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

Hello, everyone. Good evening and good morning. Thank you for joining HUTCHMED 2025 R&D Day event. For your reference, you can go to our website to download today's presentation slides. The performance and results of operations of the HUTCHMED Group contained within this presentation are historical in nature, and the past performance is no guarantee of future results. [Operator Instructions] So now let me welcome our CMO and Head of R&D, Dr. Michael Shi, to start the today's presentation. Michael?

Thank you, Ng. Good morning, good evening, everyone. Happy Halloween. And so today, I'm going to give you a research update for HUTCHMED pipeline. So today, we're going to talk about the -- our main antibody target therapy conjugate platform and really showcase some of the new next-generation platform. And also recently, last week, we actually presented our first candidate, HMPL-A251 at the EORTC meeting in Boston. So I'm going to highlight some of the progress and show you the results and our overall preliminary development plan strategy. And then I'm going to show the late-stage pipeline progress and with a closing remark and then we're going to start a Q&A session. Okay. So for the ATTC platform we introduced to the investor early this year is really the new development for the past 3 years at HUTCHMED. We're really looking at some of these progress and the platform. So before we go that and we really talk about the current development in the toxin-based antibody drug conjugate, ADCs. As we know, there are 19 ADC has been approved worldwide. And despite the design and the rationale expanding the therapeutic index, the traditional toxin-based ADC also have a very similar toxin profile. And microtubule and the tubulin isomerase inhibitor and both have some common feature for toxin-based toxicities such as myelosuppression, thrombocytopenia and hepatotoxicity and some of the ocular toxicity or neurotoxicity. So far there's really the limitation. There's certainly room to improve to overcome these challenges. And the HUTCHMED antibody target therapy conjugate really designed to target a protein required to [indiscernible] cancer growth. And one of the important feature of what we believe it has the synergistic combination activity with antibody because the antibody we chose really have the antibody and the function to really have a potential synergistic effect. And more importantly, we know the ADCs has very difficult profile to combine with the traditional chemotherapy, which is often required for frontline chemotherapy. So we think the ATTC will overcome this chemo-resistant and also have the potential to be dosed long term. And from toxicity perspective, although the -- it have the antibody-based toxicity but we believe the antibody target therapy payload have the low on-target and off-target tumor toxicity. And also, they bypass some of these traditional small molecule systemic toxicity, for example, liver toxicity and QT prolongation, et cetera and low myelosuppression and also support a long-term use. So we think this just will be a unique platform to really enhance some of these and overcome some of the resistance and difficulty for the toxin-based ADCs. So when we select these development for ATTC, really selecting some of the functional antibody and conjugated with the target therapy, which traditionally a small molecule have poor solubility and very hard to link the antibody. So we're really working on the linker and the payload to have this ATTC platform develop. And with the lower free target therapy in the circulation and also have a wider therapeutic window compared with the oral systemic exposure. And also, it has a great opportunity because they can combine with the other therapies, for example, target therapy, immunotherapy and more importantly, the chemotherapy. So this will potentially have a opportunity to be used in the frontline. So to show some of the -- highlight some of the first target therapy, the -- really the unique invention here is the target therapy payload targeting the PAM, PI3K/mTOR pathway. So the PAM pathway, PI3K/AKT/mTOR pathway is very attractive therapeutic target because it has a very -- cover a very broad range of the tumor type, have a high frequency mutation in some of the most common tumor type. For example, in breast cancer, the PI3K PAM pathway mutation representing about 70% of the patient -- breast cancer patient. Also in endometrial cancer, for example, has very high mutation rate. Also in the other common tumor type, it also have a very high frequency. So -- and also, this is in the development stage, there are quite some small molecule, pretty much the previous effort focused on the small molecule development but have a very few success. And also talking about the mutation is really play a role in the toxin-based ADC resistance. So this is one of the report last year from ESMO showing that HER2 ADC disitamab vedotin RC48 in breast cancer patient type. And in the clinical study in the overall patient population, the PFS and ORR is better but with patient with PAM-altered pathway really show for poor prognosis activity. For example, the PFS, that's actually lower, response is lower because this driver mutation really leading to the drug resistance for ADC product. And also in the DESTINY-CRC01, also showing the driver mutation for PIK3CA and also RAS mutation, patients with these mutations also have a lower response rate and shorter PFS compared with the wild-type patients. So really leading to -- there's opportunity to really improve to develop a target therapy as a payload to overcome this resistance. I also mentioned about the traditional development for PI3K/mTOR pathway, really focused on small molecule. There are quite a pipeline of development, including multiple companies invested in this PI3K inhibitor development and -- but with very few success. And the first generation and second generation pretty much halted due to the systemic toxicity. And later on, there are mTOR inhibitor, for example, everolimus, PIK3CA alpha, alpelisib and capivasertib is AKT inhibitor, leading to the approval but they also have a pretty hard to handle tolerability profile and also the overall survival has been hampered. And there are -- 2 weeks ago, we see the new PI3K inhibitor gedatolisib really showcase some of the activity in the breast cancer but it still has a very high difficulty in toxicity, for example, mucositis and some myelosuppression as a side effect. So targeting PAM pathway alteration really showing as a promising approach for breast cancer. For example, in the slide here, we show in the overall breast cancer patient population, you can see the PAM pathway mutation, including PI3K mutation, AKT mutation and PTEN loss, representing about 70% of the patient with this mutation. In HER2+ patient population, including hormone positive or negative patient population, the PI3K PAM pathway mutation is representing close to 40%. And in the HER2- patient population, triple-negative patient population, these mutation even have a higher presence. So really presenting a big opportunity for developing PI3K inhibitor