Hutchison China MediTech Limited - Special Call

Sep 30, 2019 PM UTC 查看原文
HCM.L - Hutchison China MediTech Ltd
Hutchison China MediTech Limited - Special Call
Sep 30, 2019 / 12:00PM GMT 

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Corporate Participants
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   *  Christian Hogg
      Hutchison China MediTech Limited - CEO & Executive Director
   *  Marek Kania
      Hutchison China MediTech Limited - Senior VP & Chief Medical Officer - U.S.
   *  Wei-Guo Su
      Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director

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Conference Call Participants
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   *  Christopher Liu
      Canaccord Genuity Corp., Research Division - Research Analyst
   *  Daniel Wilkinson
      Edison Investment Research Limited - Analyst
   *  Francesco Gregori
      Trinity Delta Research Limited - Research Analyst
   *  Richard J. Parkes
      Deutsche Bank AG, Research Division - Director
   *  Stephen McGarry
      HSBC, Research Division - Analyst
   *  James Yao;University of Oregon;Professor

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Presentation
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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [1]
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 Welcome, everybody, to the ESMO conference call in which we plan to take everybody through the surufatinib SANET-ep Phase III data, along with the further information around surufatinib and neuroendocrine tumors.

 What we're going to try and do today is try and get through the presentation in about 35 minutes, leaving 20, 25 minutes for Q&A at the end.

 So if we go to Page #3, the agenda. I'll give a brief introduction on where surufatinib is at the moment. That will be followed by a discussion on -- of the presentation that was given at ESMO yesterday by Dr. Wei-Guo Su, our Chief Scientific Officer and main Board Director of Chi-Med. That will be followed by a presentation around the Phase Ib data for surufatinib in the U.S. by Marek Kania, our SVP and Chief Medical Officer in international, basically United States and Europe. That will be followed by a discussion on neuroendocrine tumors by Dr. James Yao, one of our key investigators. We're extremely happy and pleased that Dr. Yao could make time to join us today. Dr. Yao is chair of the Gastrointestinal Oncology at MD Anderson Cancer Center in Houston. So Dr. Yao will be able to give his insights -- clinical insights on surufatinib and NET. And then I'll finish it off with a brief summary at the end, and then we'll go into Q&A.

 So if we go quickly into -- onto Page 5 on the introduction. So we see the kind of the latest situation for surufatinib with regards to China and NET, neuroendocrine tumors. We -- on the top part of the slide, you can see the 2 Phase III studies that we have been -- registration studies that we've been enrolling and running for the last few years.

 The top section, SANET-ep is the Phase III study that was presented yesterday and has obviously met all its primary endpoints and efficacy endpoints, and we'll go into that in more detail later.

 Below that, the SANET-p study is a Phase III study in pancreatic neuroendocrine tumors. We hope to be able to reach an interim analysis on that study early next year. So that would complete the set, as it were, really show surufatinib's efficacy across all neuroendocrine tumor patients. SANET-ep is everything excluding pancreatic, and SANET-p is pancreatic. So that would be all neuroendocrine tumor patients covered by those 2 big Phase III studies.

 You can see at the bottom of Page 5, we're now very occupied in preparing for our NDA submission at the end of this year, in the coming month or so, and also looking forward into 2020. It's about navigating the whole NDA process of inspections and regulatory interactions. And you can see on the bottom part of Page 5 there, it's also about building out our commercial team. Today, we have about 70 people in our oncology commercial team. And we would expect, by the end of next year, to be fully covering China in readiness for the launch of surufatinib. So that's a lot of work that's ongoing.

 Page 6. Briefly, what else is going on for surufatinib? In the top section, you can see Marek is managing, along with Dr. Yao, the -- call it, the U.S. or global Phase II, Phase III thinking and planning. We at ESMO yesterday presented data from our Phase Ib/II study in pNET. Very interesting, because you get to see how patients who have failed on Afinitor do on surufatinib, and Marek will talk about that later.

 We plan to have an end of Phase II meeting at the end of this year, hopefully, if the FDA is able to do that. And our plan would be to start global registration studies on surufatinib in NET early next year sometime. So we're extremely excited about that global plan, and we've worked hard to build a team underneath Marek to run all of this.

 The second section, biliary tract cancer, this is a very difficult indication in which we are interested. We've been running studies in China for some time now and is sort of early Phase II studies. Now we're in a Phase IIb/III study. And we hope to reach interim analysis on the first 80 patients of that biliary tract cancer study, the Phase III study, middle of next year.

 And then finally, the PD-1 collaboration with Junshi. That's one of the first PD-1 -- local PD-1s launched in China. We're now very aggressively working on dose expansion -- or planning dose expansion into multiple tumor types with surufatinib in combination with Tuoyi, which is the Junshi PD-1.

