Exact Sciences Corporation (EXAS) Earnings Call Transcript & Summary

Good morning. I would like to welcome you to the BLUE-C New England Journal of Medicine Publication Call. [Operator Instructions] I would now like to turn the conference over to Nate Harrill, Vice President of Investor Relations, you may begin your conference.

Thank you, Jeannie. And thanks to everyone for joining us for Exact Sciences BLUE-C New England Journal of Medicine Publication Call. On the call today are Kevin Conroy, the company's Chairman and CEO; Jorge Garces, our Chief Science Officer; and Dr. Paul Limburg, our Chief Medical Officer of screening. Jeff Elliott, our Chief Financial Officer, will also be available for questions. Please note that during Q&A, we'll limit questions to our BLUE-C New England Journal of Medicine publication. Exact Sciences issued a news release yesterday afternoon detailing the study results. This news release and today's presentation are available on our website at exactsciences.com. During today's call, we will make forward-looking statements based on current expectations. Our actual results may be materially different from such statements. Descriptions of the risks and uncertainties associated with Exact Sciences are included in our SEC filings, which can be accessed through our website. It is now my pleasure to introduce the company's Chairman and CEO, Kevin Conroy.

Thanks, Nate. We are thrilled to announce the pivotal BLUE-C study is now published online in the New England Journal of Medicine. A special thanks to the many people who contributed to this important study, including thousands of patients who participated all the study authors, site investigators and of course, the Exact Sciences team members. Cologuard has revolutionized colon cancer screening and our next-generation test, Cologuard Plus, sets a new high bar. Our #1 goal when developing Cologuard Plus was to reduce the false positive rate of Cologuard, which would lead to fewer unnecessary follow-up colonoscopies. Major innovation was required to improve the false positive rate by 30%, while increasing sensitivity for colorectal cancer and precancerous lesions. After a decade of research and development, Cologuard Plus will be the most efficient, noninvasive way to screen for colorectal cancer. Cologuard plus represents a major advancement in colorectal cancer screening and will help us achieve our goal of getting 16 million unscreened people in the U.S. screened, and potentially expanding outside of the U.S. When presented with the BLUE-C data, 2 out of 3 health care professionals indicate they plan to increase their use of our proprietary test. Our world-class commercial team will begin offering Cologuard Plus in 2025 pending FDA approval, and the test will be supported by our unrivaled technology platform. Fewer unnecessary follow-up colonoscopies will provide savings to the health care system, improve the patient experience and create more opportunities to keep people screening with Cologuard Plus every 3 years. Today, we'll discuss the process of developing an even better colorectal cancer screening option, the design of our BLUE-C study and how to interpret the study results. I'll now turn the call over to Jorge Garces to discuss the R&D process.

Thanks, Kevin. Our science has followed a methodical approach to developing Cologuard Plus and are using the same discipline for future tests. Over the past decade, together with the Mayo Clinic, we have identified highly accurate biomarkers across 16 different cancer types. Our approach to biomarker selection for cancer detection begins with well-characterized tissue samples across multiple stages along the natural progression of disease. Deep genomic, epigenomic and proteomic profiling of large and diverse clinical sample cohorts allows us to identify the most discriminate cancer signals across multiple organs. The discovery process starts with tens of thousands of markers, which we down-select through iterative training, validation and testing. By employing machine learning and advanced statistical methods through this process, we achieved smaller minimally overlapping high-performing subsets. We generate predictive models and fine-tune them to improve the predictive accuracy and ensure strong generalization of the data. This work led to the discovery of a new panel of 5 highly discriminate markers, which power Cologuard Plus. We validated the accuracy of this novel marker panel by analyzing thousands of samples and case-control studies designed to simulate a real world screening population. We subsequently tested our final assay design using a locked algorithm on more than 7,600 banks and blinded samples from the prospective DeeP-C study. As a reminder, DeeP-C was our pivotal study supporting Cologuard's FDA approval in 2014. This allowed us to better predict Cologuard Plus' performance in BLUE-C and to directly compare the performance between Cologuard and Cologuard Plus in the same study population. Our innovative science and industry-leading clinical studies support Exact Sciences' mission to help eradicate cancer. We're incredibly proud of our team's unwavering dedication to improving patient outcomes. Cologuard Plus will help more people get screened and lead to a better patient experience with fewer barriers to adoption. It will also increase lab throughput and efficiencies. This New England Journal of Medicine publication marks a major milestone in our product development efforts and Exact Sciences is just getting started. We're conducting rigorous and innovative clinical studies focused on generating practice-changing clinical evidence in support of a comprehensive pipeline of new tests that will change how we diagnose monitor and treat cancer. This year, you'll see several sets of performance data spanning molecular residual disease, colorectal cancer screening and multi-cancer early detection. I'll now turn the call over to Dr. Limburg.