targeting breast cancer patient population. In the gedatolisib study, we do see there is a improved PFS and activity in not only in overall patient population, representing inhibiting target in HER2+ patient population also show good activity and -- but adverse events such as stomatitis also pretty high. Okay. So here's the profile for our pan-PI3K pathway inhibitor, PI3K/PIKK inhibitor. And this is HM606 (sic) [ HM609 ], in short, we represent 606 (sic) [ 609 ]. This is our first targeted PI3K inhibitor using as a payload. So the profile for this molecule and showing in the kinome, you can see the major inhibition really showing focus on the PI3K and PIKK activity is very high selectivity and very few -- small off-target activity. And this is the profile compared with the other kind of PI3K or PIKK inhibitor. Gedatolisib and dactolisib and buparlisib, you can really see 609 has a very robust and potent inhibition against all these PI3K and PIKK pathway. Here's the biochemical characterization of this -- our first ATTC is the A251. And as we can see, using this we look at the payload, you can see this has a pretty potent inhibition of the PAM pathway. When this pathway is activated, it's commonly in the breast cancer cell lines, you can see very robust dose-dependent inhibition of the PAM pathway, including AKT S6 or so. And also in the PIKK pathway, when you enhance the PIKK pathway by treating with bleomycin, you can really activate all this DNA repair process and using the payload 609, you can see also a dose-dependent inhibition of this pathway. And also in the panel of 130 cell lines, we can see in many cell lines with mutation of a PAM pathway, HER2 pathway alteration, RAS/RAF pathway mutation and other cell lines. 606 (sic) [ 609 ] has a very potent activity with IC50 about 1 nanomolar. And also on the right-hand side is the cell growth inhibition of 609 by tumor type. And also show -- demonstrate a nanomolar range and also high potent activity across many different tumor cell lines. So now let me talk about the antibody part. The first proof-of-concept molecule where we develop is using HER2 as a antibody. We all know HER2 alteration really leading to a poor prognosis in cancer, in many tumor type. For example, HER2 amplification and overexpression has been shown is as a poor prognosis factor and HER2 amplification or overexpression lead to the patient with a shorter half-life -- shorter lifespan. And also HER2 overexpression and amplification really cover many tumor type. So what we also looking at the anti-HER2 therapy is really, for example, developed by trastuzumab is a functional antibody with intact Fc and leading to ADCC activity. So it works by blocking extracellular domain cleavage to prevent the formation of its active form of HER2 and also block the dimerization of the molecule and reduce the signal transduction pathway and also mention the antibody leading to the antibody-dependent cell-mediated cytotoxicity and also the HER2 antibody downregulation through the endocytosis through the lysosome. So to sum up for our concept and for the development of ATTC, we use HER2 as a therapeutic antibody and PI3K/PIKK pathway inhibitor as the payload. This provide opportunity to really inhibit the most major oncogenic driver and the downstream signaling pathway of HER2. And it has the potential to overcome the resistance for trastuzumab-based therapy and also the antibody and the payload will have a synergistic activity to -- with the enhanced antitumor activity. So this pan-PI3K-based HER2 ATTC is really expected to increase the efficacy and synergism and also improve the safety profile to overcome some of the narrow therapeutic window for the traditional PI3K inhibitor. So now let me move to the first candidate, A251. We showcased this molecule at the EORTC meeting last week in Boston. So here's the structure for PI3K -- the A251. It has the payload 609 and is a highly potent PI3K/PIKK kinase inhibitor and has the potential synergy with the HER2 antibody. And we also show you some of the data we have the potential for combination with chemotherapy as ATTC and also show the bystander effect. The [indiscernible] portion is the HER trastuzumab biosimilar and with a credible linker and with the antibody -- drug to antibody ratio of 4. Here's the in vitro binding activity. It does show A251 and the HER2 antibody has a very similar binding activity. And also this figure show the internalization of the antibody A251 ATTC and also the naked antibody. So at 37 degrees, we can see the internalization. On the right-hand side, you can see the intracellular trafficking of the antibody drug conjugate. So here is the blue color is showing the nuclear staining and the red color is really with the HER2 antibody. Green color is showing the lysosome. And when you incubate cells, you can see it has a time-dependent internalization of the antibody, both the naked antibody and also the A251. As you can see, with the time when you merge the signal, the red color and the green color will overlap with the times of incubation, really showing the antibody has been internalized into the lysosome. And also, we show you the activity for payload 609, now for the whole antibody target therapy conjugate has a similar feature as the payload alone when you do the in vitro cell inhibition assay in HER2+ PI3K mutant cell lines. We can see a potent inhibition, dose-dependent inhibition of the, first of all, AKT S6, for example, really showing the target pathway inhibition and leading to clear the pathway PARP inhibition and leading to apoptosis. And also on the right-hand side is the PI3K -- PIKK pathway inhibition showing this molecule also have a in vitro inhibition of the PIKK pathway and also leading to the DNA damage when you use the A251 has increased the DNA damage. And also next, we show the activity in the panel of cell lines for A251, showing the growth inhibition on the left-hand side. You can see in the 26 cell lines we have tested, HER2+ cell line with PI -- PAM pathway alteration or without alteration, it has very robust potent activity, actually 0.2 nanomolar range to have a very good tumor growth inhibition effect. And in HER2 low PAM-altered pathway, it still demonstrated potent activity, although the potency compared with the HER2 overexpressed positive patient population, it has less potency and also has some less magnitude [indiscernible] in HER2 low, the cell lines. And here down the right-hand side, we show the bystander effect. In the HER2+ cells, we can see the A251 showing very potent bystander tumor killing effect. And it doesn't work on the HER2 low cell lines but you co-culture the HER2-positive and HER2 low cell lines, you can clearly see the robust tumor killing with the bystander effect. And also, we test this molecule in the -- in HER2 resistant cell lines. So one, on the left-hand side, we can see the comparison of the A251 with the HER2 in cells, in breast cancer cells with using the siRNA silencing of the SLX4, which is one of the key gene to turn on the resistance because it's one of the DNA repair enzyme. And when you're really silencing the SLX4, you can see a right shift of the potency