 So that's, in summary, the situation. Now I'll hand it over to Dr. Wei-Guo Su to take everybody through the SANET-ep data. Over to you, Wei-Guo.

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [2]
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 All right. Thank you very much, Christian, and hello, everyone. I'll just -- in the next 10, 12 minutes also, I'll take -- I will take you through basically the ESMO presentation on the SANET-ep trial.

 Maybe we can go to Slide 10, some background information on SANET-ep. So basically, treatments are very limited. So NET patients and extrapancreatic NET patients, in particular. Available type therapies today include Sutent for pNET and Afinitor for pNET and GI and lung. Surufatinib has a unique MOA, targeting both angiogenesis and immune modulation, particularly on TAMs and MDSCs, targeting 3 major targets: VEGFRs; FGFR1 and CSF-1R. Previously, we reported encouraging efficacy on surufatinib in NET patients, including those failed on everolimus.

 Well, next page, here is the study design for the SANET-ep. Patient population, progressive advanced extrapancreatic NET patients randomized at 2:1 ratio, with 3 layers of stratification to receive either surufatinib or placebo and continuous treatment until disease progression. Patients on placebo, once confirmed disease progression, had an opportunity to cross over to open-label surufatinib treatment. The study also set up a blinded independent image review committee to help assess PFS and to ensure that the results will support the primary endpoint, which is investigator-assessed PFS.

 Next slide. Here are the key criteria -- eligibility criteria. Grade 1, 2 advanced, the patients with locally advanced or metastatic, documented radiological disease progression within the last 12 months. A key point to note is that prior use of VEGF/VEGFR inhibitors were excluded.

 Next slide. At the date of cutoff, which is March 31 this year, a total of 198 patients were randomized, 129 patients into the surufatinib group and 69 patients in placebo group. As a data followup, roughly 68% of patients in the surufatinib group were discontinued, and about roughly 77% discontinued treatment in the placebo group, 53 patients. Out of the 53, 30 patients also to open-label surufatinib treatment.

 The next slide, this baseline demographics, overall, reasonably balanced between the surufatinib and placebo, except in a few categories, for instance, ECOG status, a bit more ECOG PS 1 in the surufatinib group comparing to placebo group, 44% versus 33%. Also in subtypes, well, you can see in the lung, 9% -- 9.3% in surufatinib group versus almost 16% in placebo group. And toward the end -- toward the bottom of the table with regard to previous, loco-regional therapy of the liver mets. Again, a bit imbalanced, 34% in surufatinib group comparing to 23% in placebo group. But overall, reasonably balanced across all the subgroups.

 And of note in this study, this is actually the first randomized study in this patient population in China. As you can see, these patients, 84% -- roughly 84% of these patients were grade 2, comparing -- as compared to most -- in the previous studies with Sutent or everolimus in global studies, typically, 70% to 80% grade 1 patient. So these were much more difficult patients probably with more aggressive disease.

 Next slide. Here is the result for the primary endpoint -- efficacy endpoint. Clearly, surufatinib has significantly improved the PFS with a hazard ratio of 0.334 and a p-value of less than 0.0001. And based on that, the IDMC recommended early termination.

 Next slide. The subgroup analysis revealed that all subgroups favor surufatinib treatment.

 Next slide. BIIRC-assessed PFS was conducted, as I mentioned. And the result supports surufatinib efficacy. The discordance is common in this field, in particular. But post-hoc adjudication for 35 patients with PFS discrepancy greater than 4 weeks between the investigator assessment versus IRC was conducted by a radiologist, Dr. Choi, and a clinician, Dr. Pavel. The conclusion again supports the primary endpoint.

 Next slide. A sensitivity analysis was conducted and appeared to show that the prior loco-regional therapies of liver met might be a contributor to the discordance between the investigators versus IRC-assessed PFS. As you can see here, a total of 60 patients with prior loco-regional therapy, and if we -- if these patients were taken out and the discordance between investigator and IRC was much smaller, all things under those hazard ratio and the p value.

 Next slide. The study also met the secondary efficacy endpoint. Both ORR and DCR were significantly better in the surufatinib group. The OS was not statistically analyzed because it was immature on the 18% event.

 Next slide. Median duration of surufatinib treatment was roughly 7 months, and the relative intensity, considering dose interruption and reduction for surufatinib, was 86% comparing to 97% for placebo, suggesting very good tolerability.

 The next couple of slides summarize the safety profile. And clearly, the safety profile was consistent with previously reported, nothing special to note, with hypertension and proteinurea as the most common AEs, which were readily manageable.

