Status Update

Jun 8, 2021

Slides

Good afternoon. This is Tim Power from IR at Bristol Myers. Welcome to our investor event at ASCO 2021. And as you have seen, we had some important data from our oncology pipeline presented over the weekend, including for our next generation IOH and melasma. So There's a lot to cover today in a short time. And I'm joined for today's discussion by Saman Hirwa, our Chief Medical Officer and by Chris Boerner, our Chief Commercialization Officer. Sumit and Chris will go through the slide presentation and then be available for Q and A at the end. If we can go to our next slide, which contains our forward looking statements, I'll hand over on Slide 3 So, Simon, we get the presentation started. Thank you, Tim, and good afternoon, everyone. I'm happy to have this opportunity to discuss The data presented from our pipeline at this year's ASCO meeting, which is of course a very important medical Congress as always. At this year's ASCO, BMS demonstrated that it continues to be a leader in oncology. We are pleased to be able to say that BMS is the only company that has successfully developed and executed pivotal trials For 3 separate IO agents with Opdivo, Yervoy and now relaptamab. And with these agents, We've built a broad program that includes monotherapy and combination approaches. These therapies have provided improved outcomes across various tumor types And address the need for both early and advanced diseases. So what did we learn at this ASCO? First, we continue to deliver important new therapies with nivolumab, including those that are in the new adjuvant setting for non small cell lung cancer and in upper GI and in the upper GI and M Regencies. There is continued strengthening of evidence For the durability of benefit provided by nivolumab and ipilimumab. And importantly, we presented clinically meaningful data For our latest IO doublet, rilatinib plus nivolumab in a fixed dose combination. With rilatinib being a novel anti LAG-three antibody And the first of its kind to deliver successful Phase 3 results. Moving into the data right away, We wanted to highlight some important results from study CheckMate-eight sixteen for nivolumab plus chemotherapy in the new adjuvant setting for non small cell lung cancer. In April, this trial met its co primary endpoint for pathologic complete response rate as you've heard before. As you can see on the left, The PCR rate was a meaningful 24% in the nivolumab bar versus nearly a 2% in the chemotherapy alone on. At ASCO, we also presented data on the surgical outcomes post treatment. 1st, adding nivo to chemo did not increase post surgical complications. Moreover, the majority of patients who received nivo plus chemo had timely surgery with more complete resections and fewer pneumonectomies. Finally, the graphic on the right shows that with nivo plus chemo, an increased number of patients We're able to undergo minimally invasive procedures compared to those treated with chemo alone. Overall, these data would present a potential option For patients with early stage lung cancer when approved. I'll now move on to the data we shared in GI cancers. In particular, I want to highlight the data presented for CheckMate 648, our Phase 3 trial in first line esophageal cancer, Which met its primary endpoints of overall survival and additionally progression free survival in patients with PD L1 expressing tumors. I won't go through all the details because I know you've heard them all. But here are, as you can see, the trial design, Which studied nivo plus chemo as well as nivo plus CP compared to chemotherapy alone. On the next slide, here are the Kaplan Meier curves for the nivo chemo arm from the medical presentation. Let me share with you what's important from our perspective about what we see here. 1st, superior overall survival, Not just in PD L1 expressors, but in all randomized patients as well. And secondly, a very clinically meaningful result In both populations. On the next slide, here is a similar seen that you can see now showing superior overall survival for the nivo plus EPR with a hazard ratio of 0.64 For the PD L1 expressors and 0.78 for all randomized patients, which potentially could present patients with a chemo free option When approved. And finally, reflecting on each of the 4 curves shown, you'll notice that over 50% of patients were alive at 12 months. On the next slide, you can see a manageable safety profile was demonstrated for both active arms, Nivo Chemo And nivoipi. Note that while nivo chemo had more treatment related adverse events, fewer of them were deemed serious. All in all, No unexpected safety signals. Now switching to dual IO with Opdivo plus Yervoy in melanoma, Where we presented additional data this ASCO for CheckMate-sixty seven. At 6.5 years, These data represent the longest follow-up for a dual IO trial. Nearly half of the patients who receive this therapy remain alive. You can see the durability of this regimen continues to be demonstrated by the consistent shape of the overall survival