of the payload DXd or DS-8201 in HER2. It has less -- need a higher concentration and also the less -- the inhibitory effect, compared with the A251, the -- compared with the payload itself and A251, you can see there is no right shift and the payload and ATTC maintain the same potency to inhibit this resistant cell line. And on the right-hand side is the developed cell line resistant to -- in HER2 or the payload. And you can see, again, right, the DXd treated cells and in HER2 treated cell have a right shift and less potent killing effect compared with the parent cell. But in the payload 609 and ATTC A251, you don't see -- you don't observe this right shift and maintain the same tumor killing effect, cell tumor killing effect. And here is the, one of the proof-of-concept study we have done for A251. And here, you can see the black label is the vehicle treatment and the red color is the payload 609 itself at 0.5 milligram per kg IV injection biweekly. And the pink color is the trastuzumab plus 609. You have also increased cell growth inhibition. And A251 at 10 and 30 milligram per kg, really showing robust tumor inhibition activity and causing tumor regression. So this is very important because this is HER2+ and PTEN loss xenograft model. We can see a single dose injection of A251 can have 2 weeks sustained tumor suppression, unlike the small molecule. So you need multiple dosing to have a modest antitumor effect because this is actually the MTD level of the payload for 609. And also on the safety side, you can see this -- on the left-hand side is the same model. You can see the ATTC A251 and then that does not lead to the body weight change. But the small molecule, 609, the payload and the 609 plus trastuzumab, you actually see when you dose the small molecule, you can see actually a quite significant body weight loss and they recover, when you dose again, it will lead to additional body weight loss. So this is pretty much the -- this is really the maximum tolerated dose for this small molecule payload. And so as you can see, really in the preclinical model, you can see this activity of the A251 has a more safety profile compared with small molecule or small molecule combined with the company -- with the antibody. Also on the right-hand side is a very classic example because the small molecule 609, when you see the dosing, the [indiscernible], it has a very transient and high glucose increase, same with the 609 plus antibody. On the other hand, A251, the glucose level remain unchanged because the PI3K inhibition leading to hyperglycemia is really a classic hallmark for this class of PI3K inhibitor. So in this preclinical setting -- model, we really demonstrate using the ATTC concept, you can really increase the safety profile for this PI3K inhibitor because it's a targeted delivery of this conjugate into the tumor cells, leading to the release and inhibited the tumor unlike the small molecule, really have a higher systemic exposure and lead to HER2 PI3K pathway inhibition leading to the toxicity. We also test the A251 in multiple xenograft model. And here is the 2 model we have shown is the breast cancer cell line with HER2 overexpression and the PI3K mutation. And also the lower one is the ovarian cancer model with HER2 expression and HER2+ PI3K-mutated model. On the red line is the 10 milligram per kg in HER2 as a control. I can see in these 2 models, we can see a faster and deeper response for A251 leading to the tumor growth inhibition compared with the DS -- compared with the HER2 itself. Here, we also test the panel of HER2 low PAM-altered cell line, endometrial cancer cell line. And in the -- with the tumor xenograft model. Again, we can see in HER2 low model, we can see a more rapid tumor growth inhibition of A251 compared with -- in HER2 in the [ upper ] model. And in the cervical cancer model, we can see the activity of A251 is similar to -- in HER2. We further test some of the model without PAM pathway alteration. In HER2+ PAM nonaltered xenograft model, we can see in HER2 and A251 has about similar antitumor activity. So in all of the model we have test, we can see the A251 pretty much have a stronger activity or at least comparable to DS-8201 in HER2 at the equivalent dose level. Here's the pharmacokinetic profile for A251. We can see on the right-hand side, you can see a single dose injection of the A251. We can see the total antibody and the antibody and A251 have the high sustained exposure. And 609, the free payload, which has remained very low concentration compared with the conjugated ATTC. And the right-hand side, we also conduct a stability -- plasma stability study compared with -- in HER2 A251 have a more stable half-life compared with the -- in HER2 in the monkey and the human plasma. Here's the in vivo pharmacodynamic activity for A251. We have the vehicle control and also A251 10 milligram per kilogram IV injection and monitor the time course for the phospho-AKT, phospho-S6. You can see there's a time-dependent inhibition of this PAM pathway. And H2AX [indiscernible] H2AX is a marker for DNA breakage. You can see the increased DNA damage and also leading to increased cleaved caspase which is [indiscernible] representing the apoptosis. And the CD68 is a marker for macrophage inhibition. You can see the macrophage infiltration into the tumor cell. You can see really leading to the ADCP, antibody-dependent cytotoxicity. And also, we look at the distribution of the payload in the tumor cell. In the tumor cell, we can see a sustained and high exposure of the payload into the tumor cells and the [indiscernible] in the plasma level is actually remained low. And again, they just representation of the inhibition of the pathway leading to the PAM pathway and -- with inhibition leading to apoptosis and DNA damage and ADCP activity. So in summary, A251 is the first-in-class PI3K/PIKK inhibitor conjugated with HER2 antibody, has robust and potent antitumor activity in HER2+ model without or without PAM moderation, also showing quite good activity in HER2 low tumor model with the PAM mutation. And also it has a favorable PK profile and have a much improved safety profile compared with small molecule payload itself. And so we have completed the GLP tox study and filed a China and U.S. IND. And we already received FDA clearance for this U.S. IND and our Phase I clinical study is starting to enroll patients later this year. Here, I'm going to show you some of the high-level clinical development plan. Of course, the Phase I, we're going to start with the single dose escalation. We are now -- we are enrolling HER2+ or low patient population. And PAM pathway alteration will be tested retrospectively. It's not the requirement for enrolling patients. And further dose expansion will be tested in HER2+, PAM+, HER2+ and PAM nonaltered pathway patients. And also we'll test the HER2 low and PAM mutated patient population. And we will further expand in multiple tumor type with or without the PAM alteration. And also, we will test when we define the dose for a single agent, we also will start the A251 in combination with standard chemotherapy in the earlier line, in the frontline setting. And also, we're