GRAL - NASDAQ

Good day, ladies and gentlemen, and welcome to the GRAIL Fourth Quarter 2025 Earnings Call. [Operator Instructions] Please be advised that this conference call is being recorded. GRAIL Investor Relations, please begin.

Thank you, operator, and thank you all for joining us today. On the call are Bob Ragusa, our Chief Executive Officer; Aaron Freidin, our Chief Financial Officer; Josh Ofman, President; Sir Harpal Kumar, Chief Scientific Officer and President, International; and Andy Partridge, Chief Commercial Officer. Before we get underway, I'll remind you that we'll be making forward-looking statements based on current expectations. It's our intent that all statements other than statements of historical fact, including statements regarding our anticipated financial results and commercial activity will be covered by the safe harbor provisions for forward-looking statements under federal securities laws. Forward-looking statements are subject to risks and uncertainties. Actual events or results may differ materially from those projected or discussed. All forward-looking statements are based upon currently available information, and GRAIL assumes no obligation to update these statements. To better understand the risks and uncertainties that could cause actual results to differ, we refer you to the documents that GRAIL files with the SEC, including GRAIL's most recent quarterly report and upcoming annual report. This call will also include a discussion of GAAP results and certain non-GAAP financial measures, including adjusted gross profit and adjusted EBITDA, which exclude certain specified items. Our non-GAAP financial measures are intended to supplement your understanding of GRAIL's financials. Reconciliations of the non-GAAP measures to most directly comparable GAAP financial measures are available in the press release issued today, which is posted to our website. And with that, we turn to Bob.

Good afternoon, everyone, and thank you for joining us to review results for the fourth quarter and full year 2025 and discuss recent business updates. 2025 was a year of significant commercial growth for GRAIL, and we have shared a number of exciting developments so far in 2026. We issued a press release this afternoon with top line results from our NHS-Galleri trial. We observed a substantial reduction in Stage IV cancer diagnosis, increased Stage I and II detection of deadly cancers and a fourfold higher cancer detection rate, outcomes that matter for patient care. While there was a trend towards reduction in combined Stage III and IV, the trial did not meet the primary endpoint of statistically significant reduction. These data show the benefit of multi-cancer screening with Galleri and provide the strongest evidence for the recommended annual screening interval. Harpal will talk through the top line NHS-Galleri trial results shortly. In our earnings press release, we also noted full results from all 35,000 participants in PATHFINDER 2 and were consistent with data presented from the first 25,000 participants presented at ESMO last year. We anticipate presenting full data from both NHS-Galleri and PATHFINDER 2 in mid-2026. Based on strong results from the NHS-Galleri and the PATHFINDER 2 study, we also announced today that we are moving forward with a planned expansion of our field sales and medical team. We believe this expanded engagement will enable us to continue to drive commercial momentum. To recap quickly on the strong commercial performance for Galleri in 2025, which we shared in January, the U.S. Galleri test volume grew 36% to more than 185,000 Galleri tests and U.S. Galleri revenue grew by 26%. Our prescriber base is now approximately 17,000 providers, up 30% from prior year. Galleri's growth in 2025 was driven by both breadth and depth of prescribing. We have been in the market with the Galleri test now for more than 4 years. And from the launch of Galleri through December 31, we have sold almost 0.5 million Galleri tests. We remain on track for continued commercial growth in 2026 with new and expanding partnerships, including digital health opportunities and further integration into health systems. We are focused on expanding awareness of multi-cancer early detection and Galleri's important performance and capability differentiation. We anticipate growing patient, provider and employer conviction in Galleri as other performance, safety and clinical utility data sets are read out. A few weeks ago, we announced that we completed our PMA submission with the FDA. The PMA marks a critical step forward, making Galleri available to more people and advancing early detection to provide a significant public health benefit. The submission represents years of focus, disciplined work to achieve design, development and validation of Galleri in large, diverse screening populations. Josh will share more about our PMA later in this call. Additionally, earlier this month, the Nancy Gardner Sewell Medicare Multi-Cancer Early Detection Screening Coverage Act became federal law. This establishes a Medicare coverage pathway for FDA-approved multi-cancer early detection tests. As a leading MCED developer, it is our privilege to stand with legislators, patient advocates, clinicians and researchers who have championed the cause. I'll now hand it over to Harpal to discuss top line results from the NHS-Galleri study.

