GRAIL, Inc. (GRAL) Earnings Call Transcript & Summary

Ladies and gentlemen, please welcome the President of GRAIL, Dr. Josh Ofman.

All right. Hello, everybody. Good to see everybody. Thank you all so much for coming. We have a great day for you today. And hopefully, many of you will also take our tour to the lab, which will be incredible. But again, it's a pleasure to be here. We're thrilled to host an Analyst Day. I think this is officially our first in-person, real effort here. So it's terrific to have you all. So we're going to go to a set of disclosures, which you're all familiar with. I won't -- did I go too far. I won't read any of them. But just make sure if you have any questions about any of this, please come to us. And now I'm going to introduce our CEO, Bob Ragusa, who's going to give some introductory remarks. Bob?

Thanks, Josh, and thanks, everyone, for joining -- yes. Thanks, everybody, for joining us. I'm sorry, I'm not able to make it there...

Bob we can't hear you yet. Any chance we can hear Bob? There we go. Bob, up to you. Go for it.

So thanks, everyone, for joining us today. I'm sorry, I'm not to be able to join you there in person, but that does not disminish my excitement for you to be with the GRAIL team at our centralized lab in Research Triangle Park, North Carolina. I'd encourage you to spend time with our leaders and various experts and attendance, and enjoy the guided tour of our lab. The lab is an operational hallmark [indiscernible] in our endeavor for population scale multi-cancer early detection. Our goal today is to share with you key highlights of the business and the tremendous progress that we have made as a public company since June of last year. We will also provide access to some critical experts. These are the physicians who designed and ran our key studies and the physicians who are on the front lines today using the Galleri test with their patients. We've had a very packed agenda. Aaron and Josh will go through a brief business review, followed by a review of PATHFINDER 2 results in the NHS study design, and anticipated milestones by Dr. [indiscernible]. and Professor Peter [ Casini ]. We will have a Q&A session at the end of the first section, take a very short break to provide lunch and then we'll come right into the reviews of our international opportunity and the commercial business. Finally, we will close the formal presentation with a customer panel. At the end of the day, we'll also provide the opportunity for [indiscernible] for those of you on site. So we hope you find this an enriching day. And with that, I'll pass it over to Aaron and Josh for the business review.

Thank you, Bob.

Thank you, Bob. Okay, everybody. Thanks for -- as Josh and Bob said, thanks for coming out here. This is the first one of these that we've done. We'll be doing more of those in the future. And I hope you can see, I mean, in a short 10 years, you have seen the data, you've seen the financials and all that stuff going on, but now you get to see the lab. You get to see the space where we're actually changing outcomes of cancer diagnoses. So I'll start here with looking at the financials and just kind of what we've done in this time period. We're focused on detecting cancer early when it can be cured. It's our mission. It's what we came up with the idea with 9 years ago, almost 10 years ago, and we're marching down that trail. We've built something special here. We're at the beginning of that, and we're really excited about where it's going. We see ourselves as a leader in this expansive field. We're first to market with an [ MSA ] test launched in 2021. We've demonstrated performance through several studies, most recently, the PATHFINDER 2 study, which you'll hear more about later today. And we've built this large commercial experience, large clinical data set over that time period. And it really puts us in a position to continue to lead, and we're excited, excited to be here. So through the research studies and our clinical experience, this data set has allowed us to improve the test. It's allowed us to really show where this can go. The data sets we've [ read out ] just phenomenal in our eyes. And this opportunity is enormous, right? It's a huge, huge space. We're at the beginning of that, and we're really excited to see where this can go. As you can see here, we did $125 million revenue in '24, [indiscernible] 9 months of 2025. We're growing at a 25% rate compared to last year. And it's, again, early days. This is a pre-reimbursement space as you'll hear more about our path to get to broader access, broad reimbursement and sell on from the rest of the team once I finish talking. So we've built this lab. We can run a million tests. You'll go see how automated that is. It's really impressive. It's one of my favorite things to do at GRAIL, just walk through the lab and get a tour and see how it all works. It's really great. And most recently, we've managed to finance ourselves. We announced a $325 million [ pipe ]. And that really gives us the capital to navigate with flexibility, this ramp over the next 3, 4, 5 years. And we're excited that with the investors that have come in, in this time period. The partnerships that we've built and sell on. It really set us up well. Next slide. There's a little financial outlook. So I always like slides like this where you can see revenues going up into the right on one side and cost going down on the other side. So we did a restructuring back in 2024. And since then, we've really managed to grow the business and execute against our milestones as we get to broad access, while growing revenues. And it's not easy. And this is a developing field. So with the financing that we've received, we now have the flexibility to adapt as the space grows, as we learn more about what's going to -- get to massive -- large adoption and so on. We've updated our guidance yesterday to be in the midpoint, the mid-range of the 20% to 30%. And we brought down our cash burn for the year to $290 million net of the financing fees for the year. So again, continue to improve and perform well compared to how we thought we would. What we've been focused on in 2024 with this new platform is really driving COGS down. You'll see that on the next slide and give you a little more color on that. So you see margins increased to 55% compared to the prior year of 41%. It's really driven by the new platform, variable cost and fixed cost improvement. The way to think about the fixed cost is, last quarter, we ran 66,000 tests, or an average run rate of 260,000 tests, somewhere in there, compared to the prior year it's about 160,000, 180,000 test run rate on the older platform. Last quarter, we ran 45,000 tests. So you can see just how much fixed cost leverage we have there. We don't expect the clinical samples that we ran last quarter to repeat this quarter in a subsequent quarter, but it's really an example to show how much fixed cost leverage we get once we put volume on this platform. Again, I can run a million samples based off of the equipment that we have today and the space that we have, and then we can add to that modularly as the demand comes in, in a pretty capital-efficient way. And so with that, I think I'm turning it over to Dr. Ofman.

All right. Thank you, Aaron. Everybody hear me okay? Great. So now we're going to do a little kick off into the real core of the meeting. And just to remind everybody why we're all here. We are here because cancer is soon to become the leading cause of death in men and women worldwide. Right now, it's cardiovascular disease. That is expected to be overtaken by cancer either at the end of next year or the following year. And it's one of the diseases that has touched all of us and our families. Is there anybody in the room who's not been touched personally by cancer? It's almost every room I go into, nobody raises their hand. So it is one of those diseases that keeps people up at night. And the problem we're trying to solve at GRAIL is why is that? Why is cancer going to become the #1 cause of death worldwide? It's because we're finding most cancer too late. And we are here and dedicated to trying to solve that problem. And we've begun this incredible journey with what I believe is one of the largest clinical genomics programs ever undertaken. It began with our observational case-controlled study, which most of you are familiar with, what we call the circulating cell-free genome Atlas. And that was how we began to discover that we had a shared cancer signal that could be identified using methylation. We've used it to validate analytically our assay and then clinically validate our assay. And we've adapted our assay and learned a lot about the very nature of cancer through a biological signal that is being shed from cancers, and that is DNA being shed into the blood. And what we learned here is that a methylation signature, a pattern, apparently methylated DNA is very indicative of cancer. And that pattern is almost never observed in people known not to have cancer. And that is when the light bulbs went off at GRAIL that we had a multi-cancer early detection test. And in that methylation signature, we can also see a fingerprint of where in the body that cancer signal is coming from, and that is the magic and the power of this assay. We've then studied it prospectively in interventional trials. The PATHFINDER study, PATHFINDER 1 and PATHFINDER 2 around clinical performance. We've put it into a randomized controlled study in the NHS, which you'll hear about, to define clinical utility. And we're putting it now into a large prospective interventional real-world study in Medicare beneficiaries called the REACH trial. And again, we only introduced Galleri clinically, into clinical practice, once we had validated the assay in an interventional study in patients actually being screened for cancer. And you may know there are other test developers now introducing tests into clinical practice based on case controlled studies. We do not think that is appropriate. And it is probably not in the best interest of patients because you cannot define the effectiveness or safety profile of a product from a case-controlled study. It has to be used in a population -- a screening population prospectively in an interventional study. And we have done that. And I think we've set the right bar for evidence for the field. This is a new field. And if we want to change the paradigm of cancer detection, this is what's needed. You have to do it the right way, you have to build the evidence properly, and you have to introduce it clinically at the right moment when you've got the right level of validation, and you understand both the effectiveness and safety profile of your product. Now again, we have shown consistently strong performance across a variety of studies. As you may know from working in diagnostics, which many of you do, it is very unusual to see the results of a case-controlled study be translated faithfully in the interventional study. The case control studies, if any of you have read my blog post, can be designed in ways that can really determine the results that are observed. So when you see a case-controlled study being recapitulated in interventional studies, it's actually not that common to see that. But what you've seen here with Galleri is across the PATHFINDER 1 study, the PATHFINDER 2 study, real-world studies, studies done at Mayo Clinic and [ Dana Farber ], our own commercial experience, you see a very consistent set of results related to what we think is one of the most important clinical measures of an MSA test, the positive predictive value. Just so that all of you are reminded, PPV positive [indiscernible] value means, if you have a positive test result what is the likelihood that you're sitting there with cancer, right then? And our PPV, you see began being modeled from our observational study at about 44%, being recapitulated in PATHFINDER at about 43%, PATHFINDER 2 now, a larger, more diverse population at 62% then, and you see the other experiences. And what we've learned about our assay is that as providers have gained more experience as providers understand how important it is to look hard for those cancer signals, you see the PPV going up. Mayo Clinic and [ Dana Farber ] are good examples. There are slightly older populations, but what we know about these sites is they were looking hard for those cancers. When they got a predicted signal that's in pancreas, over, liver, stomach, they didn't stop looking, and they found the cancer, and that's why their PPVs were so high. So again, consistent strong results is the hallmark of a well-validated assay. Now I want to share a little bit about the opportunity of what we're talking about here before I hand it over to go through PATHFINDER 2. So what we've done here on the left side of the slide is we modeled, what does the world look like today? So my belief is that if you want to really understand Galleri, you have to begin with an understanding of what is going on in the world today. So let's talk about that. The top row in burgundy there is what is happening in the world today. You have 5 screening tests today, breast, cervical colon, lung, prostate. They are finding 184,000 cancers every year in the United States. Pretty good, right? That's only about 14% of the incident cancers. But in finding those 184,000 cancers, they are generating over 8 million false positives. Okay. Let me repeat that. To find 184,000 cancers, they are generating over 8 million false positives. In this country today, we are spending almost $40 billion a year on cancer screening. Where do you suspect most of that money is being spent? Working up all those false positives. So not very efficient. That's about a signal-to-noise ratio of 1:44. Not particularly efficient. Now those single cancer screening tests are great tests, they are saving lives. But the deal we made with single cancer screening is that we have very high sensitivity and we accept very high false positive rates. That's the deal we've made with single cancer screening tests. That would never be acceptable for a multi-cancer early detection test. So we designed Galleri to be a complement to those single cancer screening test. We cannot replace those. They are highly sensitive, they find early premalignant disease, and they're saving lives. So adding Galleri to standard of care screening is the right approach. And when you do that, you add an additional 482,000 cancers, additional 482,000 and you only generate another 380,000 false positives. And that's modeled based on our data from clinical trials. If you look at this now, this new picture of what the screening system can look like, you can see that it's much more effective in cancer detection and much more efficient in cancer detection. In fact, the signal-to-noise ratio gets driven down from [ 1 to 44, to about 1 to 14 ]. And the cost to detect the cancer gets reduced by about 65%. So a much more effective and efficient system. This is the system that we are driving towards. This is the paradigm change we are proposing and are driving. On the right side of the slide is the fact that most of the cancers Galleri finds are currently unscreened. There are no recommended screening tests for the majority of these cancers. Yes, we will find interval breast cancers. Yes, we have found, and do find, interval colorectal cancers. Yes, we will find aggressive prostate cancers. But standard of care screen are going to find the majority of those early cancers. And what are we finding? The majority of what we find are cancers that currently have no screening today. And for those of you who may say, your overall sensitivity is not high enough. Let me remind you that the current sensitivity for asymptomatic cancers for cancers that have no screening test is effectively zero, unless it's found incidentally. In other words, the false negative rate is almost 100% for the standard of care today, okay? So that is now the picture that I want you to think about as you now hear the data coming from our PATHFINDER 2 study. We are now in our final push to complete our submissions to the FDA by Q1 of 2026. That submission, we believe Galleri will be the first FDA-approved [ MSAD ] test. That is our goal. That's been our commitment. We are submitting PATHFINDER 2 data, which you're going to hear about in a moment. We will submit performance data from the first 25,000, which was a prespecified analysis with 1 year follow-up. We will then submit the remaining 10,000 once that's completed. The NHS-Galleri test, we will be submitting the first year of the prevalence screening round and data from the intervention [ arm ] as part of our PMA. And then there is a bridging study, which bridges the validation from our version that was used in those studies to the version that you're going to see on your tour of the lab, which will be our PMA device. So we have a bridging study. That will comprise the FDA submission, and we are looking forward to completing that in the first quarter of next year. Now with that in mind, I want to very proudly introduce [indiscernible] from [ OHSU ], who is one of our principal investigators in the PATHFINDER 2 study. [indiscernible], the stage is yours. Thank you.