going to test the solid tumor in the HER2 low patient population with the PAM alteration. So here is, as you can see from this molecule with -- we have pretty mature HER2 pathway functional antibody and also the very broad PI3K inhibition. So the PAM pathway is quite common compared with other driver mutation, ALK alteration, EGFR in Western patients and HER2 amplified mutated patients. So PAM pathway alteration really representing a very broad range of tumor type. The new incidence for all these cancer type is very high. And also in the breast cancer, we can see HER2+ patient population represent a 15% to 20% patient by the standard testing. And as we know, HER2 low patient population also have a very robust percentage, representing 40%, 50%. And the HER2- patient population is a smaller percentage. So this will really provide a good opportunity and targeting a larger HER2 expressed patient and also with the PI3K mutation because HER2 is also a one of the downstream -- because PI3K is also downstream of the HER2 activation pathway. So we think this molecule really can cover very broad range tumor inhibition in the breast cancer area. And so just thinking about the HER2- second-line breast cancer with the gedatolisib, for example, recently demonstrated activity, the market size representing about $5 billion. So we believe even HER2-, part of the significant portion of the patient will have HER2 expression. And these will -- can still potentially be patients benefit from the A251 in addition to HER2+ patient population. So this molecule really representing a good opportunity for the broader tumor type development in the future. So I show you the first molecule, A251, as the -- our leading molecule, which is -- will enter clinic later this year. And also here, you can see the PAM pathway alteration really cover very broad range of tumor type, lung cancer, breast cancer, colorectal cancer, breast cancer, for example. And the HER2 pathway expression also show pretty -- cover broader range of the tumor type. And here represent our opportunity for our first molecule. And by the same concept, we think other important antigen, right, TROP2, EGFR, for B7-H3, for example, all these have a very broad coverage for different tumor type. By leveraging the payload, not only the PI3K/PIKK inhibitors 609 but also other target therapy, which have -- inhibiting major pathway driver mutation cell lines. We think this ATTC platform can really cover very broad range of tumor type, representing a huge opportunity for the development. So our first molecule has already get a U.S. IND clearance and starting enroll -- will start to enroll patients soon. And the second molecule, A580, which is with a different antibody and will -- we have not yet disclosed but we are targeting to have the Phase I initiation early next year in the China and the U.S. Third molecule, A530 (sic) [ A830 ] and will also enter the clinic in the second half of 2026. So we kind of update you about the ATTC platform and the lead molecule enter the clinical development. We'll -- I'm going to cover some of the new development in the late-stage pipeline. So HUTCHMED has really developed a deep pipeline covering multiple tumor types. Our first approved product, fruquintinib, we already approved in the colorectal cancer and worldwide ex China has been covered by Takeda. And in China, we also continue to develop additional indication. FRUSICA-1 was reported already in endometrial cancer. So we get NMPA approval for pMMR endometrial cancer December 2024. And also second-line RCC, we have showcased this FRUSICA-2 trial data at ESMO 2 weeks ago in Berlin. I'm going to show you some of the highlight of the data. And the NDA has been submitted and under review in NMPA. Our expectation is that we're getting approval late next year. Also MET inhibitor savolitinib also making tremendous progress. And we show the clinical data of SACHI in second-line EGFR mutated MET amplified patient population in combination with osimertinib, demonstrate the robust clinical improvement and it was approved by NMPA under fast track review in June '25. And also our partner -- global partner, AstraZeneca has also presented data in SAVANNAH, really demonstrate the high and clinically meaningful in durable response. Also, we are all very much looking forward to SAFFRON, which is the global AZ lead study in second, third-line EGFR mutant -- EGFR mutant MET amplified or overexpression lung cancer has a data readout next year. And SANOVO is the first-line MET overexpression patient population in combination with osimertinib. We have fully enrolled the patients in August. And also, we are anticipating the GC, gastric cancer in MET-amplified patient. We are conducting single-arm registration trial with the patient enrolled in April and the readout with the potential NDA in this year. And SAMETA is in the papillary renal cell carcinoma, is also lead by our global partner, AstraZeneca. And also the other approved products, surufatinib in China, we're also having a Phase II/III study in first-line pancreatic cancer in combination with PD-1 and chemotherapy. Phase II is fully enrolled and the data readout we're going to showcase later this year. And tazemetostat is the global first-in-class molecule, EZH2 inhibitor. We licensed from Ipsen. We have completed our bridging study and the study -- and the drug was approved earlier, March 2025 by NMPA in the third-line follicular lymphoma. And also, we're making great progress in the second-line lymphoma trial. Also for sovleplenib, our Syk inhibitor through the ESLIM-01study in the second-line immune thrombocytopenia, we have submitted an NDA. As we know, there is a impurity issue we have been addressed. We reached agreement with CDE, really define the intake level and moving forward with the resubmission early next year. And also our second-line autoimmune disease is warm autoimmune hemolytic anemia study. We already complete the enrollment with the potential readout and NDA next year. Newer pipeline is the second-line FGFR2 inhibitor fanregratinib and also with the potential for NDA this -- later this year. And our dual IDH1 and 2 inhibitor ranosidenib also in the Phase III study in the AML. Here's the fruquintinib with sintilimab combination versus standard of care in China, axitinib or everolimus. The data FRUSICA-2 has been presented at the ESMO Congress through the oral presentation by Professor Zhenhua Liu. Here's the trial design is the fruquintinib plus sintilimab versus the investigator choice of axitinib or everolimus. And the clinical endpoint, primary endpoint is the BIRC review PFS by independent radiology assessment. And here, it was demonstrated in the primary endpoint by BIRC analysis PFS. fruquintinib plus sintilimab versus comparator really show very robust activity with a median PFS of 22 month versus 6.9 month of the axitinib or everolimus group. And it's highly with a hazard ratio 0.37 and has a very similar results for the investigator assessment. Also in terms of response rate by BIRC review and the investigator review, we can see over doubling of the overall response rate by sintilimab and the fruquintinib combo really showing