curve With the tail of the curve clearly representing very good outcomes for many metastatic melanoma patients, as we celebrate the 10th year anniversary of Yervoy this We acknowledge this remarkable transformation in the outcomes of patients with melanoma, where only a decade ago, The median survival is around 6 months. And there is an opportunity for a similar effect to be seen in first line non small cell lung cancer patients, Where we now have 4 years of follow-up with CheckMate-two twenty seven and 2 years of data for CheckMate-9LA. With the maturity of the curves for CheckMate-two twenty seven, the longest duration of follow-up for dual IO treatment in lung cancer, you can see the flattening of the curve And a distinct tail demonstrating that proven durability once again. We then look on the right side at CheckMate 9LA, Our Phase 3 results had already validated that a small amount of chemotherapy can address the early part of the curve that we saw crossing over in CheckMate-two twenty seven. These data showed durability as they mature. In fact, 38% of patients were alive at 2 years, which is in line with what we observed with CheckMate 227. We are pleased with the evolution of the data in first line lung cancer And we'll continue to follow of course the outcomes of these patients as well. Combined with the 4 year results from CheckMate 214 in first line renal cell cancer, We now have long term data across 3 tumor types where the promise of durability Has been proven and delivered with dual IO therapy. I want to switch gears a bit and talk to you about rilatinib, Which we call Rella. Rella is a humanized LACT3 blocking antibody that restores the effector functions of exhausted T cells And reinvigorates their activity to direct an anti tumor response. Earlier studies demonstrated that inhibiting LAG-three and PD-one checkpoints By using Rella and nivo together, enabled T cell activation and enhanced the anti tumor immune response versus nivo alone. That led to our Phase twothree study, which I will address briefly on the next slide. Relativity-forty seven is the Phase IIIII 1st Phase IIIII study to evaluate the novel combination of Rella plus nivo versus nivo monotherapy, a current first line standard of care in advanced melanoma. Patients received either the fixed dose combination Or nivo monotherapy every week, every 4 weeks. And by fixed dose combination, I mean, Rella and nivo being co formulated In the same vial, patients were stratified by LAG-three and PD L1 expression as well as by BRAF mutations And metastatic disease stage. The primary endpoint of the study was progression free survival by blinded independent central review committee. Secondary endpoints included overall survival and objective response rates, both of which the company remains blinded to at this time. Looking at the primary endpoint for Relativity, you can see the Rella plus nivo demonstrated significantly longer progression free survival Compared to nivo monotherapy with the median progression free survival more than double the value seen for nivo alone. The benefit was seen early during treatment at the time of the first scan and continued over time. The hazard ratio of 0.75 was clinically meaningful and highly statistically significant. On the next slide, we also see that the PFS results consistently favored the fixed dose combination across all subgroups And stratification factors including key factors like BRAF mutation status, LAG-three expression, PD L1 expression and disease stage. Moving to safety on Slide 16. The data from Relativity shows that the fixed dose combination of Rella plus nivo was associated with a manageable safety profile And no unexpected safety signals. Overall, the type of adverse events observed were similar to those seen with nivo alone, Although with occurrences at a higher rate, as expected with the dual therapy when comparing to a single agent. Because of this manageable safety profile though, we believe Rella plus nivo provides the potential to bring IO treatment to more patients, Including and especially those who may not be considered candidates for O plus Y today. Now, as we look to the future on the next slide, the potential for Rella doesn't end with metastatic melanoma And we are pursuing several additional studies. 1st, in a Phase 3 trial in adjuvant melanoma, as we look At this ASCO, you may have seen data presented this weekend presented by Doctor. Amariya From MD Anderson, where Nivo plus Trella administered pre and post surgery achieved high rates of PCR and major pathologic response Encouraging data for an earlier stage disease in melanoma for this combination. Now beyond melanoma based on our understanding of the mechanism As well as signals from our Phase 1 basket trial, we also chose to pursue Phase 2 trials in 2 additional indications, Hepatocellular carcinoma and non small cell lung cancer. Now regarding non small cell lung cancer, we expect to see safety data from our Phase 2 trial early next year And that could enable us to move forward into Phase 3. Now, I