All right. Well, hello, everybody. Thanks again for the invitation to be here. It really is my pleasure to be, and privileged to be, presenting the initial results of the PATHFINDER 2 study that we just presented at the European Society of Medical Oncology in Berlin about a month ago. The study really is a landmark study that is really changing the way we're thinking about cancer screening. And I'm a radiation oncologist at [indiscernible] I'm also a clinical researcher. And we've had the privilege of collaborating with GRAIL for quite some time now on their prospective interventional studies from the PATHFINDER 1 study to the PATHFINDER 2 study, and the currently accruing REACH study that we're also enrolling on. And I'm going to say we probably have one of the most robust experiences in the world in regards to providing these tests to participants, and walking them through the diagnostic pathways for a signal positive. We've enrolled nearly 8,000 participants on a multitude of these studies. So again, it's a pleasure to be here, and I hope I have some insights to offer. Disclosures. So just jumping right into the PATHFINDER 2 study is the largest interventional [ MCED ] study ever conducted in the United States, enrolling nearly 35,000 participants across 32 North American health care systems, [indiscernible] being one of them, over 32 months. All participants in the PATHFINDER 2 study were at least the age of 50 with no clinical suspicion of cancer, nor diagnosis of cancer or treatment of cancer within the last 3 years. All participants had their blood drawn. The MCED test was performed and they were provided with the results. For the participants who had a cancer signal detected, further diagnostic evaluation issued by the study team. The investigators were provided with protocol recommended guidelines for diagnostic workup, targeted to the cancer signal origin that the Galleri test had predicted. The PATHFINDER 2 study will be following all of these patients for 3 years to assess their cancer status, as well as any patient-reported outcomes, such as adherence to recommended screening guidelines. And the primary objective of the PATHFINDER 2 study was to evaluate the safety and performance of the Galleri test in a large and diverse intended use population. So with this prespecified initial analysis, we analyzed 25,000 participants on the PATHFINDER 2 study who had at least 1 year, 12 months of follow-up. And the table to the right shows the baseline demographics of the study and a large and representative population was enrolled on the study across age, sex, race and ethnicity. And this is largely due to outreach efforts and recruitment strategies, and we believe that this is really important to assess the utility of the test in an intended use population. 216 participants were found to have a cancer signal for a cancer signal detection rate of 0.93%. For those participants with positive signals, the positive predictive value was 62%, meaning 6 out of 10 participants with a cancer signal where ultimately identified to have cancer. This PPV is higher than what's been previously seen with the Galleri study [ and is ] orders of magnitude higher than the PPVs of our current single cancer screening methodologies, such as mammogram or [ FIT ] testing for colorectal cancer, which have PPVs of around 5%, meaning that for patients with positive results, only 1 in 20 are found to have a cancer, and Josh alluded to the high burden of false positive there. The specificity of the Galleri test on the PATHFINDER 2 study was 99.6%, which is consistent with previous reports of the Galleri test. And this was intentional. This was intentional to minimize the number of false positives, thereby driving the high PPV that you're seeing there. And we -- I agree, and I know GRAIL agrees that this is important for safe population screening. I'll pause. We don't want black on the screens, but I can keep talking on my screen here. All right, there we go. Can we go back one slide? There we go. So yes, specificity was high. For interventional studies like the PATHFINDER 2 study, it's not known at the time of testing whether or not a participant has cancer. Thus, we calculate the episode sensitivity, which is a measure of a test identify cancers within a prespecified time frame, and in this case, 12 months. And the episode sensitivity for all cancers across 18 broad cancer types was 40.4%. These sensitivity was even higher in clinically relevant subgroups. For the 12 cancers responsible for 2/3 of U.S. cancer deaths, episode sensitivity was 74%. It was 72% for 6 cancers, 6 aggressive cancers, low 5-year survival, 56% for all cancers, except breast and prostate, and 55% for cancers with outcome and screening options. And again, I want to remind folks that comparing episode sensitivity, one should not compare episode sensitivity from interventional studies like the MCED study to test sensitivity from case-control studies as they're designed completely differently. Within the 1-year time frame of this initial analysis, 329 participants were diagnosed with the cancer. 200 of them, or 61% were screen detected, far higher than the currently 14% of U.S. cancers that are screen detected. The MCED test detected 133 cancers, and the MCED test identified sevenfold more cancers when considering the cancers that were screened detected through single cancer screening methods of breast cancer, cervical cancer, colorectal lung cancer. When also considering the 47 screen detected prostate cancers, the MCED test increased the number of screen detected cancers by threefold. Cancer is identified on the PATHFINDER 2 study were clinically relevant. 114 were new primaries, 18 were recurrent cancers and 1 participant had a cancer of unknown primary site. 2/3 of these MCED detected cancers do not have recommended screening. Furthermore, most cancers that were identified were in early stages. 69% were between stage 1 and 3, 54% between Stage 1 and 2. And of these early- Stage 1 and 2 cancers, 74% of them do not have recommended screening strategies. One concern with MCED testing is the fear of a diagnostic odyssey, particularly when -- particularly if a test does not provide a cancer signal origin to help guide diagnose [indiscernible]. The PATHFINDER 2 study showed a prediction -- accuracy of prediction for the cancer signal origin, 92% for true positives. And this accurate cancer signal origin helped guide efficient and targeted diagnostic workup, with the median days to diagnose a resolution after a positive signal being 46 days for all participants, 36 days for true positives, and 75 days for false positives. Another fear with MCED testing is a fear of too many invasive procedures. We found this fear unfounded as well of the 25,000 participants who received an MCED test, less than 1% -- 0.6% and had an invasive procedure due to a positive MCED test result. Participants that did not have cancer had far fewer invasive procedures. And at the time of initial analysis, there have been no serious study-related adverse events reported during the diagnostic workup. So in summary, these initial PATHFINDER 2 results demonstrate robust performance and safety across a broad population. It's the largest interventional MCED study conducted in the U.S. to date, increased the number of cancers detected by screening by more than sevenfold when added to recommended screening, demonstrated robust performance with a 62% positive predictive value, substantially higher than observed in prior clinical studies. Majority of cancers that were identified were early stage. The majority of those cancers do not have recommended screening strategies. The test also enabled prompt efficient diagnostic resolution with a favorable safety profile. And I believe these results really illustrate Galleri's clinical utility and potential to improve outcomes in an intended use population. And I think we have a Q&A session after this. I'm happy to answer questions. Thank you all. And I'll be -- yes, so I should introduce our next speaker. Professor [indiscernible], who is from the U.K., who is an instrumental lead in the NHS-Galleri study that we're anxiously waiting.

