. And, you know, but the regulatory environment has quite changed. You know, we have discussed with the NMPA about the registration path using single arm, you know, completed the trial, as originally development agreed upon. But there, because the withdrawal all the PI3K delta inhibitor in the global market and also some of the latest data shown, the CDE has expressed a concern. You know, through the development, they actually requires us to randomized trial in this setting to demonstrate the safety and efficacy. So from the trial development landscape and the return on investment, we do see the timeline for randomized trial is gonna impact our financial return. So for the end result is that, we as a company, we have, you know, stop our further development in the FL and the MCL indication because the feedback from CDE is really require randomized trial. So the ROI is really not justified for the, you know, our original development plan and the timeline and the launch timeline to really achieve the effect. So that's the status for the IDH. For surufatinib, it is also kind of a little bit unfortunate decision, you know, last year, the year before we announced with the, you know, for the, for the neuroendocrine tumor NDA, we, you know, withdrew the application in the U.S. and E.U., because the original development plan, even though the discussion with the regulatory agency, the original plan was really using the SANET-ep and SANET-p, the China phase III trial, along with the bridging study to support the E.U. and the U.S. registration. Even though at initial stage, the discussion was with the potential, but later on it was really the response we got a CRL and so it's not reflecting. The comment is really now reflecting the global kind of a patient population. So this is a kind of a communication with the outside world. So for the registration, I think in terms of your question for China, right, we are already a leading product, second marketed, you know, leading product in neuroendocrine tumor space and it's very robust. So I know there are a few compounds like a PRRT and some others in development and registration. But in terms of the in China market, we still think surufatinib is a very competitive product and we have good product and familiarity from physicians. So we're with all the data, we think we has a very good, you know, marketing and the strategy to defend our market. Globally, I think, because the landscape change, right, for your endocrine tumor, there's a PRRT and, you know, other products, already, in the second line kind of, neuroendocrine tumor. So the landscape has changed very rapidly. So in turn, the BD on the global development, we're really thinking about the other indication, right, such as the case for we presented here, you know, where the combination of the VEGF and the CSF1R activity for surufatinib addressing other indication still has a potential for the global development. Thank you, Dr. Shi. We see a couple of, analysts online, that have raised their hand. So, the first question, let's go to Clara Dong of, Jefferies. Clara, you can ask your question now. Hi, thank you for taking my question and great presentation. This is Clara for Kelly from Jefferies. So maybe one quick question for savolitinib in ITP. Can you give us a quick update on your commercial preparation of launching in China, given it's your first, you know, commercial launch in autoimmune? And I think last time you also mentioned you scheduled an FDA meeting to talk about the regulatory path for ITP. Could you give us an update on this and what kind of data you need to see in phase I dose escalation to support you to go forward to pivotal trial? Thank you. Yeah, thank you. So, I'll, you know, address this commercial part first briefly and then I can turn to Dr. Su, right? And so I think we are, you know, building our internal marketing team. So we are well prepared to, you know, for the hem marketing. Even traditionally we are on the solid tumor side, but from, we have done very good market research and, brand, you know, strategy. So I think internally, HUTCHMED is very good. We intend to build our commercial team to launch the product. For, in, in terms of global development, as I mentioned, the phase I trial, the dose optimization study has already discussed with the FDA and agreed upon with the FDA. So we already initiated this trial and it's open for enrollment. Global development, I think, once this dose optimization is completed, there are multiple potential we can, you know, there are multiple clinical development paths we can go to, to really expand to the global patient population. So I don't know, Dr. Su, maybe can also addressing some comments for this question. Yeah. Yeah, sure. I mean, in terms of commercialization in China, as Mike kind of alluded to already, we are building a hem team that would include both benign and also malignant hem indication. So, savolitinib, the first product, to be launched, you know, in China. So we are preparing, both on the marketing side and also the sales side as well, to support the launch of savolitinib, with the first indication ITP, you know, obviously potentially with the wAIHA to follow in the future and potentially, you know, additional non-hem indication, autoimmune disease for that matter. However, you know, the initial indications ITP and wAIHA, these belong to the benign hem and in China, oftentimes they are in the same department in the hospitals. So, at the same time, we are also building up our malignant gene as well because we already submitted NDA in China for follicular lymphoma, and we expect the approval