Thanks, Jorge. The BLUE-C study was designed to answer the key questions that patients, clinicians, advocacy groups and payers need addressed. This study was conducted at 186 sites across the United States, spanning rural and urban areas. The study population included asymptomatic individuals ages 40 years or older, who were scheduled their plan for screening colonoscopy. Stool specimens were collected prior to beginning the preparation for colonoscopy and were analyzed with Cologuard Plus and an independent fecal immunochemical test or FIT test. BLUE-C study participants were also invited to provide a sample for evaluation of a novel blood-based colorectal cancer screening test developed by Exact Sciences, representing the only opportunity to directly compare colonoscopy, FIT test, Cologuard Plus and blood-based screening performance in the same study population. To optimize data quality, all tissue findings during colonoscopy were reviewed centrally by independent pathologists. Endoscopists and central pathologists were blinded to Cologuard Plus and FIT test results. Nearly 27,000 participants were enrolled more than twice as many as DeeP-C, making the BLUE-C study one of the largest colorectal cancer screening studies conducted to date in the United States. Importantly, the BLUE-C study cohort was diverse and truly reflective of the U.S. population with about 40% of all participants identifying as Hispanic or Latino, black, Asian, American Indian or Alaska Native or Pacific Islander. This enrollment diversity helps assure that the BLUE-C findings and Cologuard Plus are relevant for all screen eligible individuals regardless of race or ethnicity. All participant samples were tested on 1 prespecified locked algorithm to produce a positive or negative testing result. BLUE-C included close to 100 cancers over 2,000 advanced precancerous lesions and nearly 7,000 nonadvanced adenomas, providing excellent statistical power for analyzing our predefined primary and secondary outcomes, which were all successfully met. Cologuard Plus achieved 91% specificity when including patients with small polyps and other incidental findings or a 9% false positive rate. This is a 30% relative improvement compared to the false positive rate observed in the DeeP-C study for current Cologuard. This means fewer people will undergo unnecessary colonoscopy and improves the efficiency of the test. Cologuard Plus' positive predictive value for advanced neoplasia was 38%. This is a 60% improvement to the positive predictive value observed in DeeP-C for current Cologuard. To provide the most robust comparative performance assessment, the BLUE-C study included head-to-head evaluation between Cologuard Plus and an independent Fit test. Relative to the independent FIT test, Cologuard Plus showed superior sensitivity for colorectal cancer, advanced precancerous lesions and high-grade dysplasia, the most aggressive type of precancerous lesions. Cologuard plus' sensitivity was 94% for colorectal cancer, 93% for screen relevant Stage 1 through 3 cancers, 43% for advanced precancerous lesions and 75% for high-grade dysplasia. Further, only 4% of cancers in the BLUE-C study were on stage Cologuard Plus detected all of these, while the independent fit test detected 75%. Modeling Blue-C performance data using USPSTF assumptions shows that Cologuard Plus will be the only noninvasive test on the efficient frontier for colorectal cancer screening. Bottling studies for the USPSTF and other guideline groups use the efficient frontier to compare screening strategies based on the combined consideration of projected benefits and burdens as measured by life years gained per colonoscopy. This efficiency ratio guides USPSTF's test, age and interval recommendations. Based on BLUE-C data, modeling analyses demonstrate that Cologuard Plus every 3 years generates more life years gain per colonoscopy than any other noninvasive colorectal cancer screening strategy, including annual fit and reported blood-based tests. I'll now turn the call back to Kevin.