Thank you, [indiscernible]. Thanks, [indiscernible]. Thank you very much. It's a pleasure to be here. So my disclosures, I'm on the Scientific Advisory Board for GRAIL, and I should perhaps say that I'm not a physician. So you've heard a little bit about the [indiscernible] the [ SIMPLIFY ] study you have heard about and PATHFINDER 2. So I just want to say a little bit about this before talking about NHS-Galleri. The [ CCGA ] really was a very large case control study, which provided data on the ability of the test to detect and locate multiple types of cancer. And then also to demonstrate that a positive test result was extremely rare in people without cancer. And that was done in taking a large number of people with cancers before they were treated, but after diagnosis and a large number of people without cancer. The SIMPLIFY study, which was done in the U.K. was done in people who were referred for diagnostic workup because of symptoms that their doctor felt were likely to be due to cancer. Only about 7% of those people actually had cancer. But nevertheless, the test was done the results were not disclosed. So they actually were mostly -- the sample was taken, but the result -- the test wasn't analyzed for some time. And the results show that actually the if you have a positive result, indeed, the chance that you had cancer is extremely [indiscernible] for symptomatic people. It was much higher than you saw in PATHFINDER 2. And the -- the other thing, which the new results from [ SIMPLIFY ] show that the people who had a positive test result, but no cancer was found initially over the next 2 years, 1/3 of them had a cancer diagnosed. And then PATHFINDER 2, as you've heard, shows that you can actually detect cancers before symptoms are found using this test. So these are people who are coming for screening, and it showed that you really do find cancers and that there were no safety concerns whatsoever. But all these studies are, if you like, showing that the test does what it sets on the [ care ], there's nothing to say that there's really a good advantage of having the test done. And that's what we wanted to set out in NHS-Galleri. That not only can we detect and locate multiple types of cancer. But by doing that, there is some benefit to the individuals. And so if you like, the first 3 studies are all to do with clinical validity whereas the other one is really the utility. Is there an advantage to you of having your cancer found early by going for screening? So NHS-Galleri is being done in England, possibly because we say that the lifetime risk of cancer in England is 1 in 2, not 1 in 3, but I think that's probably just because we calculate things a little bit differently. Cancer rates are very similar in the U.S. and in the U.K. with a few exceptions. It's a very large study, 140,000 people. I was a graduate student at [indiscernible], the [ Husky Stadium ] takes 70,000 people. That's the number we've got in each arm [indiscernible] NHS-Galleri. I think a lot of you are from New York, I think 140,000 is like 3x the capacity of the [indiscernible] Stadium. We wanted to make sure that we could compare actually what happens if you add the test and if you don't have the test. So all 140,000 people had a blood sample collected and we only randomized them once we had that blood sample. And then they were randomized to analyzing the blood sample, or storing it for future work. So half the people, 70,000 have had their test screen. And if it was positive, our team called them up. So [indiscernible] were analyzed here in the states some of them here, some of them in California. And the results we got back mostly within 2 weeks. We phoned the people up to tell them about the positive result and made an appointment for them to go to an appropriate clinic straight away. All individuals, so we didn't tell people which arm they were in, unless we phone them up to say you've had a positive test. So all individuals were then invited back for a second blood sample at 12 months, and a third blood sample at 24 months. And in that way, this study is going to be able to tell you a lot about the performance of the test, not only when you first do it, but also on a subsequent test as what we call an incident screening round. So if you saw in PATHFINDER 2, there were quite a lot of Stage I cancers found initially on screen. I really hope that there'll be far fewer found at 12 months and 24 months, and this will give you very large amounts of data to look at the performance of the test in that way. But it also means that we can compare what's going on in the 2 arms. And is it true that the people who have screened are less likely to get an advanced stage cancer [ Stage III ] and Stage [ IV ] cancer than those that were not screened. And if we can do that, it's Stage [ 3 ] and Stage [ 4 ] cancers that mostly are what kill people of cancer. Most Stage 1 and Stage 2 can be cured. And so if we can shift that we will really be doing something very useful, and you can say, be sure that screening with this test annually is a good thing. So I want to talk about the time lines of the trial for a moment. We promised GRAIL that we would start recruiting in August 2021. My team were not so happy. They thought there were all sorts of problems. So we recruited a few people on the 31st of August 2021. But then in September, we sorted out all the teething problems, and we recruited 140,000 people in 10.5 months. That's the fastest recruiting clinical trials since the [indiscernible] vaccine trial in 1954. I've said that a few times. No one has corrected me, so I think it's probably true. We collected blood samples at 12 and 24 months. So the last of the blood samples was collected in July last year. The main analysis that we hope to publish next year is on [ Kansas diagnosed ] up to July of this year. It takes some extra months because cancer registration doesn't happen instantly. And in fact, it's incredible that we're going to get results within about 6 months. That is a quarter of the time that it would take typically -- the cancer registry has been trying to get to 2 years and often, it's been 3 years before they've been able to publish results we've got complete data on cancer. So it takes a long time for the data to get from the hospitals to the registry and to be clean. And [indiscernible] then be to other waves of publication so that the individuals in the study will be followed up for mortality, did they die, what did they die off? 2 years beyond that time and then a further 3 years. So it will be 6 years from the last person having an appointment in the trial, or 8 years from the from when they were last randomized. So the main endpoint is a reduction in advanced stage cancer. And this is a little bit controversial. So I want to talk about it a little bit. And the first is that I think it's really important to think about [indiscernible]. Much of my career, I worked on parcel cancer, HPV vaccination. So I want to talk about that for a minute. We now know that [indiscernible] cancer is caused by HPV infection. If you have a persistent infection, it can start to lead to a precancerous lesion [ soapeneoplasia ]. If that's not treated, it can go on and to become invasive [indiscernible] cancer. And if you had a [indiscernible] cancer and you didn't treat it, or even if you did, you can get death from [indiscernible] cancer. If you can prevent the infection, you'll be able to prevent the death of [indiscernible] cancer. No one said that you had to wait and show a reduction in mortality from [ cervical ] cancer in order to introduce HPV vaccination. And in fact, it was only 17 -- no, slightly less, about 15 years after we introduced HPV vaccination that we were able to show a reduction in [indiscernible] cancer as a result of that vaccination. Similar argument [indiscernible] cancer screening. Cancer progresses through stages. For most cancers, prognosis gets substantially worse for the more advanced stages. If you find a cancer earlier, screening will lead to fewer advanced-stage cancers then the -- because the advanced [indiscernible] had substantially worse prognosis, you're going to likely to reduce cancer-specific mortality. What data that exists shows that this is true. So these are metro analysis, each dot on this graph corresponds to a different randomized controlled trial comparing screening to no screening, different types of cancer screening. On the vertical axis, it's the relative reduction in cancer mortality. And on the horizontal axis is a relative reduction in advanced stage cancers. And you can see that the results are highly correlated. Virtually everything is either in the top right, saying that screening worked on both measures, or the bottom left that it really didn't work. And there's a second paper, which had more studies in it showing there. And so if you reduce late-stage cancer, it makes [indiscernible] sense, that is going to result in a reduction in advanced stage. And if you wanted to look at mortality, we're going to have to wait longer and we'd have to screen more people. The study would probably have had to be 50% larger to last twice as long, and we would have no results for a long time. In that period of time, you could be making a lot of progress in terms of rolling out screening if it works. And this graph, which is from the same sorts of studies, but here, there's one dot for each type of screening. So each one is a meta-analysis of that type of screening. And this is the significance. And you can see that if the results were not significant for a reduction in late stage, they were not significant for a reduction in mortality. And if they were significant, they were significant for both with one exception, and that was in liver cancer, where at the time these studies were done, everyone who got liver cancer even if they were [indiscernible] stage 1, died from liver cancer. So how are we doing this? So first of all, we're going to test for a reduction in Stage 3 and Stage 4 cancers from these 12 prespecified [indiscernible] that account for 2/3 of cancer mortality in the U.S. and the U.K. If that significant -- the result is significant, the trial has shown that it can reduce advanced-stage cancers from these 12 types. But if it is, we want to look further. Does it have an effect on other types than the other than [indiscernible] or does it have an effect overall. And so we can do additional testing, first looking at everything other than prostate cancer, then everything, including prostate cancer. And because we're doing the sequential testing, we're only going to do the test, if the test before is significant, there's no problem with multiple testing. There are lots of secondary objectives and some of the key ones is to see if there's a reduction in Stage 4 cancers, which are the most deadly cancers. We also want to look at the test performance. There will be 10x as much data from this trial than there has been so far from PATHFINDER 2 in terms of test performance. It really is a massive study. We'll look at the overall cancer detection rate. It's not important, if you like, that the sensitivity is poor compared to other screening tests because it's screening for lots of cancers at once. What's important is how many cancers you're finding, how many cancer deaths you will be preventing for every 100,000 people you screen. We'll be looking at safety, important. We're not expecting any adverse safety signals, but it's really important to demonstrate that at scale, this is safe, health care utilization. What actually happens, how many tests are we having to do in all these people are going to be testing positive. And we'll be eventually comparing cancer-specific mortality between [indiscernible]. So in terms of kind of specific mortality, hopefully, towards the end of next year, we should be able to look at predicted mortality, which is sort to say, based on the cancers that we have diagnosed, the stage that they were at, what do we think about when those individuals might die from cancer. We'll then in 2 years' time -- 2 years later, look at the actual mortality on a nested analysis, which gives us far more precision in able to look at that. And then 3 years after that, we will look at the observed mortality in the whole cohort. Thank you very much.

Okay. Thanks very much, [ Peter ]. My name is Harpal Kumar, for those of you who haven't met, great to see you all here. So have time now about 15 minutes for any questions that anyone has. So straight over here.

There's a roving mic. So if you just wait until the mic gets to you for any of our 4 speakers so far. Someone get [indiscernible].

I'm Subbu Nambi from Guggenheim. This question is for Professor [indiscernible] You articulated the endpoints on the NHS trial on Slide 36, basically the primary endpoints. Is this how the FDA will also look at this study?

Just someone else want...

Let me take a stab at that. Yes. So the FDA has been pretty clear in their several advisory boards. They are not looking at mortality. So the FDA is going to be looking at what they call clinical validation, clinical performance. And that's why in our submission, we're just submitting the data that we have now, which is the prevalent screening round from NHS-Galleri. They are on record saying mortality is not anything that they're looking at. And clinical utility typically is not something that the FDA looks at for approval. They're really looking at clinical validation.

Got it, Josh. And Josh, could the [ SIMPLIFY ] trial data, which was presented at [ EDCC ] be sufficient to be a supplemental to existing [ PMA ] so you get approved as a diagnostic test for symptomatic patients?

It's a terrific question. We talk about that often. Remember, and maybe Harpal you're better to answer this. It was an observational study. And so what our thinking is, is that should we decide to pursue that, which is a good idea, we would likely need to do an actual prospective study in that population. Because remember, we -- as Dr. [ Casini ] mentioned, we did not return results in that particular study, but the results are quite compelling.

Okay. I saw lots of other hands. So can you just put them up again? Right next, and then I'll come to you.

This is Doug Schenkel from Wolfe Research. Actually, let me build off of Subbu's question on [ SIMPLIFY ]. So I remember being part of the pre-IPO process and you guys actually having a product in the pipeline called [ DAC ]. And I should be able to off the top of my head, remember what that acronym was for. But essentially, that's essentially what I think SIMPLIFY is getting at. So the follow-up question, to Subbu, is I think the -- we need to think of that assay, and just correct me if I'm wrong. But that's where you really want more of a rule out test rather than a rule in. So again, I want to make sure I'm thinking about it correctly. And if I am, from a negative predictive value standpoint, which I think would be the more important metric, I think there were studies that showed 97% and 99%, I think SIMPLIFY was in that range. Is that high enough for that population?

