HUTCHMED (China) Limited (HCM) Earnings Call Transcript & Summary

Okay. Thank you very much for attending today the HUTCHMED company update. We're going to cover R&D. We're going to cover commercial updates. And most importantly, we'll also cover the 10 abstracts that have recently been published for ASCO, covering many of our assets. So if you could move to the agenda, the agenda today is quite varied, a varied update. We will have Dr. Wei-Guo Su, our Chief Scientific Officer; and Dr. Marek Kania, our Head of International and Chief Medical Officer in international, cover our pipeline, our development pipeline. And Wei-Guo will also give more color on our early programs, our discovery strategy. I will touch on the market potential of various of our assets. And that will be followed by Chen Hong to talk about China commercial and Tom Held, the U.S. So Chen Hong is our Chief Commercial Officer in China; and Tom Held is our Senior VP of Commercial in the United States, building our team. We'll then briefly touch on our manufacturing strategy. Dr. Zhenping Wu will cover that. And then we'll go into a conclusion and Q&A. What we're going to try and do is present for maybe 1 hour and 15 minutes, possibly 1 hour and 20 minutes and then follow that with about 0.5 hour of Q&A. So it's a fairly detailed session today, and I think we should cover a lot of ground. Next slide, please. As mentioned, the speakers today are all well known, senior management in the company, senior scientific management, commercial management, and manufacturing management of the company. Next slide, please. So just very briefly, as I always start with this chart, it's important to remind ourselves of our differentiation in terms of being a China biotech. We really do have a global ambition. And I think as we go through the presentation today, it will become very evident the scale of our activities, both inside China and outside of China. There are not many. I don't think there are probably any Chinese-based companies that are moving such a broad pipeline of homegrown innovations through global development. And this is a key point of differentiation and a very important aspect of our strategy. The second area, obviously, remains to build out our fully integrated oncology business in China, and we're making great progress in that area, having launched multiple products now and making a lot of progress commercially. Now we have our product in the market. Next slide, please. So what you're going to see today is really a number of things. The development programs that we have running in China and outside of China will be covered in great detail. Savolitinib, Wei-Guo will cover the latest on savolitinib. We have multiple Phase IIIs that are now being tooled up, ready to start in lung cancer, kidney cancer, gastric cancer. And we're eagerly awaiting our first approval on savolitinib in the next short period of time, hopefully. Fruquintinib and surufatinib, surufatinib, obviously, the NDA submission has already been made. And our European MAA submission will be sometime in the middle of the year. So that will be our -- hopefully, our first innovation onto the global market. Obviously, also, our PD-1 combos are now entering into registration studies in multiple areas. Our transitioning pipeline in hematological malignancies is significant. Our PI3K delta is moving rapidly. We've just started registration studies in China now in follicular lymphoma and marginal zone lymphoma. And our Syk inhibitor, IDH1/2 and ERK inhibitors are all making good progress. Early-stage pipeline. The FGFR inhibitor 453, we have our third-generation BTK inhibitor that's progressing rapidly towards IND, and we have 3 more INDs planned for the second half of this year. And finally, on the commercial side, we're really -- we've always had strong presence on the commercial side in China. We've built that out rapidly recently behind our oncology launches. And now the U.S. team behind the leadership of Tom Held is being built up really quite rapidly. So that's what you're going to see today is details on all of these areas. Next slide, please. So I'll hand it over now to Dr. Wei-Guo Su, our Chief Scientific Officer; and Dr. Marek Kania, our Managing Director and Chief Medical Officer for our international operations. Thanks very much.

Okay. Thank you, Christian. Good evening, good morning, wherever you are. So Marek and I will take you through the pipeline, start off with savolitinib. Savo was designed to address the kidney toxicity of the first generation compounds. Currently, we are testing in multiple tumor types, actually in 4 different areas: non-small cell lung cancer with Exon 14 skipping mutation, EGFR mutation positive non-small cell lung cancer with MET amplification, MET-driven PRCC and MET-amplified gastric cancer. Next slide. Just starting off with MET Exon 14, a brief update where things are. So MET Exon 14, non-small cell lung cancer accounted for about 3% of all non-small cell lung cancer other in certain subtypes, for instance, pulmonary sarcomatoid carcinoma. Some reports up to about 22%. And it happens mostly in elderly patients. Currently, there is no effective treatment, and these patients have very poor prognosis. As you recall, we conducted a Phase II registration study in China, completed last year and submitted the NDA. Currently, the NDA is under review. And we believe it's on track for midyear approval. MET Exon 14 skipping alterations are also found in many other tumor types listed up here, secondary GBM, GI tumors, his -- certain types of sarcoma, actually more than these as well as other in relatively low incidents in all these tumor types. We believe could find application in these other tumor types as well once approved. Next slide, so EGFR mutation-positive and EGFR TKI refractory patient population with MET amplification, we've been testing in 2 studies, TATTON and SAVANNAH. The TATTON study helped to define the patient population, patients coming off first-generation or third-generation EGFR TKI, patients with or without T790M mutations and so forth. SAVANNAH further helped to refine the dose regimen and also the biomarker strategy. Basically, we are now developing a diagnostic kit to enable the Phase III study. So currently, we are planning 2 studies separately, 1 in China, 1 outside -- 1 globally. And we'll be starting off later this month, second half of this month, both studies. Next slide, please. So moving on to PRCC. As you recall, we previously had a Phase III study called SAVOIR comparing savo with sunitinib in MET-driven PRCC. The study was prematurely terminated, and the data was reported earlier. And with really intriguing efficacy, both in terms of ORR, PFS and the trend of OS. At ASCO this year -- at the ASCO this year, we are presenting the CALYPSO study which is the savolitinib in combination with Imfinzi in PRCC. The data is highlighted in the right column, in the right figure, in particular, the table at the bottom. ORR, 57% for MET-driven population comparing to 29% for the ITP patient population. PFS also doubled, MS median, OS as well, more than doubled. And based on this data, we are planning together with our partner, AstraZeneca, a global Phase III study evaluating efficacy and safety of Imfinzi in combination with savolitinib comparing to sunitinib in MET-driven PRCC. This study should be kicked off later this year as well. Next slide, please. And finally, for savolitinib, we are starting a Phase II potentially registration intent study with MET amplification. This is based on some data published last year from VIKTORY study, which was a study carried out in South Korea, demonstrating strong efficacy of savolitinib monotherapy in this patient population. And we are now kicking off the Phase II, again, with registration potential study in China, and this study could be extended to a regional study and with global registration potential. Next slide, please. So to sum it up, I pointed out that MET Exon 14 NDA is now under review, on track for approval midyear this year. Second line EGFR mutation-positive non-small cell lung cancer, we are planning for 2 studies, 1 in China and 1 outside China. The China study should kick off and anticipate the first patient in, in 3Q this year, while the global study, the second line Tagrisso combo will kick off towards the end of the year. The gastric study again, kicked -- sorry, I skipped that the first-line EGFR mutation-positive patient population with MET overexpression. This study is being planned and with the first patient in anticipated also in Q3 this year. It's named the SANOVO study. And this is to really help to block MET activation or the MET amplification induction by EGFR TKI at the first-line setting. And in China, also, finally, as I mentioned, the gastric study with the potential for global registration. This study, first patient in should be imminent, maybe next week or so. Globally, I mentioned that the PRCC study, this is going to be led by AstraZeneca team called SAMETA study, targeting MET-driven PRCC patients and will be savolitinib in combination with Imfinzi versus sunitinib. And we expect the first patient in, in, again, Q3 this year. Next slide, please. So moving on to surufatinib. As you know, we had great success in neuroendocrine tumors, 2 studies published back-to-back in the Lancet Oncology last year. The NDA for epNET was approved in China late last year and the pNET on the -- NDA under review currently, and we expect it to be approved very shortly as well. Next slide, please. So just to sum up for neuroendocrine tumor, NDA approved last year for -- in China for epNET, launch in January. Currently, we are preparing for NRDL discussion. And the NDA for the pNET is under review, as I mentioned, and will be approved fairly shortly. Now I'll ask Marek to cover our global activities for surufatinib in neuroendocrine tumor.

Thank you, Wei-Guo, and hello, everyone. And so from a global perspective, this is our first great global example how we take China studies, in this case, to randomized, robust, well conducted Phase III studies into global registration strategy. This hasn't been done in -- of this scale anywhere at any time before. So we are setting precedents here in a significant way, 2 Phase III studies plus the U.S. Phase I. This study we supported our initial U.S. IND and now supports NDA, leads to truly global unified strategy registration package. We agreed based on last year agreements with U.S. FDA that this package will support U.S. NDA filing, which we did in April '21. We are currently in validation phase. So we're expecting the acceptance by end of June. We are under fast track designation. So it allowed us to have rolling submission. We also obtained orphan drug designation for pNET. We're also in the final stages of preparation of our EMA MAA submission, which we'll be complete by end of June as well as we have a defined path for registration with Japan PMDA. We are starting a small safety and efficacy study in Japan as we speak, which will complement the package described below. So very exciting and a unique way of taking something which was historically developed by Wei-Guo's team in China and now supports global patient registration studies for registration efforts globally. We also are updating our data from our ongoing study during ASCO 2021, which I will briefly discuss in next slide. Next slide, please. So as you can see on this slide, this study was reported before in prior conferences. As you can see, very consistent efficacy continues to prevail across both pNET and epNET cohorts with medium PFS of 11.5 in more than 15 months. On pNET, we have still continuing patients on study. So this is fluid. As you can see, even in this highly refractory, highly pretreated patient population, patients are still obtaining overall response, objective response and what's notable, obviously, in this case, a very high disease control rate around 90%. Our safety profile continues to be consistent with prior data sets, both in other studies as well as Phase III studies, characteristics to mechanism of action. So very encouraging signals. Move to the next slide, please. Behind every consolidated data, there's always a single patient story. On this slide, just to illustrate what surufatinib can do to highlight 2 heavy pretreated patients who failed pretty much all other options. You have example of 74 years old patients with pancreatic MET who fails prior lines of therapies, including everolimus, didn't obtain really a benefit, short lasting, stable disease and had to stop for toxicity and had opportunity to benefit for 15 months on surufatinib without really any toxicities. On the right-hand side, you can see the more dramatic picture of patients who pretty much failed every possible options, including sunitinib, including everolimus, didn't have any benefit, or lasting benefit. And as you can see, patients more than 2 years on our study continues to enjoy life as well not -- or avoid any toxicity. So those are cases where they make my day. And I'm sure every scientist who is behind this program, that's the reason why we're striving for every day to push this program towards fruition and registration globally. Move to the next slide, please. I'll let Wei-Guo to continue describing our program.