Thanks, Paul. BLUE-C was designed to help expand the eligible screening population in 2 ways beyond the current market for Cologuard. Cologuard is indicated for average risk patients ages 45 and older. Blue-C enrolled a subset of participants having a first degree relative with a history of colorectal cancer. Sensitivities for colorectal cancer and advanced precancerous lesions were consistent among participants with and without first-degree family history. Also, the BLUE-C study enrolled individuals aged 40 to 44. These data will support a potential label expansion for Cologuard Plus in the event the FDA and guideline groups consider recommending colorectal cancer screening in younger populations. These are significant opportunities as there are 22 million average risk Americans between ages 40 and 44 and 13 million with a family history of colorectal cancer. We're now happy to take your questions.

[Operator Instructions] Your first question comes from the line of Doug Schenkel with Wolfe Research.

Kevin, it was interesting to read one of the New England Journal of Medicine editorials, which got it the question of appropriate testing intervals for this category of tests, blood and stool. As was showcased again in this presentation, you've done extensive work modeling out life years gained versus colonoscopy. The model in the past has demonstrated significantly fewer live saved versus colonoscopy for an assay with the advanced atenoma and Stage 1 sensitivity of the blood data that's out there today. That's, again, updated and included on Slide 9 of your presentation. I guess my question is, how much higher would advanced adenoma detection have to be all other things being equal to allow for a 3-year interval because this does seem like a pretty important differentiation amongst others for Cologuard versus some of the other tests in development.

Thanks for the question, Doug. Let me first just say how proud we are that the team worked really over a decade to set a new higher bar for colorectal cancer screening. And we can't emphasize that enough. The PPV improvement, the overall sensitivity and advanced adenoma improvement and importantly, the improvement in the false positive rate. This is -- it's herculean to do this. And the other thing we're really proud of is the quality of the study. We're really -- Doug, we want to focus our energy this morning on our study results. I know there are going to be a lot of questions about others that aspire to be here and to participate in this important space. And let me start by saying we agree with that there are needs for new and innovative ways for screening. And you're highlighting an important aspect is what is the detection rate for adenoma? And how does -- at what rate does that have to be in a blood test to get into guidelines? That's a complicated analysis. We've tried to simplify it, simplify where the data are today. And I think that there's going to be more modeling done to show what that adenoma detection rate needs to be. And the real answer, Doug, is it depends. It depends on what the false positive rate is and what the interval is, and those are multiple variables that go into a really complicated formula. So it's just not that easy to answer. Suffice it to say a lot higher than we have seen with blood-based approaches.

Okay. I know I put you on the spot to answer a really complicated question. So I appreciate you giving it a shot. My second question is just what comes next? What are the time lines from here? Has anything changed in terms of how you're thinking about process from a regulatory and reimbursement standpoint for next-generation Cologuard?

We'll talk more about time lines on our next call. Our program continues to move rapidly. The team is really focused right now and making sure that we respond to all the FDA request for Cologuard 2.0. We presently expect to launch, I guess, now we call it Cologuard Plus. So Cologuard Plus will be launched -- we're targeting the beginning of next year and hopefully the end of this year for FDA approval in terms of blood. We'll get into the details of that more on our next earnings call.

Your next question comes from the line of Jack Meehan with Nephron Research.

So I had 2 questions just trying to compare and contrast the data here. First, can you just talk about how you handle the unstaged cancers? It was a little bit less than your study. And then the second is a biology question. So your study had a higher mix of CRCs in the proximal colon, I think Garen had more distal and rectum. I was just wondering if you could comment on what influence that might have on relative sensitivity?

I think Dr. Limburg will handle that.

Yes. Thanks, Jack. So with respect to your first question about the staging process that we utilize. So we used a very rigorous study design at all levels for our BLUE-C study, including how we reviewed and categorize the findings. So our central pathologist reviewed the tissue reports and submissions to adjudicate the colorectal cancer diagnosis and then also the staging criteria. So with that very rigorous process with that independent central pathology review, we were able to categorize to stage all but 4% of our cancers. Interestingly, those 4% cancers that were unstaged the Cologuard plus test detected all of them, so a sensitivity of 100% in that subgroup. Moving on to the second question about what was the distribution of proximal and distal cancers. Again, I think we showed that our colorectal cancers had a relatively even proportionality between proximal distal and rectal. That is in line with what we would expect given the demographics of our BLUE-C participant population. There is a difference between our study and the other study that was reported in the New England Journal of Medicine. We don't fully have an explanation for that, that we can provide today. But as we look into more details and comparison between the 2 study populations, hopefully, that will become more clear.