just wanted to end here with a brief reminder of where we've been And the potential of what is yet to come. We look forward to sharing more data in the future as we continue to follow exciting and emerging science And bring more options to patients in need. And with that, I will now hand it over to Chris to give you his thoughts from the commercial side of things. Chris? Thanks, Sam. That is a great segue from my first slide as I'd like to remind you of the legacy that we have had in IO for over 10 years now. Combined sales for Opdivo and YERAVOY have grown to $8,700,000,000 last year, reflecting the success of these two products, which either alone or in combination, are And as we've said previously, we expect Opdivo to return to growth in 2021 and that our IO business We'll play an important role in company growth beyond 2021. We see that growth supported by several recent approvals and positive data readouts. First in first line lung where we have 2 different regimens to offer patients. 2nd in upper GI, We have had 2 recent approval as well as a positive Phase 3 readout, which will round out a very comprehensive book of business in upper GI cancer. 3rd, we have important opportunities in other tumors, notably first line lung first line renal, where we have launched the 9ER regimen and in muscle invasive bladder cancer with CheckMate 274, where we have a PDUFA date of September 3. Finally, we're excited about our next IO combination, rilapamib, which you just heard about from Summit and the ability to expand our leadership with first line melanoma with a fixed dose combination and I'll talk to you more about that in a moment. But let's first take a look at our growing upper GI franchise where we have options for patients addressing multiple areas of unmet need including, first, the first approved IO-eight adjuvant treatment For esophageal GEJ cancer with CheckMate 577. 2nd, the first approved IO treatment in first line metastatic gastric cancer with CheckMate 649 and with the recent success of CheckMate 648, a potential launch in first line metastatic esophageal. Overall, we have the most comprehensive offerings across upper GI cancers, including Those involving the esophagus, GDJ and some. Shifting now to metastatic melanoma. Bristol Myers has demonstrated its leadership With Opdivo plus YERAVOID and that regimen over the last number of years, we now have an additional potential opportunity with the fixed dose combination of RELA plus nivo. As Samit mentioned, RELA combined with nivo delivered a clinically meaningful PFS benefit versus PD-one monotherapy, which is a great accomplishment knowing the high bar of PD-one monoefficacy in melanoma. On slide 11, We're also able to see the PFS for this option as well as demonstrated with OPDIVO plus YERVOY. This new regimen provides an opportunity for additional first line melanoma patients to receive a combination treatment. On this slide, you see the current U. S. Market landscape in first line melanoma, which you can broadly think about in 3 distinct segments. Today, the combination of Opdivo and Yervoy represents roughly a third of the market, reflecting the significant durability and long term survival benefit This regimen affords patients. The next third of the market represents PD-one monotherapy use. For a regimen like RELA plus nivo With a differentiated safety profile and a demonstrated clinically meaningful PFS benefit versus PD-one monotherapy, this segment There remains further opportunity for IO penetration in the BRAF mutant type segment, The last one third of the population. Many times those patients with a BRAF mutation are automatically prescribed with TKI. Over time, we expect that prescribing behavior could shift allowing these types of patients to benefit from the durability of IO. Overall in melanoma, physicians are looking for additional options to achieve strong efficacy and long term durability for more patients. Over time and with additional data, we'll be able to determine where we can further expand the commercial opportunity. While we were only able to highlight a few elements of our ASCO data in oncology program today, remember, we have a broad franchise that is expanding over time. In our solid tumor business, our in line brands continue to perform well, including Opdivo, where we expect growth later this year. We look forward to the potential launch of the fixed dose combination and extending our existing leadership in melanoma, which also Continuing to develop while also continuing to develop new agents with novel targets across various platinums. On the hematology side, we continue to advance our new launches including our 2 CAR T products Briansy and Apegma and further establish new medicines in myeloid disease with Revlisil and Onuray. Finally, we look forward to strengthening our leadership In multiple myeloma with additional developments in our Cellmod agent portfolio and with other BCMA assets like our T cell engager and ABC. To sum it up, as you've seen at this conference, we continue to meaningfully