Thanks, Marek. So beyond neuroendocrine tumors, surufatinib is now being tested in PD-1 combinations. We believe surufatinib has a unique MOA. Targeting both angiogenesis and tumor microenvironment, particularly the tumor immune microenvironment through CSF-1R inhibition, making it further activating the T cell. And the early data release at the AACR indicated really promising activity during the dose-finding study for this particular combination. Next slide, please. After the completion of the dose finding, we kicked off multiple cohorts, Phase II studies, testing the combination of surufatinib with toripalimab in a variety of different tumor types. At this year's ASCO, we are releasing 2 cohorts with most maturing data. One is in neuroendocrine carcinoma, which is called NEC, different from the NET. And the other is in gastric second line. Both cohorts generated promising data comparing to current standard of care, both in terms of ORR and DCR as well as median PFS. Based on the data -- as a matter of fact, following the submission of the abstract, as the data continued to mature, the efficacy data is getting even better. So based on data, HUTCHMED and Junshi decided to move forward with the first registration study in NEC. And we are pretty much aligned now with the CDE as well with regard to the study design, and we hope to kick it off later this year. The registration study or strategy for gastric cancer is also currently under discussion. Given the changes in the landscape and also the standard of care, we are discussing with the KOLs and the PIs as well as between HUTCHMED and Junshi to identify the opportunity in terms of which line, in terms of which specific patient population to study. We'll expect to have a conclusion on the gastric cancer going forward. And currently, the remaining cohorts continue to mature and both HUTCHMED and Junshi see promising data coming out as well. We'll -- once the data matures, we will make decisions based on the data. Now in addition to activities in China in combination with toripalimab, we decided to partner up with BeiGene, primarily due to our shared international or global aspiration for innovative product development. So we are kicking off surufatinib with [ tisle ] combination globally. I'll ask Marek to give you some more details on the next couple of slides.

Yes. So as you can see on this slide, this is really high level design summary of a study, which Wei-Guo mentioned. This study a kickoff. It's in the Part 1 dose-finding, relatively simple. It should move quite quickly to expansion cohorts. As you can see on our colorful slide, we have a number of cohorts with really limited treatment options across colorectal cancer, neuroendocrine tumors, small cell, gastric and soft-tissue sarcomas. This study is ongoing in U.S. and will expand. Actually, Europe will participate in expansion cohort. So we are ready to replicate some promising signal coming from our China studies with multiple partnerships into this global aspirational goal of creating multiple potential proof-of-concept signals potentially leading to a number of accelerated paths for potential approvals. So we're very encouraged by that. Next slide, please. I'll let Wei-Guo to discuss fruquintinib on the China side.

Okay. Thanks, Marek. So fruquintinib is a highly potent and selective VEGFR-1, -2 and -3 inhibitor. It covers VEGFR-1, -2 and -3, 3 isoforms equally potently and resulting in consistent clinical benefit for patients who failed bevacizumab, which is selective for VEGFR-2. It's also highly selective, probably the most selective small molecule, VEGFR TKI that we are -- we know of. And as a result, it has demonstrated clinically very favorable safety profile with relative manageable adverse events. And also, we have demonstrated that fruquintinib can be readily combined with chemotherapy, such as paclitaxel, targeted therapies, such as EGFI inhibitor [ ERASA ] and IO. And we think it's quite unique, and it should really broaden its potential in the combinations. Next slide. So you have seen this before. This is the FRESCO data that led to the registration of fruquintinib in China fulfilling CRC. Next slide, I'll ask again, Marek to talk about our global status or global strategy.

Thank you, Wei-Guo. So this slide is looking familiar to surufatinib study. This is yet again, I would tell you template or blueprint to how we maximize and efficiently use data generated in China in developing our global strategy. As you can see, FRESCO study, which led to approval in China. It's the integral and very important part of this registration package. And it will be 1 of 2 pivotal studies supporting our U.S. NDA, EMA filing as well as Japan. We reached agreements with all regulatory bodies, including U.S. FDA, EMA as well Japan PMDA, the FRESCO-2 study, which is truly first global study. We were conducting in 14 countries across 150 sites. And the study is progressing extremely well and will finish enrollment before year-end. So we are very encouraged by, actually, enthusiasm and support from global [ third ] leader community, who sits our steering committee of FRESCO-2 study as this reflects unmet medical need in this refractory setting of colorectal cancer. So the FRESCO-2 study is positive, supported by U.S. ongoing study which is extremely important data in overall decision in bridging between FRESCO and FRESCO-2. FDA agreed with us that this package will support -- may support third line and above in colorectal cancer center. As you know, FRESCO study is a little bit less criteria population in China and FRESCO-2 is very refractory population. So 2 and 2 together, will definitely support a broader label. So we are very encouraged in the prospects of fast pace development here. We are under fast track designation granted by FDA last year. So it will afford us rolling submission if FRESCO-2 is positive and leads to next steps. We are also encouraged very much by participation of Japan. And the fact that Japan is integrally part of global study will enable PMDA submission simultaneously across U.S., Europe and Japan. Next slide, please. I will let Wei-Guo to discuss our combination strategy.

Right. So taking advantage of the clean safety profile of fruquintinib and its ability to combine with other therapies, we have partnered up with this Innovent in China and to evaluate fruquintinib and simtuzumab combination in a variety of tumor types. At ASCO this year, we will publish the initial data of this combination in late-line CRC. As -- and in parallel, we kicked off a multiple-cohort Phase II, evaluating in HCC, endometrial cancer, RCC and gastric cancer, cervical cancer and non-small cell lung cancer first line. Where things are. HCC, we finished or completed stage 1 enrollment data looking very promising. And when we are on active discussion with PIs and trying to solidify the registration strategy going forward. Endometrial cancer is also complete -- fully enrolled with very promising results. As a matter of fact, we are awaiting a communication meeting with CDE to clarify the registration study design. And RCC is relatively open in China. Only 2 trials ongoing today. The data in second-line also look very encouraging. And again, on the discussion how we move forward, we're likely to move into first line. Based on the really encouraging emerging clinical activity and the really good safety profile, Innovent and HUTCHMED together kicked off another 3 cohorts, second line GC, second line cervical and first-line non-small cell lung. And these are currently enrolling. Next slide, please. So just a bit of details on the data we are publishing at ASCO. This actually includes 2 abstracts. One is fruquintinib and sintilimab combo. The other is fruquintinib with [ gepto ] combo, a different PD-1. The highlight here is that clearly, you can see comparing to fruquintinib alone as a monotherapy, overall went up almost a fivefold, more than fivefold from 4.7% in the FRESCO study to now 27%-ish, and it compares favorably to lenvatinib pembro combo, which is at 21.9%. And more importantly, the PFS is really encouraging. It went up from 3.7 months in the FRESCO study, fruquintinib as monotherapy, to now around 7 months for the PD-1 combos. And much improved comparing to lenvatinib and pembro combo. So the data for the OS is still maturing, but trending quite -- very, very favorably as well. And a clear benefit for these late-stage CRC patients. So currently, Innovent and HUTCHMED are discussing the strategy for registration for CRC indication. Next slide.

Yes. On this slide, I will summarize quickly, a continuation of the same efforts we're doing with combinations with surufatinib with our partner, BeiGene. As you can see, tislelizumab combination in 2 protocol, actually. One is led by HUTCHMED, and we have triple-negative breast cancer, IO naive and IO pretreated. And you can see on the bottom of this slide, summary of several cohorts in gastric cancer, MSS, colorectal and PD-L1 positive, small cell lung cancer, first-line cohort in combination with tisle and the study is led by BeiGene. So across 2 studies, again, this will be great proof of concept, so as for our future registration combination in a global aspiration to bring this combination to patients across U.S., Europe and potentially Japan. So we are very encouraged by signal from China across multiple partners. And as you've seen on the last slide, Wei-Guo showed the colorectal signal is definitely very promising. So we are carefully looking at this. Next slide, please.