 So going to a slide -- concluding slide, Slide 23. Surufatinib with a unique MLA, targeting both angiogenesis and immune microenvironment modulation significantly improve the PFS for this patient population. As a matter of fact, all the subgroups favor surufatinib treatment. And it was generally well tolerated with a consistent safety profile. And the study was, as a result, early terminated based on the recommendation by the IDMC.

 In addition, surufatinib has multiple global trials as well as China trials ongoing, including Phase III randomized registration intent study in pancreatic NETs, which Christian mentioned that we hope to read out some time early next year. And also a global development led by Marek in America is going to cover for you, the -- our global development plan.

 I will stop here and will let Marek take over.

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 Marek Kania,  Hutchison China MediTech Limited - Senior VP & Chief Medical Officer - U.S.   [3]
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 Thank you, Wei-Guo, and hello, everyone. Great to be here with you.

 I will review our Phase Ib study, which Christian mentioned we reported preliminary results at ESMO. If you can move to Slide 27. This briefly describes the design of the study. This study is part of our ongoing U.S. IND development, among other programs we have. As we've been building our team -- capable team since last year, we're also making very encouraging progress with our ongoing investigation.

 As you can see on this slide, trial was designed the -- in 2 parts. One was dose escalation part, which primary endpoint of that part was to define safety and tolerability with intent to confirm our recommended Phase II dose, which happens -- and which I will summarize later. On this slide, you'll see cohorts and escalation levels.

 On the lower end, you see several cohorts, which are expansion cohorts, the numbers to indicate next to each cohort. Today, I will be discussing pNET cohort as well BTC. We have ongoing as well enrollment for epNET, but it is premature to discuss it. We also are ready to start enrollment on our sarcoma cohort, which would start very soon. Primary endpoint of that cohort was the definition of PFS and secondary endpoints objective response rate, disease control rate, typical endpoint in this phase of development.

 What I would like to highlight, as you can see on the left-hand side, we've been working with distinguished and very experienced site in the United States, and we continue expanding our collaborations globally. And those investigators were very productive in enrolling to our studies. As Christian said, Dr. Yao is with us, and we are grateful for his contribution in his -- and progress of this study. And he may comment on his experience later on.

 If we can move to Slide 28. This slide really summarizes, in a high level, both safety and efficacy. On the left-hand side, you can see a summary of safety, which I'm not going to go to too much details, but pretty much is very consistent with what Dr. Su discussed. Nothing unexpected. Diarrhea, fatigue, nausea was one of the most common treatment-emerging adverse events. Of note, relatively low hypertension and proteinuria grade 3, all manageable. Numerically, actually, up here, it's still a bit on the lower end.

 On the right-hand side, you can see 25 evaluable patients, 12 in pNET and 13 in BTC. As you can see in the table, we observed 2 confirmed objective responses and disease control rate of very encouraging levels.

 On the BTC efficacy side, (technical difficulty) highest activity, one unconfirmed responder. Both studies are still ongoing.

 If we can move to the next slide, you can see more details, and this is a very important slide. A very busy one, but I think it illustrates how heavily pretreated those patients are in this Phase Ib study. All patients enrolled, the criteria was required to fail over all lines. So as you can see depicted in this slide, so it's highlighting that fact. All patients were heavily, heavily pretreated with up to 8 lines of therapies. Some patients were pretreated with everolimus and sunitinib. And of note, what was very encouraging to -- for us, we had 2 confirmed responders as well 2 unconfirmed responders. Most patients are still ongoing. As you can see, 9 out of 15 still on study, with relatively short duration on studies. So obviously, this data will be maturing. And we'll be completing and reporting as we progress with the study. I think what this slide also highlights the importance of multiple lines of therapies as well as different mechanism of actions where patients have options and physicians have options to choose between different mechanism of action, and actually overcoming some resistance to prior therapies. So definitely, addition of new treatment option is very encouraging, and we are very encouraged to see these results. But also [surufatinib] results altogether, I think, paints a right picture.

 If we can move to Slide 30. I will conclude with few really summary conclusions. This study helps us to define and confirm, actually, 300 milligram as the maximum tolerated dose and recommended Phase II dose for international development. This is consistent with our studies in China, and we'll continue this level of development with this dose level. Antitumor activity we see in heavily, heavily pretreated patients is very encouraging, and we'll definitely take great lessons from that.

 And as Dr. Su highlighted, we have a number of ongoing studies, end to end, and we see encouraging responses. And as we go, we're in the process of planning our global plan, development plan, as well as regulatory paths for next steps, we can discuss in the later part of this call.

 So thank you very much for your attention. This really brings me to a great opportunity to again hand over to Dr. Yao, who can put everything in a perspective from Western perspective and what does it mean for him and his colleagues. Dr. Yao?

