Document Details

# GSK plc GSK plc - Special Call - GSK plc

Tuesday, December 17, 2024 8:00 AM

# Event Participants

#### Executives 5

Mick Readey, Tony Wood, Hesham Abdullah, Kaivan Khavandi, Luke Miels

#### Analysts 10

James Gordon, Simon Baker, Zachary Dunn, Emmanuel Papadakis, Peter Welford, Graham Parry, Jo Walton, Rajan Sharma, Richard Parkes, Eric Le Berrigaud

#### Mick Readey Executive

Hello, everyone. Welcome to today's meet GSK management event, focused on the next wave of our pipeline. This is an interactive event with a presentation sent through our distribution list by e-mail, and you can also !nd it on gsk.com. Next slide, please. This is our usual safe harbor statement.

Next slide, please. Our Chief Scienti!c O"cer, Tony Wood, will take you through the presentation before Hesham Abdullah, Kaivan Khavandi and Luke Miels join for Q&A. And with that, I'll hand over to Tony.

# Tony Wood Executive

Thanks, everyone, and welcome. Today, I want to talk to you about our Next Wave of R&D...

# GSK plc GSK plc - Special Call - GSK plc

Tuesday, December 17, 2024 8:00 AM

# Event Participants

#### Executives 5

Mick Readey, Tony Wood, Hesham Abdullah, Kaivan Khavandi, Luke Miels

#### Analysts 10

James Gordon, Simon Baker, Zachary Dunn, Emmanuel Papadakis, Peter Welford, Graham Parry, Jo Walton, Rajan Sharma, Richard Parkes, Eric Le Berrigaud

#### Mick Readey Executive

Hello, everyone. Welcome to today's meet GSK management event, focused on the next wave of our pipeline. This is an interactive event with a presentation sent through our distribution list by e-mail, and you can also !nd it on gsk.com. Next slide, please. This is our usual safe harbor statement.

Next slide, please. Our Chief Scienti!c O"cer, Tony Wood, will take you through the presentation before Hesham Abdullah, Kaivan Khavandi and Luke Miels join for Q&A. And with that, I'll hand over to Tony.

# Tony Wood Executive

Thanks, everyone, and welcome. Today, I want to talk to you about our Next Wave of R&D, innovation and GSK. At the pace we're now working, some of these medicines will contribute meaningfully to our growth this decade while others will reach patients in the 2030s. At the core of our approach is deepening our expertise and science related to the immune system. Taking it beyond our current understanding of its role in autoimmune disease and infection to a deeper understanding of !brosis and autoin#ammation, for precision treatment and ultimately to target interventions that support healthy immune system aging.

We're doing this through investment in scienti!c partnerships and advanced platforms and data technologies to substantially increase our use of genetics, functional genomics, biomarkers and immune phenotyping, all of this to identify the right target, the right drug and the right patient. Our aim is to develop signi!cant competitive advantage for GSK with deep expertise inside the company and full advantage of a bespoke world-class network of partnerships. Data collaborations with experts like Oxford, Cambridge and Boston universities, Okra and Finjan together with platform tech partnerships like Flagship, Wave and our recent acquisition of LC are enabling us to understand underlying disease processes,

reach previously inaccessible targets and better identify patients for treatment. With the progress we've now made, I believe we have a clear path to develop a di\$erentiated pipeline of !rst and/or best-in-class medicines and vaccines across a range of signi!cant diseases that will deliver bene!ted scale to patients and ultimately sustainable value to shareholders. Next slide, please.

Today, I'll be focusing on our approach in oncology and respiratory and immunology. These are 2 areas where we have signi!cant opportunities for growth in 2025 with respective launches of BLENREP and depemokimab, and where we're increasing and prioritizing capital investment to accelerate key pipeline assets. In oncology, our plan is to rapidly expand beyond our current focus on hematological and gynecological cancers to develop antibody drug conjugates, or ADCs, for the treatment of solid tumors. And in respiratory and immunology, we're building on decades of knowledge and in#ammatory mechanisms to lead in COPD and to target !brotic lung, liver and kidney disease. We plan to provide a similar update on HIV in the second half of 2025 with infectious diseases following in due course.

But for today, let's start with oncology. Next slide, please. Just last week at ASH, we presented statistically signi!cant and clinically meaningful overall survival results for a BLENREP combination with a 42% reduction in risk of death over current standard of care, which may translate to giving patients up to a median additional 3 years of life based on projections. With an acceptable safety pro!le, including on eye-related side e\$ects, we believe BLENREP has the potential to transform treatment for people with multiple myeloma. We've already completed 7 regulatory !lings, including in the U.S., where we expect a decision by July of 2025.

Next slide, please. We've already seen promising results in newly diagnosed patients as well. For example, from the BelaRd trial, which showed a 100% response rate. So we're increasingly con!dent in BLENREP's !rst-line potential and plan to start the Phase III DREAMM-10 study in newly diagnosed transplant ineligible multiple myeloma patients this month. The trial will compare a BLENREP combination with standard of care, looking at minimum residual disease or MRD negativity and progression-free survival as primary endpoints.

We expect initial results by the end of 2027. BLENREP reinforces the signi!cant potential of antibody drug conjugates as targeted cancer therapies. Next slide, please. In addition to BLENREP, we have 2 exciting opportunities with our B7-H3 and B7-H4 assets as well as the potential for further BD in this space, as demonstrated by our exclusive option agreement with Duality Biologics, recently announced for DB-1324 in GI tumors. First, let's look at our GSK'227 ADC, which targets B7-H3.

The B7-H3 antigen is overexpressed in a wide range of solid tumors, including lung and colorectal tumors. These tumors are sensitive to topoisomerase inhibitors, which means we can deliver potent medicine targeted to cancer cells, sparing healthy tissue unlike traditional chemotherapy. The topoisomerase payload in -227 is clinically validated and preliminary data suggests potential antitumor activity across a range of indications. Next slide, please. These early data from the ARTEMIS-001 Phase I trial in advanced solid tumors were presented by our partner, Hansoh at ASCO in 2023.

They show promising initial clinical activity in small cell cancer, non-small cell lung cancer and sarcoma with multiple con!rmed responses and a manageable safety pro!le. Next slide, please. This slide shows further results from ARTEMIS-001 presented at the World Lung Conference in September this year in patients with extensive stage small cell lung cancer, with disease progression on or after platinum-based chemotherapy. The trial showed a 61% and 50% overall response rate for 2 di\$erent doses of -227 for patients at this extensive stage of disease, standard of care is typically single agent chemotherapy with an expected response rate of under 20%, illustrating the impressive nature of these results. These 7-H3s transformative potential has also been recognized with breakthrough designation from the FDA.

Phase I and II trials will start in coming months with a comprehensive development program, including in lung, GI, GU and beyond. Next slide, please. Like B7-H3, B7-H4 is expressed across a number of solid tumors, particularly in endometrial, breast and ovarian tumor types. Our B7-H4-ADC, GSK'584 has best-in-class potential in ovarian and endometrial cancers with additional opportunities in other solid tumors. We're exploring a range of potential biomarkers in our development program to determine the patients most likely to respond to treatment and using AI/ML to understand the mode of action of ADCs in di\$erent tumors to guide and accelerate combination development, including with Jemperli.

Next slide, please. Phase I data presented at ESMO in 2023 showed promising proof-ofconcept for GSK'584 in patients with advanced solid tumors refractory to standard therapy. This trial primarily enrolled breast cancer patients with a focus on triple-negative breast cancer, but also included small numbers of patients with ovarian and endometrial cancers. Across the study subject to a heavily pretreated with a mean of 5 prior lines of therapy. As you can see here, GSK'584 showed broad antitumor activity in advanced solid tumors, with encouraging clinical activity in triple-negative breast cancer.

We believe these data are representative of the type of activity expected in gynecological tumors, an area of strength of GSK. We're moving quickly to generate further evidence, including in combination with Jemperli. Next slide, please. Given their potential, we are prioritizing and increasing investment in -227 and -584 in 2025 and 2026, and accelerating their development with a plan to deliver the !rst Phase III results in 2027. B7-H3, we're developing this asset in lung, colorectal, head and neck and prostate cancers and evaluating our result tumors.