Yes. Just to kind of sum it up where things are for fruquintinib. The ongoing Phase III study in second-line gastric cancer in combination with paclitaxel, we expect the full enrollment before end of this year and top line results second half next year. And the PD-1 combo, we are running multiple Phase II studies. CRC are currently in discussion to formulate the registration strategy. Endometrial cancer, we are moving forward with the registration study, pending discussion with CDE to finalize or get aligned on the study design. Data is really, really promising in EMC. And HCC and RCC data continue to mature. We are discussing particular -- the targeted patient population to go after, given all the competitive trials ongoing in China, and the initial 3 cohorts, EMC, HCC and RCC looked really robust and with a great safety profile. So we are adding 3 new cohorts, as I mentioned, second line GC, second line cervical and first-line non-small cell lung. And this will enroll very quickly. And I would expect that we will wrap up the Phase II, all these cohorts around -- before end of the year and we'll select if data supports additional indication as to moving into registration studies. Marek, you can cover the global quickly.

Yes. On the global side, just to summarize what we already discussed. I think the message number one, we have a global regulatory strategy and registration path fully designed across U.S., Europe and Japan and our package, which I presented before, will serve that purpose very well. Our first [indiscernible] study is ongoing and executing very well once sort of enrollment to date and will complete by end of the year. Our U.S. [ study ] continues to prove a great source of confidence in highly pretreated population across multiple cohorts. This makes us very optimistic about the prospects of this program helping many patients globally. We are also preparing and expanding. As we discussed, our strategy is not just single agent strategy, but combination strategy. And PD-1 combinations discussed before will serve our proof-of-concept studies and signals to move future expansion and expanding life cycle of our assets. So we are very excited about this. Next slide, please.

Thanks, Marek. Moving on to our next wave of compound HMPL-689. Our highly selective and potent PI3K delta inhibitor. Obviously, PI3K delta is a very crowded area. And we believe HMPL-689 is well differentiated and has clearly potential as best-in-class globally, given its potency and selectivity. Last year -- end of last year at ASH, we published those escalation data summarized on this slide. Overall response rate, this is a patient total [ ITT ] of 56 patients. Overall response rate of 48% across all doses and tumor types, including more aggressive tumor types such as DLBCL and MZL. And also encouraging duration of response and progression-free survival. Next slide, please. And we are also quite encouraged by the safety profile of HMPL-689. As you'll recall, the first compound approved Zydelig had a black box warning for diarrhea, colitis and liver toxicity. We can see HMPL-689 has much improved diarrhea and also liver tox profile and comparing to all the other PI3K delta inhibitors. You can see a very favorable profile. We are quite confident that this is going to differentiate HMPL-689. Following the dose escalation, we kicked off -- next slide, multiple cohort expansion studies, a very sizable study, a total of 140, 160 patients in 5 cohorts. At this point, cohort A is fully enrolled. As a matter of fact, we are already moved into a registration Phase II study. Cohort B is still enrolling, cohort C in third-line and above follicular, again, fully enrolled with very promising data and the registration of Phase II kicked off as well. And cohort D in MZL, DLBCL and FL3B and cohort E in T-cell lymphoma, these cohorts are still enrolling. And next slide, we'll give you a bit more detail on the 2 registration Phase II studies. The MZL expects to enroll around 80 patients, 81 patients after first-line -- failure of the first-line [ anti-CD20 ] therapy. It has 2 stages. And will enroll -- we'll have an interim analysis for -- after the first 33 patients. Same design for follicular. We expect to enroll around -- just about 100 patients, 104 patients in total and 2-stage design as well. For both studies, the primary endpoint will be IRC assessed ORR for registration. And we expect full enrollment for follicular in the first half of 2022 and MZL by second half. Then probably, we expect the difference of 3 months for those 2 indications. Next slide.

On this slide, you can see. Yes. Thank you, Wei-Guo. On this slide, you can see a summary of our U.S. IND supporting study, which was original filing. As you can see, we are approaching end of the escalation phase. We had 25 milligrams. So very soon, we'll have defined or confirmed dose for global development. As Wei-Guo said, we are looking always at holistic totality of the data across both China and international programs always in connection, and we are certainly encouraged by what we see both in China, a little bit mature cohorts as well what we see in our escalation cohorts, which I will discuss. We will be moving very aggressively to expansion cohorts as soon as we finish those escalation. As you can see, we had 23 target sites right across 7 countries. And this -- actually, there is anticipation from most of the sites to participate in expansion cohorts. We are going to move to very intense discussions, regulatory preparation as well as discussion with U.S. FDA to confirm and define regulatory path, but we are aggressively moving -- expanding this program into registrational intent, design and expanding our expansion cohort size to confirm our signals we see. Move to the next slide. As I was showing you, I'm not ready to present to you any consolidated data. At this point we will report at ASH consolidated data from update from escalation phase. But is what is always encouraging to see that single patient cases. And Phase I is always tricky. You have actually the best bad actors in the way patients without any options. And this is a very classical example of Phase I patients. As you can see, 85 years female who failed multiple lines of prior therapies and has no benefit or short lasting benefits and entered on our study at low -- really low dose 10-milligram dose and continues on Cycle 19 without really major adverse events. A very encouraging case for senior patients like that looking for options on expanding and having good quality of life. Again, those are the cases which makes every scientists and investigators treating physicians a day. Another patient is even more interesting case, move to the next slide. This patient actually failed prior idelalisib, which was allowed in expansion -- escalation phase. As you can see, the best response was just stable disease on prior period delta. Patient received actually CR after first cycle and continues to be on study for 17 months and ongoing without major toxicity. And again, that CR happened on 10 milligrams, and patient was escalated to 20 milligrams during escalation phase. Extremely encouraging cases like that. And obviously, that makes us very excited, and we will be making analysis of totality of the data and moving to the next phase of development. Move to the next slide, please. As you can see on -- maybe I will cover global just as a continuum here. You can see that the graph on the bottom, which we already discussed across every program. This is again kind of template we are taking here, consolidating our totalities of the data and making this as a robust regulatory strategy package. We believe strongly that between ongoing data from China, ongoing data from U.S., international study and Phase II study, which just started in China, makes this extremely robust package for follicular lymphoma NDL registrational effort. As Wei-Guo said, we believe we can differentiate not just based on safety, but based on efficacy and safety, and this program has potential to be best in class. So again, as I said, we will be engaging FDA in the second half of this year, and we'll keep you updated, but strong encouragement, what we see. Wei-Guo, I'll let you maybe add a few comments on China.

Yes. So in China, we are focused on driving the 2 registration Phase II studies, FL and MZL. In parallel, we are continuing with our Phase I dose escalation -- dose expansion in 3 other cohorts. And we expect -- we submitted an abstract for ESMO to publish ongoing Phase Ib expansion results at this year's ESMO. We are really excited about -- by the early efficacy of HMPL-689 in multiple different subtypes of lymphoma. And both in terms of high level of response, particularly complete response, as well as its really favorable safety profile. We expect additional indications will be selected for registration studies. In parallel, we are preparing to submit a comprehensive IND for various different combinations, including combination with standard of care, combination with PD-1, combination with VEGFR and a combination with other targeted therapies, all in hematological malignancies. So later on this year, we hope to kick off these combination studies in tumor types with unmet medical needs. Next slide, please. So moving on to 523, our Syk inhibitor. We now completed China and Australia Phase I, both dose escalation and dose expansion, with emerging promising data in CLL and SLL post BTK treatment. Currently, we are conducting Phase I internationally. And if the data in BTK refractory CLL/SLL is confirmed, we believe we could consider to initiate a single global study for global registration, including China, in this patient population. Next slide, please.

Yes. Just to summarize what we are doing internationally. This is a similar graph what I showed you for 689. The study is approaching, again, last cohorts and those defining step. We had 700 milligrams right now, and we are less than a couple of months from defining recommended Phase II dose. Again, the study is ready to expand as quickly as we finish escalation. And as you see, a number of cohorts will be explored here similar to our PI3K-delta program. As Wei-Guo said, we'll be holistically looking at combined program and signals from those China study and global study and we will inform our next steps on registration strategy globally in a very integrated way. So we are moving aggressively on this side. As Wei-Guo mentioned, based on promising signal from post BTK refractory patients, we will be prospectively adding and expanding that cohort into U.S. international study to confirm and validate that. So again, very encouraging. Next slide, please.