Thank you, Bob. We're very pleased to share top line results from the NHS-Galleri trial. I want to begin with a huge thank you to the more than 142,000 participants who took part in this study as well as to NHS England, the cancer prevention trials unit at Queen Mary University of London, cancer alliances, investigators and the clinical teams whose dedication made this landmark trial possible. Detailed results from the NHS-Galleri trial will be submitted for presentation at the upcoming ASCO meeting in Chicago in late May. The design of the NHS-Galleri trial was informed by a large body of evidence showing that across multiple cancer types, reductions in late-stage disease are strongly associated with reductions in cancer mortality. While we did not observe a statistically significant reduction in combined Stage III and IV cancers through the trial, which was the primary endpoint of the study, there was a favorable trend after the prevalent screening round, and we saw compelling evidence of Galleri's benefit. Comparing the two arms of the study, Stage IV diagnoses in the prespecified group of 12 deadly cancers decreased with each year of sequential Galleri screening, with a greater than 20% reduction in the second and third rounds. Similar reductions were observed across all cancers. The reduction in Stage IV cancer diagnoses is a critically important outcome, which we believe can lead to more effective intervention for patients, particularly given the substantial and growing arsenal of effective treatments for many Stage III cancers. In fact, there is a dramatic improvement in survival for many types of cancer at Stage III as compared with Stage IV. These results are the first time a multi-cancer early detection test has demonstrated population scale stage shift and reduction in metastatic disease in a randomized trial. Screening with Galleri increased the overall cancer detection rate fourfold compared to standard of care and identified substantially more Stage I and II cancers in types that are typically detected at late stage. Screening with the Galleri test also resulted in a substantial reduction in the number of cancers detected clinically through emergency presentation, which are associated with significantly higher mortality and health care costs. And these benefits came with a strong safety profile. No serious safety concerns were reported in any of the approximately 70,000 participants who received the Galleri test across 3 rounds of testing. This is the first randomized multi-cancer early detection data set and is unprecedented in scale. Additional analyses are underway to better understand these rich data. As with any study, it's important to evaluate the results in the context of the design and execution. One observation is that we saw higher-than-anticipated incidence of Stage II cancers in this trial as compared with prior study experience. The number and distribution of cancer stages across screening rounds suggests the potential for a stronger effect with longer follow-up as data matures. And so we're planning to extend data collection by 6 to 12 months, and we'll reevaluate the impact with more mature data. In both the U.S. and the NHS data, the time to diagnostic resolution appears to improve over time as physicians gain experience with the Galleri test and diagnostic workup. Our learnings from this trial enrich our understanding of cancer biology, multi-cancer screening and the importance of implementation, particularly in ensuring rapid and thorough diagnostic investigation after a positive test result. Our mission is to detect cancer early when it can be cured. And we're delighted that these results show the potential for more patients to receive treatment with curative intent and have more time with their family and friends. We believe this is the best chance to bend the cancer mortality curve at population scale. As a reminder, the data we're sharing today is limited to our top line analysis. We plan to submit the detailed results for presentation at ASCO later in the year. I'll now pass it to Josh Ofman to review more about our recently completed PMA application.