advance our leadership in oncology with a broad set of programs across tumors and stage of disease. Importantly, the data presented here not only advanced the science of IO, but also support near term commercial opportunity. And with that, I'll turn the discussion back over to Tim. Great. Thanks very much, Chris. Drew, if we can go to Our first question, once you compile the roster, that would be great. It might take a minute to get this compiled. If we go to the first one, you're ready. That would be great. Thanks. Our first question is going to be from Geoff Meacham from Bank of America. Go ahead, Jeff. Hey, guys. Thanks for the question. Thanks for hosting the event. Just have a couple for you On melanoma, on the development side, are there lessons to be learned from mutations in LAG-three as a resistance mechanism? I'm just trying to think of Indications beyond what you've highlighted. And then from a commercial perspective, how do you think about the positioning of who is more optimally suited For nivoipi versus nivoirella? Thank you very much. So maybe, Jeff, thank you. I can start and then certainly Chris can chime in on the commercial front. On the mutations of LACT3, one of the strengths that we carry at BMS It's because of the conduct of the studies and collection of tissue and materials over the years from our various trials, we have the ability to now mine the data, Go back and take a look. Also, as you saw at the presentation this time, we did have the preliminary data from a LAG-three Question perspective, but now we can go back and dig deeper into the correlation, as you said, of where patients may not have responded Because they carry the LAG-three mutation, but those are data that are still to be produced. We still need to dig deeper into it. Things that will follow in the future. That will also, as you very correctly said, will help us in our pipeline as well as we bring more treatments Into the melanoma landscape. But today, we don't have that data to really comment on. And on the commercial side, what I would say, Jeff, is first, We continue to believe, as I mentioned in the presentation, that the initial opportunity for RELA plus nivo is going to be Again, should be roughly 30% of the business that is currently IO monotherapy today. Given the data that we presented at ASCO, we think that's the most obvious near term opportunity. In terms of how physicians are going to think about ipinivo versus relinivo, I think there will be some physicians who may wish to avoid some of the toxicities that you've seen with ipi. So they may choose to use the relinivo combination for those subset of patients. However, what I would say is that given the A considerable long term OS benefit that we've seen with ipi plus nivo and as we said in the presentation, we are going to need to see the RELANIVO data continue to mature to better understand exactly which portion of those patients are going to be preferred for physicians to go with RELANIVO versus And then of course longer term as we mentioned there may be additional opportunities in that BRAF mutant population. Thanks Chris. Thank you guys. Drew, can we go to the next question please? Our next question is from Greg Gilbert from Stuest Securities. I can hear you okay? Yes. Great. Thanks. Two parter. First, can you speak to your confidence in filing with PFS data? And secondly, I realize it's somewhat early days for LAG As a mechanism, but do you see the potential for differentiation between LAG-three's that does not seem to exist In the sort of PD-one versus PD-one world, I'm talking about drug versus drug here, not driven by clinical trial strategy. Thank you. Joe, thank you. On the first question on filing with PFS, so PFS is an accepted primary endpoint from a regulatory And we certainly look forward to sharing the data with the regulatory authorities and using that for our filing. We Certainly are continuing to follow patients for overall survival. As I said earlier, we at the current time remain blinded and we'll supplement that data in the future as that becomes available. On the potential for differentiation versus other LAG-three, I think it's early days. We don't know what others have that might be different. But what we do have at the current time It is the fixed dose combination with Opdivo and we are going to continue to pursue that. As you know, we have the Phase 2 studies ongoing In non small cell lung cancer, hepatocellular carcinoma and then soon to start the adjuvant setting melanoma and we'll continue to pursue that fixed dose combination. But in terms of differentiation, I think we have to see what the data evolves and how we then are able to compare our data to the others in the same indications to see if there are any Differentiations to be really followed from that perspective. Thanks. Laura, can we go to our next question please? Yes. The next question is from Chris Bott from JPMorgan. Great. Thanks so much and thanks for taking the questions. Just 2 for me. First, can you talk a little bit about the adjuvant