So on the immunology side, we made a lot of progress, testing HMPL-523 in ITP, immune thrombocytopenia. Obviously, it targets both the B-cell and the macrophages. It's a validated target for ITP. Fostamatinib has been approved in the U.S., but we believe HMPL-523 is more potent and better tolerated. We now finished a Phase I/II study in China with a very encouraging efficacy and safety. We are now planning a Phase III that we believe that could -- we submitted a meeting committee -- end of Phase II meeting with the China CDE, and we expect to discuss with the CDE to align with the Phase III study design. And we expect to kick it off later this year, a Phase III registration study in ITP. Next slide. So just to recap for 523, China/Australia, Phase I completed with promising data in BTK refractory CLL/SLL and we are pending international to finish off the Phase I study and confirm activity in this patient population and would consider a global study for global registration, including China, for this patient population. In the immunology area, really finished off the Phase Ib/II study with promising data, and we are awaiting for the end of Phase II meeting with China CDE to discuss the Phase III study design, and likely Phase III initiation later this year. In addition, we are planning to -- preparing to kick off a Phase II study in autoimmune hemolytic anemia, AIHA, which is, by mechanism, very similar to ITP. We believe HMPL-523 should have good effect against this particular disease. Next slide. So I think we are running short of time here. Just a brief update on the early programs. HMPL-453, our FGFR1/2 and 3 inhibitor. We are currently in Phase II in iHCC, the cholangiocarcinoma, intrahepatic, with FGFR2 fusion. We are seeing early signs of clinical activity. More importantly, we are submitting an IND next month to enable combination studies. We believe the way to move forward is to move into first line. So we'll be in first-line in combination with chemo and in combination with IOs. HMPL-306, our IDH1/2 inhibitor with brain penetration. Designed to overcome resistance due to isoform conversion associated with the first generation IDH1 or IDH2 selective inhibitors in hematology, and also taking advantage of its brain penetration, explore glioblastoma, both in China and the U.S. Right now, dose escalation is, we believe, we're halfway through in China in AML. We believe we can complete the dose escalation before end of the year. Internationally, we kicked off dose escalation in both AML and solid tumors early this year. HMPL-295, our first candidate, it targets ERK1 and ERK2, our first candidate in MAP kinase pathway. We are -- as we talked before, we are working on multiple targets along MAP kinase. This is our first candidate and more to come later this year, more against upstream targets. This compound, we just kicked off the initiatives of Phase I and patient -- the first patient is now under screening. We should have the first patient in very soon maybe next week, actually. Next slide. Just want to share with you, this year, we have 3 new INDs planned. HMPL-760, our third-generation BTK inhibitor. It's a reversible, non-covalent and very potent oral compound, active both against the wild type as well as the C481S mutant. Has very good efficacy in, in vivo models comparing to ibrutinib or ARQ-531. Again, in both the wild type tumor models and the C481S mutant models. We believe it has great potential in addition to competing with the first generation BTK inhibitors, also combining with our assets in the hematologic malignancy space, for instance, HMPL-689 and HMPL-A83, our CD47 candidate. The IND &D submission for China and the U.S. will be in Q2 and Q3 this year. So this will be our first candidate for really global development. As a matter of fact, the U.S. will be probably ahead of China. HMPL-653 is a potent and selective CSF-1R inhibitor targeting the CSF-1R driven tumors as well as potentially targeting the immune -- the tumor immune microenvironment, potentially in combination with IOs. The IND submission is planned for Q3 this year in China. And finally, HMPL-A83, our first monoclonal antibody into our pipeline. It's a monoclonal antibody with a unique epitope and high affinity, highly efficacious in our models comparing to other CD47 compounds, with much reduced effect on red blood cells. And again, clearly, positions well with our hematologic malignancy portfolio of compounds such as 689 and 760. The IND submission is planned for end of this year, both China and the U.S. Next slide. Just to sum it up, it's going to be a busy year for HUTCHMED, China and globally. We are targeting 10 new registration studies, 5 for savolitinib, at this point, anyway; 1 for surufatinib; 1 for fruquintinib; and 2 for 689; and 1 for HMPL-523 in ITP. And this is what we've been working on, and we would expect additional registration studies once the data becomes -- the data become more mature of a lot of ongoing Phase Ib, Phase II studies. Again, 3 new INDs I already talked about. Next slide, just very quickly, the discovery update. We continue to work on 3 different areas, targeting the tumor cells, on this chart, the tumor antigen release type targets. We also are working on our IOs, CD47, our first monoclonal antibody. We are also working on a number of bispecific antibodies as well. And maybe next slide, I'll just give you a snapshot of also covering different MOAs, both in terms of cell signaling, apoptosis, epigenetics and so forth as well as large molecules now targeting both IOs and tumor antigens. And new technologies, probably for future candidate selections, both in terms of PROTAC, antibody-drug conjugates and so forth. I think in the last slide, just give you a quick snapshot of the type of programs we are working on. I think my time is up. Maybe -- what's the next slide? I'll probably hand it back over to Christian. Christian?

Great. Thanks, Wei-Guo. So if we can go to the next slide, please. So I'm going to very briefly talk these slides. I don't expect us to cover them in-depth in this short 3 or 5 minute section. But these are -- it will be posted to our website and they're available for further review. These are our assessments of the available patient populations for each of the indications that we're working on for savolitinib, and I'll go through fruquintinib, surufatinib and the other assets in a moment. As you can see here from this chart, you can see MET Exon 14 deletion in the brown box. This is hopefully our first approval, as Wei-Guo has said, in the middle of this year. But you can see in China and actually outside of China, the vast MET-driven patient populations that exist in EGFR mutation-positive non-small cell lung cancer, MET gene-amplified non-small cell lung cancer, gastric, esophageal and even colorectal cancer. So being the first-in-class selective c-MET inhibitor in China, we will be the only treatment option for these patients, not just the Exon 14 patients, but any patients with aberrant MET activation. The green column on the right-hand side shows the current latest information on the median duration of treatment or median PFS that we're seeing for each of these indications for these patients. The yellow signal there is the data that Wei-Guo had touched on earlier in papillary renal cell carcinoma. The 10-point 5-month median PFS, which really is a big step forward for those MET-driven patient population in papillary renal cell carcinoma. So this chart is a lot of detail, but basically gives a sense of the overall opportunity. And also the areas where we're going outside of China. So the third-generation EGFR TKI refractory patients post Tagrisso, you can see that's the global Phase III that is being planned. And then the PRCC study there is a global Phase III going across all of the major markets. So it's a big year for savo and big opportunity. Next slide, please. Fruquintinib, you can see the highlighted in yellow there, the ASCO data that Wei-Guo mentioned in colorectal cancer in combination with sintilimab and gepta from Genor. You're seeing a median PFS up around 7 months relative to the high 3s or 4-month duration of treatment for monotherapy fruquintinib. So it's a big improvement in combination with the PD-1s, and we're looking at that. Gastric cancer, you can see a very large patient population, the FRUTIGA study will complete enrollment later this year and mature out over next year. If we're successful there, that will be a pretty big step-up for fruquintinib in terms of market potential in China. And then all the PD-1 combos that we've talked about, specifically endometrial cancer that Wei-Guo has mentioned earlier is the first one that we're moving on. Next slide, please. Surufatinib. You can see in neuro endocrine tumors, obviously, China in brown already approved, but the dark red there, these are the activities to bring surufatinib to approval outside of China being led by Marek and his team. We also have been looking at biliary tract, neuroendocrine carcinoma, gastric, all highlighted with data at ASCO this year. And as Wei-Guo says, the data that's presented at ASCO is still maturing and still improving. So we would hope that the numbers in the far right column there in green are actually, ultimately, higher than those shown here. Next slide, please. 689, you can hear from the enthusiasm of Wei-Guo and Marek that we're extremely excited about what's going on with 689 at the moment, moving very rapidly in China, now in registration studies in MZL and FL. Looking at multiple other non-Hodgkin's lymphoma subgroups to go after in China as well. And then also Marek and the international team moving rapidly on follicular and MZL and will be the plan. So engaging as quickly as we can to determine our registration pathway outside of China. Next slide. Finally, the Syk inhibitor. ITP has been well explained. And I think very encouraging for us is the BTK refractory patients in indolent non-Hodgkin's lymphoma, where we're seeing great efficacy. Right now, in China, there aren't many of those patients. The BTK inhibitors haven't been on the market very broadly in China. So most of those patients are outside of China, and that's where Marek and the team will be concentrating. Next slide, please. Okay. So now I'm going to hand it over to Hong Chen, our Chief Commercial Officer for China, to give an update on our commercial activities in China. Following Hong Chen, it will be Tom Held, our Senior VP of Commercial in the U.S. So over to you, Hong Chen.