Your next question comes from the line of Catherine Schulte with Baird.

This is Tom Peterson online for Catherine. I wanted to maybe touch on the 2 areas of potential market expansion first on family history. Wondering if you could kind of remind us as to the rationale for wanting to enroll patients with family history. What does the path forward look like? What's the potential market and market development look like? And then similarly, on the choice to age to enroll down to age 40. I guess what's the path forward here? What are your thoughts around performance in the age Group? And what are the next steps and thought or expectations around additional data you might need or the thoughts around the recommended screening age stepping down over time?

Yes. Let me start, and then I'll pass it over to Paul. Let's start with family history. We know there are about 13 million Americans with the first degree family member history of colorectal cancer. And the unfortunate thing is that those 13 million people are not all willing to undergo colonoscopy. Many of them remain unscreened. It's is surprising. But that means that there is a big need for alternate approaches to get people screened. These are people who are at an elevated risk of colon cancer, and maybe I'll pass it over to Paul.

Yes. Thanks, Kevin. So both very important questions. Starting with the family history, I do want to just remind that we did not include any participants who had the most obvious family history, familial syndrome. So they were not part of BLUE-C. What we are talking about here is somebody who may have had 1 first degree relative with colorectal cancer at whatever age. As Kevin pointed out, these patients need more screening options. Right now, colonoscopy is the predominant method used to meet the needs for that population. And so what we wanted to do in the BLUE-C study was allow for a demonstration of the performance characteristics of this stool-based assay to see how the test performed and compare that to the group of patients without a family history of colorectal cancer, and findings were similar. So we're pleased with those results, again, pointing towards another potential option for this patient population that is looking for more solutions. For patients who are younger ages, we know that there are rising trends in colorectal cancer incidents, mortality, in patients who are younger than age 50. In order to prepare for the future state of colorectal cancer screening, we wanted to enroll participants between 40 and 44 years of age in the BLUE-C study so that we can begin to build that evidence space when and if the guideline recommendations consider moving from 45 years even to an age that's lower than that.

Your next question comes from the line of Dan Brennan with TD Cowen.

Kevin, can you remind us just you flashed the efficient frontier and how much better now, the BLUE-C, the new Cologuard Plus is going to screen. Is the expectation that -- I know you don't want to focus on the blood test coming in, but that is an important question. Is the expectation that the blood tests are going to be mapped against the existing kind of choices like Cologuard and FIT and colonoscopy or do you think they'll eventually get on to their own efficient frontier? And kind of how does that impact this equation, do you think?

I think Paul is probably best to take that question.

Yes. Thanks, Dan. We don't know for sure. So USPSTF commissions the CISNET modeling team to conduct those analyses. The way CISNET defines the efficient frontier and compare across different testing modalities is that they do group test options. They do that for different reasons. One of them is they want to look at how many noncolonoscopy tests are required to achieve the benefits or are associated with the burden of the screening strategy. Because of that, they have grouped tests like the FIT test and Cologuard or multi-target stool DNA together in a single class. Now how they would consider a new modality like blood-based screening remains to be seen. In our modeling analysis, we combined stool tests, blood tests under a single umbrella called noninvasive screening tests. And when we do that, the stool-based test, Cologuard Plus again, is the only screening option at 3 years over with USPSTF assumptions. It's the only one that shows up on the efficient frontier compared to the other stool test and the blood test.

Got it. And then I apologize, I kind of hopped on a minute or 2 late. Are the blood options that you're showing on an efficient frontier, is that Cologuard blood? Is that some competitor blood? Or just can you remind us kind of what those are?

Yes. Those are the numbers and illustrative data for reported blood-based results from other studies not the exact sciences test.

Your next question comes from the line of Dan Arias with Stifel.