data in RCC we saw from Merck this weekend And what that means in terms of the size of the frontline metastatic market as we think about Bristol's portfolio positioning there? And then my second one was on LAG-three and just some of the newer indications. Can you just elaborate a little bit more in terms of what you're seeing in the basket studies And the scientific rationale for LAG-three in HCC and non small cell versus the signal we're seeing in melanoma. I'm trying to get a sense of Your confidence in those additional indications versus the signal that we've now kind of confirmed in melanoma? Thank you. Sure. Maybe I yes, go ahead, Chris. I'm sorry. Yes. So As it relates to the adjuvant RCC data, I mean, obviously, it's a little bit early to comment specifically on how that market is going to evolve. I think what we're now to wait and see is exactly the percentage of patients who get responses when if and when the regimen is approved And then what exactly those responses look like including their durability and how fast they occur. One of the things that we have learned from our experience in melanoma and the adjuvant setting is that, in general, physicians do view these as 2 distinct segments. And so we are seeing real world data where patients who have been to an I O therapy in the adjuvant setting and unfortunately that patient does progress into a metastatic setting that those patients are then again Considered eligible for I O therapy and we've seen that in other non I O indications as well, for example, in the breast cancer setting. So I think it's a bit early to give a precise answer to the question, but as where we sit today, we don't see any obvious near term impact on our first line metastatic business as a result of these data in the adjuvant setting. Yes. And in terms of the LAG-three indications and why we are pursuing the non small cell lung cancer, hepatocellular carcinoma indication is Some preliminary data that we saw in the study 20 for LAG-three when we were looking at combinations are responses that we saw in non small cell lung cancer as well as indications of activity in hepatocellular carcinoma. But I think we need to certainly delineate the activity due to nivo Or what could be driven through nivo Rella. And that's why if you look at the trial design for non small cell lung cancer, we're looking at nivo Rella chemo versus nivo chemo. That serves two purposes. 1 defines the dose at a higher dose that are being tested in this particular study and second gives safety and third Gives us a good insight into the contribution of components that we don't then have to do in a Phase 3 trial that we will pursue further. So those are the reasons why the trial design is the way it is and the basis of pursuing based on the prior indication and prior data that we saw In the earlier trial, which was a non randomized study and that's why our randomized Phase 2 study, we thought was important to garner that confidence before we started a Phase 3. Thanks, Sala. Laura, can we go for next question please? The next question is from Matt Phipps with William Blair. Hey, good afternoon. Thanks for taking my questions. Nice data at ASCO overall. I was wondering if How are you all thinking about the potential of the Opdivo, Yervoy combination in esophageal based on the 648 trial? Maybe not as impressive as VIVO chemo, but there did seem to be some physician interest in a chemo free option. And then as far as LIG3, this is something that I guess from an investor standpoint, initial data was not really impressive enough for many people to Look at it too much, but you all obviously move forward and had a bit of a gated development to get to this point. Is there any learnings From the lag through experience, I can help you out with any of the earlier IO combo pipeline. Thanks. Tommy, do you want to start and then I can Sure. I can certainly start from the second question, LACV first, I guess. So there are 3 elements that one has to really look into and not just from the melanoma perspective, which of course is a big deal as Chris pointed out earlier, if you think about today, many of the patients are not getting treated with a doublet IO, onethree of the patients are not even getting the IO background therapy For their melanoma. So generation of a Phase 3 trial data to us does seem quite a game changer, I would say, Because look at the competitor arm, which is single agent PD-one, which is a very active therapy. So showing more than doubling of the progression free survival In the Phase 3 trial is to me, I think pretty impressive from a patient and physician perspective. The second part of LAG-three is, if you look at the totality of the data that are present that have been presented at ASCO, not just by us, but shared by others as well in other tumor types, It starts to tell you a story that LAG-three does have a place, but we just need to ensure the right combination in the right patient population or the right indication needs to be Tod, we've seen the data in melanoma. We I talked a little