Okay. Thank you, Christian. I'm happy to introduce HUTCHMED's commercial capabilities with my U.S. colleague, Tom. So next slide. So -- yes, let's recap for HUTCHMED. Three novel drugs already launched or in the process for the registration review. The first is the fruquintinib, approved in 2018 and already listed in NRDL in 2019. HUTCHMED took the promotion rights from Eli Lilly since Q4 2020 that can let HUTCHMED have 70% to 80% in-market sales as revenue. The second one is, surufatinib, which was approved at the end of last year and already launched in January this year. HUTCHMED owns all China rights. The third is savo, which is supposed to get approval as early as Q2 this year. AstraZeneca has the commercial rights in China. For the total 3 novel drugs, it's supposed to bring consolidated around USD 110 million to USD 130 million for this year. Next slide, please. HUTCHMED has 2 commercial organizations before established oncology commercial platform. The first one is the Shanghai Hutchison Pharmaceuticals, which is focusing on the traditional Chinese medicine promotion. It has more than 2,500 sales force covering around 20,000 hospitals and more than 80,000 physicians. The second one is the joint venture with Sinopharm. Sinopharm is the largest pharmaceutical distributors in China. So HUTCHMED established its own oncology commercial capabilities since 2018. Right now, it has more than 480 dedicated commercial staff, covered more than 2,500 hospitals and also 20,000 oncology specialists. So with the established oncology commercial capabilities, it can leverage the previous 2 commercial organizations. Next slide, please. We have a very comprehensive function departments for our oncology commercial team, including sales, marketing, medical affairs, government affairs and so on. It can led us to a response book for detailing channel management and also patient education. We are still -- have plan to expanding the sales force size with the sales revenue growth and the future new product launch. Also, the sales force productivity also will increase in the future. Next slide, please. This is the oncology commercial team leadership. We can see they come from both multinational and local companies, which is a lot of us have higher compliance standard and also to be very practical. Next slide, please. As for the market access capabilities, actually, we have very strong market access team and have a very good record to get the fruquintinib listed in NRDL, and we are also working on the government funds and the hospital listing as well for market access. Next slide, please. As for the KOL relationships and engagements, we can see that we have very good coverage for national, provincial as well as local specialists and KOLs. So we can get their support for the guideline recommendation as well as the consensus recommendation. Next slide. Just a good example that even without approval for the pNET indication of surufatinib, it also has been recommended by the latest version for the guideline for the diagnosis and treatment of pNET patients in China by CMA. Next slide, please. We also have very good experience to handle patient advocacy groups and the PAP programs. Already more than 2,000 CRC patients benefited from the fruquintinib PAP program. Right now, we are running the surufatinib PAP program, too. Next, please. So also, our OBD, oncology business development, run a lot of academic promotion, which includes both online/off-line activities and also including the digital programs. Next slide, please. Here, it's a very good example to show the HUTCHMED oncology capabilities. Before I mentioned that we took back the promotion right from Eli Lilly since Q4 last year. So we can see the performance in Q4 and in the first 2 months of this year. Last Q4, fruquintinib achieved USD 10.2 million, which is the peak sales -- quarterly peak sales for last year. And in January and February this year, we still kept a very good sales performance with USD 14.3 million, which is -- account for more than 40% of the total sales for the last year. Next slide, please. So comparing Eli Lilly, HUTCHMED oncology team, we moved very fast to -- for the hospital pharmacy listing. If we compare April -- the end of April this year versus September -- the end of September last year, we have more than 95% of the hospital listing. And comparing -- if we are comparing the commercial team size, we have 177% higher than Eli Lilly, also 129% higher than -- in terms of the hospital covered and 40% in terms of the city covered. We are very confident for the future faster growth for fruquintinib because CRC already became the second highest incidence in China, with 550,000 new cases in 2020. So the third line CRC patients will increase accordingly. And the good effects seen for the fruquintinib/PD-1 combination will help to extend the DOT for fruquintinib in the future use. And also plenty of the IIT studies ongoing to explore the treatment for the second line CRC patients. Also, it allows to explore more higher potential opportunities. Of course, the Phase IV study (sic) [ Phase III study ] for GC is ongoing, so -- which gives a very good indications in the future. Next slide. For surufatinib, brand name is SULANDA, which was approved at the end of last year and launched in January this year. And we just used 14 days to catch the first phase marketing to the market. And until the end of January, we are already at the prescription in over the 30 provinces. For the first 2 months sales, we achieved around USD 5 million. So next slide, please. So it allows to negotiate SULANDA in the -- this year around NRDL. And for SULANDA, we also have very high potential future growth opportunities. First, if the pNET approved this year, SULANDA will be the first product to address all patients regardless the tumor origin. So that's the first. The second, the combination with the PD-1. Because of the SULANDA's very unique MOA allows we can explore more high potential growth opportunities in the future. So that's all for China. I hand over to Tom. Tom, please?

Thank you. Thank you, Chen Hong. It's great to see the early success you're having with fruquintinib and surufatinib, and we hope to follow in your footsteps soon. For our view of our U.S. efforts, I'm going to focus on 4 things: our team, our imperatives, the opportunities we have in the marketplace and importantly, how we're going to win. So first -- first, the team. As you can see from this slide, the commercial leadership team is deep in oncology experience, but 2 things to point out about this team is one that Ed Barnes and Leslie Blair have both recently worked in the neuroendocrine tumor space. So along with me, they have the relationships. They know the space. They'll be able to really accelerate our understanding and drive to a great positioning in the marketplace as we advance. Ushank, who's our Head of Commercial Operations, launched an oncology agent in the pandemic period. So he's very experienced in leading teams in our new challenging reality of how we're going to reach physicians. Finally, Dr. Raina has value and access and pricing experience in the IO space and has worked in U.S. account management and global value and access. So he'll be able to kind of help us not only in the U.S. establish a framework, but also globally as we establish our early portfolio. Next slide, please. We'll build our capabilities across 3 distinct groups. And first, having a differentiated brand value proposition. We're -- like all agents and all commercial entities and teams, we're going to find actionable insights into the patient journey. We're going to build on our key points of differentiation, which I'll highlight a little bit later on. And of course, we're well funded by our China leadership team with Christian, really making a strong investment in our U.S. launch. We're taking that investment and building a robust operational framework and platform. Working on recruiting top talent with a premium in oncology and NET experience. Along with [indiscernible], who's our Head of Medical Affairs, we're building a robust medical affairs commercial alignment around the customer and we're rapidly accelerating our IT systems to build out our capabilities to operate efficiently in the U.S. marketplace. Finally, our optimized go-to-market model. Our experienced team is going to know what competitive share of voice we will require to be successful in this. From my experience and experience of the rest of the teams, we'll have somewhat of a rare disease patient acquisition model. The incidence and prevalence of NETs is, as I will go through, is reasonably low, but patient acquisition will be an important dimension that we'll be careful and plan thoughtfully around. As I said, we'll build value, access and pricing models for the U.S. and beyond. But finally, what I think what makes our model kind of most unique compared to a lot of other start-ups is with surufatinib leading into fruquintinib, we'll be able to kind of have a very clear focused GI cancer commercial model that will allow us to build on our success with surufatinib and then expand on that success when we hopefully launch fruquintinib. And that will establish a great anchor and put us in a wonderful position to expand out for the near-term hematologic indications. So we're very focused now, but with the ability with our great foundation to advance and grow. Next slide, please. So a little bit on the market landscape for surufatinib and fruquintinib. There's currently 170,000 or so patients living in the U.S. with NET. 30,000 of these are under active treatment in the metastatic setting. What's unfortunate for these patients is nearly 50% of them are diagnosed with distant metastases at the time of diagnosis. As you can see by the chart on the right, the percent of NET cases by location are pancreatic, extrapancreatic and then of unknown origin. What will be a unique competitive advantage for surufatinib in this space will be our activity across all NET patient types. If we are approved, we will be the only agent approved for NETs regardless of origin. Now the treatment landscape includes and is dominated by somatostatin analog is really kind of the anchor and the strongest first-line therapy. Targeted agents are sunitinib and everolimus. Cytotoxic agents are uses in these patients as well. And of course, PRRT has been a little bit of a disruptive therapy for patients with high somatostatin receptor positivity in the foregut and midgut space. So that's a fairly narrow indication for PRRT against our kind of broader indications. Next slide. What's -- we -- when we started to dig into this market, what we found was most interesting and really kind of underscores what the opportunity for surufatinib in the U.S. is. Less than 10% of eligible patients in that metastatic patient pool are treated -- were treated with everolimus or sunitinib in 2018. And that kind of leads to a hypothesis that we're really forming out as we continue to do our market insights is that physicians are really hesitant to use these agents because of the toxicity that accompanies modest clinical benefit in this setting. And what we're going to try to understand is the sweet spot for surufatinib with our strong efficacy data, combined with a really well-tolerated approach for patients, which Marek kind of highlighted earlier when he was kind of going through those patient case studies. So we believe that's our kind of unique, ownable position in that space. Next slide, please. Switching gears to fruquintinib, it's a similar story, in that beyond the FOLFOX and [ hair fall theory, foundation of hair ], only 20% to 30% of patients in the third line and plus setting gets stivarga or regorafenib. And really, a lot of these patients are recycled through original chemotherapy and this really underscores the unmet need in this marketplace, where there was 67,000 patients treated for colorectal cancer in the metastatic setting in 2018. The fast-evolving treatment landscape includes these targeted agents, but there are some significant toxicity to manage in this setting. And really, there's an unmet need that's tremendous here because the 5-year survival rate in metastatic colorectal cancer is really only over -- slightly over 14%. Next slide. Going back to surufatinib and talking a little bit about how we win. And you've seen the slide before. These are the Kaplan-Meier curves for the extrapancreatic and pancreatic programs. As you can see, we have superiority over placebo that lines up well with everolimus. And in fact, in some ways, lines up better than everolimus, being careful about cross-trial comparison. And that the vast majority of patients in our SANET-p and SANET-ep programs were patients with G2 tumors, which is different from the everolimus radiant studies where there were more G1 patients. So we feel that this unique mix of efficacy in a challenging patient population, combined with our tolerability, really gives us a chance to really compete and win for these patients. Next slide, please. Last slide here is with fruquintinib. And the FRESCO study in China already gives us some real optimism around how we can win in this space. If you look at the disease control rate of 62% to PFS over 3.7%, again, accounting for how to be careful about cross-trial comparisons, we do better than TAS-102 and regorafenib and nintedanib in these settings. What's also promising is the median OS in these patients of 9.3 months. And we're hopeful that the FRESCO-2 study, as Marek indicated earlier, which is advancing with great pace, will kind of reconfirm these results, therefore, giving us a real ability to compete in this space. So on that quick note, I'll turn it back to Christian.

Thanks Tom. So we're running a little over. So I'll ask Zhenping to be relatively brief. But Zhenping will give us a brief update on our manufacturing strategy for both small molecules and large molecules. Zhenping, over to you.