this activity in this patient group with a very high unmet need. We have seen the 63% reduction in the risk of disease progression by the combo drug, really impressive PFS by central assessment, about 15-month difference. And so it's highly significant, very robust response rate. It's highly clinical meaningful. The NDA is currently under review by CDE. We're expecting approval next year. Also, we are conducting the Phase II/III first-line pancreatic cancer trial. Surufatinib and the camrelizumab, which is [indiscernible] PD-1 along with the standard of care gemcitabine plus nab-paclitaxel versus gem versus nab-paclitaxel. So the Phase II results will -- has been accepted by the ESMO Asia. So we'll present this top line data in the ESMO Asia meeting in December. On the savolitinib side, the MET -- SAVANNAH study by AZ presented data at ELCC in March in Paris, showing the high response rate of 56% and 55% by the BIRC review. And METex14 skipping patient population, we also presented our confirmatory Phase III study at ELCC and really showing very impressive overall survival for the second-line, 25 months and first-line, 28 months in ELCC. Clearly demonstrate this is one of the longest overall survival has been reported among all the MET inhibitor in METex14 non-small cell lung cancer setting. SACHI data really provide a future growth. The OSI+SO really showing the clinical robust activity was presented as a oral preliminary presentation at ASCO and the manuscript has been accepted to be published in Lancet. We are looking forward the SAMETA trial in the PRCC, the savolitinib with IMFINZI versus SUTENT. So this trial has been recruited. The readout will be next year. And also AZ lead the SAFFRON study also has reached the enrollment target. And we expect a positive -- we expect the results next year. If positive, this will really be hopeful for our second molecule can go to the global NDA. And in China, for this SANOVO study, first-line OSI+SO MET amplified overexpressed patient enrollment is completed and we are really hoping for the readout later. On the gastric cancer in MET-amplified patients, we also will have the potential to submit NDA. The next molecule is an EZH2 inhibitor, tazemetostat. It -- we have conducted a bridging study, really showing a very consistent study compared with the global trial, Ipsen trial and really showing a robust complete response rate of about 18% and 63% overall response rate and very high percentage of clinical benefit rate. So the drug has been approved. We are further conducting along with our partner, Ipsen, to conduct a global SYMPHONY-1 trial. And this is the tazemetostat in combination with R square, rituximab and lenalidomide and versus placebo with R square. And we are very happy that China wild-type patient has completed the enrollment. And this global trial will not only move the -- if positive, will not only move the tazemetostat to the second line but also has the potential not only in the mutant patient population but also the wild-type patient. So our partner and Ipsen and HUTCHMED are really working towards the full recruitment for this patient group. Fanregratinib is the FGFR2 inhibitor. And we have previously agreed with the CDE and using the single-arm registration to -- in order to potentially have their conditional approval in this registration cohort in the 2 week on/1 week off schedule, 87 patients were recruited. And so we are expecting the data readout and if positive, we'll file the NDA this year. Sovleplenib is the Syk inhibitor and we first report our ESLIM-01 result at EHA and really showing a very robust or durable response rate of 48%. And last year, we showed the follow-up long-term study demonstrated overall response of 81% and durable response for 51% and has very fast [ on-site ] to increase the platelet. And also unlike the TPO-RA, which also stimulate the platelet production but also has the opportunity to overshoot. So TPO-RA has a potential for [indiscernible] thromboembolic events, which in the ESLIM-01 study for sovleplenib, the thrombocytopenia is -- thromboembolic event is not a safety concern. So it has a highly differentiated clinical activity and safety profile. We know we reported earlier this year, right, the -- although the previous NDA was delayed through a impurity issue but we have reached agreement with CDE, really defined the intake level and we are continuing to conduct a stability study, bioequivalence study with this new formulation. Our targeted resubmission is in the first half of next year. And also, we have completed the enrollment of our Phase III ESLIM-02 trial in wAIHA autoimmune hemolytic anemia and we are potentially with the readout next year and if possible, the submission in China. And the -- here's the Phase I data we have shown in the wAIHA patient population -- in previously treated wAIHA patients, we have demonstrated overall 66% overall response rate and also the 47% the durable response rate and really showing the highly robust activity for the Syk inhibitor, not only in ITP but also in wAIHA patients. So I gave you an overview of the ATTC platform and also the -- our late-stage pipeline advancement. So to summarize, so for today and beyond, we are really striving for global commercial success. And our partner, Takeda, really showing the fruquintinib global sale first half of this year really increased by 25% to $162 million, showing robust growth. ORPATHYS or savolitinib with our partner, AstraZeneca, we have the potential to really -- if the SAFFRON data is positive, will be our second molecule [indiscernible] potentially registered internationally. And ELUNATE is, fruquintinib is continue to grow with the new indications with the endometrial cancer approval will certainly will help the commercial launch. And also with the new RCC trial, we hope the fruquintinib plus sintilimab in the RCC trial will receive the approval in the next 12 months. And SAFFRON, of course, SAFFRON and SAMETA led by the AZ development will all have Phase III readout next year. And if positive, will potentially strong catalyst for the company. And surufatinib PDAC in combination with PD-1 and chemotherapy will have the data readout. And again, the FGFR inhibitor, fanregratinib and also the Savo GC in gastric cancer with the MET amplified patient will have -- all have the potential for NDA submission. And more importantly, looking for the future, we are thinking our next-generation technology platform, antibody target therapy conjugate, ATTC profile has a huge potential. And we have multiple selective candidates currently at the -- enter -- will enter the clinic. And the first is already reached the IND clear in the U.S. And also with the company has a strong balance sheet and also relative small market cap, we think our future potential is really have a great opportunity. And along with our robust cash position, certainly, we are continue to looking at in-licensing and out-licensing opportunity. So hopefully, our effort and advancement can be appreciated in the investment road and really leading to long-term growth and generate value for our shareholders. So with that, I'll just wrap up and opening for questions.