bit earlier about what we saw as hints of activity In non small cell lung cancer, hepatocell carcinoma, and that's why we've initiated those trials. We saw some data at ASCO in colorectal cancer in the MSS type. So I think in totality, there is activity, but LAG-three will require a little bit of a finesse in terms of choosing The indications, choosing the combinations and how we proceed in the right tumor types and the right indications. On the esophageal side, O plus Y, I think you already mentioned and from a development perspective, I would say, we're very proud that we've now got 3 different trials showing The activity of Opdivo and Opdivo Plus Yervoy in the upper GI malignancies starting from the adjuvant setting To the first line metastatic setting, as you very correctly said, not all patients may want chemotherapy, not all prescribers may want chemotherapy. So there is space for that O plus Y combination once approved to be able to deliver for patients an additional Effective therapy that has shown an improvement in overall survival. I don't know if there's a commercial perspective that Chris you would like to add. We're obviously, As Amit mentioned, very pleased to have yet another positive trial here in this case for patients with squamous cell carcinoma. Obviously, we're pleased to have 2 regimens that we could potentially offer to these patients. As Samit mentioned, we have heard from A number of physicians we've shown these data to and you've heard it a little bit even in the ASCO presentations that there will be patients who would like a Chemo free option and obviously Opdivo, Yervoy provides that. I mean it certainly provides optionality physicians to target the regimen that they wish to choose to The patient they see in front of them and along with the approved indications that we have, this gives us the broadest opportunity in first line metastatic upper GI cancer. So Obviously excited about it. And once it's approved, we very much look forward to being able to launch it from a commercial standpoint. Thanks, Chris. Laura, can we go to the next question, please? The next question is from Dane Leone from Raymond James. Thank you for taking questions and congratulations across the entire set of updates that your teams had at ASCO, Great outcomes across the board. I want to ask what some of the feedback has been at ASCO today. We actually had Session that did focus on some of the new BCMA therapies for multiple myeloma. To date, How many treatment centers do you have up and running that have access to Abekma? And what's been the feedback in terms of Getting patients on Avekma as a commercial product versus enrolling patients in some of these other BCMA directed Let me say at the outset that the 2 card therapy launches are All is going very well from a commercial and medical standpoint. We have over 60 accounts that have been activated with Briansy And we're certainly increasing the number of accounts that are activated to treat with APECMA. And so I think that in general on the APECMA side, The feedback from accounts has been very positive about the profile. The demand for the product has been very significant. And in fact, The demand for Opecma is pushing the boundaries of our ability to supply at the moment. We're obviously doing everything we can to continue to ramp up Supply in order to meet the demand that we're seeing for these patients, as you know, is the first BCMA cell therapy here. We've demonstrated Significant improvement in the available options that are available to these patients and the feedback from physicians has been very positive and there's a Significant desire to get patients on to therapy. And so we're very much in the mode right now of continuing to ramp up Apply to be able to meet this demand and we continue to work very closely with the customers. But what I would say at the outset is that The feedback has been very good from a commercial and medical standpoint and our focus is on continuing to push forward both this As well as leverage the broader platform that we have in cell therapy with the launch of Brianca as well. Thanks, Chris. Laura, can we go to the next question, please? Yes. The next question is from Steve Scala from Cowen and Company. Hi, thank you. The addition of rolatlumab appear to have most Pronounced benefit in PD L1 low melanoma patients. Does Bristol expect a label Along these lines or used to be stratified by biomarkers? That's the first question. Second question is Roche is developing a PD-one LAG 3 bispecific and they cite some theoretical advantages of that modality. What are your thoughts on that modality? And are you pursuing a similar Thank you. Sure. So on the first one, Steve, Samit here. On the first one around the label As specified by subgroups, we obviously will not comment. The way I look at the data, the way we've looked at the data and the way the physicians and presenters have looked at the data Across the board, there is benefit for the patients. If you look at the hazard ratios and how the overall forest