Thank you, Harpal. At the end of January, we completed the submission of the final module of our PMA application to the FDA for Galleri. We're extremely proud of this pivotal milestone in advancing early cancer detection and addressing unmet needs in cancer screening. From the beginning, GRAIL has been completely committed to rigorous scientific and clinical evaluation to ensure that multi-cancer early detection testing is supported by strong data. The PMA submission is focused on test performance and safety results from 2 large registrational studies, including the first 25,000 participants in the U.S.-based PATHFINDER 2 study with 1-year follow-up and data from the prevalence screening round or the first year of the NHS-Galleri trial, the largest and only randomized controlled intended use trial of any MCED test. The PMA submission is also supported by a bridging analysis to compare performance of the version of Galleri used in our registrational trials to the updated version that has been submitted to the FDA for premarket approval. The results from the first 25,000 participants enrolled in PATHFINDER 2 were presented in October at the ESMO Congress. And we've now completed the analysis of the full 35,000 participants and the results are consistent. The performance data from the prevalent screening round of the NHS-Galleri study, including metrics focused on test performance, clinical validation and the clinical benefit of detection at Stages I through III, including a reduction in Stage IV were also included to further enhance the data set and provide additional data on more cancers to the FDA. As a reminder, the FDA designated the test as a breakthrough device in 2018. The PMA was submitted at the end of January, and we are anticipating about a 12-month review period. To discuss our fourth quarter financial results, I'll pass it off to Aaron.

Thanks, Josh, and good afternoon, everyone. I'm pleased to present our results for the fourth quarter and the full year of 2025. Fourth quarter results were strong with revenue of $43.6 million, up $5.3 million or 14% as compared to Q4 2024. Total revenue for the quarter is comprised of $42.3 million of screening revenue and $1.3 million of development services revenue. Development services revenue includes services we provide to biopharmaceutical and clinical customers, including support of clinical studies, pilot testing, research and therapy development. Full year total revenue was $147.2 million, up 17% from full year revenue in 2024. Full year 2025 revenue was comprised of $138.6 million of screening revenue, up 28% over full year 2024. U.S. Galleri revenue in 2025 was $136.8 million, up 26% over 2024 and in line with our guidance of 20% to 30% growth. Revenue also included $8.6 million of development services revenue, a decrease of 49% from 2024. We are seeing continued demand for the Galleri test, and we sold more than 57,000 tests in the fourth quarter and more than 185,000 tests for the year. Screening revenue of $42.3 million in the fourth quarter was up 34% as compared with the fourth quarter of 2024, primarily based on an increase in sales volume. In 2025, we began leaning into the price elasticity we see in the market and are finding success in expanding access with our discounting programs. Development service revenue in the fourth quarter of 2025 was $1.3 million. Net loss for the fourth quarter of 2025 was $99.2 million, an increase of 2% as compared to Q4 2024. Net loss for the full year was $408.4 million, an improvement of 80% as compared to the full year 2024. Net loss in 2024 included goodwill and intangible asset impairment of $1.4 billion. In addition, net loss for 2025 and 2024 included amortization of Illumina acquisition-related intangible assets of $138.3 million. Non-GAAP adjusted gross profit for the fourth quarter of 2025 was $23.1 million, an increase of $5.2 million or 29% as compared with Q4 2024. Full year non-GAAP adjusted gross profit was $73.6 million, an increase of $15.8 million or 27% as compared with the full year of 2024. Primary drivers of the increased margin were revenue mix and efficiencies of scale related to increased Galleri volume. Adjusted EBITDA for the fourth quarter of 2025 was a negative $71.8 million, representing an improvement of $12.2 million or 15% as compared to Q4 2024. Adjusted EBITDA for the full year 2025 was a negative $320.6 million, an improvement of $163 million or 34% as compared to the full year 2024. We ended the quarter with a cash position of $904.4 million. This balance included $436 million in proceeds from both our private placement of equity in October as well as our ATM equity issuance program in November and December. As a reminder, we have shared in the past our long-term gross margin target of 50% to 60% at scale. We are making good progress on attaining these margin targets. And as we saw in the third quarter, volume efficiencies make a big difference. In connection with our supply agreement with Illumina, we are obligated to pay them a royalty on revenues. Those royalty payments are suspended until December of 2026. When resumed, we expect to pay Illumina a royalty in the high single digits, subject to certain terms and perpetuity on net sales generated by our products on revenues in oncology. We expect that these payments will make an impact on our gross margins beginning in 2027. Given strong performance in the self-pay market and the momentum we are seeing with positive data readouts, we are reiterating the guidance we shared in January today of Galleri sales growth of 22% to 32% and cash burn for the full year of 2026 to be no more than $300 million. Our cash runway extends into 2030, and we are well positioned to navigate growth over the next several years as we pursue critical milestones toward broad access. Bob, back to you for concluding remarks.