Together with Hansoh, we expect to share updated small cell lung cancer and osteosarcoma data at ASCO and dose escalation at ESMO next year with pivotal studies planned for Q4 2025. For B7-H4, we're developing this asset as monotherapy and in combination across multiple indications in ovarian and endometrial cancers. We expect to share early ovarian and endometrial data at ASCO and ESMO in 2025. Dose expansion data are also anticipated during the year, with a targeted pivotal study start in 2026. For both programs, we'll apply extensive biomarker work supported again by AI/ML to determine the patients who will bene!t most from treatment.

Next slide, please. As you can see, the ADCs complement and strengthen our oncology pipeline, expanding our presence across multiple tumor types with signi!cant opportunity. ADCs could disrupt conventional treatment regimens alone and in combination with PD-1s, complementing our Jemperli programs and replacing chemotherapy in later lines. Next slide, please. Our clear focus is to prioritize and accelerate development of assets with the greatest potential with e\$ective stage gauging and checkpoints in place to drive timely investment decisions.

Gynecological cancers remain a cornerstone of our portfolio with Jemperli and now our B7- H4 ADC. And we're moving into additional solid tumor types, including lung, colorectal and head and neck, with both our B7-H3 ADC and Jemperli. As a reminder, we expect initial results from the AS01 and AS02 trials exploring Jemperli and rectal and colon cancer in 2026 and '27, respectively, with the Phase III JADE study in locally advanced head and neck cancer expected to read out in 2028. We're con!dent that B7-H3 will serve as a signi!cant cornerstone in many of these cancers. Beyond these, we continue to evaluate our TIGIT monoclonal antibody belrestotug mindful of data we've seen elsewhere, and our development strategy will be informed by additional data generated over the next 12 to 18 months.

With that complete, now let's turn to our respiratory and immunology portfolio. Next slide, please. Our unique understanding of the role that in#ammation plays in airway disease is based on decades of research in chronic respiratory conditions like asthma and COPD. In respiratory, our focus on the underlying biology and heterogenetive in#ammation notably in COPD is leading to a di\$erentiated pipeline of long-acting options with multiple mechanisms of action. In immunology, we're researching how in#ammation contributes to the development of !brosis in the lung, liver and kidneys.

Fibrotic diseases are thought to account for up to 45% of all deaths worldwide, so this is a major area of need. As I share through examples of our work in COPD and liver disease, we are transforming our approach with the application of advanced technologies. Next slide, please. As with our work in cancer, our approach starts with understanding human biology, in this case, for COPD. This disease a\$ects more than 300 million people globally and is the third leading cause of death worldwide, excluding COVID.

It's a complex and heterogeneous condition driven by multiple in#ammatory pathways. We were pioneers in establishing the role of IL-5 through our work with Nucala. I'm delighted with the positive headline results of MATINEE, our Phase III trial in patients with COPD with high eosinophil levels. We're applying the unique insights we've collected in the Nucala Phase III COPD studies to progress our wider COPD pipeline, including for depemokimab, where we aim to start Phase III development in COPD next year. Next slide, please.

Both IL-33 and TSLP also have strong genetic evidence supporting their potential as promising targets for intervening in COPD. People with naturally occurring lower expression of IL-33 and TSLP proteins have a reduced risk of COPD and the lower activity of both TSLP and IL-33 seems to decrease susceptibility to COPD in an additive manner, providing strong rationale for a combination therapy that targets both of these pathways. Next slide, please. By integrating a range of diverse data from disease phenotyping human genetics and genomics cell biology, and insights from our own scale clinical studies, we've built a sophisticated and unique understanding of di\$erent COPD populations. Together with insights from partners

like Cambridge and Boston universities, we've amassed a vast data set to help answer key questions on COPD progression, predictive outcomes and biomarker measures for disease stability.

Factors, including T2 in#ammation, eosinophil levels and a host of others in#uence both disease progression and response to treatment. And we're now using modeling to map prospective treatments to speci!c patient types. This work strongly supports the need for multiple mechanisms in addition to IL-5 to help as many patients as possible. Next slide, please. This slide shows the range of mechanisms of action in our pipeline, which target di\$erent biological pathways to reach the broadest range of COPD patients.

The chart is split by eosinophil levels and disease severity but you can also map against factors like smoking status and exacerbation history. It's important to note that while we're already well positioned to compete in COPD with our IL-5 assets, these will only be suitable for about 40% of patients whose disease is driven by eosinophils. Next slide, please. There remains a signi!cant need for improved biologic options in COPD to stop patients exacerbating and improve persistence with therapy. We see ultra long-acting medicines as a critical di\$erentiator, providing sustained suppression of in#ammation to impact disease progression for new e"cacy benchmarks such as exacerbation and hospitalization reduction as well as adherence and convenience bene!ts.

We have deep understanding of patient payer and HCP preferences in this space. As the only company with this range of mechanisms and ultra-long-acting format, we believe we're very competitively placed to extend our leadership in this disease. Next slide, please. In the next 2 to 3 years, we anticipate a series of pivotal trial starts in COPD, which could transform the treatment landscape. Next year, we're targeting approval for COPD for Nucala and expect to begin a Phase III trial for depemokimab with a potential !ling by 2031.

Our IL-33 program is currently in Phase I, and we're targeting a potential Phase III start in 2027. For TSLP currently in Phase II, we expect to begin Phase III around the same time frame whilst also evaluating the combination potential of these 2 molecules. This is an ambitious development plan, conducting multiple large-scale pivotal programs in parallel. But given our signi!cant experience and strong heritage of working with respiratory investigators, we believe we're well placed to deliver. Next slide, please.

As I laid out earlier, our work in human genetics and phenotyping is also generating insights that are informing moves into other areas, including liver disease. One example I'd like to share is our progress on steatotic liver disease or SLD, a chronic progressive disease that a\$ects around 5% of the global population and has signi!cant health burden. Steatotic liver disease includes several conditions associated with the accumulation of fat in the liver, including metabolic dysfunction associated steatohepatitis or MASH, also known as NASH, and alcoholic liver disease. Over 12 million patients globally have MASH and a further 26 million have alcoholic liver disease. This accounts for half of liver-related deaths in developed countries.

There are currently no pharmacological treatments available for ALT, which is associated with signi!cant emotional and psychological issues. Many patients also struggle with alcohol addiction, making lifestyle changes di"cult. These conditions typically been seen as di"cult

to treat. But new modalities, including oligonucleotides have shown real promise in targeting liver diseases due to their ability to speci!cally modulate gene expression in the liver. Next slide, please.

HSD-70 and B-30 is a gene involved in lipid metabolism and is primarily expressed in the liver. Human genetic studies show that naturally occurring variants in this gene are protective against both alcohol-related and non-alcohol-related liver disease, providing a 30% to 50% risk reduction in carriers compared to noncarriers. This is one of the strongest levels of genetic validation we've seen for any target. And reassuringly, this protective e\$ect is maintained even in the case of continued alcohol consumption. Next slide, please.

GSK'990 is our second oligonucleotide in the clinic following the pireverson for chronic hepatitis B. '990 is an siRNA therapeutic designed to selectively target HSD17B13 reducing its expression and slowing or halting disease progression in ALD and MASH. In Phase I, it has demonstrated robust target knockdown and encouraging reduction in markers of liver injury. Next slide, please. We've now started the HORIZON Phase II study in MASH patients with advanced !brosis, and we're initiating a Phase II trial in patients with ALD called STARLIGHT.

GSK'990 is another fantastic example of our tech strategy in action, building out our oligonucleotide platform. The program has also been strongly informed by genetics, and we've used single-cell imaging to con!rm the expression of the target in liver cells, an approach which roughly triples the chance of a target reaching Phase III. Our clinical development program for -990 is being informed by biomarkers. So we're able to predict the patients most likely to bene!t from treatment. We've identi!ed several well-established and noninvasive tests that have excellent predictive value for clinical outcomes.

Next slide, please. Looking beyond -990, we see further opportunities in liver disease, enabled by our growing expertise in this space and enhanced bio collaboration with Wade Therapeutics. We're evaluating 2 additional targets, which complement GSK'990. These both have strong genetic association with a range of steatotic liver diseases and oligonucleotide tools have shown promising early activity in validation studies. While this works on an early stage, we see future potential for an emerging portfolio of complementary mechanisms of action informed by genetics to reach a broader group of patients and address the signi!cant burden across steatotic liver disease.