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 James Yao;University of Oregon;Professor,    [4]
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 So good morning. So I'll start with Slide 32. So to put this morning's data -- ESMO data into some context and perspective, I just want to share some data on both the need, and where we are in the disease in the context of the SANET-ep trial.

 Neuroendocrine tumors previously were thought to be fairly rare diseases. Harvard-diagnosed incidents has been continuing to be on the rise in the population base registries. Here's the update our group did in GIM oncology showing that the diagnose incidence rate is rising. Likely, this is due to improved diagnostic and recognition of the disease.

 Because this group of cancer patient, now to Slide 33, have relatively longer survival comparing to their more aggressive adenocarcinoma counterparts, the patients also tend to have higher -- longer survival, which means the prevalence of the disease is also continuing to be on the rise. Here, again, just looking at disease prevalence in terms of the rise, especially in well-differentiated neuroendocrine tumors and the rise by prevalence in terms of different primary site, which is -- you've seen the rise in all the different primary sites.

 We have made progress, now on Slide 34, in terms of the developing new treatment for neuroendocrine tumors. However, today, I would say the treatment landscape is still quite fragmented. If you look at available therapy and where the Phase III data gives evidence, you see that in different areas, the -- there's very different scenarios.

 In lung neuroendocrine tumor, currently, there's only one drug that's FDA approved and have demonstrated efficacy, which is everolimus, for example. In the GI tract, you have somatostatin analogs in the earlier phases of the treatment. And in the tubular GI tract, you have then the everolimus in -- based on the RADIANT4 data. And in small bowel base, NETTER-1, although the U.S. approval includes other portion of the GI tract as well for Lutathera. And for the pancreatic NET, there's more treatment options available, including somatostatin analogue chemotherapies, sunitinib and everolimus.

 Beyond the fragmentation of the kind of what's available therapy by primary site, there are other limitations as well, which is Slide 35. In lanreotide, Somatuline analogs, we are lacking data in lung neuroendocrine tumors and no data in the more aggressive neuroendocrine tumors, those with Ki-67 above 10%.

 With Lutathera, we do not have approval in lung neuroendocrine tumor and because of its mechanism of action, it is limited to high somatostatin receptor expressing tumors. This will have different implications in different primary sites. As for example, in small bowel, the percentage of tumors with somatostatin receptor expression is quite high. But in other primary sites, such as in rectum and so forth, the rate of somatostatin receptor expression may be lower.

 Then you have everolimus. The data for everolimus right now is probably the broadest in terms of primary site. Nonetheless, it is not FDA approved for functional extrapancreatic neuroendocrine tumors. And it's now funded in some countries after other targeted agents. Then following, you have sunitinib, which is only in pancreas and similar to everolimus, is now funded in many countries after other agents.

 But then if you look at -- in Slide 36, the slide showing VEGF inhibitor in extrapancreatic neuroendocrine tumors. This is an area, I think, many investigators has been very, very interested in. In fact, we did some earliest trials so as far back as nearly 20 years ago. But most of the study have not been able to show definitive benefit, likely due to the fact that these were smaller single-arm Phase II studies. So that will be true for sunitinib and sorafenib and cabozantinib showing encouraging PFS. But in a single-arm study, it was unable to draw any definitive conclusions.

 And by the way, the conclusion column there are from the primary papers and the presentations of -- from the authors themselves. For pazopanib, we did do both single-arm Phase II and, more recently, the corroborative group did a randomized Phase II that showed improvement in progression-free survival. And for bevacizumab, it showed no difference to -- compared to interferon.

 So you have, in the SANET-ep, which is the first clinical trial, that's a randomized Phase III trial to definitively show improved progression-free survival, and that's the context of the data at this point.

 Going to Slide 37. The data from the ESMO presentation, the surufatinib in extrapancreatic NET showed improvement in progression-free survival and with a hazard ratio of 0.334.

 So a number of sensitivity analysis and supporting analysis were also presented. Remember, the -- in slides now, we're on Slide 38, that the primary reason we do Phase III studies is to do hypothesis testing. And the primary analysis showed it significantly improves progression-free survival. The secondary endpoint, overall survival -- I'm sorry, overall response rate and disease control rate showed the benefit consistent with the treatment benefit in terms of improvement in both overall response rate and disease control rate. Then a number of sensitivity analysis were conducted, and these all show the same direction in terms of benefit in terms of the benefit in PFS, so confirms the statistical robustness of the primary analysis.

 So overall, you have a positive Phase III trial in area with unmet need. And secondary endpoints in the sensitivity analysis supports the statistical robustness of the study itself. So I think that's the context I would offer in terms of the contribution of the SANET-ep study to the field of neuroendocrine tumors.

 So I'm going to conclude there and hand it back to Christian.