Thanks, Christian. Yes, I'd be happy to talk about our manufacturing capability and organization and I will be very brief. So this first slide is the overall strategy for our manufacturing activities. Of course, our goals are two-folded. First, we aim to support the rich pipeline that you have heard tonight. We are very excited about pipeline. We want to make sure we can support the advancement of the programs. And secondary, we are building capacity to prepare for the next wave of the commercial product launch. So -- and that's the portfolio. So in this slide, we have 3 parts which I want to talk about. So on the left -- in the middle column, the top line is the drug product strategy, our formulation strategy. But that activity, we do it in-house. So we already have a facility in Suzhou, which can support the current 2 products with about USD 0.5 billion revenue capacity. And most importantly, I'm going to talk about a little bit later. So we are building additional capacity for future products with up to $2 billion revenue in Shanghai. And for API, we mainly use CMO in China. There are a lot of high-quality CMOs here, and we have established quite a few top-quality manufacturing in China, which I also will mention a little bit later. And then on the right-hand side, it's the -- for the -- in the biologic field that we are starting to see them coming into development. So in the near term, we will use CDMO to support the program. But we have a plan to build on capability internally with the facility in Shanghai. So all these manufactured facility capability, we talked about for global, not only for China, but for China and ex China. Next slide, please. So here, I'll talk a little bit about the organization we have. So as you can see here, we have a very experienced team here other than -- except the biologic CMC, which is a relatively new department we established. For all other functions, we have people with average about 20 years experience in the industry and also they have been with HUTCHMED for a long time, even average about 10 years. And this is a very capable team, and they are the people who process the 2 product launch in China, and we are supporting all the problem in China. And we -- as I said, we are building further activity in the future. Next slide, please. So for the API manufacturing, we continue -- we intend to continue to use the top-quality CMOs in China. I gave 2 examples here, WuXi STA and Asymchem. They are very high-quality organization. They support many multinational companies globally. So what's important is that we have established very good relationship with them. We have used them since our very early stage of our program during clinical manufacturing. So we've had that relationship for over 10 years now. And that's very important. So for this commercial manufacturing, we intend to use 2 sites just to mitigate any supply risks. Next slide, please. So here, I just want to talk a little bit about our future plans. Actually, it's something that's going on, but it's going to meet our future needs. So the Suzhou plant is manufacturing 2 commercial products that we are marketing now, and it's meeting our current needs, but we are actually initiating a very ambitious project near Shanghai, it's about 10 or 15 kilometers from our research site here. And it's a huge project, as you can see from the data in this table. From the land size, building size, it's much bigger than our Suzhou facility. Most importantly, it's about 5x for the Phase I, which is intended for the combination production, and then for the Phase II, we have more room for biologic capability building in the future -- in the next couple of years. So this project is ongoing. We're well on our way. We hope to see this in for operations in the next 2 years or so. And our future products will start to launch from here. So in the next slide, just want to give a quick update. So basically, the manufacturing organization is well positioned to support all the manufacturing capabilities -- activities for global products, the small molecules and biologics. And we have a very strong organization with more than 100 scientists. And we are leveraging CMOs in China for clinical manufacturing and also for commercial API manufacturing. For drug products we're doing in-house, we're using the Suzhou facility for the current 2 products, but we are building a large facility for future needs. And that's it for manufacturing. Thank you. Back to you, Christian.

Thanks, Zhenping. Thanks. If you could move to -- you can pass this slide, we already discussed it. This is an important slide because it lays out our global ambition and strategy and the kind of the 2 core centers of our focus and of our excellence. You can see highlighted on the left-hand side of the chart, China, where we will -- we have and will continue to build our global discovery organization and, as Zhenping has just said, our global manufacturing organization. So China will represent a global foundation for both discovery and manufacturing. Obviously, also, we have the objective to build a fully integrated company in China. So why growing the clinical development and regulatory organization as well as Chen Hong and the commercial team really give us a fully integrated operation in China. In the U.S. from a strategic standpoint, the U.S. market is critical for us. And we want to control as much as we can our commercial operations in both China and the U.S., which represent about 50% of the global pharmaceutical market. So in the U.S., in order to support that, Marek and the team have built an international headquarters for clinical development and regulatory that covers not just the U.S. but actually Europe and Japan as well. And now with Tom, we're building out our commercial platform there. So with those 2 markets in our control and in control of our own destiny, we can cover close to 50% of the global pharmaceutical market. We can capitalize on our established development and manufacturing capabilities in China. And outside of those 2 markets, in Europe and Russia, Latin America, et cetera, we're already talking to potential partners to bring our products to those markets. Over the next 5 years, that will be our focus in those noncore -- well, those are important markets, but noncore short-term markets for us is to find the right partners. Next slide, please. To finish it off, before we go to Q&A, this gives a sense of the ambitions that we have. As of today, we've received approval for fruquintinib and surufatinib in China. But if you look at our targets and our ambition for the period through 2025, you can see we have intention to launch a broad range of therapies. On the global -- in the global setting, we expect to have 5 therapies launched by 2025, including surufatinib, fruquintinib, savo and Tagrisso combo, savo Imfinzi combo and HMPL-689. Those will all be launched in -- at least our target is to be launched during that period, from now until '25. In China, we expect 9 launches during that time. And these are individual therapies, not of indications. There'll be, for example, surufatinib monotherapy, we'll have hopefully 2 approval, 2 approved indications this year alone. So this is -- these are the therapies launched. And in addition to that, we expect, on the right-hand side of this chart, to have a further 6 therapies in registration studies by 2025 and in China, further 9. So you can see a vast increase in bringing assets and therapies to market versus where we are today. I mean we've made great progress in the last couple of years and particularly this year as we are commercializing products in China and seeing the revenue growing rapidly. But if you're able -- if we're able to achieve these targets, these ambitious targets, and bring these -- this quantity of approvals to both the global market and the China market, Zhenping is going to probably have to build another factory because even the Shanghai factory we're building at the moment may not be sufficient. So it's a very ambitious plan, and I think we are at a turning point as a company in our development of our programs. So I'll leave it there, and maybe we can open it up for Q&A from this point on. Thank you.

[Operator Instructions] Our first question is from Louise Chen at Cantor.

So I had a few. First question I had for you is, in the past, you've talked about 900-plus oncology reps in China by 2023. And what level of product sales would that support? And how many more items or products do you think you could add to the bag for those sales reps? Second question I had is, how are you planning to develop or build out a heme malignancy franchise? Where do you think you differentiate yourself on a portfolio level? How are you thinking about this, the first-in-class, best-in-class combination of both? And then last question I had for you is one that investors ask us a lot about is how do you think about pricing for your oncology treatments in the U.S. given that there potentially could be a discrepancy between the NRDL pricing versus the U.S. pricing?

Okay. Thanks, Louise. Maybe I'll try -- because we're short of time, I'll try and answer these quickly and ask my colleagues if you need further explanation. So by the end of this year, Chen Hong and the team in China will likely be close to 600 commercial people on the ground. That 600 is not all medical reps. You've got probably -- at that point, it's probably around 480 medical reps, probably another 120 commercial and head office stuff. And as was stated on Chen Hong's charts, our targeted productivity for those reps is around USD 400,000 per rep. So if you are thinking about the existing team, to be able to get to that level of productivity, is going to take a couple of years, 2 or 3 years. I would expect by 2023, we would have 900 reps on the ground -- sorry, 900 commercial people, 80% of those -- 80% to 90% are field sales reps doing about $400,000 per rep, and you can do the math. It's probably around $300 million, give or take, in sales from a U.S. dollar standpoint. So hopefully, that answers your first question. On the hematological malignancy franchise, how are we going to differentiate? I think Wei-Guo and Marek have explained it fairly clearly today. We believe the 689, which will be our lead asset in the hematological malignancy space, has clear points of differentiation in the area of tolerability, safety profile, and then that plays out into efficacy. So I think 689 will differentiate itself in that sense. I think the combination opportunities from the broader hematological malignancy portfolio that we have is really important in the context of differentiation. I don't know too many other companies worldwide that have a potential best-in-class PI3K delta, that have a potential first-in-class Syk inhibitor, a differentiated third-generation BTK inhibitor, a CD47 antibody, an IDH 1/2 dual inhibitor, the list goes on. So I think when it comes to hematological malignancies, it's going to be about the portfolio, how we develop those assets, how we combine those assets to differentiate ourselves. But I think we have great opportunity to establish a very powerful hematological malignancy franchise. And then finally, on the pricing in the U.S. relative to China. Obviously, Chinese pricing and the NRDL is -- tends to be lower, but the reason you've got in the NRDL is so you can access these very large patient populations. There are many examples of multinationals that have quite different pricing strategies in China versus outside of China. And I don't expect us to be any different. The cost of developing assets, marketing those assets in the U.S. is materially higher than it is in China. So no doubt, the pricing in the United States will be materially higher than it is in China. Hopefully, those answer your questions.

Our next question is from Alec Stranahan from Bank of America.

Okay. Great. Thanks for taking our questions and for hosting the session. It's been very helpful to see everything in one place. A couple from us. I guess, first, when you're thinking about initiating Phase II studies for, say, savo in MET amplified gastric and also 689, which you said both are with registration intent, I guess what gives you confidence that these studies could be sufficient for approval in China? And do you think larger Phase III studies would be required for ultimate expansion globally? And then on your noncovalent BTK, you mentioned improved potency versus IMBRUVICA. But could you maybe touch on how 760 is differentiated from second-gen noncovalent BTKs such as LOXO-305, which obviously has some encouraging data at ASH last year? And then finally, on the go-to-market strategy in the U.S. for suru, what do you see as being sort of taking precedence in driving uptake? Is it physician education as the clinical benefits? Or will it be ensuring patient access through competitive pricing will be more important to driving uptake?

Thanks, Alec. Maybe I'll ask Wei-Guo to answer the first 2 parts and then Tom Held to answer the third question.