Next slide, please. So we expect a growing pipeline in respiratory focused on COPD and an exciting evolution of innovation in new areas, just a few of which we've covered today. These exemplify our approach to science and technology. We anticipate a #ow of data readouts and potential approvals for the remainder of the decade. In the near term, this encompasses approvals in a range of indications for depemokimab, the !rst long-acting biologic to reduce severe asthma attacks leading to hospitalizations by over 70% [indiscernible] in COPD.

New assets in COPD and liver disease o\$er signi!cant growth opportunity in the longer term, amongst other early-stage programs focused on !brosis. Next slide, please. So to !nish, we're making strong progress in R&D with 67 pipeline assets, 18 of which are in late stage. Our deepening expertise in immune science, the use of advanced technologies and worldclass strategic partnerships is leading to a di\$erentiated and exciting early-stage pipeline that will deliver growth to and beyond 2031. With strong momentum in oncology, a clear path

to extend our leadership in respiratory and exciting new prospects in immunology, our pipeline o\$ers signi!cant growth opportunities and high potential medicines.

As a result, we're increasing and prioritizing investments in both oncology and respiratory and immunology while continuing to pursue major pipeline opportunities in infectious diseases and HIV. We're very con!dent in achieving our prospects for growth and global impact on health. Today, I shared just a few examples and look forward to sharing more in due course. Looking forward, we have multiple data and regulatory catalysts to come, including 5 regulatory approvals next year and an increasing #ow of innovation throughout the remainder of the decade. With that, we'll now open for questions.

Thank you.

#### Mick Readey Executive

Thanks, Tony, and we'll now begin the Q&A portion of the call. [Operator Instructions] Our !rst question goes to James Gordon.

#### James Gordon Analyst

James Gordon, JPMorgan. Two questions, please. One was AI machine learning. So I think - if I understand it right, that you're going to use that sort of work out cuto\$ for your ADCs. So can you help us out in terms of how big would the eligible treatment populations be for these 2 ADCs, so '227 and '584 based on the biomarkers that you envisage using?

And what are the actual biomarkers that you'll be looking at? Is this a bit like UCS that we've seen for data in terms of how you assess what's being expressed? So if you could elaborate on that, please? How it works and what the eligible populations might be? And then the other one is just a clari!cation on the biologics for COPD.

So is the idea that the IL-5, TSP and IL-33, they're all going to be 6 monthly? Or do you need to see on that?

# Tony Wood Executive

James, let me start just with the ADC point. I'll make a broad point and then Hesham, perhaps hand over to you in terms of how we're thinking about bringing on some additional precision to the ADC landscape and then Kaivan over to you for pharmacokinetics for the COPD assets. James, the !rst thing I'll stress is that clearly one of the attractive features of both the B7-H3 and B7-H4 ADCs is that they are broadly expressed across various treatment populations. And so what we're interested in, and we're not going to give away a great deal at this point, as I'm sure you'll understand, are other features associated with the cancer that might indicate a greater or lesser response. And Hesham, I might just hand over to you to add a little bit to that.

# Hesham Abdullah Executive

Yes. No, absolutely. I mean, James, I think one of the things that we've learned certainly with antibody drug conjugates and the targets that they actually selectively go after is the target expression levels are not the only thing that really matters. So I think the !eld has moved

beyond that. So certainly looking at not only target expression, its natural distribution, its density and how the ADC is actually being processed within the cell are really critical factors.

And so as part of our translational strategy, these are elements and variables that we will prosecute and look at. I'd like to maybe just call your attention to the fact that at least based on the data that's currently available to us in the Phase I study that's being conducted in China, both for B7-H3 and B7-H4, we're seeing data that says that there's clinical activity across a broad array of tumors, irrespective of biomarker or at least target expression at this point in time. So we're going to learn more, and we certainly have already initiated our own development program. And we have a translational strategy set in place that helps us even go after bigger treatment e\$ects potentially that could be de!ned through this biomarker strategy. But as of now, the data tells us that the drugs are active across both high and low expression levels.

# Tony Wood Executive

Thank you, Hesham. And moving over then into COPD and PK. Kaivan, perhaps you might just give James and everyone listening a sense of where we are on the quali!cation of the pharmacokinetics for the 3 assets.

#### Kaivan Khavandi Executive

Yes. Thank you. So for depemokimab, of course, the pro!le has been established in the TSLP studies as a 6-monthly administration. For the anti-TSLP, the data that we had at deal signing from exposure in China and Australian participants demonstrated through modeling con!dence that, that will also be amenable to a twice-yearly dosing regimen. We are taking that into Phase II study in asthma, which we've just had IND con!rmation was safe to proceed in Q1 next year for dose selection.

And then for the anti-IL-33 program that's currently in a Phase Ia/b. We're moving into patient cohorts next year, where we're going to do repeat dosing. The !rst date will be after 12 weeks, and then we're going to follow up after the second dose for over 6 months to con!rm whether it's going to be a 3 or 6 monthly dosing regimen, both of which would meaningfully di\$erentiate versus other anti-IL-33 molecules.

## Mick Readey Executive

Next question is from Simon Baker.

## Simon Baker Analyst

Three quick questions, if I may. Just starting o\$ with BLENREP. At ASH a week or 2 back, it was showing that the dose reductions related to ocular tox led to a fairly rapid resolution and did not impact e"cacy. So in light of that, I just wondered if you could give us the feedback you've had from physicians on their enthusiasm for using BLENREP and their comfort with the side e\$ect? I kind of get the sense that physicians are probably a bit more relaxed than we are.

So any color on that would be handy. And then on -227 and B7-H3, there was a poster at San Antonio last week, showing B7-H3 being targeted through CAR T. You didn't mention CAR-T

today. So I just wonder if you could give us your thoughts on that as a modality for GSK? And then !nally, moving on to the long-acting IL-33.

There was work published earlier in the year showing potential utility in cystic !brosis. I wonder how interesting that is to you given it's an obvious adjacency to your respiratory work and an adjacency, which has orphan drug potential?

## Tony Wood Executive

Yes. Thanks, Simon. Let me see if I can get through all 3. Please remind me if I miss any component of it. Why don't we start, Hesham, with you, just quickly on the physician feedback with regards to BLENREP and the emerging pro!le over e"cacy versus safety e\$ects.

I might then come back and just make a quick comment on CAR-T before we hand over to Kaivan. So over to you, Hesham.

### Hesham Abdullah Executive

Yes. Thank you, Tony. I mean, it's certainly the feedback that we've been getting from physicians that have had experience with BLENREP is it's relatively easy to administer, especially given the context around, of course, the fact that we have 70% of patients, multiple myeloma patients that are sitting in the community. So the ability to be able to administer this on an outpatient basis, the ability to not require hospitalization is really important and critical for them and the fact that it can be given immediately. So there's no need to wait for certainly patients going through apheresis, lymphodepletion or of course, for them to really have to experience some of the side e\$ects that are associated with other therapeutic modalities like CAR-Ts or T-cell engagers.

Now again, it's a familiarity that physicians have to acquire, of course, just as is the case, of course, with any new class of drugs that emerges in oncology. I think you think back to, let's say, for example, checkpoint inhibitors, right? And this was a class of agents that initially when it came on to the scene in 2014 was associated with these immune-mediated adverse events, not everyone was very familiar with them. But once everyone realized that they were in#ammatory nature can be managed by steroids, and that they can certainly interrupt the dosing until they resolve and then resume it afterwards. You look at it now, at least, no one's really talking about them at this point in time when they're thinking about checkpoints.

The same holds true here in terms of starting out with the 2.5-milligram dose to induce the depth of response, and we've seen that, whether it be the MRD negativity, whether it be the duration of response. And then basically, over time, increase the dose and extend the schedule. You saw the data at ASH when the dosing intervals were extended to every 8 or 12 weeks, the response was sustained and maintained. And you saw that the ocular toxicity in terms of its incidence and discontinuations resulting from it decreased over time. So I think that's the message and the feedback that we're getting from the physicians as well is their ability to e\$ectively use the dose reductions, the dose interruptions help them to manage the ocular side e\$ects quite well.