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [5]
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 Thanks very much, James. Very helpful. Okay. So I'll just finish off on the last 2 slides of the presentation then we can go into Q&A. If you go to Page 40. Now these 2 slides are just to get the sense -- some of it's already been covered in the discussions so far today. But Page 40's a very detailed slide, but what we tried to do is lay out the treatment landscape in the United States primarily, where you've got a prevalence of neuroendocrine tumors of about 140,000 patients. So it's not a small prevalence. Generally, a relatively low incidence, but a high prevalence, given patients tend to live for a fair amount of time with this disease.

 I think looking across the chart from left to right, you see as, in -- on the right -- sorry, the left-hand side of the chart, there's some other statin-based therapies, generally are used in earlier stage patients, the targeted therapies generally in more advanced patients -- but this is -- the point that's really is drawn from this chart is how fragmented everything is and how -- and as James has just said in his presentation, how treatments today are generally approved in relatively narrow subsections of neuroendocrine tumors. And that's what we're trying to do with surufatinib, is to bring a therapy to market that truly has efficacy across broad spectrum neuroendocrine tumor patient population. And as Marek said earlier, these are patients living with the disease for many years, in some cases, and they need to have a portfolio of treatment alternatives to use.

 So Afinitor, or everolimus, is obviously approved in many subsets of NET, but patients progress on everolimus, and they need something else. And that's really what we are looking to do with surufatinib, broad spectrum efficacy and also addressing patient populations that have essentially run out of treatment alternatives. Moving on to Page 41, the China NET environment. Very interesting chart from James in his presentation around the increased prevalence or per population prevalence of NET over the last 30 years as diagnosis or improvements in diagnosis have emerged.

 If you look at Page 41, you get a sense of the China opportunity. There's a lot of assumptions on this chart. But the one number on this chart that is not an assumption is the annual incidence of NET in China, which is 67,600 at the last reported date. The incidence in the U.S. is a little bit under 20,000, I think around 19,000. So you've essentially got 3.5, 4x the amount of NET patients in China as you do in the United States. But the big question we have to ask ourselves is: Are these patients, are these patients really the full extent of the problem in China? Or is NET under-diagnosed in China? I would assume that the sophistication of diagnosis in the United States is pretty significantly far ahead of that in China. So we may actually be looking at an even larger patient population in China than this chart would show.

 Even with these, this base, sort of conservative view, we would estimate there's probably between 200,000 and 300,000 nonpancreatic neuroendocrine tumor patients in China. And today, those patients have very limited treatment options. So we are working to bring our program, our surufatinib to these patients as quickly as we can. As we've mentioned earlier, I think, ultimately, we're looking to bring those -- bring that therapy to these patients at a price that is accessible to patients and get it on the reimbursement list and really try to provide a broad therapeutic opportunity or option for these patients.

 So we will be training up physicians in China to identify NET as early as it can be so that our treatment, surufatinib, can be used as early as possible in China. So I'll leave it at that.

 I think we've done pretty well, 38 minutes versus the 35 we set out to do, and we'll leave the next 20 or so minutes for Q&A. So hand it over to [Courtney] to manage that.

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Questions and Answers
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Operator   [1]
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 (Operator Instructions) Our first question comes in from the line of Richard Parkes calling from Deutsche Bank.

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 Richard J. Parkes,  Deutsche Bank AG, Research Division - Director   [2]
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 Yes, this is Richard Parkes from Deutsche Bank. Hopefully, you can hear me okay.

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [3]
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 We can, Richard.

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 Richard J. Parkes,  Deutsche Bank AG, Research Division - Director   [4]
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 Okay. Perfect. So I've got a few questions. First one, could you just talk about the importance of -- to the regulatory agencies of the independently-reviewed PFS versus the investigator-assessed PFS? I know that seems to be a regulatory debate, juggling this area in the past. And just sort of your confidence that a single trial will still be acceptable for approval, given that the independent review wasn't significant, but at a lower statistical hurdle. So that's just the first question.

 Maybe we'll just take them one-by-one first, okay?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [5]
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 Okay. Maybe I'll ask Wei-Guo to answer that question. And maybe James, also.

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [6]
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 I think it is, this is obviously more of a review issue, so I can't really comment on the regulatory behalf. But all I can say, we've been in contact with China's CDE, and every step of the way, including the primary endpoint being investigated assess to PFS, the BIIRC and being supportive. So all I can say is, we are all on -- we are on the same page. And I, I can't comment any further on that. And I think it's -- either way, it's -- it clearly demonstrated the efficacy of surufatinib in this patient population.

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 Richard J. Parkes,  Deutsche Bank AG, Research Division - Director   [7]
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 Okay, great. And then the second question. Could you talk about the totality of the evidence that you now have supporting the activity of surufatinib in patients that have either failed or lapsed after Afinitor treatment?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [8]
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 Maybe give that to Wei-Guo, also.