Should I take this one? Doug, thank you. So largely remembered very well. [indiscernible] for cancer. So what we did in SIMPLIFY was we looked at patients being referred to a number of different types of clinic based on what their primary care physician suspected was the type of cancer that they had. And your memory is extremely good. But just to boil it down, the best performance in terms of negative predictive value was in patients suspected of having upper GI cancer. So liver, pancreas, stomach esophagus and so on. And there, the negative predictive value was 99.1%. So that is probably good enough as a rollout test, given that the background incidence of cancer in that population is higher than that. But that's exactly what we want to sort of test further in a prospective interventional study as Josh referred to just there. It was lower in some of the other types of clinics. But again, that was an observational study, and we would want to test that in an interventional way. What's really important is that a large number of patients who are suspected of having cancer have very nonspecific symptoms. So these might be things like kind of unexplained weight loss or abdominal pain. And it can be very difficult for primary care physicians to know which clinic to send them to because it could be several different types of cancer, or it could not be cancer at all. And often, that initial choice of clinic turns out to be wrong. And so that's how patients end up going through a diagnostic [indiscernible] and taking a long time to get diagnosed. So there is a real opportunity there that we want to explore.

Maybe just two more points on this. So the CSO predictive capability of Galleri in this setting is uniquely important because, as Harpal said, it's almost impossible to know to send them to the [ OB/GYN ] clinic or the GI clinic what to get worked up. And even those false positives that were then converted to true positives, the CSO was right almost every time. There was like one exception, I think. And the other thing I'll point out to you about negative predictive value, it was very high in the SIMPLIFY trial. It was just as high in PATHFINDER 2, okay? Negative predictive value was 99%. And that's, I think, critically important to get the right balance of sensitivity and specificity, PPV and NPV.

So you'll indulge me a little bit more on this, and that was all super helpful. And I understand, I mean, ultimately, the vision for the company is getting through the FDA, getting CMS reimbursement and having this as a test that's available broadly amongst the population you talked about. If at the same time, there's a limit to what you can [indiscernible] there, right? I mean you're doing all you can do from a study standpoint. You're going through the FDA. You're still waiting for a congressional action to actually put you in a position where you could get reimbursed broadly. With that in mind, when I think about SIMPLIFY, when I think about, Josh, what you just said about what you saw in PATHFINDER, when it came to symptomatic patients and how the study or how the assay performed there, when you looked at the detection rate of patients who want -- or individuals who once were patients in had cancer, there is a very good argument for this assay in a more symptomatic population, or a population that is at higher risk. Either they had cancer before or they had hepatitis. So they're at heightened risk for liver or dense breast women who really can't benefit for mammography. If we think of -- I could go on, but I won't and I've talked a lot already. My question is, are there alternative paths to reimbursement? From CMS, I could see where this goes from being seen as a screen to more of a surveillance tool, which might allow you to get reimbursed [indiscernible] I've heard about some self-insured employers looking at this as an attractive way to earlier detect cancer in higher-risk self-identifying populations. I just might be wrong. But if not, am I thinking about this thinking about things that could give you alternative paths to getting paid?

Yes. So it's a great point. Let me take a stab at it and jump in. I think -- in the United States, you've correctly identified the challenges with current -- getting to broad reimbursement. But -- and there are alternatives. We've looked at the alternative around surveillance and it's not quite so certain. And we've explored that directly with [indiscernible] and others. And there's a lot of uncertainty around that as well. If it was so clear, I think we might have thought about it a little bit differently. We do know as a diagnostic test, there are clear pathways through [indiscernible] that are not available for screening. And we've contemplated that. We definitely made a very conscious decision at the time of the spin to get very focused on Galleri. And that took all the company's resources to get where we are today. As we emerge from that effort, we are looking at these other opportunities very carefully and Harpal's leading our charge really and looking at that symptomatic population. Just to clarify one thing you said, we didn't have symptomatic people in PATHFINDER 2. I was just pointing out to the high-end PVA symptomatic screening, which I think is -- we're making the same point that, that's really high even there. But there are opportunities in the symptomatic. We do know it is being used in that population by doctors today and these other high-risk populations, people with prior viral infections, people with prior cancers are elevated risk groups that should have access to Galleri's screening test. Whether we do surveillance or diagnostic in them, I think is yet to come. So stay tuned.

I want to make sure we get some more questions in because there are lots of other hands on. So yes, over here. Yes.

This is David Westenberg at Piper Sandler. So just on the positive predictive value, can you talk about the time that elapsed from a positive diagnosis on GRAIL to a, say, ground [indiscernible] positive? And is there a way if you found that maybe you are finding cancers a little bit later, is there a way to [ run ] a supplement, or submit a supplement to the FDA, if that one being the case?

So [indiscernible], do you want to take that first?

Yes. So I think you're speaking to the metric of the time to diagnostic resolution. We call it diagnostic resolution, a time point whenever the investigator feels that we've exhausted all of our methods of trying to find a cancer. And for all patients, it was 46 days. It was faster for true positive patients. An example is somebody with a hepatobiliary signal. You get a CT scan, you almost immediately see a cancer, and you call it pretty quickly, whereas false positives were longer than that because you're going down the next step pathways of trying to find a cancer. And certainly, I think there's an element of us looking harder now because PATHFINDER 1, with a high PPV, kind of encouraged us to maybe not set aside some indeterminate imaging finding, but to kind of aggressively pursue it. Many times in my experience, uncovered novel cancers. And yes, I mean, it's I guess the second part of your question was...

It was related to the FDA. Can you repeat that part of your...

Wanted to ask if you found cancer, say later in some of the submission data, like 2 years later, they come up with the cancer or anything like that?

So that didn't happen. So what we're referring to in the SIMPLIFY study was in symptomatic individuals, which is not our PMA submission to the FDA. In symptomatic individuals when we looked at those false positives and followed them for 2 years more, I'll let Dr. [ Casini ]

But it is worth saying in PATHFINDER 2, we are going to be following up all of those patients for a further couple of years. So we will know if the same thing happens what we've seen in SIMPLIFY whether the same thing happens in PATHFINDER 2 patients. The suspicion is, yes, that is going to be the case, but we don't have that data yet.

So it won't be part of the PMA submission right now. But to Harpal's point, we're going to learn a lot about that over the next 2 years of follow-up.

I'd ask one little follow-up to that. I will not ask my second question given the time. Just in terms of -- I believe your policy is to run a second Galleri test when you do have a false positive. Can you talk about what results you -- the statistics that you found when you ran that second Galleri test? Whether you've seen positive revalue and negative it value improve on that second one or not?

So what we can say and jump in anybody who knows in commercial practice today in the United States. If a doctor, and we will ask our doctors on the next panel, if you get a positive Galleri test and you do a workup and it's unrevealing rather than suggest whole body imaging, or ask you to just give up, we actually offer a free repeat Galleri test. And in that setting, if those repeat gallery tests are negative, we have found almost very few instances where those individuals end up being diagnosed with cancer. So it's got -- we don't have enough sample size to compute a valid negative predictive value yet, but it's very high. And similarly, when that second Galleri test comes back positive, again, they are most often found to have cancer. I'll just give you an anecdote to what [ Nima ] just said. We've gotten several phone calls, I get these phone calls from doctors who've had positive pancreatic signal, or the 2 that are the most common. And they have ill-defined imaging findings, subtle inflammatory changes in the pancreas, for example. And I get called saying, hey, should we give up? And my answer is usually no, do not give up. And they do an endoscopic culture sound and in the 2 cases that have just most recently happened, they found head of the pancreas tumors in both of them. So again, if you get another positive signal, it is very likely to have cancer. Yes. The false positive rate gets cut. I can't give you the exact statistics. But that -- it almost eliminates if there's another positive signal, it takes the false positive rate way down.

Over here, yes.

Its Alex Vukasin on behalf of Canaccord Genuity. Aaron, just 2 on the business generally to start. What will the impact of discounting beyond ASP going forward?

Yes. So we've got a list price of [indiscernible], and we discount down from that based off of volumes. As we get more and more large physician practices or digital health platforms that are offering the test, they'll hit higher volume tiers and the test price will come down. We've -- we're prepared for the test price to come down. If you look at the CMS legislation, it reimburses at around $500 a test. We built this platform to be able to accommodate that. And so we're prepared for that. But that -- how rapidly that changes will really drug be driven by how fast uptake is in -- with our current pricing scheme.

Got it. And one more quick one from me. So in a perfect world, the NHS study is successful and enables wide-set adoption across the geography. My question would be, provided the study is ultimately successful with a strategy of leveraging other national health organizations to run studies in a similar fashion, becoming such a part of the adoption strategy going forward, or something of that nature already in the works or front of mind?

Yes, why don't I take that one? We don't think we're going to need to replicate something like the NHS-Galleri study in other countries. This -- if you look at any new medical innovation, you tend to have one major pivotal registrational study. We've actually got a couple of registrational studies. You don't need to repeat them in other countries. Some countries do want to have smaller local studies done really to test it in their population. Usually, that's for reimbursement purposes. Sometimes it's for regulatory purposes. But those are typically much smaller. They're not big randomized studies of the sort of nature that we've been talking about for NHS-Galleri.

Okay. We're going to have to cut it there. I'm afraid for time. We now have 10 minutes, I believe. I'm looking at Alex at the back. Yes, where you can grab your lunch, go to the restroom if you need to, and then we'll start again in 10 minutes. And the lunches are right back here, behind this well. Right here. Thank you, everyone. [Break]

Ladies and gentlemen, please welcome back to the stage, sir, Harpal Kumar.