# Tony Wood Executive

And look, Luke, I'll give you a chance to speak to there's some feature on developing and understanding of managing the treatment population as well. But before I go there, Simon, just quickly on the CAR-T question. Obviously, whether it's ADCs, CAR-T or TCs, what we're doing is exploiting the same antigen proposition, but bringing a di\$erent feature associated with the cytotoxic component. One is, the things that we !nd particularly exciting about the B7-H3 and B7-H4 ADCs is that we're able to deploy them to cancers for which we already know topoisomerase inhibitors are e\$ective. So we feel that given that background, the ADC approach is all that is likely to bring the most e\$ective therapeutic index and in the dose session stressed earlier in the comparison, the more straightforward process for treatment.

With that, Luke, I don't know if there's anything you want to add just on the question over. Yes, please.

#### Luke Miels Executive

Yes. I think, Simon, I completely agree with the direction taken practicing hematologist, oncologists -- I mean they are empirical by nature. And I think -- I mean, !rstly, the overall survival, the pro!le that we've got in DREAMM-7 and DREAMM-8, I think, essentially resets the discussion in the minds of many physicians. And the other thing is, and Hesham, correct me if I'm wrong, if you look at the percentage time that a patient actually experiences blurred vision or ocular events, it's a single-digit percentage of the total time they're on the drug. So it's not a sort of ongoing durable disturbance, blurred vision, et cetera.

It's a relatively con!ned point of time and as Hesham has said, it's reversible. I think the other thing is if you just print out the PI, the safety pro!le of CAR-T, where you've got all sorts of novel things, Parkinsonism, excess early mortality, unusual and partly irreversible AEs with CAR-T. So you've got excellent e"cacy, but they are sophisticated and di"cult to use, a physician said, in the community, that's just practically not accessible. And if you look at the biospeci!cs, I mean we're really getting a sense of the pro!le there. I mean the MajesTEC-2 data, okay, there was a di\$erence in terms of the rate of infusion, but that had 22% infusion death, right?

I mean other data earlier I think neutropenia is around 1/3 of patients got Grade 3. So I just look at this and I try to be as objective as we can and talking to experts using the drug, in that context, BLENREP is looking increasingly like an accessible product. And as Tony said, we're going to do a lot of work to manage that interface between the optometrists and the ophthalmologists. We need to see what the REMS that we get from the FDA is. But the bene!t of the product is -- the bene!t risk of the product has dramatically changed.

Now that we've got overall survival against the CD38 regimen.

### Tony Wood Executive

Thanks, Luke. Simon, will move over now and deal with IL-33 in cystic !brosis. I mean, I guess, Kaivan, we might talk more broadly about obstructive lung disease and what we see in the opportunities from the phenotypes there.

## Kaivan Khavandi Executive

Yes, absolutely. So I think in upstream schematics, you often see TSLP and IL-33 occupying the same space together as an upstream alignments, but actually, Tony presented some of the multiomic approaches that we're able to prosecute. And what we see is that whilst TSLP-413 and 5 map together, you get a clear bifurcation where IL-33 is clearly moving towards more TH1/TH17 pathways and therefore maps more closely to this neutrophilic COPD obstructive lung phenotype. We're actively exploring the possibility of evaluating IL-33 in non-CF bronchiectasis, and we're fully enabled to start that study next year if we wish. And of course, consideration can be made whether we include CF patients within that same trial design.

### Mick Readey Executive

Our next question will come from Seamus Fernandez.

# Zachary Dunn Analyst

This is Zach Dunn. I am on for Seamus Fernandez. So just to start o\$ with it. Looks like you're not pursuing combination strategies with IL-5. Can you explain the rationale behind this?

And then shifting over to MASH afterwards. Do you believe that your pivotal trials will require a biopsy? And more broadly speaking, what do you see for the opportunity in MASH as this market evolves. And then, third and last question, just curious, Tony, what do you think is the most underappreciated asset that you presented on today?

# Tony Wood Executive

Great. Thanks for the questions. Kaivan I'll hand straight over to you on the IL-5 and MASH questions. Obviously, if you can include the context of the sort of temporal nature of the evaluation of all of that. And then at least in the context of MASH address the biochemical components in post GLP-1.

And I will, in the meantime, take a look amongst all of these exciting assets and !gure out which one I like the most.

# Kaivan Khavandi Executive

Yes. So Tony presented earlier, a genetic risk score that we've created for IL-33 and TSLP and you saw there that the combination of activity results in additivity for these pathways. I just described some convergence of TSLP-413 and 5. Therefore, it's unlikely that we pursue a TSLP anti-IL-5 combination. However, there is a rationale for an anti-IL-33, anti-IL-5 combination strategy, and that's something that we would consider.

Moving on to MASH. We're conscious that there's a number of mechanisms that are exploring antisteatotic mechanisms in MASH. The unique di\$erentiated value of HSD17B13 is that we've got really quite exquisite human causal data from genetics that we presented showing that this pathway is most relevant in advanced MASH and !brosis and cirrhotic segments of disease. And those are the segments of the natural history that are going to be underserved by emerging standard of care. And what we see is that we're able to pay that genetic

con!dence with a cell level understanding of what the pathway can do to ballooning of hepatocytes, in#ammation and !brosis.

And so the population we're studying in the Phase IIb horizon trial is MASH patients with F3 !brosis -- F3 stage disease, and we also include an F4 exploratory population in that study. We will be biopsying of course, because we need to demonstrate either MASH resolution or improvements in !brosis. And given that therapeutic hypothesis, that's particularly relevant to alcohol-related liver disease where you see a very fast progression through to !brotic phenotypes. And where, of course, there's currently no pharmacological treatments for what is the #1 cause of liver transplantation in the U.S.

#### Tony Wood Executive

Yes. in answering your question with regards to which ones I'm most excited about. I think the !rst point I would make is the one I did right at the beginning of the presentation, these are all areas in which we are investing in because we see the potential for signi!cant growth driven by a combination of the medical need and indeed the underpinning signs. So if you don't mind, I'm going to answer it with 2 examples because I think they illustrate nicely the sort of features that science and programs which are now emerging from our research activities into clinical from our BD focus are going to carry for the future. Obviously, B7-H3 represents a very exciting opportunity.

Hesham laid out the broader context of that. But what we have there is through form studies, the opportunity to look for early e"cacy, the con!dence that the topo inhibitor brings and then a range of additional either genotyping or phenotyping approaches that will, in time, begin to disclose, which will give us a sense of who's going to be the most likely patients to respond even within the breadth of the antigen expression. So very excited about that one given both the opportunity and the link back as well to the translational science that we're building within Hesham's group under Tony Ying, for example. With regards to Kaivan's world, for me, HSD17B13 is a really great example of something that carries tremendously strong genetic credentials. You can think about this one as being PCSK9 like, but what we have on top of it, and we didn't have time to go into detail, is single-cell work through spatial transcriptomics that then links the transcripts that are expressed as a consequence of that genotype against the cell types, ballooning hepatocytes and indeed, looks at it relative to alcohol as, for example, a given in.

So we're reaching a degree of precision and understanding target modulation and the patients who are most likely to bene!t from these agents in both oncology and in NASH, which is going to characterize the approach that we take in the future. And so those 2 programs that -- they for me, represent probably the pinnacle of what we've presented today, but it's important to stress that this is not a portfolio against which I'm making relative choices.

## Mick Readey Executive

Our next question comes from Emmanuel Papadakis.

### Emmanuel Papadakis Analyst

So a few, if I may, please. Firstly, on oncology, the pipeline. So if I recall correctly, BLENREP was discovered internally, but you've now largely have to resort to in-licensing the next wave of assets from Chinese companies, both ADC, I mean, even beyond B7 molecules we talked about today, Crovalimab, Iscalimab, they all came from outside of the company. So what's been the hold up on building upon the early success of BLENREP, either within ADC or beyond oncology in last year? That's question number one.

Question number two, -990 and MASH. Thank you for the evidence on genetic validation. What about translational rationale, so what does the B30 protein actually do, if I missed it, you didn't tell us? What would suggest it should deliver a functional bene!t when modulated and do any better than previously promising genetic targets? You've outlined them, thinking things like CCL17.