Thanks, Aaron. To close, our teams at GRAIL continue to do great work advancing towards our vision of population scale multi-cancer early detection. We are approaching our 10th anniversary as a company this March, and we are energized by recent milestones and achievements, including the consistently strong performance we are seeing for Galleri across our studies. We presented positive registrational clinical study results for the first 25,000 participants in the PATHFINDER 2 study in October and today shared top line results for the NHS-Galleri trial and the full 35,000 participant PATHFINDER 2 study. We're looking forward to data presentations for both studies later in the year. The business continues to grow, and we are excited about expanding our partnerships with digital health companies and health systems to continue to expand access to Galleri. We have now completed our PMA submission with the FDA and new federal law provides the pathway for Medicare to cover FDA-approved multi-cancer early detection tests. We're in a strong financial position with more than $900 million in cash as of December 31st. I'd like to thank each of our employees for their incredible commitment and dedication to our mission to detect cancer early when it can be cured. We'll now turn the call over to question and answer. Operator, please go ahead.

[Operator Instructions] Our first question will come from Subbu Nambi with Guggenheim.

Can you confirm that you don't expect the FDA approval decision to be impacted by the miss of the stage shift endpoint? We know the FDA PMA package only included the prevalent screening round of NHS, but reasonably reviewers at the FDA will see this outcome, right?

Yes. Thanks for the question, Subbu. So as you know, the FDA will look at the effectiveness and safety of our submission. And so with the data that we have both from PATHFINDER 2 as well as the current -- the prevalent round of the NHS-Galleri, they'll be looking at that data. So there's not an obvious correlation or obvious impact between the final results of the NHS-Galleri study and the FDA's view on the test.

And one follow-up. Is there any read-through from missing the NHS-Galleri stage shift endpoint to the Medicare REACH study, which has a primary endpoint of incidence rates of Stage IV cancers, right? And does that have any impact as Medicare -- as you look to getting some coverage?

Yes. Thanks again. Josh, do you want to take that?

Sure. Yes. No, you're absolutely correct. So the primary endpoint of the REACH study is a Stage IV reduction, which is what was observed quite strongly in the NHS-Galleri trial. So I think the only read-through is that we believe that it's critically important and clinically important to reduce the incidence of metastatic disease in Stage IV cancer, and that's a really important clinical endpoint, and we're looking forward to assessing that in the REACH trial.

And Josh, what if we don't reach the statistical significance there, would that have any impact? Or you're saying because it's 50,000, the study is not powered enough?

Yes. No, we believe the study is properly powered. It will have a control group, and we believe it is properly powered for that type of study, given the effect size that we know and the cancer detection rate that we're seeing. So we're very optimistic about observing that effect, but we need the study, obviously, to read out, and that's going to take some time.

Your next question will come from Kyle Mikson with Canaccord Genuity.

Hopefully, you can hear me. I guess first one would be, how does the results here kind of impact your strategy to expand Galleri to other countries in terms of data generation and rollout plans? How would that differ now? And then maybe you could just touch on what are next steps in the U.K. Have you had any discussions with them so far? Or is that later on?

Yes. Thanks for that, Kyle. So we do think as we outlined in the releases that strong reduction that we saw in Stage IV cancer, the fourfold improvement in cancer detection rate compared to standard of care, the absolute number of Stage I and II cancers increasing and the reduction in emergency presentation. We think all of those will be important as we go to other countries and the discussions with them. Obviously, other countries will -- each one will evaluate those elements independently. But we do think that's going to be a strong data set to go out there. So I think that's going to be very useful. Maybe I'll pass it over to Harpal to comment on the U.K. and the impact there.