Okay. Thank you, everyone, for coming back promptly. I hope everyone has managed to get some lunch. Please do carry on eating while we're talking. So we're going to move into more of a commercial section now. So I'm very briefly going to cover some comments on the international opportunity, and then Andy Partridge will talk about some of our experience in the U.S. so far. So on the international opportunity, many of you will have seen this slide before, and Josh alluded to it earlier, cancer is a huge global problem. And we talked about the fact that it's the #2 cause of death currently around the world with the latest statistics, more than 10 million people are diagnosed every year. But to give you some context about what's coming in the next 15 years, that's projected to grow to nearly 29 million incident cases every year -- sorry, 19 million currently, projected to grow to 29 million in 15 years. So about a 50% increase in the next 15 years, and it's going to continue growing thereafter. These are World Health Organization projections. For those of you who are more interested in the U.S., the projection is that by 2040, cancer cases are going to grow by more than 1/3 from where they are today. So the numbers are growing really very, very rapidly, and we are, as I just touched on, we see this as a huge global opportunity and one where we want to bring this technology to bear on participants, individuals right across the world, not just in the U.S. or U.K. The numbers are staggering. So we see, as you'll have seen before, the opportunity in the U.S. is a TAM of about 100 million people. If you add in the EU, U.K. and Japan to that, it takes it up to about 300 million people. But of course, there are many, many other countries besides that. There's all of Asia, there's all of Africa and so on. So this is really an extraordinary -- both opportunity but also challenge given the [indiscernible] of cancer cases we have coming our way. So what have we been doing? We've really been focused in the short term on identifying partners we can work with in specific countries where we can rely on their local expertise and infrastructure to bring Galleri to their populations. And at the moment, while we're in this largely pre-reimbursement phase in the U.S., we're looking for ways in which we can do that in a very resource and capital-efficient way. In other words, not having to embark on building a lot of sales and marketing infrastructure in those countries, but as I say, identifying partners that we can work with. And so where are we today? Well, we've launched in a few countries around the world. We launched in Israel just about 10 months ago, 10 or 11 months ago. We announced just a few weeks ago that we've launched in Canada -- sorry, Israel is with a partner called [ Oncotest ], Canada is with a partner called [ Medcan ]. And obviously, in the U.K., we also have our partnership with the NHS, where pending results from an NHS-Galleri next year, we hope to have conversations about moving that forward. And as you know, a few weeks ago, we also announced a collaboration with Samsung to bring Galleri to Asia, starting in South Korea, and hopefully expanding thereafter to Japan and Singapore. These are all very substantial market opportunities. But as I say, where we're relying on our partner to be able to bring Galleri to them -- to those individuals in those countries for now. Of course, there's a big wide open space in terms of countries we have not yet launched in. But I will just tell you, perhaps this is no surprise, I'm getting calls from pretty much every country around the world. On a pretty regular basis about how we can bring Galleri to those countries. The challenge at the moment is finding the right partner to work with in those countries. So but we are having many very interesting and encouraging conversations. So continue to watch this space. And so just a couple of more words on the Samsung collaboration, which we announced a few weeks ago. So this will be Samsung developing an infrastructure to bring the Galleri test to individuals in South Korea, as I say, possibly extending thereafter to Japan and Singapore. At the outset, those tests will be performed here in [indiscernible] We're also going to be exploring some potential opportunities to collaborate with Samsung Electronics, which has a very wide array of interests in health care and medical technologies more generally. And those conversations haven't started yet, but there are some potentially interesting avenues that we want to explore with them. And then also, as you know, between the Samsung Holding Company and Samsung Electronics, they will be investing $110 million into GRAIL, subject to us finalizing the closing conditions that we've told you about. So a really exciting collaboration that we are moving forward. And again, just to give you a quick insight into some of what we're doing internationally. And with that, I'm going to hand over to Andy Partridge, our Chief Commercial Officer, who's going to tell you about our U.S. experience.

Thanks so much, Harpal. It's an incredibly exciting time to be in the commercial organization at GRAIL. I really do believe we've got a tiger by the tail with the Galleri test. We have a huge unmet need for cancer screening, a large addressable population worldwide, and best-in-class product performance with Galleri. We're detecting cancers every single day. Many of them early stage. Those of us -- those of you who are here with us in [indiscernible], can see all of the posters throughout our laboratory here of patients that we picked up with early-stage cancer due to the Galleri test. We're also years ahead of other companies in terms of the expansive clinical evidence generation program that we've embarked upon, which is now reading out, generating excitement with our customers and building palpable momentum for us. We're also a long way ahead in terms of the partnerships that we've developed over the last 3 years, and we have [ 2 ] upcoming milestones that are going to generate additional customer confidence and excitement with the PMA submission and ultimate FDA approval, and the readout of our NHS-Galleri study. We're continuing to drive volume, 26% growth year-over-year that we reported yesterday for Q3. That's driven by growth in our provider channel, which was 37%. That growth is due to increases in both breadth and depth of prescribing. So, so far this year, we've added almost 3,000 new prescribers for Galleri. And we've also increased the depth of prescribing for those prescribers by 20%. The drivers of the increases in depth have been repeat testing, contracting and discounting targeted media and new customers that we've added. And in terms of repeat testing, we're now seeing 29% of our volume is from repeat tests. And it's exciting because some of these repeat tests with patients who are on the second or third year now of Galleri testing after they had no cancer signal detected in the first or second year, are now seeing cancer signal detected in those subsequent years that end up with earlier stage cancer detection, increasing physician confidence even more about the Galleri test. And in terms of volume, we've done about 40,000 tests over the last 12 months, which were repeat tests. Also, our electronic order integrations have increased the depth of prescribing as well with partners such as Quest and Athena Health. So year-to-date, since we moved forward with a number of these integrations, we've had about 13,000 tests go through these new electronic integrations, which is essentially an easy button for physicians. As we've now incorporated Galleri into the workflow that they have every single day, making it much easier to prescribe Galleri. And we've seen a number of benefits from that. We have about 1,000 providers now that are prescribed through either the Quest or [ Athena ] integration. These integrations have led to new providers coming on board. So over 300 of those 1,000 providers were new prescribers for Galleri. Those were physicians that did not want to prescribe until we actually built Galleri into their regular work order flow. We've also seen an increase in prescribing. So for those prescribers that were already using Galleri after the electronic order integrations, we've seen an increase in the depth of prescribing from these prescribers. Initially, a big bump which then plateaued down, which is a meaningful increase post electronic order integration. And we've also seen improvements in efficiency. Improvements in efficiency as you see from Quest with things like kitless, shipping, bulk order that's improving our efficiency and also the electronic order integration has reduced accessioning issues. So with paper orders, we see a higher accessioning issue rate, which takes our customer service team time to resolve those. With these integrations now, that significantly reduced those accessioning issues. And with [indiscernible] Health, that's our telemedicine partner. They support orders coming through on [ galleri.com ], and they also support many of our enterprise clients as well and [indiscernible] Health has proven to be a very reliable partner for us. We're also the leader in digital health. This is part of our overall market access strategy. Longer term, we're focused on securing broad public and commercial reimbursement focused on Medicare through the legislation. But shorter term, digital health with access to large patient populations who are health focused and cash pay through partners like [ function health ] and [indiscernible], give us an opportunity to increase the market access to Galleri immediately in the short term. These are also scalable and also digital health partnerships are driving health system engagement. As we work with the digital health partners on that post positive follow-up for cancer signals that they detect, as those are referred to health systems, either they are already partnering with GRAIL and have already incorporated Galleri, or those health systems have them, that's a catalyst for those health systems to engage with us so that we can integrate Galleri into those health systems going forward. It also gives us an opportunity in terms of our international expansion, as many of these digital health partners, even though they're U.S.-based, have global operations. That's also an opportunity for us to expand Galleri with these digital health partners ex U.S. We're also growing in the self-insured employer space. We have now over 150 self-insured employers that have incorporated the Galleri test across multiple different industries. The key driver for many of these self-insured employers is that cancer is the top condition now for 4 years in a row, driving increases in costs for employers, for their health plans. So there's a big focus for the employers to get those costs down. We're working with 14 national and regional payers now that are supporting these employers, and those 14 national and regional payers are processing claims giving them access to Galleri data for their beneficiaries, which is helping us engage with those national and regional payers going forward. And this ecosystem also means that health systems get involved for for positive Galleri tests, again, driving this ecosystem, connecting employers, health systems and payers. In terms of these health system partnerships, we have the Mayo Clinic and [ Dana Farber ] publications, which are real world evidence, which have shown performance in the real world has actually exceeded our clinical trial data with -- you saw for earlier PPVs in excess of 70% published by both Mayo Clinic and [ Dana Farber ]. We have multiple additional health systems who have partnered with us who are working on their own publications of their own real-world evidence. We have a number of health systems that have incorporated Galleri into their primary care and specialist workflows, such as [ Rush, Community and Mercy ]. Many health systems have taken the next step and incorporated it into their own employee populations. So Intermountain, HCA, Community and Children's Health offer now the Galleri test to their own employees of the health system. And again, this is driving more payer engagement as health systems come on board. So with that, enough hearing from me. I think it's now time to hear from our customers. If we can bring up Anil Saldanha. He's led the integration at [ Rush ] in Chicago, where they, this year, integrated Gallery into their primary care and specialist organizations. Dr. Andrea [ Clemes ], Chief Medical Officer of MDVIP is going to join us. They were one of the first, if not the first partner for GRAIL back in 2021. They've done tens of thousands of Galleri tests throughout their network. Dr. [ J. Friedman ], internal medicine physician from Scottsdale, Arizona. Incorporated Galleri in 2021. Done, I think, over 2,000 tests in Scottsdale for his patients and Dr. Eric [indiscernible], I think, incorporated Galleri in 2022 and now done over 1,000 tests in his practice in Century City in Los Angeles. So please come up and Josh is going to moderate a panel.

Okay. We're back on. Please. And do we have [indiscernible] on video?

I'm here.

[ Andrea ], thank you so much for joining us. Can you hear us okay?

Yes, all good.

Oh, there she is. Great. All right. Well, it's a pleasure to have you. I guess we've done introduction, so we might as well jump right into it. But before we do that, is there anything you'd like to say about your background? Is anything else, Erik, Anil, Dr. Friedman? No? Okay. So let's jump right into it. So let's start kind of big picture. Let's talk about what drove each of you in your own ways to adopt multi-cancer early detection testing, and how you do that within your practice or your organization? So Eric, maybe we'll start with you.

Sure. So I only became aware of GRAIL and Galleri cancer screening in September of 2022, a little over 3 years ago, and I only became aware of it because one of my patients asked me about it and I never heard about it before. So we reached out the GRAIL and they presented us a lot of the information that you're hearing today, and it sounds really incredible. My first thought was, is this going to be the next [indiscernible] where it's a lot of smoke, but is the technology actually there? But here I am 3 years later, 1,034 Galleri screenings with [ 62 ] positive Galleri tests. I think it's incredible stuff, and I think it's only going to get better.

And Eric, maybe just to follow up. How do you communicate the value of early detection to your patients?

Well, we all know the toll that cancer can take not only on patients but on families and loved ones. And if heart disease and cancer are the top 2 killers in the country, and most of our patients are hopefully not dying from cardiovascular disease because we're proactive from that standpoint. How can we be more proactive from a cancer screening standpoint? And so with the 5 current cancer screening guidelines that we have available, we're not really doing that great in terms of being able to detect cancers that people are dying from. So by offering Galleri [indiscernible], we're doing is offering ourselves an opportunity to take a huge step from a proactive screening standpoint when we know the early detection matters.

That's great. Anil, tell me a little bit about how -- what led [ Rush ] and your push at the Rush Health System to include gallery and how does it kind of align with what Rush is trying to do as a leader in health care?