Sure. So regarding our Phase II registration studies, it's really a fast to market, faster approval type of strategy. And likely, these will be conditional approvals and will require confirmatory studies. So that's kind of the strategy we are taking to get these products quickly across the finish line. And doing -- and for the study design with regard -- specifically for the targeted patient population, the treatment, diagnostics and so forth, we hope that we could design a study to hopefully support the global registration. So that's to really leverage the study we do here, we conduct here in China. Yes, to your question is that, ultimately, depending on the patient population, very rarely, the single-arm studies will have -- will grant full approval. It has precedence but not all. So that's the current strategy. Although with the single-agent approval from the single-arm study, the confirmatory study can be randomized and it could be even moved upfront -- to the front line, for instance. You don't need to be in the same line, for instance. Your question about third-generation BTK, we have seen clear [ outage ] of ibrutinib as well as ARQ-531. We have not compared head-to-head with LOXO-305 at the time when we were running the programs at discovery stage. We did not have the information on the structure -- chemical structure of LOXO-305. But we are quite happy with the level of potency we are seeing, the level of complete responses we are seeing in our studies with 760 and also the great safety profile. Actually, ARQ-531 in our hands, it actually hits multiple kinase. It's not that of a selective BTK inhibitor. LOXO-305, we have yet to make comparisons head-to-head.

On the U.S. go-to-market model, the short answer to your question is we'll do both. We'll kind of be highly focused on the clinical benefit and ensuring access. But to go back to this, one of the things we're uncovering when we're doing our patient insights and understanding the journey is that neuroendocrine tumors have a long fan in the metastatic setting. These patients are treated for a long time. At the same time, this is a very heterogeneous patient population with degrees of severity depending on the site of the net. The tumor, though, has a little bit of a reputation of being a good cancer to get because of this kind of long duration of therapy in the metastatic setting. That's a little bit of a misperception, I think, because this disease is uniformly fatal in the metastatic setting. When patients do well on somatostatin analog, that's, of course, something that is a great tool for the medical oncologist because it's a fairly low-risk return that tamps down the disease for a period of time. But eventually, all of those patients progress. And we haven't had great tools at progression. And we think surufatinib will kind of be that tool right at that point of progression, which will maintain the quality of life that the patients were getting on somatostatin analog with some real targeted benefits. And then hope for life cycle down the road is that we can take advantage of the mechanism of action of CSFR1 to combine with IO therapy to really amplify that benefit for these patients even more. So we're hopeful about that space we can occupy in the metastatic setting. And then in the access point, our job and what my team will be focused on is once that prescribing decision is made, to clear the path and do as much as we can compliantly to ensure that, that prescription is filled with an engagement strategy that includes payers, looking at unique distribution models with specialty distributors and specialty pharmacies and giving, hopefully, those patients a little bit of white glove treatment as they advance to try to get the drug. At launch, this isn't always easy, but the team is really focused on making that pathway smooth for these patients.

Our next question is from Paul Choi at Goldman Sachs.

I also want to follow up on the 760 BTK program, and I was wondering if you could please just sort of elaborate on how you're thinking about the developmental path there given that LOXO-305 already is in Phase III program for CLL and SLL in either BTK experienced or intolerant patients, just how you're thinking about the development path there. Second, I think with regard to your MAPK program, I thought I heard the phrase upstream. And so can you maybe just articulate what you mean there? Are you focusing on a KRAS monotherapy program or some sort of combination program, what the strategy is there? And then third, maybe at a higher level for Christian or Wei-Guo. Just with regard to the investment in biologics, either as antibodies or in bispecifics, just -- can you maybe just articulate, is this going to be the priority more on a 3- to 5-year view? And just sort of the rate of investment and just how you think about the future of HUTCHMED as a biologics company. And will that be the focal point versus your historical focus on small molecules?

Thanks very much, Paul. I think maybe I'll ask Marek to talk about the 760 development plan in the U.S. And maybe Wei-Guo can add to that if you've got additional comments, Wei-Guo. Then Wei-Guo can pick up the MAP kinase upstream question, and maybe I'll talk the biologics question #3. So go ahead, Marek.

Yes. Thank you. Thanks, Paul, for questions. So as we are approaching IND and first-in-human, obviously, you've seen Wei-Guo differentiating attributes. Based on the nonclinical data, we feel positive we can compete in the space of the refractory resistant BTK with this third-generation molecule. Obviously, at this stage, our focus is to define a safe dose and going through several cohorts of activity before we're making any clinical judgments and statements. Wei-Guo can add during his parts of any nonclinical differentiators that I think we established that theme of that high potency, high selectivity across multiple of our programs, which is actually translating into early clinical settings, and obviously, we will not start IND if we not believe we have chance to differentiate. But we are driven by data. And when we see it, we'll position our proof-of-concepts that the results are [indiscernible]. So Wei-Guo, I'm not sure if you want to add anything to this.

So specifically for BTK, obviously, you have 2 different approaches. One is to target BTK refractory patients, patients with C481S mutations. But again, as you say, right, LOXO is ahead of us. So the other way is to actually look at wild-type -- let's say, for instance, in second-line mantle cell cancer in [indiscernible] setting or some other even more aggressive tumor types where ibrutinib has been approved for. You could do a study with PFS as the primary endpoint, for instance, knowing that in our -- in 760, for instance, you're not going to see any C481S mutations emerging because there is no point for that to emerge. It will be inhibited by 760. So based on that, this mutation covers almost 50% of the resistance. So given that, you would expect a much longer PFS. The tumor cells will have to come up with other ways to stay alive basically. So that's another angle that you can actually target from earlier lines head-to-head, basically, with a BTK inhibitor, with ibrutinib, for instance, the first-generation BTK inhibitor. But ultimately, Paul, I think in the heme malignancy space, we are going to be a portfolio approach -- a portfolio company rather than a single compound. So I think, for instance, a combination with our PI3 delta combination with our CD47 might take us into much more aggressive tumor types such as DLBCL. We have a lot of [indiscernible] data that will support that these combinations would significantly improve efficacy, or you take it to first line, for instance. We are doing a -- we're working on the CD20 bispecific, which could be a perfect combination with 760, and take it all the way to first line. I think, today, you're talking about -- in CLL, SLL, for instance, you're looking at 80% ORRs and 50% CR with the rituximab-based combos. We think that there is still space. You could go almost up to 80% CR rates with a more careful selection of combos. So we believe that, ultimately, we'll be a portfolio kind of approach. You're going to see -- maybe you want to establish quick-to-market strategy behind BTK, targeting C481S mutation, or you can be more aggressive to go head-to-head with ibrutinib in actually multiple tumor types. Obviously, you don't want to go after CLL, SLL because ibrutinib, the PFS is very long, almost 5 years. The study would be too long. However, against some of the more aggressive tumor types, mantle cell is only about 10, 12 months. [ WM ] is relatively short as well. These -- you can go after -- at least amenable for PFS as a primary end point. Just shutting down the mutation from the beginning, we think the PFS should be much longer, much improved. The second question was MAP kinase. Yes, I've been mentioning, obviously, ERK is the downstream, the very last, the gatekeeper of the MAP kinase. At the same time, we are working on multiple targets, upstream of ERK, all the way up to the very high -- very top level. So basically, we believe this is a very different signaling pathway comparing to PI3K/Akt pathway. This is more of a proliferation rather than survival. Single-agent activity will be limited, even though we've seen encouraging activity coming from KRAS G12C, although the [ overall ] seems to be acceptable in non-small cell lung but much lower in other tumor types, for instance, the CRC. And the PFS is much less than optimal, for sure. So we believe, ultimately, the combination of the target [Audio Gap] inhibition from upstream and downstream, hopefully, we'll be able to optimize both the response and the PFS or the duration of response. Yes, we are -- we actually expect additional candidate selection in this pathway this year as well as next year, a few targets.

Great. Thanks, Wei-Guo. Paul, on your question about our investment in biologics, it actually sort of carries on from what Wei-Guo has just said. As you look at our discovery strategy, we are looking to attack those cancer cells and the immune microenvironment or the cancer microenvironment -- cancer cell microenvironment from multiple angles. So again, our strategy is very much a portfolio strategy, creating multiple assets that can be combined together and go after the disease from multiple angles. So biologics for us and our investment in building out biologics capability and CMC and also the work that Wei-Guo and the team have already put in on the discovery side to be developing or creating large molecule innovations, all of that is with the intention of using that large molecule platform to combine with our small molecule platform in a portfolio approach. I mean if you think about the colorectal cancer data that's just -- the abstract at ASCO that's just been presented or have been published, where you're seeing a doubling of the median PFS in third-line colorectal cancer, when you combine fruquintinib with PD-1, that's a great example of why large molecule sort of backbone assets are important to our broader small molecule portfolio. So our CD47 initiative, we've talked about that today a little bit. Yes, we believe there are points of differentiation versus other CD47 antibodies, but more important for us is to have that weapon in our arsenal to be able to combine with our hematological malignancy, small molecules, the BTK, the Syk, the PI3K delta, the IDH 1/2. That's why we're doing it, not so that we can suddenly sort of switch track and become a large molecule company, no. We are a portfolio-focused company looking to be able to discover and develop all the assets we need to attack cancer and immunological diseases from every angle we need to attack them.

Our next question is from David Ng at Macquarie.