I wanted to ask just one maybe on commercial activities sort of in the spirit of a couple of the others that have been asked already here. Kevin, as we think about the physician detailing effort over the next several years, as the testing landscape changes the way that it started to, how do you think that's going to evolve? I mean do you think that there will be a need for messaging and dock conversations to include more of a focus on the finer detail, staging information age cohorts, just sort of nuances on precancer. And do you think that the GP population will be receptive to that. I ask because it feels like a pretty healthy percentage of PCPs just generally couldn't tell you what adenoma sensitivity rates are, if they didn't look them up. But as the testing options expand here, you have these comparisons that maybe you didn't need to make before. So just curious about your thoughts on the way in which the conversation with the physician population might change?

We expect there will be -- at the appropriate time, of course, Dan, a robust conversation with physicians regarding the data appropriately focused on the most important data. And here, the most important data are the sensitivity, both for cancer, precancer and also importantly, that 75% number for high-grade dysplasia, that's -- the purpose of screening is to find the problems. And that's -- so sensitivity is critically important. And then the specificity too, that's the improvement that you -- one of the improvements that you see here. And it's the one that the Primary care physicians have consistently over the last decade, asked us to address, which is to have a lower false positive rate. And we were able to deliver that through exquisite science. So that's where our commercial organization is going to focus. We have a team of MSLs, medical scientific liaisons, who are able to go as deep as a Chief Medical Officer at a health system wants to go. So we are going to be educating Chief Medical Officers, large institutions, organized health systems that employ many primary care physicians and set policy. And because Cologuard Plus sets a new higher bar for performance, we're able to go pretty deep and get really rich here. And I think one of the nuances that Paul pointed out here was the improvement in the positive predictive value, a 60% improvement. And if you dig into the data, what you'll see is that in DeeP-C, I think it was about -- and Paul will correct me, but I think 55% of the patients with a positive result had no finding. And that is now only 30% or maybe it's 45% with no finding at all. So a perfectly clean colon despite a positive Cologuard test. And now that's brought down to 30%. So 7 out of 10 people with the positive Cologuard result in the study had something removed from their colon. That actually matters because GIs are rank-based or their adenoma detection rate, what they find basically, they are tracked and measured based on -- that's a key quality metric for them. And so I think a positive Cologuard test, going to a colonoscopy is they're finding things. And it's important to note in this study, the GIs were blinded to whether the Cologuard test was positive or not. So one of the things we have seen in other studies is that when they are unblinded when they know the result, they're even better at finding that. So we would expect that the -- that proportion 7 out of 10 would be even higher of finding something. Do you have anything to clarify or correct me, Paul?

No, I thought you did that really well, Kevin. Thank you. I just want to go back to the main goals of the study, and that was to reduce the false positive rate. Sensitivity, specificity, those are terms that we continue to work with colleagues on understanding, explaining et cetera. But the bottom line is we need to have an accurate, acceptable, accessible option for colorectal cancer screening. 60 million people are unscreened or underscreened. We now have a noninvasive test that sets a new higher bar and it reduces the false positive rate, which was what we heard most often over the last decade. And I would say credit to the team, we were able to improve the sensitivity both for colorectal cancer detection and for advanced precancers, including the most aggressive ones high-grade dysplasia. So the total package is in my opinion impressive. I do think that this is a way forward. I think that Cologuard Plus will be an important option for meeting screening needs even more so than current Cologuard when the test becomes clinically available.

Your next question comes from the line of Puneet Souda with Leerink Partners.

Congrats on the publication and I'll wrap my 2 questions into one. Can you talk a little bit about the high specificity, just talking about that in terms of 45- to 49-year olds, 97%, 96%, I believe, for 50 to 54. So again, what does this do to your conversations on the specificity side for the younger population, which is -- has been more in the news and a concern lately? And then on the -- Kevin, on the actual expansion, market expansion side, how do you think about the international market now you should have better gross margins with this product? So give us your thoughts as to expansion beyond U.S. for Cologuard if that's how you're thinking about it.

Why don't we -- Paul will take the lower specificity in the younger population question, and I'll come back to the market expansion.