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [9]
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 Well, in -- I just want to clarify your question, are we talking about surufatinib activity, post Afinitor treatment, definitive?

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 Richard J. Parkes,  Deutsche Bank AG, Research Division - Director   [10]
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 . Yes, yes.

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [11]
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 All right. So in the Phase I/II study that we already published, when we initially note just the activity of surufatinib, actually post both surufatinib and Afinitor. So clearly indicating a very different MOA of this particular agent. And also now further confirmed in SANET-ep, this Phase III randomized study. I think all the data, the subgroup analysis data will be further published. Right now, we are just sharing the top line results, we will publish more with this additional analysis. But clearly, the compound is active post Afinitor treatment in this particular patient population. And also, supported to some extent by our study in the U.S., where almost 100% of patients had seen Afinitor earlier. Although most data today, most the data today were generated from pNET rather than epNET, rather consistent from our Phase I/Phase II, and also now Phase III data.

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 Richard J. Parkes,  Deutsche Bank AG, Research Division - Director   [12]
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 Okay. And then my final question, and maybe this is for -- maybe Dr. Yao can take this one. This one's a bit -- you could help us compare and contrast the SANET-ep study to the RADIANT-4 trial, to put those 2 in context. And maybe talk about your anecdotal experience with the drug versus Afinitor. Also, as I'm trying to understand, is this going to be -- always going to be a second line option to Afinitor, or offer those via -- it's important in the future, physicians want to prefer to use surufatinib on them.

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 James Yao;University of Oregon;Professor,    [13]
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 Yes. So I'm happy to talk about that a little bit. The patient population for these trials are both deemed essentially nonfunctional and in the extra pancreatic neuroendocrine tumor, both are rating for in SANET-ep. Both of them use a 2:1 randomization, both of them had a primary endpoint of progression-free survival. So the -- so I would say the -- there are some differences, minor differences in the trials. But in terms of the overall populations, were -- they are relatively similar in terms of the eligibility and so forth.

 And then I think the other part of the question is, so what's my experience with surufatinib in anecdotal. So with all the caveats, anecdotal experience, as you mentioned, the U.S. Phase I and Phase I expansion trials are in an everolimus pretreated population. And at least in my experience, we've seen activity, and with a very favorable safety profile and is really pretty well tolerated by the patients.

 So I think there is a need for sure of additional therapeutic option for this group of patients and having this available would be very good. And I think your other question, in terms of lines of therapy, I think that's probably better for the company to discuss in terms of -- because that's more like a labeling issue.

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [14]
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 Thanks, Richard.

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Operator   [15]
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 The next question comes in from the line of John Newman calling from Canaccord Genuity.

 It appears that we're having difficulties connecting with John, so we shall move on to the next question from Daniel Wilkinson, calling from Edison.

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 Daniel Wilkinson,  Edison Investment Research Limited - Analyst   [16]
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 I've just got a few. Just first off, on the SANET-ep data. Obviously, with this just kind of, with NET, we're looking at long OS. Are you expecting any OS data for this next year, and would you want to include that in the regulatory package? I'll go with that and have the next questions after.

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [17]
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 Maybe Wei-Guo, if you'd want to take that one?

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [18]
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 The OS will not be included in the NDA package because it's not the primary endpoint. And also, remember, this is a study with a crossover design. So -- and patients were crossed over at the time of disease progression. So would not expect to see any meaningful OS difference, although we'll continue to follow-up with the OS and publish at some point of time.

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 Daniel Wilkinson,  Edison Investment Research Limited - Analyst   [19]
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 And then, just I know you haven't kind of reported on this, but looking at the strongest trends you've seen with that SANET-ep data when it comes to primary sites, has any particular primary sites for the cancer beat had shown a particular strength?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [20]
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 Again, Wei-Guo?

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [21]
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 Yes. I'll probably take on this one. Basically, it's really heterogenous, very fragmented. And when I get to all the different subtypes it get -- the sample sites gets really small, basically, for each particular category.

 What we are seeing is that we are seeing a consistent, clear trend of efficacy for surufatinib. Although for some small subtypes, the sample sizes get too -- getting too small for any meaningful statistic analysis, basically. But the trend is all very consistent.

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 Daniel Wilkinson,  Edison Investment Research Limited - Analyst   [22]
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 Okay. And as my final question, just on the U.S. trial. You've obviously chosen soft tissue sarcoma as part of the expansion. Any thoughts around why that was attractive and why you're looking to go into that?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [23]
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 Maybe Marek can answer that one.