Yes. Thanks, Bob. I mean just adding to what Bob said first, I mean, we think this is a really strong data set that demonstrates compelling clinical benefit. We know that there is now a growing arsenal of very effective treatments for many types of stage -- many types of cancer at Stage III. And so the potential benefits that we're talking about here from the NHS-Galleri study are going to be applicable worldwide. And so I don't think it has any -- certainly no negative bearing on our international approach. Indeed, I would hope it has a positive bearing on our international approach. So we feel really, really very pleased with the overall set of results. With respect to the U.K. specifically and the NHS, yes, look, we've just got these data. We haven't started having those conversations yet. My anticipation would be that they would want to see the full results before engaging in meaningful conversations, and we expect to have those at ASCO.

And then I hate to nitpick, but if you're expanding the sales force, if the results didn't meet the endpoint, I guess, like what's the thought process there. You're very bullish on the future here. I'm just curious what's driving that.

Yes. So again, if you think about the things we saw in terms of reduction in Stage I and II, the -- excuse me, the increased Stage I and II cancers, and the reduction in Stage IV cancers, those are things that we've looked at within the U.S. that are very, very relevant to clinicians. And maybe to give a little more color, I'll pass it over to Andy, our Chief Commercial Officer.

Yes. Thanks, Bob. Based on the market research studies that we've done and also consistent customer feedback that we've received from early adopting customers, the NHS-Galleri results that we've released today, we believe, based on everything we've heard and done will be both compelling and meaningful to our customers in terms of the magnitude of both the Stage IV reduction that we've disclosed and also the increased cancer detection rates of fourfold. And we believe that's going to increase both the depth and breadth of prescribing. Hence, we're expanding the provider sales force territories in the U.S.

Your next question will come from Doug Schenkel with Wolfe Research.

I'll try to get them all out there upfront and then listen. So first, really a follow-up to the very first question, and I think it's the most important question tonight given the stock reaction in the aftermarket. So I want us to be airtight on this. Is the probability of FDA approval unchanged as a result of the NHS-Galleri readout? Because if the answer is, the probability is unchanged, it would mean the value associated with FDA approval and by extension, CMS reimbursement is also unchanged. So that's the first question. Yes or no, has the probability not changed? The second question is on NHS coverage in the U.K. I know, again, you just got a question on this, but I'm curious if there are any examples you can point to where a diagnostic has been reimbursed after missing a primary endpoint. And then my third question is, has your analysis of NHS-Galleri results led you to any explanation regarding why you came up short of the primary endpoint? Are there potential design issues or population SKUs, anything like that?

Yes. Thanks, Doug. Maybe, Josh, I'll hand over to the FDA questions to you.

Yes. Thanks for the question, Doug. Everything we've learned from the FDA, their history with us, our conversations has been, their focus is going to be on clinical performance and safety. And the data set that we are -- that we have submitted includes the full PATHFINDER 2 study of the first 25,000 participants and the first year, which is the performance period of the NHS Galleri trial. In their advisory board meetings and their public comments, they have been quite clear that their focus is on clinical validation and not clinical utility. And what we've tried to demonstrate in the NHS trial is a population level effect well beyond clinical validation and clinical performance. And we were able to demonstrate a really important finding of a substantial reduction in Stage IV cancers and a fourfold improvement in the cancer detection rate. But those are things that are not part of our submission right now to the FDA. And based on their own comments, they're going to be focused on clinical validation.

And maybe Harpal, you want to maybe just comment...