And then a very quick one on IL-33. Is that actually a totally new molecule? Or is it same backbone as a molecule where you discontinued several years ago for asthma?

## Tony Wood Executive

Okay, Emmanuel, thank you. I will, again, brief answers and then perhaps -- in fact, actually, in this case, I'll hand over to you, Hesham, to talk about the internal build in oncology discovery. I would say, !rst of all, this is not a re#ection of a lack of internal e\$ort, but rather a re#ection of a deliberate strategy in which we recognize that by focusing on the sort of technologies that we've just been describing that enable us to make better choices of targets and patients and combinations, then our e\$orts are more e\$ectively deployed there. It gives us an insight into -- but as you -- I'm sure are fully aware, it's a very active potential BD landscape. Now sitting behind that, of course, we are continuing to develop internal programs.

And follow-ons, for example, in the Poltheta arena that Hesham, you might just brie#y mentioned. And then I'll take up the genetics and translational rationale in a moment. But why don't you just mention a little bit about the internal earlier portfolio, Hesham.

# Hesham Abdullah Executive

No, I'm happy to. And Emmanuel, thank you very much for the question. I'll start !rst by saying even I'd probably say industry leaders in oncology have relied on certainly in-licensing to build parts and complement parts of their portfolio, including certainly other organizations that have, for example, a leading PD-1 inhibitor as well, right? So I think we just have to keep that in mind. So the ability to have the right mixture and balance between business development, but also in-house research and development activities is really important and critical.

And I think with that in mind, I think, Emmanuel, you highlighted, of course, BLENREP was developed internally. We've complemented that now with B7-H3, B7-H4. And then, of course, the recent deal that we're doing an option deal that we're doing with Duality on another ADC with another validated linker payload technology for a target that's directed towards gastrointestinal tumors. With that in mind, in parallel, we've been developing an internal linker payload platform as well. And you'll be hearing more about this over the next 12 to 18 months as you see the !rst asset from that platform come into the clinic.

So that's one. Two. We do have T-cell engagers. And we actually have gotten access to them and are in the process of developing both bispeci!c and trispeci!c T-cell engagers that will be applied across prioritized tumor types and areas, whether it be in solid tumors or heme malignancies for that matter.

And then three, what I would highlight, of course, to Tony's point, we're continuing to look at small molecules as a means of synergy and as combination partners for some of our assets, including antibody drug conjugates. I think one area to highlight, of course, is DNA damage response and the potential for that, of course, to synergize with the topoisomerase warheads in our ADCs. The Poltheta program is one example of that. It's currently in the clinic and being explored in combination with niraparib across gynecologic malignancies and breast cancer as well. But you could imagine that it could be certainly a key combination partner for antibody drug conjugates moving forward, along, of course, with dostarlimab, no doubt.

So we found really a good balance between giving time for us to be focused and selecting the right technology platforms within our research portfolio, but then complementing that with clinical stage assets that we can certainly get access to through business development.

### Tony Wood Executive

Yes. And just to reiterate then, of course, not unusual for late-stage clinical pipelines to come at least 50% from BD related activities and a deliberate choice on our behalf to focus our early-stage work on technologies, which will give us a better opportunity to make those selections based on an understanding of the patient landscape and potential combinations, coupled with very focused internal work in areas where we already have a clinical lead that informs discovery programs. As far as moving on to the other 2 questions are concerned, let's do the oligo program !rst. Kaivan, you can add a little bit more to this but one of the big advantages of oligonucleotides is that we don't need to understand fully the biology associated with the target. And I'm sure you're probably aware that for HSD17B13, actually, that's still remains to be fully illuminated.

But the key advantage we get from oligonucleotides once we understand the direction of the factors, the e\$ect is one can recapitulate the phenotype simply by addressing the target at a message level. As far as IL-33 is concerned, it is the same molecule that we had earlier, it carries some half-life extension technology, and there was no basis given the pro!le that we accrued of the molecule to want to search for an alternative. But Kaivan, anything else you'd like to add on HSD17?

# Kaivan Khavandi Executive

Yes. So I think whilst the mechanism is not fully identi!ed, what we do understand is that it's able to target the lipid part scores that sits on the surface of hepatocytes. And I brie#y described some spatial transcriptomic work that we have done in primary human hepatocytes that shows that targeting that pathway reduces ballooning, which is the most powerful agnostic cell phenotype that is linked to outcomes. And so that really represents quite distinct pathway from any other mechanism to target in#ammation and !brosis in those advanced stages of disease.

### Mick Readey Executive

Our next question will come from Peter Welford.

### Peter Welford Analyst

Apologies if this has been asked. I joined a bit late. So !rstly, just on Jemperli, I think you mentioned for ASO1 and ASO2, but I may have missed this. Was it 2026 and '27 you said for the readouts for that? Was it '27 and '28?

And I guess curious, given your recent breakthrough therapy designation you've got for rectal. Is this possible to good to !le based on just one of those readouts? Or is it even possible based on an interim read before then, do you think, to potentially consider discussions with the FDA? Just moving on then to the respiratory portfolio. For depemokimab, presumably we should be assuming to COPD that there are 2 Phase IIIs planned, and you can't possibly piggyback on any of the Nucala data for depemokimab at all.

But I just wanted to con!rm that. And then just for IL-33, I guess, 2 things here. One is when you talk about the combination, I'm right to understand that is 2 separate drugs. You're not considering a bispeci!c or any single molecule that hit both of those targets? And if you looked at all of the biologic rationale when you think about the Phase III for IL-33, are you targeting the ligands?

And if so, have you potentially looked at whether or not you should be targeting a prior smokers population?

#### Tony Wood Executive

All right. Thank you, Peter. Let me start, Hesham, with just time lines for the Jemperli program and the clinical strategy for rectal, I will hand straight over to you on that one.

## Hesham Abdullah Executive

Thank you, Tony. And I think let me start o\$ by !rst by just reiterating the data, of course, which is extremely promising, great news for patients that was presented at ASCO 2024. And speci!cally 42 patients with locally advanced dMMR, MSI, high rectal cancer, all had a clinical complete response, 100% clinical complete response, which is quite, of course, unheard of, but just shows how exquisite the science is here in terms of the sensitivity of these patients to checkpoint inhibition. With that in mind, of course, we designed these ASO1 and ASO2 study. The ASO1 study, of course, is a Phase II study.

It's a single-arm trial in locally advanced dMMR MSI high rectal patients. And then ASO2, of course, is a Phase III study in neoadjuvant adjuvant locally advanced colorectal cancer patients. So the readout for ASO1 anticipated in 2027, and then the same holds true for ASO2. So both of them actually theater our plan for 2027. But bear in mind, of course, that if ASO1 data is available early we will plan on, of course, being able to !le o\$ of that.

So both studies are not necessarily required to make a !ling, only one of them. And if you may recall, of course, we did have a discussion at an ADCOM, at an Oncology Drug Advisory Committee meeting in 2023, whereby we got agreement on the single-arm design of ASO1

as well.

#### Tony Wood Executive

Thank you, Hesham. And just moving over then to the questions on COPD where we might start actually, obviously, the standard will be 2 Phase III clinical studies, but it might be worthwhile commenting on what we've learned or how we'll be designing that relative to the lessons from Nucala K at a high level, bearing in mind that we were yet to disclose those data that will come in the second -- in the !rst half of next year in May. And then as far as IL-33 is concerned, perhaps you might just talk a little bit about what we see with regards to the behavior in COPD for the nonsmoker and ex-smoker populations and our view of whether or not they are distinguished phenotypes for the future. I might just say one thing with regards to targeting the ligand versus the receptor. Obviously, you'll appreciate from our experience with IL-5 that one can make arguments on both sides of that equation.

Typically, though, when you're targeting the receptor is often the case that you see higher turnover of those molecules and given that we are focused on a long-acting portfolio that was a factor in our decision. Although the total pharmacology associated with each side of that axis obviously remains to be determined and we will continue to examine the phenotypes associated with the diseases in question as the development program, we saw proceed. But Kaivan, over to you just in terms of high-level lessons thinking about the depe COPD program.