sometime next year. So, you know, slowly, these are coming to market, and ultimately we'll have a solid tumor team as well as a HEME team, basically covering both benign and also malignant HEME indications. Super helpful. Thank you. Yeah. Thank you. Next question goes to Kyle of Goldman Sachs. Kyle, you can ask your questions now. Hi everyone. Thank you so much for taking our questions and thank you for the great presentation. I guess we had a couple quick questions on savolitinib and then one quick one on savolitinib. So I guess on savolitinib, one, like, if you could provide any additional color on your expectations regarding the timeline of the ex-China ITP trial, and when you might move on to a registrational trial there. And then two, how do you think about the timing of the potential approval in China? And And do you expect to be included on the NRDL list, given that we understand from our understanding that if the drug is approved too late in the year, it may not be included on the January list until 2026? And then quickly on, on SAVANNAH, we're just wondering if you could maybe frame expectations on what you expect from that later this year and, and how quickly you expect to file for or expect for your partners to file for approval in the US. Thank you so much. Okay, So, let me comment first on the phase I trial, right? And we are intending to, you know, do the dose escalation and for the global trial. So my anticipation is we can complete it this year and, you know, the dose optimization we are still working because I think we have a lot of PK, PD data and also in China and the Western patient population. So we are hoping, right, with the dose we can have the dose defined, you know, shortly, even some of these future registration trials could potentially be launched sooner with, you know, building those optimizations into the phase III trial, phase II/III trial setting to accelerate the development. So this is kind of the global development. And I also mentioned there are a lot of opportunities for us. I mean, finding the right dose for the Western patient population is the important first step. We think, I kind of alluded to, there are quite a few clinical development areas we can tap into, the traditional phase I trial or even the combination, even in the early line, even in the secondary ITP. So there are a lot of options in wAIHA, right? So a lot of opportunity exists. So once we defined those, I think multiple areas we can get into the global development stage. And so that's kind of the savolitinib. And there are a few other questions, right? For the China approval, I think also we have the breakthrough designation, also under, you know, priority review in NMPA. So we think our anticipated timeline is later this year for the approval for ITP indication. I think I stop here. Maybe I'll see if Dr. Su can also have some comment first. Sure. Yeah. So, anticipated approval timeline, potentially end of this year. But you know, even though it's a priority review, that could still run 12 months. So, NDA was submitted January this year. So it could be either end of this year or January, or you know, early next year. Regarding NRDL, you were absolutely right. It's too late for this year's discussion and we'll work on submission for NRDL inclusion next year, to be effective by January 2026. Regarding SAVANNAH, really don't have much to update on. And as we communicated previously, we expect NDA submission by our partner AstraZeneca in the U.S., end of this year. You know, we believe it's on track. We don't have anything to update at the moment. Thank you. Got it. Thank you so much, Dr. Su and Dr. Shi. Thank you. The next question goes to Adam McCarter of Cavendish. Adam, you can ask your question now. Thank you very much. Can everyone hear me? [crosstalk]Yeah. Yep. Yep. [crosstalk]Yeah. Yep. Yep. [crosstalk]Yeah. Yep. Yep. Excellent. Thank you very much. Thank you for the great presentation as well. Great to see an update and obviously the pipeline's progressing. So, a couple of questions really. The first one's on savolitinib as well. So we've obviously had quite a few clinical events in 2024 in terms of the development of new ITP therapies. So obviously Sanofi's, BTK inhibitor in the phase III LUNA- 3 study. And we also had some quite encouraging data from Takeda, only a couple of weeks ago for their anti-CD38 antibody, which seemed to have some good responses in phase II. So I guess it's really, and sort of my, my first question's really about how we should view the competitiveness of savolitinib really sort of, on a global stage, considering that there are some sort of assets that are further ahead in the clinic and how we should view that in terms of ex-China development. And then my second question is actually just on your, what you talked around the RAPHAEL study for HMPL-306. So there's also, I've just come across some sort of interesting data from some investigator studies, which has looked at sort of IDH2 mutant populations where enasidenib and venetoclax combinations have actually been more effective in certain IDH2 mutants versus others. And I just wanted to see, understand whether or not the RAPHAEL trial is statistically powered or would you be able to see IDH2 mutant subpopulation differences in the way that the trial is designed at the moment, and going forward? Thank you very much. Yeah. Yeah, certainly I think, for the global development, right, for the ITP, we are well aware of the rozanolixizumab and the CD38, Takeda's antibody development, right? And, I'm a little bit surprised, for rozanolixizumab, but not yet present their data at the EHA or the ISTH, right? International Society on Thrombosis and Haemostasis, you know, in Bangkok, right? 