So I just want to take like a historical break in terms of what Rush is. So Rush kind of started with the medical college and it was incorporated in 1837, a few days before the City of Chicago was incorporated basically. So we are pretty old like 170 years plus. And Rush was named after Dr. Benjamin Rush, if you remember, who signed the declaration of independence. So we have a long history of being in Chicago, a major city and catering to our communities. And Rush is focused on a mission, which is around something called Chicago's [indiscernible] gap. And it's very interesting. We have -- depending on where you are born and work. So if you are in what you call the magnificent mile in Chicago downtown and you take like 4 subway stops west, you live 16 years less. So an interesting [indiscernible] a discrepancy that we -- our research has found a few years, and we have called this the Chicagos [indiscernible] gap. And if you go south, it's 30 years and beyond. So Chicago has a life expectancy issue. And when we looked at some of the contributing factors and cancer was one of them. Fast forward in different directions, I work for a health system. That's really complicated just for me to say health system. It's -- we have 3 major hospitals, multiple outpatient centers. And when you have a complicated system, there's a lot of problems, right? And one of our mandates is to improve cancer screening as part of our quality efforts. And if you look at the challenges that you see in cancer screening you will appreciate a test like [ Galleri ], right? The screening, we do really well. Not just Rush, but as an industry, we do really well on breast cancer screening. Lung cancer, we suck. Absolutely suck. And we only looked at like 5 cancer types for which you have like designated, like screening or diagnostic tests. When GRAIL was basically talking to Rush in the early days. Of course, I had a history with GRAIL. I was on the founding leadership team of the company called Tempus 10 years ago. And I used to talk to researchers from abroad who used to tell me, there's this new fascinating area called liquid [ bioxy ]. And I was like, wow, this is going to revolutionize cancer detection. This was 10 years ago. So when GRAIL started talking to us, our Director of Iris Screening, Dr. Lisa [indiscernible] at Rush, she's screening patients, leading programs, this mammography, vans and stuff, we really find it very, very hard to screen patients. Of course, there's quality numbers to meet but it's not easy as a system to do this recommended screening. So when you have all these challenges with screening, where you looked at this test, it was very attractive. There was one more reason which our [indiscernible] risk screening Director, Dr. [indiscernible], She's an oncologist. She was very fascinated by the prospect of using GRAIL for aggressive cancers, right, for which there's no other biomarkers, no recommended test. So all of this put together, it was very attractive for Rush to embrace. Not only to offer it to our patients, but also to look at this mission we have, which is to reduce the [indiscernible] discrepancy or Chicago's [indiscernible]. So we did it for our mission for our patients. Some of the other systems may have done it for other reasons. But for Rush, we want to offer the best outcomes for our patients, basically.

Well, thank you for that fascinating answer. Andrea, over to you. And how do you think -- or how has Galleri really fit in to the preventive care model that you've implemented at [indiscernible]?

Sure. Thanks, Josh. And sorry, I'm not with everybody today. They had a really bad travel thing over the weekend, and I decided to stay put this week. But [indiscernible], just a little bit of background also. We're not as old as Rush. But we have been around for 25 years, and we're a national network of primary care physicians, like over 1,300 over the United States, taking care of about 400,000 patients. Patients pay a membership fee for an executive style physical. But unlike getting one at Cleveland Clinic, or Mayo Clinic, you get a doctor all year long to work with you on your health span and action plan for wellness and prevention. Our mission is making healthier lives happen for doctors and patients. We'd like to take care of them both. We have [ 11 pure review ] studies showing that -- we identify more patients at cardiovascular risk, better control of chronic disease, more preventative care services done. We have less heart attacks and strokes and our patients live longer if they're at risk. And we save the health care system millions of dollars a year. So you can see we've been focused for years wellness prevention, early detection but mainly cardiovascular diabetes metabolic health. And my doctors would always ask me, what can we do about cancer and brain health? And so when GRAIL came to me before they launched, and my doctors, I know like to be at the forefront of medicine, we did a pilot with them just to see how would we work in our network? If our doctors would enjoy? I don't know [indiscernible] enjoy using it. We have relationships with cancer genetic testing companies. There wasn't a lot of uptake with that. Once we finished our GRAIL pilot, we rolled it out. And over the last few years, we've done 55,000 tests. Almost every one of my doctors has ordered at least one. This has been the greatest innovation I've ever seen uptake in my network. And so it gives my physicians that extra piece to focus on cancer prevention and really identifying it early because that's what we're all about.

Thank you, Andrea. James, for you, maybe you can share a little bit about why you've been adopting Galleri, but also maybe starting another threat about what you found as the most compelling and relevant performance metrics that made you kind of want to adopt this technology?

Well, my background is a busy practicing internist in Scottsdale, Phoenix area. So very heavy hospital work for 30 years. I am one of the early adopters of [ CT coronary ] calcium score back in 1987. I probably ordered more than anybody else in the Phoenix Valley. That has changed the trajectory of how we have managed [indiscernible] disease, and it has been proven to be a great way of risk stratifying and now it is just now standard after maybe 35 years. So I'm an early adopter, the physicians need to obviously manage complex patients, but we need to diagnose patients early. It's just the earlier, the better. And so I read about this multi-cancer detection serologic test. And I knew it was going to be probably early when I adopted it, but I have followed it really going back to my days in molecular biology study at UCLA. I knew that the answers are going to be in the DNA. And so I started using this test in '21, and it has made a huge difference. One thing that's not emphasized, but I sat on our tumor board for 30 years on our campus at our hospital, I'm part of the Honor health system. And at any stage that we diagnose cancer earlier than the later stage, we make a difference. The interventions, the targeted therapies that we have today, the pathway inhibitors, our cancer patients are doing so much better. I don't think that's baked into the data here. But in a real world where I see and deal with patients, these patients who are diagnosed in Stage 2 rather than 3, or Stage 3 rather than 4, I do see the outcomes, and it's far better than just patients showing up with symptoms. So we can catch these patients early. It makes the difference. It's worked out great in my office. I have a discussion on top of all the other cancer screenings are all emphasize, it would be a disservice to patients to focus on this Galleri test without them understanding that this is in addition to everything else that they need to screen for. Really important because year after year, they go, I had it last year, and I go, well, this is not a genomic test of your DNA looking for mutations. This is looking for circulating cancer. So now the patients understand that most of my patients want a year after year, and the uptake has been excellent, and I'm very excited about the data. The data just proves what we're seeing, but obviously, anecdotal to my patients, now we get to see supportive data that just makes it even more exciting.

Was there any particular area of performance like the false positive rate or the false negative rate or the PPV that was most impactful to you?

I think all of that, the PPV is excellent, getting better. I also know that through machine learning and through the AI that's still evolving, it's just going to get better. Like all the DNA tests, we know this is going to get better. We know it. And so I'm very excited for the future.

That's great. Thank you so much. All right. So we can see that across very different health care settings, different health care systems, there's this belief in the power of early detection, and how it can translate directly into improved outcomes for patients. But let's talk about what implementation really looks like on the ground. So Anil, how did Rush actually operationalize this? Or how do they go about doing it? And then we'll get to everybody on the panel.

Yes. I think I did mention I work for a health system, right? I want to say it again. I work for a health system, right? So I mean, until you work in a health system, you don't really appreciate the complexity of health care. So we started talking to GRAIL about a couple of years ago. So just going through the, I would say, the legal regulatory side of the house, it took some time, but we also -- I think when we look back, it was a great decision from Rush where we required GRAIL to integrate into our [ EMR Epic ]. So that took some time -- and this, of course, challenges with integrating with a major EMR, such as [ EPC ]. So -- but when I look back, that was a great decision or a requirement from Rush, mandating that we want this, right? So we wanted our primary care physicians to offer this to our patients, right? It took some time. There were integration challenges and [indiscernible] mentioned about some of the changes GRAIL had to do last year. So it was difficult from an integration perspective. But for -- but that was just more on the ordering side of things. But inside Rush, we had to change a lot of things. So we had to update or whatever standard operating procedures, SOPs, the clinical workflows, train or employ basically clinical staff. So it took a long time. And of course, you have to get people excited about a screening test, right? I mean not everyone is focused on cancer. And here, we were just primarily focused on the primary care side of the house, not even cancer right, and at the system level. So just to give you insights into the complexity, we today offer GRAIL, at 4 sites, or 4 centers in the Chicago land area. 3 major hospitals, but also a brand-new cancer center that we built, I think it was $70 million last year. It's a brand-new standalone because for [ Ruche ], access to care is one of our primary strategies. And when you say access to care, it means health systems start building new buildings new hospitals all over the place. So we offer GRAIL at 4 places. And -- so we had the [indiscernible] integration, which allowed us to order. But also we had to put together a clinical team, including a nurse [indiscernible] across all sites who are available whenever like we offer like these tests to patients. And I want to say this is a work in progress. We started offering GRAIL, I think, in September. Right around like maybe a week after that, we had a feature in Chicago Tribune highlighting [ Rush's ] choice of GRAIL and this blew up the entire region. We have not seen the kind of interest among our patients, among our executives, the family members of executives and of course, it makes me look really good.

Well, thank you for that. Eric, maybe over to you. As you've introduced Galleri to patients, two things. One, what kind of language is resonating best with the patients about this? And then you've actually, secondly, managed to have a very high retesting rate, annual retesting rate. You've achieved upwards of 70%. What do you think is driving that level of patient engagement?

For me, I think it's primarily about starting a conversation. And -- so I'll have a conversation with a healthy 25-year-old. And I'll preface it by saying I'm going to present some information to you, not because I think you need it, or [indiscernible] I think you need to consider it. But just because I think it's something people should be aware of. Might this be something that you would want your parents to consider. So you asked, have you heard about Galleri cancer screening? And barely the answer is no. Well, it's a newer blood testing that's looking for tiny DNA changes when normal cell tissue becomes cancer, self tissue and it can screen for 50 different kinds of cancer. It's being described as a liquid, [ biopsy ], it's a snapshot in time. Where if it's negative, you've got a 99% certainty of not having any of those [indiscernible] of cancer at that moment in time. There's no predictive value for a negative test, but it's technically being recommended to consider for anyone over the age of 50 because that's when everyone's risk of cancer increases. But particularly, if you have an own family [indiscernible] has kind of cancer and then to consider doing it on an annual basis not as a replacement for any current cancer screening guidelines like annual [ MAMR ] [indiscernible] females starting at age 40, or periodic colonoscopy starting at age 45. But it's meant to be as an adjunct to try to give ourselves the best chance to identifying any one of these cancers, most of which we don't have any ways to screen for. And we mentioned that the overall risk of a false positive Galleri test is 0.5%, which is unheard of in the cancer screening world. If you did get a positive Galleri test, the positive predictive value historically based on PATHFINDER 1, and actually meaning you have cancer was 43.1%. Oftentimes, people will hear that and say, so I do this test, I get a positive test. I have less than 1 in 2 chance of actually having cancer. That's not great. Do I really want to do this test and subject myself to that potential in going down that rabbit hole, not being found to have cancer. But what's the positive predictive value of an admirable mammogram and actually meaning someone has breast cancer? 4.4%. What's the positive predictive value of a positive cologuard stool test and actually meaning someone has calling cancer? 3.7%. So 43.1% positive predictive value of a positive Galleri test and actually meaning you have cancer is an order of magnitude better than what we're doing as standard of care. And based on this PATHFINDER 2 trial data from just released a few weeks ago, now that positive predictive value has improved to 61.6%. Fascinating stuff. And so when you present that information, it's really compelling. And then you'll oftentimes get the question of, okay, so if I do this test, do I need to do it every year? Can I do it every other year? Can I do it every 2 years? And my response is, well, if you find merit in this enough to start doing it. And you get that negative test with that 99% [indiscernible] any of those state kinds of cancer at that moment in time. There is some data to support GRAIL's recommendation to do it on an annual basis. There is an American Cancer Society study from several years ago, completely seperated from GRAIL. They looked at 300,000 patients who are at relatively low risk of cancer, ages 30 to 65 mostly female, nonsmokers. They [indiscernible] their blood and they've banked it. And they [indiscernible] over the course of 3 years for any incident development of cancers. When GRAIL became aware of this study, they asked to access some of that bank blood for the people that were diagnosed with cancer. And what they found was a Galleri campus signal might have been detectable on average of 323 days before the cancer was diagnosed, essentially a year. So there are some data to support the recommendation to do it on an annual basis. And if you think about starting to do it, getting that negative test with that 99% certainty and not having any of those in kinds of cancer at that moment in time, and you get into a cadence of doing it every year. If [indiscernible], you as my patient is going to get cancer, we're presumably giving ourselves the best chance of identifying it as early as humanly possible. So it's as treatable as possible with the least amount of toxicity from a treatment standpoint. [indiscernible] I want that for my patients? Why wouldn't I want that for my family and loved ones? And that's the conversation.