So I think -- Doug, I think your second question was around endpoints on diagnostic studies. I think it's just worth pointing out that it's extremely rare for any diagnostic to go through a randomized controlled trial. It's very common for drugs to go through randomized controlled trials, but you actually very rarely see a diagnostic test evaluated in as rigorous a way as we have done through the NHS-Galleri trial. I just think it's really important to make that point. Not only have we rigorously assessed it through an RCT, but it's enormously large trial, 142,000 people. So we have a data set the likes of which I am not aware any other diagnostic has been through other than sort of really significant interventional diagnostic type products. So I think that's the first thing to say. The second thing to say is this is an enormously rich data set, and it has a large number of components to it, and we've shared those with you today. It's absolutely right to say we didn't hit the primary endpoint. But what we did see was a very compelling clinical benefit here. And I think that story stands in terms of generating excitement out there in the clinical community around what's possible with a test like this. Being able to reduce Stage IV cancers gives clinicians the opportunity to use curative treatments that they otherwise wouldn't have the opportunity to use. So I think that's really very compelling. And then your third question, I think, was about what are we learning looking at the data. And just a couple of comments on that. First of all, it's -- we've not had this data for very long. We're looking into it. There's a lot of data to work through. One of the things we've seen is that -- and if I break apart the primary endpoint, it's a combined Stage III and IV reduction. And so when you break that apart, we did see a Stage IV reduction. But as we've commented on, we saw an increase in Stage II cancers. And one of the things that looks to be the case when we look at the data is that we expect to see a stronger effect if we were to continue to follow up this cohort for a longer period of time. And that's why we're saying we want to extend the follow-up for a further 6 to 12 months, and that's why we'll be doing that. So that's one of the things that we've seen when we're looking at the data, but there's a lot more to learn.

[Operator Instructions] your next question will come from Catherine Schulte with Baird.

I guess, first, just on that last point of extending the trial follow-up by 6 to 12 months. Is that something that you and NHS have already agreed on? And I guess, what is the goal of what you will see in that 6 to 12 months? Is it to push more on the Stage III reduction? Or is there something else that NHS is hoping to see?

Yes...

Yes. Thanks, Catherine. We haven't discussed it in any detail with the NHS yet, but I think it's -- I really can't see any obstacles in being able to do that. What it requires is not going back to participants or clinicians. It would be a continuation of passive data collection, which is already being recorded. And so it's just about the passage of time and agreeing with the NHS team that we can get access to that data. I think that will -- I don't foresee any significant obstacles in that regard. And in answer to your second question, yes, what we want to see is particularly the control arm data maturing more than we've been able to see. And perhaps if I just elaborate a little bit on that, what you tend to see in a screening trial -- in any screening trial is that you're finding cancers that would have been detected later. And so if you think about what that means in practice, you're pulling forward into your intervention arm cancers from the future. For a control arm of the study, those cancers may not yet have manifested. So when you're comparing 2 arms of the study, what you'd like to have is long enough follow-up that you can compare the 2 arms really, really well together. And what we've concluded looking at the data is we probably need a longer follow-up time to be able to do that adequately.

And then for the NHS, I know they put out their National Cancer Plan earlier this month and still reiterated their commitment to and interest in multi-cancer early detection. We've got OLS closed an application process for what sounds kind of like a AdAC-related study using multi-cancer tests in primary care to triage patients with nonspecific abdominal symptoms. Is that something that you guys are involved in? And maybe just talk to the broader relationship with NHS.

Yes, happy to do so. So we've been having ongoing conversations with the NHS really over the last 5 or 6 years. Those conversations continue very actively and certainly will continue here on in. Of course, we were very pleased to see in the NHS Cancer Plan a couple of weeks ago, a number of references to multi-cancer early detection and indeed, the excitement within the NHS and the Department of Health in England for the possibilities that this new technology offers for really transforming the landscape for cancer patients. So the multiple references in the Cancer Plan, I don't think it's an exaggeration to say, comes from the conversations and relationships we've been having with the NHS over the last 5 or 6 years. With respect to the second part of your question, yes, there is a process underway to further evaluate the role of multi-cancer detection in a symptomatic context. And this is a follow-up from our SYMPLIFY study that we reported a couple of years ago. Necessarily, the Department of Health has to go through a competitive application process. It doesn't -- it can't just offer that opportunity to GRAIL. So that application process is underway. And as you might expect, we are applying to be part of that process and are hopeful that, that will move forward. Certainly, we believe our data from the SYMPLIFY study is very strong and very encouraging in that context.