Okay. Thank you, Dr. Shi, for the detailed analysis. [Operator Instructions] The first question comes from Alec Stranahan from Bank of America.

Really great to see progress across the pipeline. I guess first on the ATTC platform, how important is it for you to really drive monotherapy efficacy in your molecular design of your ATTCs versus, I guess, optimizing safety to align it with frontline combo opportunities, especially when we're talking about assets like A251 that go after broadly expressed targets?

Yes. Thank you, Alec. Yes, it's a very good question. So for us, right, of course, the traditional development is really try to see some activity in the late-stage setting. So that's why we enrolled patients with -- previously treated patients. And our belief it is in the target patient population, for example, HER2+ and with the PAM altered or nonaltered patient, we will expect to see the activity. Certainly, we explore multiple cohort in the late-stage setting if we have defined the patient population could have a more robust activity, could certainly lead to the potential accelerated registration approval. But the main difference here for the ATTC, for A251 example, is what we consider is the opportunity to really advance to the frontline. And we have demonstrate multiple model, have synergistic activity with the traditional chemotherapy or standard of care therapy. And a lot of these toxin-based ADC really have difficulty to combine with other chemotherapy. So that's why we think this is a advantage for us. And also, this is a unique opportunity to really take on this combined U.S.-China trial, right, to really simultaneous development to advance our pipeline because, as you know, the FDA is really encouraged the earlier line development, right, instead of just the frontline setting -- late-line setting because through this project frontrunner activity. So we think even at the -- when we have the dose escalation and even we have this [indiscernible] design with a backfill strategy to expand the dosing. Once we see activity or certain signal, we will have the opportunity to start a combination study and soon to really advance this development because our hope, we have shown this -- the combination, not only with the chemotherapy and some -- even the model with toxin-based ADC also shows synergistic activity. So the key driver for this ATTC platform is really moving to the early line and to compete with the standard care. In combination with the standard of care versus standard care, we think that will be the future growth driver. And as you know, even the toxin ADC has a lot of efforts to combine with chemo but the data really from the safety profile, discontinuation, combinability really show strong limitation. So we believe that's where we can compete in for the tumor type because this unique profile for this ATTC platform.