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 Marek Kania,  Hutchison China MediTech Limited - Senior VP & Chief Medical Officer - U.S.   [24]
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 Yes. So obviously, that is another area of high unmet medical needs where our mechanism of action was just considered by many experts, a novel mix of VEGF and CFR1 (sic) [CSF-1R]. I think there's a high level of interest in sarcoma space.

 As you may know, with one withdrawal of approved agent in that space, there's even more hunger of innovative medicine. So obviously, working with memorials in this case, and actually MD Anderson and others will be exploring single agent. But also we are looking at a combination with PD-1 -- PDL-1 combos, where there's actually even more interest. So I would say, stay tuned. I want to report when we have signals and if it's all going (technical difficulty).

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Operator   [25]
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 The next question comes in from the line of Franc Gregori calling from Trinity Delta.

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 Francesco Gregori,  Trinity Delta Research Limited - Research Analyst   [26]
------------------------------
 Forgive what may seem a very naive question. But Dr. Su, when you presented the results I believe, on Slide 13, where you had the patient flow chart, can you explain why so many patients discontinued treatment? I accept that it's much higher in the placebo group than it is in the active arm, but I was surprised at the how high the discontinued treatment is, especially in line of the clean side effect profile we have. Is this something that I'm missing, I'm not simply understanding?

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [27]
------------------------------
 Well, actually, we had to wait for a long time for these -- to reach this level of discontinuation, or majority of these were because, due to disease progression. So we were -- the interim analysis was predefined in the protocol and driven by a number of PFS events. So we actually had to wait until we reached this level of discontinuation rate or level of the -- well, the majority of it was just -- patients who had discontinued due to disease progression. And we have a meaningful -- if you have a meaningful interim analysis, we need to have -- you just need to have that level of progression, disease progression or study discontinuation.

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [28]
------------------------------
 Also, Franc, just one point. I mean, the SANET-ep study was started, I believe it was the end of 2014. This is a 3, 4-year study.

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Operator   [29]
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 The next question comes in from the line of John Newman calling from Canaccord Genuity.

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 Christopher Liu,  Canaccord Genuity Corp., Research Division - Research Analyst   [30]
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 This is Chris on for John Newman. Congratulations on the data. So just for the first question, could you remind me what was in the placebo group? Was it an active ingredient or anything like that?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [31]
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 No, it was a placebo-controlled study.

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 Christopher Liu,  Canaccord Genuity Corp., Research Division - Research Analyst   [32]
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 Okay. And for the -- to the different populations because the study was unchallenged, wondering if there are any meaningful differences between a more homogenous group, like the full Chinese study in the Phase III trial versus a more heterogenous group like one done in the U.S. or in the EU? Are there any potential subtypes to this or is there anything like that?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [33]
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 Maybe Wei-Guo?

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [34]
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 Well, not so much in terms of rates. The -- it's all Chinese. But I think the heterogeneity of this patient population is really due to different subtypes or the origin of -- and the tumor origin.

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Operator   [35]
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 The next question comes in from the line of Steve McGarry calling from HSBC.

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 Stephen McGarry,  HSBC, Research Division - Analyst   [36]
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 A couple of questions. Firstly, just following on from one of the previous questions. Could you give us the -- any more detail on the timing of the discontinuations on the active drug? Some in -- was an average of like 6 months, a year, before you saw the discontinuations happening? And what was the overage time overall?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [37]
------------------------------
 I think on Page 20 of the deck, Steve, it talks about the drug exposure and the median amount of time. So it's about 7 months, was the median drug exposure on surufatinib and the relative dose intensity, about 86%. So as Wei-Guo said when he gave the brief presentation on that page, that's an indication of very good tolerability.

 And so, as we just said with Franc, the reason for high level of discontinuations is because we met the number of PFS events to be able to run the interim study, or run the interim analysis on the study.

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 Stephen McGarry,  HSBC, Research Division - Analyst   [38]
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 I don't completely get. I was just trying to get a bit more detail as to when you sort of force discontinuations. Was that because of tolerability issues or was it disease progression early in the treatment cycle?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [39]
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 Wei-Guo, do you want to -- any thoughts on that?

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [40]
------------------------------
 Patients were allowed to have drug holidays, right. If they have -- if they experience intolerable side effects, they can stop taking the drug for a few days. They can come back on. So that -- and that's for both groups, both treatment and placebo groups. They have the option to do that. And there's a limit, of course. You cannot stop for a very long time, defining the protocol.

 So I have to say, 86% relatively intense, to the maximum. For these patients, they stay on the treatment for -- median PFS is 9.2 months. I think -- personally, I think it is quite good and certainly acceptable.

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 Stephen McGarry,  HSBC, Research Division - Analyst   [41]
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 Okay. Secondly, about 19% of patients had grade 3 or high proteinuria and you said it was relatively easy to manage. Did that include dose reductions or drug holidays or how did you manage that?