I've got a couple of kind of also more strategic type of question. I think it's quite exciting to see preliminary good results in combination with various PD-1 drugs. And if we look forward, it may not be too far away that the pricing of PD-1 drug in China will come down very, very significantly, if not already down a lot, such that it become a commodity. So a combination, definitely a good break away from that. But is it more even more sensible to focus on something like a PD-1 sales strategy, like patients who fail PD-1 and then the line after that will be maybe a PD-1 in combination with a small molecule coming from HUTCHMED? Is there a deliberate thinking behind that in anticipation of PD-1 becoming increasingly commoditized, especially in China? So that's my first question. Second one is -- and I guess this is also related to PD-1 due to the intense competitive environment. The competitors are trying to move to earlier line and much -- actually much faster than most people expectations. So -- and to go to earlier line, of course, you also call for a very smart clinical strategy, I guess, specifically interim analysis, potentially allowing earlier filing of a product. And of course, that has to be based on strong confidence in the efficacy of a product before the full data set is available. So again, along that line, is HUTCHMED thinking maybe even more aggressively to push some of your products to early line? And in order to achieve that, is there any particular drugs that you think will be the most likely to hit the earlier line setting than the others? So that's my second question. And last one is, I guess, the -- between now and 2025, of course, a very ambitious target, but if we can achieve that, do we anticipate extra funding needed from external in order to achieve that target? That's my 3 questions.

Thanks, David. Maybe I'll ask Wei-Guo to answer the 2 questions on the PD-1s, the first one being using sort of the treatment regimen, do we go after PD-1 failure patients following those patients? Or do we try and move sort of into the first-line setting? Wei-Guo, over to you.

Yes. Very good question, obviously. So PD-1 refractory patients, if you notice that both in China and in the U.S., we are adding cohorts targeting specifically previously PD-1 therapy treated patients. So we are exploring with our VEGFR combos targeting this patient -- specific patient population. But longer term, we think perhaps PD-1 or PD-L1-based bispecifics may be also useful for this particular patient population. So obviously, it will take much longer time in discovery stage. At this point, we are looking into these type of bispecifics. With regard to front line, yes, clearly, given all the competition out there, for instance, I mentioned the fruquintinib and sintilimab combo in endometrial cancer. We are moving into a Phase II study. This Phase II would be a registration study. It's a single-arm study, OR as the primary end point in second line and above. However, the confirmatory study, we plan to do actually in first line in comparison to current standard of care. So while we are just initiating in the second-line setting for faster approval, we're already planning the confirmatory study in first line. And this -- there are multiple other tumor types where we are looking to, not only just first line. They are already moving towards even earlier in adjuvant setting, for instance, or in stage 3, for instance, stage 2, stage 3 kind of disease as well. So it's a reality. And these patients benefit, and we need to move these therapies forward to the front line, yes.

Yes. Thanks, Wei-Guo. On your question, David, about our sort of ambitious targets for 2025, it's a big increase in our activities, clinical development programs, sort of -- but most importantly, that overlaps onto our commercial launches. So we'll be generating significant net income from those commercial launches to help fund the broadening of our clinical development activities, particularly as Wei-Guo says, you've got 10 registration studies kicking off this year and 3 more INDs being submitted before the end of this year. So it's just an ever-increasing portfolio of activities but helped by the fact that our commercial assets are moving well and starting to generate income. So I think we're in a good position to be able to support the activities of our business over the next 2 or 3 years.

Our next question is from Rajan Sharma at Deutsche Bank.

I've got a couple. So firstly, we noticed that Lilly and Innovent filed their P-1 inhibitor sintilimab in the U.S. based exclusively on data generated in the U.S. So just be interested to get your thoughts on that. And do you think that may mark kind of a potential change in the FDA stance on the topic? And do you think there's maybe something that becomes more common going forward? And then particularly kind of thinking about your portfolio, do you think there are any opportunities within the pipeline to follow a similar path? And then secondly, just outside of the Shanghai facility, could you talk to any key CapEx investments that you foresee as you grow the geographic presence? And then it sounds like surufatinib in Europe is a candidate to partnering given it's kind of a noncore geography for you. So could you just perhaps give us an update of where you are in any process that may be going on there given the regulatory status? And then finally, just one more, if I could squeeze on in. You'd previously also talked to developing capabilities in biologics s a potential source of -- from M&A. And now it looks as if you may be focusing on doing that in-house. So could you just provide a little bit of clarity on that, please?

Sure. Great. Thanks, Rajan. Maybe I'll hand it over to Wei-Guo to discuss the Lilly, Innovent PD-1 registration in the U.S. He's probably most familiar with that. On the CapEx, I'll answer that one. On the EU partnering, I'll answer that one. And on the biologics M&A, I'll answer that one as well. So Wei-guo, if you could answer the first part of that question.

Well, I mean, certainly it adds complexity, right? I mean -- so Innovent out-licensed sintilimab to Lilly for outside China. We've been working with them inside China and generating really promising proof-of-concept data. So how do we -- I think this licensing would add complexity. But at the same time, it could provide Lilly really some valuable data that they should consider, for instance. If we got EMC registered in China or other tumor types registered in China, they may be able to take advantage and quickly. So we are discussing with them and both Innovent and Lilly as well for outside China. However, they also have ramucirumab, for instance, and they might consider ramucirumab combinations. Although the data we generate here in China are really exciting in many tumor types. You saw CRC today. We expect to publish our Phase II data in EMC, HCC and RCC later this year. And they have a really strong, exciting data and could provide Lilly opportunities for early registration outside China. The problem is that they have to work with multiple partners now, Innovent in China and someone else outside. And that's, frankly, the reason we are also in partnership with BeiGene. BeiGene has also global ambition, global aspiration similar to HUTCHMED. And we think that at least to mitigate the potential risk to navigate through the complexity with Innovent, Lilly and kind of relationship strategies, so we have a solid partnership with BeiGene to move forward with.

Thanks, Wei-guo. On the CapEx question, beyond Shanghai facility, are there any other major CapEx items to be taking note of? The answer to that is not really. The majority of our CapEx, around $130 million investment in the Shanghai facility is -- that's our focus. Beyond that, the second phase, as we get into broadening our large molecule platform, that will incur additional CapEx, but that will be further down the road. So nothing major. In terms of suru and European partnering, we are undertaking at the moment to engage with a number of material-scale European specialty pharma companies and pharmaceutical companies around surufatinib. So I expect that something will come of that over the balance of the year. I mean the MAA will be submitted in Europe in the next few months. So we've got a bit of time to identify the right partner and the right deal. But there is no shortage of interest in surufatinib outside of China and outside of the U.S. As far as the building out of the biologics platform, as we've mentioned today, there's a focus on doing what we can control and building out our own platform. Zhenping is already building a team. Wei-Guo has already built a discovery organization on the large molecule side. And so we're pressing ahead. On the M&A side, we had in the past thought that M&A might be the right approach. We tended to find the M&A opportunities in China. We looked pretty hard. And we tended to find the types of opportunities that were attractive to us were really overpriced. So we determined to kind of go ahead on our own. It doesn't mean that we won't keep our eye open. So if the right large molecule opportunity, a platform presents itself, we would certainly be open-minded to considering it. But as a sort of a base case, we're pressing ahead on our own. Hopefully, those answer your questions.

Our last question will be from John Newman at Canaccord.

I just had one question on in HMPL-689. You've shown us that your safety profile was indeed quite favorable when comparing to other agents. I'm just curious, in terms of the low-grade ALT increase and AST increase, I'm just wondering if those events are mostly transient so that patients can, generally speaking, continue on therapy.

Maybe to Wei-Guo or Marek.

Yes. The ALT on liver enzyme elevation typically is transient, unless you have Phase III or if you have further increase in bilirubin, then typically it gets more serious. They are -- ALT/AST elevation, these are typically transient, and you can either stop -- interrupt it for a week and then you can rechallenge, although grade 3 or above can be more difficult to manage. And if rechallenge is not impossible, then it becomes a problem. So with 689, we are seeing mostly grade 1, grade 2, which -- there's no need to actually dose interrupt, that they can continue to take that medication. And if they progress to phase -- grade 3, they'll need to take the drug off for a week or so and wait until it comes back down to grade 1, that can be challenged. Typically, if you -- grade 1, grade 2 relatively speaking, easy to manage.

Just to add to Wei-Guo, I agree on the liver. But I think what we are encouraged most and physicians enrolling to our study, rate of colitis and laminitis, which, so far, obviously, in our limited sample size, we haven't seen any of those. And that's the biggest problem of this class. And when we see it, obviously, we need to continue collecting data and observing, especially long-duration therapy. And this truly -- if this continues this way, it will be truly differentiating from other options.

Thanks, Marek. So I think from the moderator side, we're going to get -- we're going to shut down the Q&A at this point. But I'd like to remind everybody that tomorrow at 12 noon Hong Kong time, we'll be having a second session aimed primarily at the Asian analyst community. So that will be an extended Q&A that will follow this presentation, which is available on our website to review ahead of that. So 12:00 tomorrow, that will be happening. So if there's anybody on this call that didn't get their question in, there's a second opportunity tomorrow to do that. So as a result, I'll just thank everybody for your patience. We went a bit long. It ended up being 2 hours, 24 minutes, which is a bit longer than we planned, but there's a lot to cover. I'm very appreciative of everybody taking the time to join us. And as always, please feel free to reach out to the company, to myself or to our Investor Relations team at any time to engage and set up conference calls as necessary. So thank you, everybody, for your time, and look forward to speaking soon. Thanks very much.

Thank you.

Bye-bye.

Bye.