Okay. Okay. That makes sense. And I guess one on the frontline PDAC opportunity for surufatinib. I guess, what do you sort of see as the bar for efficacy in the Phase II readout in December in combination? And I guess, how should we be thinking about the activity of surufatinib here versus PD-1 alone, given the control arm only includes gem/nab-paclitaxel?

Yes. So we are looking quite some historical data, right? Because pancreatic cancer is highly fibrotic and is usually considered as a immune desert. So PD-1 plus chemo alone, right, really haven't shown very robust activity. And from our perspective, the surufatinib is not only a VEGF inhibitor, it's also inhibit CSF1R and FGFR, really has a very strong potential through our early study. The initiation is a Professor [indiscernible] trial with the PD-1 and surufatinib combo with different chemo regimen and showing the ORR rate is about -- over 50% and compared with standard of care about 25%. And in particular, the ORR reported at ASCO GI earlier this year, showing the OS benefit is really beyond 12 months, right, about 15 months. So that's what we think not only for the PS side -- PFS side but OS side, this combination has a unique advantage compared with the chemo alone or chemo plus PD-1 alone. So the bar, we think, right, is if you compare with the gem/paclitaxel and the -- usually the overall survival is very short, like 9 months or so. So I think with over a year OS, with the robust PFS, we think this combination really show pretty impressive opportunity from the early phase data. So again, the data presented will really show how we evaluate the bar. You will see this soon. And that will really define what is the bar we want to overcome to lead to the Phase III.

Next question from Goldman Sachs, Khalil Fenina.

This is Khalil, calling in for Paul Choi. I guess a couple of quick questions from us. One on the earlier-stage ATTC program and one on the later-stage pipeline. I suppose starting with ATTC, you've identified prostate cancer as the second largest commercial opportunity here in the longer term. And just given the emergence of nuclear medicine in the space, I'm just curious like in your view, do you envision perhaps running a study in like Pluvicto experienced patients to see if those types of agents amplify PAM at all? And then the second question is just on ITP. You mentioned looking to further develop it ex China. Just curious what the status was on that.

Yes. Thank you, Khalil. For the prostate cancer, right, because what we think this, the payload targeting PI3K/PIKK has very broad opportunity really against in multiple tumor types. And so we think, at least from a development perspective, we have very many options where to go to. And certainly, we'll probably choose a few tumor type through the company, see what is the late-line setting will -- readout will be and also start a combo study to really get the clinical evidence-driven kind of a development plan, right? Because certainly, in the nuclear medicine, evolving nuclear medicine, certainly, I see the Pluvicto data is quite impressive. And -- but in terms of future development, we probably will have to see how the expansion cohort readout and where the strongest evidence or opportunity will lead us to guide our future development plan. Certainly, prostate cancer is on the book but we have to look at how the data readout in many tumor types to really make the decision for the early line development in the future. In terms of sovleplenib and so we have quite communication with the CDE because it was submitted and under review because we reported early this year, we certainly have reached the -- mutually agree that the [indiscernible] limit, right, to be acceptable. And in order to accomplish that, we have to kind of change the new formulation. And through this, we're going to work on the BE study and also with the stability testing to really satisfy the requirements. So the targeted resubmission is early next year. And so this is -- we think with this clear agreement guidance, I think we have a path for the sovleplenib in China, not only for the ITP but also with wAIHA when it's readout earlier next year. So in terms of global development, we believe this newly agreed -- I mean, this agree with the limit actually with the CDE is the most kind of industry standard, including the global FDA, EMA is [ agreedable ] intake limit. So I think that formulation will certainly satisfy the global development for this product for a global potential. So I think that really opened our store. Again, we mentioned we paused the U.S. and EU development just really because of this issue. But now I think we are in a position to really looking at international development. As you can see in the ITP study, at least, for example, the ESLIM-01 data is show -- clearly show a highly durable response rate. And the long-term exposure demonstrate a sustained platelet increase and a durable response compared with all these existing product of -- including a new one, right, the FcRn with the [indiscernible] and all these activity, we think Syk inhibitor really representing a probably best-in-class modality to really in this patient group. And because ESLIM-01 data is really heavily pretreated patient, they filled all the first line and also the 75% of patients filled the TPO-RA. And so certainly, in the heavily pretreated patient, we can see this most robust ORR really showing this as a opportunity. Certainly, we will reposition and really thinking what is the fast track for the global development. And in parallel, I think we can reengage some of the discussion with the partner and to really leverage this molecule's unique -- because this dual mechanism inhibiting the, engulfing the platelet or red blood cell and also the blocking the B-cell activity. So these are certainly a strong clinical evidence activity. We think this -- with this newly developed formula, it certainly have a pretty good opportunity to be further developed globally and open the door for discussion for future partner. Yes. Also, by the way, we're going to present our long-term, the final ESLIM-01 data at ASH. It has been selected as a oral presentation. So I think it will reignite the interest for sovleplenib.

Next question comes from Jefferies' Clara Dong.