Yes. I think the higher specificity in the younger age group is important for 2 main reasons. Number one, this is a population that is new to screening. And we know that in that 45- to 49-year-old age band, only 1 in 5 individuals is currently up to date with screening. This is a population that's probably still actively working. They're managing families. They may be managing parents. So finding, again, an acceptable accurate, accessible option to meet their screening needs is critically important. So having a noninvasive test that performs as well as Cologuard Plus may better meet the needs and improve that 20% participation rate from where it is today. I think that the other important point to note is the differentiation between Cologuard Plus and FIT with respect to specificity in these younger age populations, is now gone. So the performance with Cologuard Plus and fit for specificity in the younger age groups, is near equivalent or equivalent and the sensitivity differential remains. So you have a better performing test that hopefully will be more acceptable to this younger audience. And again, we know that colorectal cancer rates are rising younger individuals. We need to get them screened. We have an effective test to do that based on the study from -- the data from BLUE-C.

So international expansion. Puneet, we have a team that is focused on it. We've been in market in the U.S. for 10 years. We've obviously transformed the company from a financial perspective, and we're now able to make some investments to bring Cologuard to people all over the world. There are a couple of key things that we're working on to facilitate that. One is to have a separate smaller collection device less expensive that will be used around the globe. And then also selecting our initial markets wisely areas that we can first see some out-of-pocket pay as we work with the large organized health systems and payers in Europe and globally to bring in innovation like Cologuard Plus to patients all over the world. So that's the -- we'll be working on that over the next couple of years and lay out those plans on future earnings calls.

Your next question comes from the line of Vijay Kumar with Evercore.

Kevin, maybe my first one for you on -- you mentioned 2/3 of docs you surveyed said they would increase CG usage with the 2.0. Any thoughts on why they said they would increase? Are these docs who are existing Cologuard users? Or are these new physicians? some perspective, I think, is helpful.

So the dynamic with Cologuard over the last decade has been that some patients who have a false positive pay more for the colonoscopy that follow-up colonoscopy, which then gets back to the ordering physician. And then they have ordered more slowly. Because -- first, because of the false positive; secondly, because of the -- the cost to the patient. Now that cost issue has been largely dealt with by regulation in the federal government, both for Medicare patients and for commercial plans. And so that -- the financial piece has lessened. The goal here has been to squarely address the issue raised by primary care physicians to keep this the specificity as high as possible close to the FIT test, so that fewer of their -- the people that they serve go on to an unnecessary colonoscopy. The benefit, of course, to exact as those patients remain as Cologuard Plus users in subsequent 3-year intervals rather than moving over and getting a colonoscopy and moving into that modality of screening. So the 2/3 of doc surveys come from both Cologuard users and nonusers. And that was a pretty broad study and is -- gives us reason to believe that we will see an increase in utilization with Cologuard Plus lower cost of goods, more efficient, more patients stay within the screening. That's why when we say Cologuard Plus sets a new higher bar, it truly sets a new higher bar.

That's helpful, Kevin. And maybe my follow-up here. I know there's an AdCom coming up for blood-based test. I know you have a blood-based test in the pipeline as well. I'm curious, given USPSTF has our criteria. I think that's the efficient front here. CMS has laid out the bar for reimbursement. So why is -- any thoughts from the team on why we're having an AdCom? And perhaps what is incremental here that should -- will be discussed or expected to be discussed?

Well, it's not our AdCom. So I'm not going to comment on the AdCom that has been called. I will say that with Cologuard, we had an AdCom. It's a new screening methodology, and it's not unusual for a technology that would be used on up to $100 million healthy patients, healthy people or not patients yet, healthy people that the FDA wants to make sure that they really get it right, whether it is how the study was conducted. There's a deep, deep, deep dive into that. We went through this with Cologuard, and it's very rigorous. The FDA brings very serious people to the panel and they want these important questions of safety, efficacy and the balance of the 2 to be figured out. I think one of the things to note that with Cologuard, the FDA, we and the FDA have discussions over time was what is the appropriate interval. And it's important to note that there is nowhere in our label that the FDA gave us an interval. That did not come from the FDA. That came from the guideline groups. First, American Cancer Society and then USPSTF. There was -- there is some confusion about what the manufacturer recommends. I want to be clear, that was not a recommendation that the FDA created because there was no study evidence that supported that. So AdCom is going to look at a lot of different things. We wouldn't be surprised if our blood test also had AdCom. It's just the nature of going through the FDA process for something as important as a screening test.