Our next question will come from Dan Brennan with TD Cowen. [Operator Instructions]

Maybe just one on Medicare. So assuming you're successful with FDA, I'm just wondering, I know Medicare, you have the favorable pathway, obviously, and FDA approval, assuming you get that, that would be terrific. But we're under the impression that Medicare does consider clinical utility. So how do you think they would look at the NHS trial? And how would that potentially impact the Medicare decision?

Josh, do you want to take that?

Great. Yes. Obviously, Medicare is going to -- upon FDA approval now has the statutory authority to provide coverage for multi-cancer early detection tests and we'll initiate a national coverage analysis and really look very carefully at the data. And we believe we're going to have a very robust package of data to submit to CMS, including all of our registrational trials, everything about NHS-Galleri, including the substantial Stage IV reduction, the fourfold increase in the population cancer detection rate, the increase in detection of Stage I and II cancers and also very strong clinical performance overall. And so we think that, that combined with our real-world evidence, our clinical surveillance program and the REACH study in Medicare patients at the time of the NCD will be a very robust package for them to evaluate. Again, Medicare has never evaluated a multi-cancer early detection test before. There is no known bar that has been set. And so we feel like we're going to be able to provide them an incredibly robust package of evidence to consider coverage for Galleri.

Okay. And then maybe just on -- I appreciate the Stage IV is down, which is terrific, but the III, given some of the anomalies you discussed was up. Like collectively across Stage III and Stage IV, can you say if there was a decrease and kind of what the level of that decrease was?

Yes. I can't really comment any further at the moment. There was not a statistically significant reduction. But what we did see was a trend towards a reduction over time, and that was a favorable trend. I think that's as much as I can say at the moment, but we are planning to present the full results at ASCO later in the year.

And I mean if I can sneak in one final one. So the trial was set up for 3 years. Obviously, it was going to be a surrogate for mortality because mortality would just take too long. So I think that was pretty well established. Was there a decision when you set it up for 3 years as opposed to maybe setting it up with a longer follow-up period, kind of how that decision was made? Obviously, it sounds like now you're hoping, obviously, the longer follow-up will still prove out the study. But I'm just wondering when you went into it, how was that decision made?

Yes. I mean, look, as with any study, it's designed and sized and powered with the best information you have at the time. And at the time, we felt that 3 rounds of screening followed by a year of follow-up would be sufficient. I think with the benefit of hindsight, we probably should have allowed for a longer follow-up period. There have interestingly been a number of publications over the last couple of years about screening studies in general, not just about NHS-Galleri, which make this exact point that the trial should be followed up for longer than 12 months post the last appointment. As I say, this trial was designed 6 years ago, and that was the best information we had at the time. But as I've already touched on, on this call, we have the ability to continue follow-up. So that's what we're going to be doing.

And it's probably just worth noting that most screening trials have gone on for decades, at least 1 decade, if not 2. And so this was a very -- in the context of screening trials, this was actually a very short trial with a very ambitious endpoint. And that's part of the story here. But it is the first time that an MCED test has shown the ability to shift the stage diagnosis for the population in a randomized clinical trial. And I don't think we should let that kind of go by.

For our next question, we'll return to Kyle Mikson with Canaccord Genuity.

So just given you see these results now, at this point, can you go to the FDA kind of narrow or adjust, let's say, your label maybe to the 12 cancers that you performed the best in or maybe like an older patients, like an older subset perhaps? And just generally, like how does this impact your thoughts on the -- like a potential advisory committee meeting based on there was an -- there was an AdCom back in '23 already?