#### Kaivan Khavandi Executive

Yes. So just to reemphasize, given that depemokimab, of course, is a di\$erent molecule, the assumption would be that we would have to replicate pivotal studies. But what we're exploring is whether we could use one of those studies to evaluate populations that could provide a di\$erentiated label, one area that we're exploring is an earlier disease and predicting those at risk who have either had no exacerbations or one exacerbation in the year prior to enrollments. Obviously, with respect to the variables that we identi!ed at the MATINEE study with Nucala whilst say is that if you have a like-for-like comparison with tier mechanisms of COPD were very competitive. There are variables that we'll take through as learnings for the design of the Phase III for depemokimab.

As regards to anti-IL-33. I think what we -- what you would have seen is varied data across, again, peer companies that may be targeting receptor ligand and then reaction, I'd say, to relatively small empirical data sets for subgroups in Phase II. What you saw in Tony's presentation is that we're taking a much more data-driven approach and using these proteomic and multiomic and genetic approaches to be able to evaluate explainability rather than reacting to small data sets. In our Phase I study of anti-IL-33 we're stratifying base making, and we're doing a number of mechanistic assessments within that, including our inhouse clinical units out of Brooks and Cambridge. So I think that we're going to be making data-driven decisions that might be based on more mechanistic rationale than just reacting to small subgroups in clinical studies.

#### Tony Wood Executive

Thanks, Kaivan. I wonder, Luke, if it's worthwhile giving you an opportunity just to talk about

how we see the long-acting portfolio in lung disease at this stage?

#### Luke Miels Executive

Thanks, Tony. I mean, I think there's a degree of natural synergy, of course, and having others validate using short-acting programs, the target as we've done ourselves, obviously, with mepolizumab, Nucala, with depemokimab, which attempted to do that with TSLP. And if we could replicate that with the IL-33 program, yes, I mean, there is also the synergy, of course, in terms of EOS and T2 in#ammation positioning the IL-5s and 33s in -- obviously, in people who are former smokers and then stratifying them based on their eosinophil level. So yes, I mean, I think the market research that we have is that there's a potential to disrupt the relatively low penetration of biologics in respiratory disease. I mean, it's still below 30%, which I think is somewhat disappointing considering the pro!le of these assets.

And so shifting into products, which can be administered in the U.S. context by physicians in o"ce obviously, has a lot of bene!ts in terms of just barriers to injection, compliance and other parameters, which are favorable to that method of adoption for physicians and also the patients. So the market research is very encouraging. We now need to get out there. And I think the pro!le of depemokimab is very, very competitive in what we're seeing so far.

#### Mick Readey Executive

Our next question comes from Graham Parry.

### Graham Parry Analyst

A few on respirator actually. So depemokimab, the Phase III data, I think you showed 74% reduction in exacerbations leading to hospitalization, which looks like the best comparator to the existing data. So when you go out with that one, this is a question for Luke, do you feel that is a best-in-class or is it just a convenience argument you'll be looking to commercialize that on? And then are you looking to sort of match existing COPD data that we've seen in the COPD study? Or do you think, again, that could be a best-in-class asset there?

And are you looking at a broad population in COPD, so across all biomarker subtypes? And then on the IL-33, just wondering if you have any data to say whether it works on both oxidized and reduced forms of IL-33? Does it prevent oxidation of IL-33? So any impact on RAGE EGFR pathway, which is one of the di\$erentiating points, one of your peers points out for their products? And then on your combo strategy on IL-33 TSLP, is it co-formulation or is it actually just the safety and e"cacy data in combination, that's the rate-limiting step in taking that any further forward?

#### Tony Wood Executive

Okay. Thanks, Graham. Let's make a start with the data in Phase III. And I presume then Graham is a bridge from asthma into COPD, and it might be worthwhile just emphasizing Kaivan before I give you a chance to speak to that. As I've said on a number of occasions, what we see there is more the advantage associated with the breadth of coverage and across di\$erent phenotypes.

When one looks at comparable populations, the e"cacy is probably slightly lower than that

for dupi, for example, in the high eosinophilic bronchitic population, but you'll see when we disclose the data next year that we have advantage with breadth of coverage. I'll come back to Luke at the end to talk about the advantage for best-in-class for the longer acting agent mix, so please remind me to go there. I want -- before we go into Kaivan just make a point on the co-formulations versus bispeci!cs because I forgot to answer Peter's question in that context. And at the moment, we very much see this as a matter of, !rst of all, establishing a clear understanding and proposition for the contribution of components both in terms of appropriate doses and the most responsive patient populations. And taking that then into coformulation will obviously depend on understanding just exactly what the doses are when really can't make a start on that until you have a solid grasp of that.

And in terms of bispeci!cs, look, we've evaluated these as potential areas. They always bring the challenge of how one gets the dose proposition accurate on both of the arms. And so we prefer at the moment to take a more optimized approach, particularly in an area where it may be the di\$erent patient subgroups are more responsive to one pharmacology versus another. So Kaivan, you might want to add a little bit more just in terms of COPD and the comment on the oxidized IL-33 pathway.

### Kaivan Khavandi Executive

Yes, sure. So I think you hit the main point, Tony, that the MATINEE study excluded patients with chronic bronchitis and those with emphysema. If you look at the group with chronic bronchitis, again, you'll see this data in detail next year. It's competitive and comparable with the best data that's available for other mechanisms. But really, the di\$erentiator here is that we recruited these patients with severe distal airway disease and emphysema.

And we're seeing e"cacy in that population. Those are patients who, of course, have the worst outcomes. And importantly, of note in the recent gold guidelines there was a stipulation for 413 being recommended for those with chronic bronchitis. Of course, the data that were generated for Nucala wouldn't have that same restriction in terms of societal guidelines. But for IL-33, again, I think I touched on it earlier that some of the -- and perhaps overly simpli!ed arguments around smoking, oxidization and what we're seeing clinically might require a more nuanced description.

Our molecule binds to IL-33 in its reduced form, but it also, of course, and, therefore, blocks the ST2 signaling pathway and the direct pro-in#ammatory e\$ects of the cytokine. We're seeing the same data preclinically that we do have the ability to modulate oxidized forms and therefore, EGFR RAGE. We say even with our own data, there's caveats around those translational models and whether you're having the correct expression of EGFR RAGE in the relevant airway in tissue. So in summary, I think that we've got the correct molecule with respect to not being limited to a single receptor binding the ligand and also, of course, most importantly, in a population that's got multi morbidities the dosing administration, which is, I think, very clinically important to COPD.

## Tony Wood Executive

Yes. Of course, Graham, you will recall that, for example, RAGE is something that has been actively targeted in the past without a great deal of success as well. So very much part of the emerging victory we have an understanding the precision of the disease phenotypes. Why don't I hand over to Luke, any comment you'd like to add in terms of how we see the depe positioning.

## Luke Miels Executive

Yes. I mean I think, Graham, I mean, if you look at the pools data of 52 weeks, it's about 54% of memory, which is in the range of Nucala. It's very consistent, which is no surprise, considering the heritage. If you then look at that with FASENRA, it's very much in the range at their 41 week data in the 300 EOS population. I think Dupixent have been a little bit more creative in terms of how they cut the data in terms of eosinophil level and 24 versus 52 week.

But our feedback through market research is it seemed to be comparable. And I mean, the fact is it's exactly as you say, the main driver is the frequency of administration. But also what we've learned from Nucala is once you take these drugs into a real-world setting. We know there's a huge drop-o\$ of biologics once patients get after about 6 months of treatment. It's a big drop o\$, and there's a lot more control, of course, in a medical bene!t physicianadministered context where you potentially lock in 6 months of compliance through a single shot and you look at 2 shots a year versus dupilumab -- I mean, Dupixent at 26 shots.

So yes, I think, !rstly, short term, it's comparable. And it will be short burden. Secondly, over time, as we do reward evidence and see patients how they operate actually in the wild, I think that we'll see the frequency of injection and the injection burden translate to e"cacy, but we need to do those studies. And we have a big program that's starting up to do that.

## Mick Readey Executive

Our next question comes from Jo Walton.