I appreciate putting together this very informative presentation. So 2 from us. So maybe can you broadly just talk about how the programs developed through your ATTC platform will complement your existing commercial and late-stage initiatives and how kind of this integration will support your long-term strategic vision? And how do you prioritize your indication selection for those programs? And then also given the novelty of the ATTC platform, would you be able to share any color in terms of what's the bar for safety you're looking for, for the very first ATTC candidate?

Yes. Thank you, Claire (sic) [ Clara ]. And they -- for ATTC, right, I think just really leverage our traditional HUTCHMED small molecule expertise, right? For target therapy, we really work on the linker and the payload to really have a opportunity to generate this molecule and platform because from antibody selection to the target therapy payload selection really provides some good opportunity. So I think the first wave of development, of course, we are really science-driven, target-driven and thinking where the development will really leading to not only the highest clinical potential proof-of-concept and clinical success but also the development path will synergize with our expertise traditionally, as you can see, is the GI cancer, lung cancer, for example, right? So with the further development and with the antibody, with the target payload selection, really, I think we have many, many opportunity, many different type, which just really cover a very broad range of tumor type. So the development probably will focus initially in the area we think we have a strong interest to be further developed. And of course, it's data-driven, science-driven but also if it's proven to be successful, right? And so far, you asked about the bar of the safety or so at least from the preclinical data, we really see this platform and overcome some of the traditional limitation for small molecule for systemic exposure because as the example that I show you for A251, right and in the GLP tox study, we don't see this hallmark for the PI3K small molecule inhibitor. And for example, hyperglycemia, myelosuppression or so. So just from preclinical data, we know because this selected target delivery of the ATTC into the tumor cell and the very low exposure of the small molecule payload in the circulation, really demonstrate the safety margin compared with the systemic exposure for small molecule. So we think the safety level really from the preclinical data really show us this is have a substantial increase from the traditional small molecule approach. And the combination with all the multiple target development, multiple antibody development, we think it really generates a unique platform. So to just give you some color, I think our next wave product, right, after this proof of concept for the first wave molecule, certainly, there are more innovative molecule on the way, including bispecific ATTC and probably more do payload kind of the ATTC also in the research stage. So I think this will represent huge opportunity for our platform. And of course, there are only limited resource. We have to focus on area where we expertise to really develop fast proof of concept. And certainly, with the future potential partnership, we certainly think they can really broaden the indication, broaden the development because these -- all these molecule have potential targeting broader tumor type, high-frequency driver mutation overcome the resistance. So the opportunity is really quite huge from our perspective. So will be the focus of our company's new effort for these globally competitive first-in-class assets.

Our next question from Cavendish, the -- Adam McCarter.

Really interesting. So I guess the first question I have, the safety data for A251 looks really encouraging, as you say, Dr. Shi, particularly the absence of the elevated blood glucose levels. So you mentioned that this may relate to the compounds targeting ability, which is helping to limit systemic toxicity. But could you elaborate on whether you're seeing differential inhibition across AKT isoforms and tumor cells? Some of the tolerability issues seen with earlier pan AKT and PI3K inhibitors have been linked to the AKT2 inhibition. So it would be useful to understand how A251 compares mechanistically in that regard.

Yes. Thank you, Adam. Yes, also very good question. Of course, we're actually looking at these -- all these potential PI3K/AKT pathway inhibition, right? So in short, right, because we do see the free payload release in the plasma is actually quite low. If you calculate from that exposure curve, the free payload itself is actually showing pretty much less than 1,000fold or even higher kind of a differentiation. And pretty much all these free payload concentration we have seen is well below the IC50 level to reach the target inhibition. So that's why we do see the safety profile margin. And also through monitoring, right, is we understand -- is because the dose we select for the tox study, we really monitor the threshold. So we can see the certain, I would say, on-target kind of the AE profile, it's reversible, it's dose dependent. So that's why we feel this ATTC provide a very safe window for future development. So hopefully, certainly, we hope this will be represented in the human study, right? So really looking for the first-in-human study and how the safety and the activity will pan out. If it is clinically proven, I think they will represent multiple huge opportunity, right, for the next wave of product we are developing.

That's great. And if I could just ask a second question. So you've highlighted that your ATTC platform differs from the standard ADC approaches. Just wondering if you could expand on the competitive landscape here. Are there many others pursuing this targeted therapy payload strategy with similar design principles? Or is your approach relatively unique at this stage?

Yes. I think this -- the field is really evolving very rapidly, right? I think all the scientists really thinking about different way, right? You can -- there are different approach, right? Even you see this -- the most recent example, right, Innovent is linking the immunotherapy with the target -- in the antibody, right? So certainly, I wouldn't say the competitors won't invest or develop in this area. But I think we are also in a very strong position because HUTCHMED is really have a long-standing, right, small molecule expertise. I thought our strength is really in the linker and the payload. And also, we have really working in multiple target therapy development areas. So I think with a deep understanding of biology, coupled with the strong medicinal chemists and new -- newly more innovative novel antibody or bispecific antibody, we think we are in new -- I mean, very strong position to really leading and innovate in this field.

Since there's no more question, this will be the end of this presentation and our R&D Day event. Thank you again for joining us and we wish you a wonderful day. Bye-bye.

Thank you. [Statements in English on this transcript were spoken by an interpreter present on the live call.]