plot looks like, Yes, the you on from a naked eye view, it may seem as if there is a difference, but is that difference really meaningful? We don't believe so. So we'll continue to pursue our continued dialogue with regulators in terms of seeing where it goes. But certainly, we see the result Equally applicable to all patients at this time. On the second question around PD-one LAG-three bispecific from Roche, We'll have to see what the data would tell when they come through. We have the fixed dose combination that we are pursuing. Now, of course, our overall oncology pipeline is With other medicines that we are continuing to pursue beyond the LAG-three, as you know, we have the TIGIT, we have the The TGF beta, we have the IL-twelve, IL-twelve as well as the IL-two in the Phase 3 development. So We don't have a LAG-three PD-one bispecific at this time in our pipeline, but I think our approach that we've taken, we are quite satisfied and we'll continue to pursue that in the other Indications that I spoke about earlier. Thank you. We go to the next one. We have another question from Greg Gilbert from Truist Securities. Thank you. Just two follow ups. On fixed doses in general, can you talk about where you're drawing the line as a company between combination therapies that should be combined In a fixed dose versus those that should be kept apart, is that simply technical considerations or are there other Factors that you're considering because there could be presumably an infinite number of potential fixed dose combinations as you think out over the years. And my second question Is a bit more outside the box, I'd say. Are there cases where a competing PD-one or PD L1 has a favorable label versus Opdivo, where it would be unethical for you to conduct a U. S. Trial to sort of mimic that part of the label, but where you are considering doing such a study Outside the U. S. Is a way to sort of normalize labeling over time? Thanks a lot. Yes. So maybe I can start and certainly Chris, if you I want to add, we can go there too. From the fixed dose combination perspective, I think you mentioned one of them, the technical approach, whether The drugs can be formulated to be in the fixed dose combination or not. And one of the things that also is a driver is The volume of the drug that will need to be delivered, can it be actually given if it's going to be a subcutaneous. But of course, IV wise, Can the 2 drugs be formulated? And I think one of the key factors is going to be, if there is going to be a lot of dose changes or toxicity associated with 1 drug, Can you really have a fixed dose combination when you have to toggle 1 versus the other drug? So I think both from a clinical safety As well as the technical point of view, one has to keep those things in mind. It could be applicable to the larger part of our portfolio, but we have to assess it on a case Case basis as we go forward, right now we've started with Rella plus PD-one. On the second question on the label driven geographic A development part, I would say that we are a global company. As we think about development of medicines, we think about it from a global perspective And more and more so that we include Japan as well as in China as well as many of the other geographies in the overall development Alpha molecule, we have not devised strategies to shortcut the indications That we are seeking just because we can't conduct the study in the U. S, so we go outside, conduct the study and bring the data to the U. S. We've not taken that approach. We don't think that applies to OIBEWA at this time because our labels are pretty solid in either and any indication That we have pursued thus far and we'll continue to pursue the global development that we have ventured out to do at this time. I don't know, Chris, if you want to add anything. The only thing I would add on the FiSCOs combination and we've certainly heard this from physicians who have seen the RELA data is that it does offer A convenience element particularly for those accounts where infusion time is a concern or the availability of infusion chairs. And so in that regard, it has the potential to provide a real customer benefit above and beyond purely with clinical benefit. Thanks, gentlemen. Laura, can we go to the next one, please? We currently don't have any raised Hans, we were just wondering if Andrew Baum from Citi had any questions at all. And if anybody else has any questions, please do raise your hands. Laura, if Andrew would like to ask a question, will you just patch him in and we can see if he has a question for us? He's here. If he has a question, he'd be able to unmute himself. It was just in listen only mode, so forgive me. Hey, Andrew, we can hear you now. No, I was just I was literally just in listen only mode, so I didn't have any pressing questions. I think you've run through a gamut of them. Very good. All right. Well, I think that's it for today. Thanks for being efficient everybody. You know we're defined as if you've got follow ups and thanks for your time. Thank you.