### Jo Walton Analyst

Excellent. I have 3 quick questions, and they [indiscernible] question. Can you talk a little bit more about biomarkers? Because you mentioned the numbers being important, but then you go on to say -- well, the other thing [indiscernible] how were we going to decide what the appropriate populations are? Are there going to be biomarkers?

Or does everyone have to have some [indiscernible] drug that you should try !rst? Secondly, to go back to Simon Baker's question about [indiscernible] radiotherapy because that seems to be #avor of the day? And then !nally, in your presentation to [indiscernible] that tripled your chances of getting a product to Phase III. I wonder if you could tell us a little bit more about that and how you've measured that? If you tripled your chances in getting things [indiscernible] quite a lot of products to get those sort of statistics out.

So just tell us a little bit more about why [indiscernible] doing it now or we'll be doing it in the next few years?

# Tony Wood Executive

Okay. Thanks, Jo. Look, we couldn't hear you very well. So I'm going to make my best attempt at directing the question. I think the !rst one was about biomarkers and how one really

navigates the journey of, !rst of all, identifying and then making them a practical proposition when you reach late-stage studies and patient selection.

And I might actually just begin, Hesham, I mean you could describe the journey we've been on in the context of dMMR positive cancer for Jemperli in both particularly, of course, in the endometrial setting. Because I think, Jo, that sort of illustrates the general path here that one starts in early translational studies with a range of hypotheses that are tested and then validated in later stage studies with di\$erent instruments, which are more amenable ultimately to the market setting. Hesham, you can make a quick comment on radiotherapy and our focus. Jo, essentially, we have an exciting portfolio in front of us with regards to the areas that I described and Hesham has answered questions on. And then we don't see radiotherapy is an area of interest for us at the moment.

And then let me just quickly deal with the comment on the improved survival in early Phase I studies from the single cell data. This is some work coming from Sarah Teichmann's lab and it's a broad assessment of the performance of industry portfolios with and without an ability to localize targets into expression individually very carefully characterized cell types. Mick, we can send Jo the reference, but that data very clearly identi!es an improval in survival in Phase I associated with targets that carry those characteristics. But let's go back !rst of all, Hesham perhaps you make a comment on biomarkers in the context of our oncology portfolio. And Kaivan, you might just describe the journey for IL-5 in the eosinophil as an example, important, how that might develop elsewhere as well.

So over to you, Hesham.

## Hesham Abdullah Executive

Yes. Thank you, Tony. And I think probably a really good example of that is, of course, the RUBY study and speci!cally looking at dostarlimab when it was combined with chemotherapy in !rst-line endometrial cancer. I think everyone is well aware, of course, that early on, we were really exploring 2 di\$erent hypotheses, right? The !rst is how the combined assessment of dostarlimab plus a platinum-based doublet chemotherapy regimen could have a treatment e\$ect relative to chemotherapy in the dMMR MSI high segment.

And we saw tremendous treatment e\$ect there right, in terms of the interaction between the biomarker and the combination e\$ect and then, of course, the outcome in patients, whether it be on progression-free survival or overall survival, quite dramatic treatment e\$ects. We didn't stop there as well, too. So we also looked at the combination in the intent-to-treat patient population, which basically included the remainder of the broader patient segments, so about 75% of patients, which are the MMRP or MSS patient segment as well, too. And we also saw a treatment e\$ect for PFS and OS. Now while not necessarily as dramatic as that seen in dMMR MSI high, it was clinically meaningful.

So I think, Jo, what we really have to do is really look at each tumor type and the patient segments that exist whether it be based on certainly molecular characterization of those patient segments, whether it be based on proteomic characterization of those patient segments and really ensure that we have di\$erent treatment options available and to better characterize the treatment e\$ect of di\$erent types of therapeutic modalities. I believe you

were referring to antibody drug conjugates in terms of how we would think about biomarker selection for them. And I think it wouldn't be necessarily any di\$erent. There may be certain patient segments that require combinatorial based approaches based on their biomarker status. There may be patient segments that require monotherapy based approaches.

There may be patient segments that are combinations with current or existing standard of care agents. And that is the way that we're thinking about and choosing to evaluate and assess biomarkers in terms of best tailoring treatment options for patients. And at the end of the day, we're in the era of precision medicine and certainly, oncology is leading the way there and hence, how we're trying to make sure that we provide options to patients. Now, just one point around the really ligands to Tony's point as well too. So we don't necessarily have any interest there.

I think the bottom line is for us as an organization, we're really focused on making sure that we impact 2.5 billion patients by the end of this decade, of course. And if you bear that in mind, I think what you're really thinking about is treatment options that are scalable and accessible, that is very important. And so when we think about the therapeutic modalities that we're introducing across our oncology portfolio, it is a priority for us that treatments are scalable and accessible. Some of the challenges that exist with radio ligands, whether it be manufacturing of the isotopes, whether it be the supply chain, whether it be the facilities that are required to potentially manage these isotopes in the radiation, it's a di"cult space to navigate. But it's important, of course, to continue to look at di\$erent treatment options that utilize di\$erent technologies for patients.

### Tony Wood Executive

Yes. And look, the only other thing I would add to that, Hesham, of course, is we have an advantage with the collaboration that we have with Tempus, which helped us understand across a broad range of tumors and molecular characteristics the feature in the early identi!cation of potential biomarkers. Let's just !nish with a quick comment on eosinophilia and on the T2 and adjacent populations, Kaivan just to help Jo really see, again, an example of how this has worked out in practice.

### Kaivan Khavandi Executive

So I'll describe [indiscernible] example. And if I may, a forward-looking view on how we're approaching this in the pipeline. So with Nucala, of course, using eosinophils as a surrogate for T2 high in#ammation, allowed for the correct patient selection and, of course, represented the !rst precision medicine approach in respiratory medicine. And even actually in COPD, metrics and [indiscernible] really didn't pave the way across the industry for that approach within COPD. So coming back to that broader point around genetics reducing attrition.

I think the key development at GSK is that we're now able to match genetic con!dence with what Tony described from Sarah Teichmann's work, which is the cell-speci!c con!dence. That's really important as it allows you to prosecute those questions in clinical developments. And if you think about the HSD17B13 program, we had genetic con!dence, but then we're able to match that with a cell phenotype and then an organ phenotype and a clinical phenotype. And so when we look at the alcohol-related liver disease study, we're looking at

digital pathology evaluated using machine learning, but then able to pair that with spatial transcriptomics to look in the clinic at what the treatment e\$ect is to the cell and then looking at other clinical measures such as FibroScan, which is able to predict outcomes and compensated, alcohol-related liver disease and MRL lastography. So you've got that continuum from genetics to sell to patients.

# Tony Wood Executive

And Jo, just to !nish o\$, of course, across that continuum as well an increasing hopefully, simpli!cation over time as we recognize the reality of treatment decisions that will be made in a more distributed sense in the future. Okay. I think hopefully, that answers your questions, Jo.

### Mick Readey Executive

Our next question comes from Rajan Sharma.

## Rajan Sharma Analyst

I've got 2 questions on the oncology ADCs actually. And Tony and I guess, Hesham as well, begin to get your take on the mechanistic rationale of part and top rise summaries, combinations and whether that's actually feasible from a safety perspective? And I guess, ultimately, the question is whether there's a combination potential with -584 and Zejula? And then the second one was just on B7-H3 and how you expect -227 compare with the other assets that are in development? And I guess, kind of the most advanced looks like it's Merck and Daiichi's assets.

So do you think there's an e"cacy or a tolerability advantage there?

# Tony Wood Executive

Yes. Great. Look, let me just quickly deal with the PARP-topo comment, Hesham, you can add any more detail in, and I'll leave you for the competitive positioning relative to Merck Daiichi, which is sort of simply placed in the context of combination opportunities and the focus within areas of our oncology portfolio, where we're building a presence.

Look on the PARP-topo combination, there is clearly a pathway overlap when you look at the mechanism of PARP inhibitors and topoisomerase, one might envisage potential synergies. But what we've seen from the PARP class in general is that, that type of e\$ect is occurring right at the top of the dose response and therefore, it introduces questions with regards to therapeutic index. It is an active area for us actually in terms of our detailed translational research going on in Hesham and Tony Ying's teams, but not something that we're necessarily actively pursuing as a foundational thesis in clinical evaluation at the moment. But Hesham over to you.