'Cause that's where Takeda's announcement actually came even later, presented the data there, right? So, my understanding they're trying to, it is also for Rosa, they're planning to file NDA later this year. I don't know why it takes so long, but I'm not kind of a suspecting too much. I think we'll see the data and we'll understand how competitive data will look like. Certainly, ITP is a very, it will become competitive, right, with the potential novel therapy. I think in China, we're certainly ahead of the Rosa and also the, you know, the CD38. And also, quite interestingly, if you look at the Takeda data for CD38, and also, you know, the treatment period is shorter. They use the 8-week treatment. And also, what is really kind of an eye-catching from my perspective, it is really the two dose, the discontinuation rate is actually pretty high. And the 100, 600 is over 20% discontinuation rate. And, maybe this antibody drug, even though they have now shown very attractive AE profile, but I'm just wondering why the discontinuation rate is so high with the CD38. Yeah. Right. So, and, and also in terms of global development, as I mentioned before, we are really aware of this competition in the ITP space. I think from a mechanism perspective, this SYK inhibition as a dual mechanism is really unique, targeted inhibition. So, I think we have a very good combination data also in the Asian one with the concomitant medication. Majority of them is corticosteroid. So there even an opportunity to address earlier line of development. I also mentioned wAIHA. I also mentioned immune-derived secondary ITP because there's just literally, looking at the development path for secondary ITP, you know, the clinical option for these patients, unfortunately, it is really the TPO RA. And at the ASH presented the data, the French group really show these secondary ITP patients have a very high thromboembolic event status, which is unfortunately the TPO RA treated patient have the, I see 25% of thromboembolic event and also with the fatal cases. So certainly that's another area we think the targeting SYK is a good opportunity to for further development. So we are adapting our clinical strategy for global development and with the highest unmet need and the potential to be further developed. But either one is still kind of an option design, even though I think a late comer for the marketing could potentially be challenged. But there, what I'm trying to allude to, our ITP dose finding study, optimization study is gonna apply for other clinical development program. We have multiple ways to develop instead of only way everybody else is doing. Yeah. Yeah. If I could chime in here, I think again, you know, focusing on the unique MOA targeting both the B cells and also the macrophages, you know, for instance, the wAIHA is a clear case. We believe, you know, these other, you know, CD38 or FcRn or Fcγ or FcRn or the BTK inhibitors could have much less of an effect on macrophages, for instance. So it is a unique MOA and we are quite encouraged with very robust clinical efficacy, even with previously heavily pretreated patients still demonstrate very good efficacy. Obviously, you know, it is probably more desirable to move to earlier lines, maybe in combination, or as a maintenance, for instance. And I think the safety profile is quite favorable as well for savolitinib, low risk of thrombosis and, you know, particularly for patients or elderly patients with baseline or concomitant, you know, diseases, you know, for instance, diabetes, hypertension and all these, you know, particularly elderly patients with very complex, you know, baseline diseases. So I think, you know, all in all, ITP indeed is getting more crowded. However, wAIHA, for instance, is wide open. I think, and it's probably best suited for, given its unique mechanism. Anyways, I, you know, we believe, you know, there are many ways we could explore and develop with regard to your question on HMPL-306, particularly regarding IDH2. In our study, we intend to cover 140 and 172, those mutations. In our phase Ia, phase Ib/II study, we observed equipotent, you know, equal potency against these two and very similar clinical activities against these two different mutations. By the way, these are not just two mutations. So, these are just two bases that have mutations and oftentimes they have multiple different mutations. In terms of efficacy difference, really the difference is the co-drivers, the existence of co-drivers. For instance, we see, you know, RAS mutations or FLT3 mutations coexist with IDH2 or even IDH1 mutations. So, either could be these patients could have heterogeneous disease or they could have actually de novo co-drivers. And these can have a major effect, a major effect on the efficacy or, you know, with regard to potential combination with venetoclax. We, you know, obviously very interested in the combination as well, moving it to first line, a very different mechanism and it has shown very interesting, further enhanced the clinical efficacy, not only venetoclax with IDH inhibitors, but also early data shown venetoclax in combination with menin inhibitors. As Mike alluded to, we now have menin inhibitor in early development as well. So, all in all, you know, we think whether, I'm, you know, there'll be, there will be a way to combine with these target therapies with BCL-2 inhibitors. So, you know, again, more to, more to explore in clinics. No, thank you very much again and thanks for the great presentation. [crosstalk]Yeah. Thank