That's terrific. Thank you. And Dr. Friedman, you've ordered over 2,000 Galleri test since 2021. Love for you to share with the audience here what your workflow is like? And from the early education to how you follow up? And then also talk about patients who have initially tested negative and then how you have found cancer in annual testing?

So I have a large practice. So I'm coming from a zone of a busy primary care basically I'm [indiscernible]. So I have a very busy practice, lots of sick people, complicated [indiscernible]. But I do about 8 physicals a day, and I do a real physical. I mean, I am thorough. There is no shortcut to doing the right thing and taking care of patients. So I normally do address all their cancer screenings. It was a hassle. In my office staff bucked a little bit in '21, we have to have this kit, but the company has been great. This has made it so easy. So my patients know about it and some they're highly educated people. So they often actually ask me about it, even if I -- they're new patients, and I've never talked to them about it. But it's just another 20 seconds of explaining. I usually tell them that we've done a great job with breast, colon, prostate. People aren't dying like they were. 75% of the [indiscernible] now are really from head and neck, lymphatic gastric esophagy, liver, gallbladder pancreas and other aggressive cancers, and we're not doing anything for those cancers. And I think the people understand that. And so if they can afford it, they do it. And eventually, this is going to be a test that's going to be a lot less costly. I know it will be, and then we're going to do it for everybody. And I think that's going to be a [indiscernible] changing for the field of early detection.

And how about people who've had a negative test 1 year? And then what's been your experience with annual testing?

Again, I would say I have probably over 50% of my patients are getting annual testing now.

And have you found cancers and people who were initially negative?

I'm working up a lady now who had a positive endometrial signal, I did a [indiscernible] ultrasound. They didn't see something, but maybe they did. And so she's now going to get her MRI. I'll center one of my [ GYN ] oncologist getting her MRI at Mayo, I think, maybe tomorrow. But I'm working her up. I think we found it early because she -- this was her third test. So I think we probably found it early enough, hopefully.

That's great. Andrea, we've -- we've talked about how Galleri is able to flex in different systems. We can integrate with EHRs. We can be delivered in clinical practice settings and keeping that focus on prevention, you and your team have done over 55,000 tests. What's the most striking thing that you've learned about early detection, about the real-world performance and patient outcomes by looking at this vast experience within [ MDVIP ]?

Yes. I mean it's been exciting to see my physicians adopt this technology. And I think they have the same conversations as the physicians here have said. When you know about the false positive rates of other screening tests, you can have that really good conversation with patients. I know it's made a huge difference. I know of a [ doc ] in Alabama, who screened 55-year-old male with no symptoms and got stage one esophageal cancer. And those stories penetrate my network to say that this really is something. I have one of the leaders in the network, not only lectures my docs on Galleri, but also prospective MDVIP physicians. And you'll always say, we have 4 screening tests. And for everything else, we just cross our fingers and hope and this is much better than that. I was excited when you showed me the PATHFINDER 2 data to say that my cohort of 55,000 tests has the same positive predictive value, the same false positive rates, everything as the bigger studies so that my doctors are comfortable knowing that what's happened in clinical trials is really happening also in our real-world cohort.

That's great. I'll just share an anecdote with the audience here. There was a congressional hearing in D.C. about MCED legislation. And one of the patients, Roger, who had diagnosed with an early pancreatic cancer was on the stage and in the hearing. And he was getting grilled about the lower sensitivity than single cancer screening, the false negative rate. And his response to the congressional panel was current clinical care in this country has a 100% false negative rate for asymptomatic cancer. So what are you talking about? And that's what he gave back to the panel. And I think it was a fascinating way to present that data. That our ability to detect unscreened cancers before symptoms present in current health care today is effectively zero, unless something was found incidentally. I thought that was fascinating So time to just wrap up these stories and these lessons from you all are so valuable. But just in the last few minutes, in one line for each of you in your mind, and maybe start with Eric, what's next for Galleri in your practice?

Standard of care. My hope is that something like this can become standard of care. One piece of information that I share with patients that I think is quite compelling is that there are now over 10 life insurance companies that are offering Galleri cancer screening for free to their clients. because they see the data and they understand it's in their best interest to keep their clients alive as long as possible. It's an interesting dichotomy between the end game of a health insurance company, an end game of a life insurance company. But absolutely, I think my hope is that something like this can become standard of care.

And at Rush, what's next?

The key word I wanted to mention with our strategy with GRAIL is we have systemized the GRAIL test. That's a very important keyword. And we are the only system in the region to offer the systemized workflows for GRAIL. Which means we not only offer follow-ups to the patients we screen at Rush, but for everybody in the region with a positive signal, and we are already seeing those patients from conscious practices, from rival systems, who haven't systemized. So we are getting those patients into Rush for follow-up care, like diagnostics, whatever. So we -- that's why we took a long time in systemizing the GRAIL test. And this is part of our system strategy going forward already.

James, what's next for you?

I would just echo what Eric said. I really think that this -- I've been in practice 39 years, and I have not, I think, led my patients astray ever. And we have enough evidence, I have enough evidence that I know this is going to be standard of care [indiscernible] in the next few years. And so I will continue to be using this test in the future, of course.

And Andrea, let's close with you. What do you see as the next step for Galleri in your organization?

Thanks, Josh. Yes, we're looking at the differences in adoption across my network because we do have 55,000 tests, but that's out of 425,000 patients. And so we know we need more adoption across the network, how can we increase utilization? We've done some fun things like events in the doctor's offices where you guys are so nice in bringing a [indiscernible] and we do the test on all the patients who show up at the event. What other things can we do like that and what other ways can we make GRAIL available to our patients so that my doctors can say the same thing that the gentlemen in the state can say that this is the standard of care.

Well, thank you so much. So just in closing, I want to thank our amazing panelists for your contributions. Obviously, this is the type of technology that can transform the way you deliver care to your patients. And gives you a new tool to address the burden of cancer in ways that we've not had before. And I want to thank you for your efforts, for the insights that you've shared with us today. And this is just the beginning. So hopefully, we'll all come back in a couple of years and share even more. So thank you very much. And what's next? I think -- Yes, Andy, come on up. We're going to do a Q&A now to the team. Yes, Andy, we're going to join us up here for Q&A. And I'm sure there are some great questions. Andrea is still on the line as well. Where do you want to start?

Anybody, any questions from the audience? Doug?

Two quick ones. Dr. [ Saldana ], and first off, thanks to all of you for taking the time with us today to all of you. My guess, and I could be wrong is that Rush has a much more diverse mix of patients than the other panelists when it comes to reimbursement profile and economic status. Again, just correct me if I'm wrong, but if that is the case and given at least in my experience talking to physicians, there tends to be a bit of concern about accessibility and making certain tests available to some patients and not others based on insurance or economic status. How do you manage that?

So great question. So when we started offering this test, it was a serious consideration. So in our case -- so we are offering this test to the patient. So we have like 3 tiered approach. Anybody about the age of 50, we send out e-mails and we tell them, hey, this test is available. And of course, in the EMR, anybody about the age of 22 with certain conditions like smoking history, cancer, history, first level of relationship and in certain conditions, anybody above the age of 22. And the third tier, what we call is anybody wants it. So these are all the patients we offered Galleri tests. And we are highlighting that, look, this is not FDA approved and then it's not covered by commercial insurance, and it's out of pocket. But also there's certain -- if you look on the Rush website where we talk about the test, there is FAQ. And like, we have a section which you can review which says, is this covered by insurance? There's certain like, I would say, like [ TRICARE ], I think they cover for certain conditions. And that's the extent to which we have gone in terms of reimbursement. Like I said, we have a diverse population with disparities. We are looking at philanthropy and other -- we are also talking to GRAIL to see how we can offer these tests. Again, don't quote me as this like the [indiscernible] like -- but this is something we are looking at offering to our diverse populations. We've only started offering about 2 months. And already, the demand is so much just from the patient side. For the diverse, we are looking at innovative solutions through like philanthropy and others, yes.

And then just very quick, this can be kind of yes, no. The way the company -- and I think, Josh, you talked about Galleri, I mean this is truly supposed to be a [ complement ] to other tests for screening that are in guidelines. It doesn't sound like you have had any concerns, or anything in your practices that would suggest a patient getting a negative Galleri test that emboldens them to not use other tests that are in guidelines. Is that the case?

It's my concern. And I think [indiscernible], that's why you have to talk to the patient. I worry that the word will be out that this is just the holy grail, and that I don't need to do anything else. Quite the opposite. Every patient needs to know that this complements what we already do and it has to be done annually. And it is not a genetic map of your DNA that might give us clues that you have a risk. And if we don't educate the patients correctly, there are going to be patients who fail to seek out care when they have symptoms, or will declare themselves cancer-free. So this test has to always be done in conjunction with the screenings that are required.

And I'll just add one thing from our studies. We -- that's a huge safety concern for us and for the FDA, by the way. And so we've been measuring in our studies, PATHFINDER and PATHFINDER 2, by survey, by patient self-report. Are they more or less likely to continue with their standard of care screening? And what we're finding is that when you're taking Galleri as a screening because you're actually more likely to continue with your current cancer screening because it emphasizes the importance of screening as long as the education is there correctly that in no ways this ever replacement.