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [42]
------------------------------
 The patients were required to do regular urine tests and they have to monitor protein level in the urine. And I think this will be ultimately published. But also we're being a label as well, how they manage the proteinuria. Typically, grade 1 urea, proteinuria, no issue. You can continue your treatment. In grade 2, you may have to take off the drug for a few days until your proteinuria, it goes back to grade 1 or below, then you can continue the treatment. Grade 3, you have to -- grade 3 proteinuria, you have -- you probably have to, not only take off the drug for a few days, but also reduce your dose to maybe a, to a lower dose. So it's all -- it's like there's a grid, all the physicians have that grid, and how they manage the proteinuria in particular.

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 Stephen McGarry,  HSBC, Research Division - Analyst   [43]
------------------------------
 Okay. And then just finally, you have, sort of 2 cases of grade 5 tox, and we shouldn't be worried -- judged to be treatment related.

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [44]
------------------------------
 I mean, the overall deaths on treatment between the 2 groups were relatively similar. So we clearly didn't see a strong signal in terms of grade 5 toxicity and relatively low as well.

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Operator   [45]
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 The next question comes in from the line of [Ling Marcolin] from JP Morgan.

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 Unidentified Analyst,    [46]
------------------------------
 Just wondering, the median PFS that we observed in the Phase III study seems to be lower than what we saw in the Phase II study. Then also for the placebo PFS about, during quite -- 8 months, it also seems to be lower than what you guys have expected. Can you explain why that might happen? Is that because that the patient population might be different from what you have expected?

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [47]
------------------------------
 Wei-Guo, maybe you handle that.

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 Wei-Guo Su,  Hutchison China MediTech Limited - Chief Scientific Officer, Executive VP & Executive Director   [48]
------------------------------
 Yes. I think there's obviously multiple factors here. Clearly, with regard to the median PFS, we believe there are multiple factors. One in particular is the patient population, as you just pointed out. As I mentioned in the presentation, almost opposite to other global trials with Sutent and everolimus. In this particular study, the great majority of patients were G2 -- were having G2 disease, these are more aggressive obviously, as compared to 70%, 80% of the patients with G1 disease, grade 1 disease. So these are obviously patients with more aggressive disease, having progressive tumors. So should have an impact on the -- on a medium PFS. So -- and I think you need to take this in perspective. It's very difficult to compare the study, specifically to the other without paying attention to these details.

 The other thing you mentioned about Phase I versus -- Phase II versus Phase III. Obviously, Phase II is a single-arm study conducted in the handful of hospitals, where these are probably, I think only 8 hospitals involved in the Phase II open label study. These are all clinical centers and these are top physicians, very experienced in neuroendocrine tumors. A lot of it is -- the PFS, a lot of it has to do with how these physicians can manage, for instance side effects and keep these patients on treatment without going off after your holidays, to go to holidays due to adverse events and so forth.

 So why you expand to 28, 30 centers from a handful, only 6 to 8 centers, it makes a big difference. So it's not surprising. I think that this data is much more robust and more reliable than any single-arm Phase I or Phase II expansion-type studies. This is obviously [my objective].

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [49]
------------------------------
 Can I inject here? Can I add one additional point to what Wei-Guo has just said there? I mean, that's probably one of the most obvious differences between the China studies and the global studies, is the percentage of grade 2 patients in the SANET-ep study. As Wei-Guo said, it was over 84%. Normally in global studies, you see 70% or 80% grade 1 patients, is because they're being diagnosed earlier. And it kind of goes to what we talked earlier on about how in China, probably the net prevalence is underestimated because diagnosis isn't as sophisticated as the U.S., probably.

 And so I think that in general, you're seeing a more advanced patient population in China, more challenging patients, further along, and that's going to affect both the placebo-controlled median PFS as well as the treatment arm. And that's why it's very, very dangerous to be comparing cross-trial SANET-ep versus RADIANT-4, for example. You've just got -- you've got quite different patient populations and stage of disease, essentially.

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 Unidentified Analyst,    [50]
------------------------------
 That's very helpful. Congratulations.

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [51]
------------------------------
 Thank you, Ling. Thank you.

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Operator   [52]
------------------------------
 We currently have no further questions coming through. So I shall hand you back over to your host for any closing remarks.

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 Christian Hogg,  Hutchison China MediTech Limited - CEO & Executive Director   [53]
------------------------------
 Great. Thank you, [Courtney]. Well, I think we very much appreciate everybody being on the call today. I think we've managed to do it in an hour, almost exactly. And some very good questions. And once again, thank you very much to Dr. James Yao for taking the time to spend with us today. So thanks, everybody, for coming, and I'm sure we'll speak soon.




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