# Hesham Abdullah Executive

Thank you, Tony. Just to close the loop on that. I mean, we certainly look at, for example, what could be a second generation of DNA damage response, especially with our POLQ or Poltheta inhibitor as well, too. Better therapeutic index more well tolerated and potentially

lends itself to being a more combinable agent as well, too, and especially with an antibody drug conjugate. So something to consider, evaluate especially as we think about development of these ADCs across certain patient segments, including those patients that could have homologous recombination de!cient pro!les as well too.

With that in mind, the question really around the B7-H3 ADC and its competitiveness relative to other assets or compounds that are currently also in the clinic.

I would !rst and foremost of course, just draw your attention to the fact that there was data that was previously presented from the Phase I study conducted in China that showed broad, I would say, clinical activity across a number of di\$erent tumor types. And you may have seen, of course, that certain health authorities have recognized that. So we were granted a breakthrough therapy designation by the FDA based on the small cell lung cancer data that was presented at the World Lung Cancer Conference in September of 2024. And then just yesterday, we were also granted a prime designation in Europe again for the same patient population as well. So I think the development program is progressing well.

I think for us combinations are really going to play a key part in this. And of course, dostarlimab, which is an asset that's been well benchmarked to the leading PD-1 in the class gives us con!dence in our ability to have combinations with checkpoint across di\$erent tumor types. But then also, like I said, with small molecules potentially lending themselves as being key combination partners. We're also exploring potential external clinical collaborations. We know that the current clinical landscape is continuing to evolve and there may be additional assets that we may want to combine the B7-H3 ADC with, stay tuned on that front.

And then, of course, the tumor types that we're moving into. And you've seen the expression pro!les. Some of these tumor types, we have certainly key capabilities and strengthen. So they lend us -- they lend themselves quite well in terms of the infrastructure that we've developed there. And then, of course, some of the biomarker work that we currently have ongoing, of course, which we think will be very unique but also provide hopefully over time a level of di\$erentiation as we think of our development strategy moving forward.

### Tony Wood Executive

Yes. And look, at the highest level, the competitive environment is something, obviously, that I am very tuned to together with Hesham and Luke and will be a feature of capital allocation to ensure that we're moving forward in a competitive frame. I think we're on the last question now.

#### Mick Readey Executive

That's right. Our last question today comes from Richard Parkes.

## Richard Parkes Analyst

Yes, just 3 quick ones, hopefully. On B7-H3, and excuse me if I missed this because I dropped the line for a while. But can you just -- you're talking about !rst pivotal study in Q4 next year. So is that going to be small cell lung cancer? And can you give us a view on how that clinical

#### design is likely to look?

And will you have biomarkers integrated into that clinical study. So I'm just kind of looking for visibility on what that !rst Phase III program looks like. Then on cobolimab, which I think is down as 2026 is not really been talked about. So is that -- should we just see that as a high risk asset? Or are you still very con!dent about that readout?

And then !nally, on BLENREP, can you just help me understand how the FDA might deal with the likely dosing recommendations for physicians in the prescribing label? I'm just wondering how that algorithm or how they'll describe how physicians should conduct kind of dosing? If you could help, that would be really helpful.

## Tony Wood Executive

Yes, super. So Hesham these are all come to you, I guess. In terms of small cell lung cancer, obviously, we're not going to disclose the details of our clinical programs, but perhaps Hesham you can give some broad line guidance and similarly for COSTSAR, what I would say for COSTAR is obviously, the second line setting is tough, and we very much view this as an opportunity of looking at Jemperli in that setting as well. And again, Hesham, you might just describe a little bit about how we're seeing that playing out and indeed the features associated with the study. And then lastly, a brief comment on the prescription proposition.

Obviously, we're very early on with regards to label conversations. So broad considerations there. Hesham?

#### Hesham Abdullah Executive

Yes. No, thank you, Tony. And I'll talk at !rst will be B7-H3 and I'll just say we have more than, I'd probably say, one shot on goal to start a pivotal study at the end of 2025. To Tony's point, unfortunately, we can't necessarily disclose which tumor type. But what I can tell you is there's more than one shot on goal.

And so there could be one, possibly 2. So stay tuned for that to happen in 2025.

The second really around cobolimab and I believe probably, Richard, you're referring to the COSTAR study speci!cally. And this is actually a Phase II/III trial that we had initiated a few years ago in second-line non-small cell lung cancer post PD-1 post chemotherapy. So with that in mind, what we do know, and this is something that we actually had communicated back in September of 2022, is that the study actually had -- was actually gated by certain criteria to move from Phase II into Phase III. We know that those criteria when the IDMC, which is an independent body, looked at the -- at this data, they basically recommended that both investigational arms in the study actually get expanded and move into Phase III. The 2 investigational arms in the study, of course, are the triplet of cobolimab, dostarlimab and docetaxel and then the other, of course, to Tony's point, which is dostarlimab plus docetaxel and of course, the control arm is the docetaxel.

We're just awaiting, of course, now the overall survival data readout. This is an event driven trial. So bear in mind that time lines can shift, they can shift upwards. They can shift backwards depending on how fast or house slow events are growing. We have no knowledge, of course, of the data and we're awaiting the data readout, of course, from that trial.

I think what's probably important to highlight in second line non-small cell lung cancer is that we continue to see certainly a key unmet need emerge in this area. And while other ADCs and speci!cally to TROP2 targeting ADCs, necessarily haven't demonstrated the success that everyone had hoped for, there continues to be an opportunity for novel agents to be introduced into the space. And then !nally, of course, as we think about BLENREP and labeling, of course, we can't necessarily comment on the ongoing regulatory submissions, which have been made and accepted in the U.S., Europe and China and Japan and other key markets and regions. But what we can say is, I think at the end of the day, the dosing and the labeling will be driven by how the drug was administered and of course, the data that's emerged from both the DREAMM-7 and the DREAMM-8 results. And I think probably as you look at other drugs that have been used in oncology e\$ectively, no doubt the dosing decisions being driven by the toxicities that patients experience and how prescribers are able to manage those toxicities on a per patient individual patient basis is really important.

We've seen that with other labels. I think certainly looking at, for example, the label with palbociclib as an example here, that the ability to be able to, again, titrate the dosing, introduce the dose interruptions, the reductions and that each patient should be managed individually based on the set of toxicities they experience and how they're responding to treatment as well.

# Tony Wood Executive

And again, ultimately, of course, a simple framework that is easy to deliver in the clinical setting. And as we mentioned earlier, that's clearly part of the work that we're doing, but it's a bit premature to get into those conversations, I would say.

Okay. I believe we've got one more question left. And since it's Christmas, we should entertain it.

#### Mick Readey Executive

Eric?

## Eric Le Berrigaud Analyst

Thank you very much for the Christmas gift. One last question then on the !nancial aspect. You were talking a lot about prioritizing oncology and respiratory. How should we think about this in the context of the R&D budget going forward? Does that mean that you will prioritize those 2 others that will be deprioritized?

Or should we think about R&D budget going up with those 2 taking a lion's share? Should we think about any step change in R&D investment going forward to support those 2 areas?

# Tony Wood Executive

Yes. And look, we're not -- I'm not going to get drawn on individual capital allocation to speci!c areas. There are sort of 2 comments I would make in principles rather and that is we will continue to fund the portfolio in line with the expected growth of the areas in question. So this is very much a competitive process across the portfolio.

As I've mentioned in the past, it's done at the highest level by the committee that Luke and I chair together. Long term, in terms of our R&D budget right now, I'm very well positioned, I would say, in terms of supporting the opportunities that we've described. And of course, we've also mentioned throughout the year as the overall company aspirations continue to grow, then there will be an allocation into R&D budget. So to me, the same principles that we've described across the continued to apply here. And what I would say, though, is that I'm really delighted with the shift in the broad potential value in the later-stage R&D portfolio.

As I mentioned at the beginning that we're now starting to see our focus really shift into areas of going to medical need opportunity. And with that, we can !nish the call. It just remains for me to thank you all for joining us on I know what is a busy day. I wish you all a restful period over the holidays. And I look forward to seeing you in San Francisco, if you're there and at subsequent interactions.

Thanks, everyone.