Yes, sure. Again, we don't think that this finding is going to impact the approvability of Galleri with the FDA. The FDA is clearly going to be focused on clinical performance and safety and the profile of data that was delivered to them. And in that context, we will work through labeling with the agency. Should they seek clarification on the intended use, and narrowing of the indication to the things that you suggest, we'll be negotiating that with them in due time. But we feel like we have a very strong and compelling evidence package for our current intended use, which is adults at elevated risk for cancer such as adults over the age of 50 and with additional risk factors if they are younger than the age of 50. So we feel like we have a robust package, and we'll see where the labeling ends up.

Yes. And maybe just to add to that, the -- it's also we haven't really brought up this across the 3 rounds of the large participants in NHS-Galleri as well as the 35,000 in PATHFINDER 2, there was no serious adverse events across the entire trials. So those are really large numbers. So from a safety perspective, it was really good showing up.

And we think the benefit risk profile is quite compelling as a result of that.

And just to add something that Josh said, in relation to your point about the 12 cancers, the reason we specify this group of 12 cancers is because it represents 2/3 of all cancer mortality. So if you can make a difference in that group, you really are making a dramatic impact at population scale. But I would draw your attention to something that's in our press release, which is when we talk about the Stage IV reduction and the fact that it's more than 20% in the second and third rounds of screening, yes, it's true for the 12 cancers, but it's also true for all cancers. And so I don't think there's any reason at this stage to think that we should be narrowing our claims only to the 12 cancer types.

That's a great point, Harpal. Thank you for making that. And just to your last question about the AdCom. It's certainly possible that there can be an AdCom. The FDA has already held an AdCom. And so we are not sure whether that's going to happen. We will wait and see. But we've made the case to the FDA that based on their prior AdCom that they've already held and the fact that we've addressed all of those issues in our submission, which was just completed recently, that there's likely no need for one. But we'll see what the FDA decides.

All right. Super helpful. Just a quick follow-up. Obviously, the NHS-Galleri results are pretty relevant to the FDA submission, but I don't believe there's much read-through to USPSTF inclusion. So in a worst-case scenario, you don't get FDA approval, which again is not the -- you guys expect that. You could get a USPSTF inclusion, get into -- or get Medicare coverage according to the legislation and so forth. Are your thoughts on guideline inclusion unchanged? Or is that -- you still don't think that's the necessary milestone for you guys that FDA is most likely going to happen?

Well, I'm not sure I'm fully following your question, but let me try to take a stab at it. We think the first most important milestone is to get an FDA approval. And we think that, that is going to be an incredible moment for patients and provide amazing amounts of conviction in the clinical community and the payer community. Many of the payers have told us that, that would be the gating step for them. They would like to see an FDA approval before they would provide coverage or consider Galleri for coverage. And then obviously, there will be a CMS, NCA, National Coverage Analysis decision as we've discussed already. So we think those are the most critical things. And USPSTF evaluation would then come after that. And obviously, that was -- that is important if you don't have a coverage pathway within CMS. And that's why the USPSTF pathway was put into place because the CMS had no statutory authority to provide coverage for preventive services. But the CMS does have statutory authority now. So we see the USPSTF as being supplemental to that. But in terms of guidelines, we think the FDA approval is going to be one of the most critical parts and then the very strong and robust evidence base we have about all the clinical benefits that Harpal has described.

Yes. Just to clarify, I was just saying like if the USPSTF committee if they're going to take this data into account, but it's -- we're talking [indiscernible] in the future probably. So maybe it's not relevant. But anyway, thanks for the time.

There are no further questions at this time. I will now turn the call back to GRAIL for closing remarks.

We look forward to presenting full data from our 2 registrational studies in mid-2026, a longitudinal randomized controlled NHS-Galleri trial, including clinical utility and performance and the full 35,000 participant PATHFINDER 2 study. So we look forward to providing future updates, and thanks, everyone, for joining the call.