you. So, David, there are some questions online. I don't know if you see it or. Yeah. So maybe I'll just go to one question that's already on the line. And this may be a question also from for Dr. Su as well. This was actually sent in a little bit earlier. One question is regarding, you know, for our surufatinib, in, you know, multiple trials, it has been in combination with two different PD-1. So what is the thinking, you know, process behind that, you know, and, you know, how, so, you know, that's one question. The, maybe I'll just ask the other one as well. The, the each one of these have like, you know, very significant global potential. But, you know, also they may reflect the difficulty of obtaining a partner for surufatinib, you know, how attractive are these at this stage? So maybe I'll just. Well, really not. Yeah. I mean, the choice of PD-1 partner, it's really not by design. It's really, you know, we're just working together with our potential partners in China and PD-1, as you know, there are so many potential partners in China. We know that there are already 14 PD-1 inhibitors approved now in China. So great access, and so yeah, you're right for the phase III trial in neuroendocrine cancer, surufatinib is in combination with toripalimab. But for this pancreatic cancer first-line, it is now combined with the Hengrui PD-1. So, basically it's really not by design. And actually we believe any PD1 could work. Surufatinib contributes to the activity not only by VEGFR inhibition, but also more importantly, the CSF1R inhibition to modulate the immune, the tumor immune microenvironment. So, you know, however, it doesn't really help in terms of clinical or international clinical development, at the moment. I guess the best choice would be toripalimab because it's now approved in the US and studies could proceed with toripalimab. But all in all, we've done multiple, almost like a basket type, studies in combination with various different PD1s, and they produce very similar results in a variety of different tumor types, including now the lung cancer, GI tumors, you know, both gastric and lung, and colorectal, also in gynecology tumors. So, you know, we've tied up with quite a few different PD1s, PD1 products available in China. Some of these just chosen by the investigators, some, you know, by us or by our potential partners. So it's a bit complex, but long story short, you know, we believe any PD1 could work when combined with the surufatinib. But absolutely you are right in terms of international potential international development. At the moment, toripalimab is the—it wouldn't make sense because now it's approved outside China, or in the US. So. Thank you, Dr. Su. We got actually a couple of questions on partnering. Maybe I just group them together and ask at once. One question is, can you update us on the potential partnering strategy for savolitinib international development? Can we consider doing a phase III overseas without a partner? Another question is, you know, seeing that Takeda is now working on ITP, of course on using a different molecule, is Takeda a potential partner for, you know, savolitinib? The final question is kind of more macro, like, you know, what have we learned over the years from our partnership experience with Eli Lilly, with AstraZeneca, AstraZeneca and Takeda regarding, you know, how to design and time the development and commercialize these products? Yeah. So, very briefly, actually I have a hard stop at 10:30, but very quickly regarding partnership, savolitinib we have, we believe has a very high potential for global development, not just limited to ITP, as we were mentioned multiple times, right? By its mechanism of action, you know, we certainly believe wAIHA is a very high potential indication, with very limited treatment options, in the future potentially could extend to other autoimmune diseases. Regarding business development, obviously we're open for discussion as always. However, we believe, you know, the best valuation would be when we finish those optimizations, when we are ready to kick off the registration studies. So, you know, we'll all along entertain, you know, the potential partners and engage and discuss broadly with regard to working with partners. You know, we don't have any problems working with partners. As a matter of fact, you know, what we bring to the table is that we discover these products. We know very well about these products and we contribute scientifically, you know, what indication to pursue and how to design the registration studies. So, and also we, you know, we do the manufacturing of all these products. So, very clear, really, strategy to play to the strength of parties and, you know, we are quite happy with the partnerships we already have. Takeda, what you mentioned about savolitinib, but again, I think, you know, we never rule that out because it's, we don't, you know, we believe savolitinib could have, you know, many potential indications, more than just ITP. So, even with ITP, you could still think about potential combination with CD38, you know, if safety profile supports. So I would not rule out any potential possibility at the moment. So I think that, I'm sorry, yeah, I have to cut off here. So, thank you all very much for participating in this call and look forward to speaking again in the future. You know, we definitely will want to share or provide updates on our key programs periodically and including our early programs or in late- stage discovery even. Thank you. Thank you, Dr. Su. Thank you, Dr. Shi, and thank you everyone participating tonight. Thank you. Thank you.