Yes. Thank you, Josh. How important is the gallery data more to you guys? Would you ever consider switching to other vendors, given there are other NCD tests coming online?

Maybe start with Eric?

The data is super important in having that information to present to patients and to standby. I oftentimes will talk about the comparison with [ Guardant Health ], which last year came out with Shield as a blood test that's looking for cell-free DNA that's specifically looking for colon cancer. And -- it's -- if colon cancer is present, Shield has shown to be 83% sensitive and being able to detect it, which is not as good as Cologuard at 92%. And Shield has also carried a 10% risk of a false positive. But Shield was FDA approved last year. And because it's FDA approved, it's fully covered by Medicare. But you contrast that with the overall risk of a false positive Galleri test, again, 0.5%. And if something like colon cancer is present with Galleri, Galleri offers an 82% sensitivity of being able to detect colon cancer, which is very similar to what Shield is offering. And the [ Garden ] information, I think, is based on preliminary case control data, where they don't necessarily have interventional real-world trials that validate what they've seen preliminarily. And so I hope that answers your question, that I do think that data is hugely important. And I feel like GRAIL has been accumulating a massive amount of information over the course of the last 4 or 5 years, and they're only going to accumulate more.

[ James ]?

Yes. Just to follow along on that, I mean we get a cell signal of origin as well with GRAIL. It reminds me of the patient who was working up in anemia. And yes, the next month, I saw him he didn't send in the stool cards. And then finally, the following month he did, and I called him to tell him, they were normal, and he told me he would let his dog know. He wasn't about to do it from his own toilet. He went out to the front lawn and took a sample of his dog's poop. But what I'm trying to say is the patient comes in every way, and they don't understand the importance of why we're working anything up. And sometimes they want the least path of resistance. But I think this Galleri test is after the -- in addition to the screen, I keep emphasizing that. But this test is far better then Cologuard. How many patients did I call it -- and these Cologuards were done because they didn't want to have endoscopy, and they were low-risk people. But basically, 95% of those phone calls ended up with an endoscopy and we didn't find cancer. This is a far better test.

How about compared to the other MCED tests that are out there?

Again, the Cancer Guard has no cell site of origin, and I don't think it has the data. So I'm not going to use it.

Please, [ Nima ]?

Just as an anecdote, I mean the CSO, I think, is incredibly important for my comfort level of ordering this test and feeling confident with the work up. An example is last week, I was in our liver tumor board. And hepatocellular cancers are usually not worked up with a PET/CT. This patient was worked up in the outside. Somebody ordered a PET/CT, we reviewed it. They had a very large hepatocellular carcinoma that had absolutely no FDG avidity within the tumor. It was completely unapparent on the PET/CT. But if you got a contrast enhanced, multiphase CT scan, it was right there in your face. And that concerned me because I think other tests when they don't provide a CSO recommend a PET/CT and you could just be complying completely blind. And there's no impetus for somebody to be like, well, maybe let's order a CT multiphase that delivered to [indiscernible] cancer, you really wouldn't do that.

I'll also just make one other comment. We've looked because we get asked this question all the time, there are no data available today worldwide, supporting the use of whole body imaging for cancer screen. The only studies that have ever been done are in -- are outside the United States and the conclusions of those small studies were that it is not appropriate for early cancer screening. So again, I think I would recommend there are lots of approaches to multi-cancer early detection. Some have CSO capabilities. Others do not. I think I'd ask for the data to support the use of their whatever approach may be, whether it's ours with the CSO or theirs with whole body imaging. And then there are other tests, again, that just are relying on case-control data and everybody needs to know the questions to ask. When you get presented with that, you need to ask them. Is this really -- do you have any interventional data to support this? Because too often, we've seen case-control data -- I guess the best example is the THRIVE study, the DETECT-A study. [ Bird Vogelstein ], one of the world's leading oncologists did a case-controlled study that showed amazing results. It was put into a healthy 65-year-old women, the blood test barely worked. The PPV was 5.9%. They had to do whole body PET/CTs to find any cancers. So again, ask the right questions. it's really important.

Andrea, how about for you? How do you feel about the [indiscernible] data?

[indiscernible] data, sorry. Yes. And we recently had this discussion you and I. And as the Chief Medical Officer of a bigger company, I have all the companies coming after me to talk to me and try and pitch their [ wares ], if I want to say it that way. And so I am sitting through listening to data, looking at how do we analyze it. I lean on external advisers to say what's the right type of data. And for now, we're still working with GRAIL for continuing above our 55,000 tests because you have the most data and interventional not case control.

Great. Thanks, Andrea. Other questions? Yes, sir?

How do you think demand for GRAIL test will change if it gets FDA approved? And do you expect Medicare to cover it? And how many other payers will cover it too?

So maybe start with Andy. And then ask the panelists.

Yes. So as you know, we're working with Congress to get MCED legislation passed into law. Medicare cannot pay for screening unless there's an act of Congress. So that's what we're working on right now, Josh can share more about the status of that legislation. But it is our anticipation that our longer-term reimbursement plan will include Medicare once that Act of Congress is passed. So we will be able to offer all Medicare patients. So at some point in the future, the Galleri tests. We're also working with other payers right now, but we're early on in our payer engagement. The NHS-Galleri study results are going to be a key component of our payer engagement. PATHFINDER 2 is also a key component. Obviously, FDA approval as well as we know from payers the clinical data, having the clinical data published, and having an FDA approval will dramatically increase their willingness to provide coverage for Galleri. And that is our long-term plan to ensure that patients get access to the Galleri tests.

And do -- if any of our panelists want to jump in, how do you feel that an FDA approval will change the demand that you're seeing from your patients? Do you think it will measurably affect that? Or will reimbursement itself be the biggest issue?

I want to say from a Rush perspective, we'll remove the disclaimer. We have it at every place. That's the only big change we're going to do because we're already seeing the patient demand basically. So just as an example, to keep up with the demand for screening at Rush, we are holding, I think, like GRAIL camps at our 4 sites in December. So we only started 2 months ago, and we already have like really big demand for screening. So from our side, we're going to remove the disclaimer. So that only -- I think it's going to -- it's just better for patients to get covered either through commercial or Medicare or any of these. But from a system perspective, I think more, I would say, patients and the community members will have access to screening.

And I'll just remind you something Andy said in his talk, the self-insured employers are effectively payers, and they are reimbursing the test for their employed population. So there is, in that regard, reimbursement already.

And then the second question is just from your real-life experience, doing this -- do you do the second test if you get a positive test and doing two tests? How much do you lower the false-positive rate?

Well, we do a second test if the first is positive, and we've done a workup. And we have not found a cancer. We either will do more of a workup, then we'll repeat the test, I like to repeat it at 3 months. And if it's positive, then it's likely there is a malignancy. And if it's negative, then it's unlikely that there is a malignancy after we've done a good work up.

Right. But out of the -- when you get a positive test the first time, how often do you get a second test that's positive?

Well, we don't because we've worked the patient up and we found a malignancy, and then we're not going to do the test again.

I think you're asking if -- let me see if we've got your question right. You get a positive Galleri test. They do a workup, right? And are you saying the second test being like the imaging test? Or another Galleri test?

I thought a lot of doctors would -- if you just give a straight blood test [indiscernible] you just follow up with a right to a blood test.

That's not at all what happens, yes. Let's clarify that. So a positive blood test gets followed up by a directed workup. So Galleri will say, cancer signal detected, predicted origin liver. The next test is not another blood test, it's an image of the liver, hopefully, not a PET/CT. But the appropriate type of imaging test in the liver to find the cancer. If nothing is seen, and the doctors convinced it's been an effective work up, then you would do another Galleri test to try to reach resolution. And if it's negative, you can pretty confidently assume that, that first test was a false positive. I don't have a number for you that you're looking for about how it lowers the false positive rate just because we haven't done that in a large enough population yet.

If I can help answer that question. So I think GRAIL has some data on retests. Following an initial positive test, you take that diagnostic evaluation, you don't find cancer. So GRAIL offers a free retest at whatever time interval. And I think the data that GRAIL has is involving 145 patients that were retested. And 30% of them, again, tested positive, and we're persistently positive and then reevaluated for cancer and perhaps, in fact, identified to have cancer. But the other 70% had a negative test that was repeat, and they were followed for 18 months and not identified to have cancer. So I think that's where they're getting the information to say that if you repeat a test, and it's negative, that you can be fairly certain that, that first positive test was, in fact, a false positive. And that you just resume your annual gallery cancer screening as you ordinarily would.

That's right. There was only one example I'm aware of where a test, a blood test was done twice in a row, and that was in the THRIVE study. And that was again because the blood test wasn't working. I think there's a question.

Yes, I just have a really quick one, and I guess it's for both the physicians and GRAIL. Just can you remind us if it's done on a fasting basis? And if it's not, do you get some interference and that's could contribute to some of the false positives that you see and need to tell the patient maybe did you, in fact, fast? So just a quick one, hopefully.

My understanding is that it doesn't require a patient that needs to be fasting. Oftentimes, when we have patients come in for their physicals, they're fasting anyways. And then we introduce Galleri cancer screening and by starting the conversation. And if it was something they want to start doing that may be doing at the time of their annual physical would make a lot of sense because then each time they come in for their physical, they'd be able to repeat the Galleri cancer screening. But to my knowledge, I don't think that if you've eaten that it's going to affect the -- the Galleri test result in any way.

Or we offset the test by 6 months after they've been in for a thorough physical, and we've done comprehensive blood work. So they come in every year for physical. They come in every year for a Galleri, but the Galleri 6 months from their last physical. And we've done that on many of our patients. We think there probably is some theoretical advantage to that.

There's no data we're aware of that suggest that food introduction has any effect on methylation patterns. There are hypothetical things like [indiscernible] blunt trauma, other things that have happened could affect your methylation being on a methylating chemotherapy agent, for example, which is why we don't do Galleri and people who are actively being treated for cancer. But nothing we're aware of as it relates to food. Okay. Well, if there are no other questions, I think that will wrap up our program today, if I'm not mistaken, Alexis, am I correct? All right. So I want to thank our panelists. First of all, thank you so much. I want to thank our esteemed audience. Everybody who made it here despite the difficult travel schedules and the uncertainty, it's highly appreciated. I want to thank Dr. [ Clemes ] for continuing to hang in there by video. It was terrific having you to be part of this. And again, I want to thank everybody for being here and the staff at GRAIL. Hopefully, you'll be getting tours or have done tours and I want to thank all the [ GRAILERS ] for all their hospitality. So thanks, everyone -- and the other speakers. Thanks.