Your next question comes from the line of Patrick Donnelly with Citi.

Obviously, a lot of ground has been covered. But Kevin, maybe just on the AA front, I know one of the editorials talked about one of the blood tests having potentially lower AA sensitivity as a limitation to adoption your guys AA obviously stepped up. Can you just talk about the feedback since the initial data has come out here on the AA side? And then again, maybe by the age group, how you feel about the AA piece, obviously, the younger you get a little -- it gets a little bit lower, how confident you are in that 40 to 49 piece as well would be helpful.

Why don't I hand it over to Paul to answer why detecting advanced adenomas is important and the relevance here.

Yes. Patrick, thanks for the question. So when we look at the benefits the benefit side of organized colorectal cancer screening program over a lifetime -- we know that about 60% to 80% of the benefit, the life years gained comes from detecting the precancers. So this is truly an opportunity to prevent colorectal cancer, not just detected early. That's different from screening in some other organ sites. So we want to make sure that the tests that are available and endorsed can detect cancer early, but can also detect precancers at a level that allows patients that prevention opportunity. So that's what we focus on when we are developing any of our tests. We're pleased with the performance, the even better performance with Cologuard Plus compared to current Cologuard, we're looking at how can we optimize other options for colorectal cancer, blood-based screening, et cetera. But bottom line, we have to have tests that meet standards. We have to have tests that meet patients' needs, and we have to have tests that demonstrate benefit over current technologies in order for them to play a meaningful role in the screening landscape moving forward.

That's helpful. And maybe just quickly on the age side, the AA in that 40 to 49 a bit lower. Can you just talk about, I guess, why that is biologically -- and then again, the confidence level, I think it was like 28% or something. As that age potentially moves down that data being strong enough to kind of certainly be in line with what the FDA and USPSTF is looking for?

Yes, for sure. So it's maybe a little bit more complicated question. Are there biologic reasons? The event rates, the numbers are smaller, the confidence intervals are wider I think long story short, we're confident that Cologuard Plus performs well in the younger population. We need to do more studies collectively as a field to better understand what is happening to drive these trends of increasing colorectal cancer incidence mortality in younger populations? Are the pathways the same? Are the precursors, the same? et cetera, et cetera, so that we can tool our technologies to meet the patient needs and address the biology. Right now, I think we've got great data for Cologuard Plus, and we'll continue to generate that solid evidence base.

Your next question comes from the line of Matt Sykes with Goldman Sachs.

I'll just keep it to one. Kevin, you mentioned that some of the data that you get from this study could potentially be used to help inform the FDA for expansion into 40 to 44. I know you used the word potentially some a long way off. But just what else needs to happen? And how can we use this data to potentially expand the market?

Well, directly the way that the 40 to 44 age group would be broadly expanded into would be through the United States Preventive Services Task Force. Like they did now about 3 years ago when they lowered the age from 50 to 45 to start screening for average-risk patients. That is a math really does inform that in the epidemiology of the disease as it grows and increases in a younger population and becomes more prevalent, the math that is applied says, okay, well, then there's a benefit, a greater benefit to screening in that age group than the harms or the burdens in that age group. So that's going to be determined by USPSTF, not us, not FDA, probably nobody else. It's USPSTF. And probably, as the incidence, prevalence continues to increase in that age group eventually, and we just don't know when the age could be lowered again if they follow what they did the last time. So we don't know whether it's going to be in this cycle or a subsequent cycle. The last go around the American Cancer Society did a lot of research, commissioned a lot of research to highlight that alarming increase in the younger population, what we've seen today, Paul, and please correct me if I'm wrong, is that increase in the younger population has increased unabated.

Exactly. And it is an emerging trend. It's a disturbing trend. It's not fully understood. Bottom line is screening is effective. We need to get more people screened. We need to get every screen eligible American regardless of demographic to participate regularly in screening. We believe that we've got a better solution with Cologuard Plus based on the performance. We're building other solutions. We need to be part of the conversation to make sure that the age of initiation for screening is appropriately set, whether that's 45 or younger, and that we can all contribute to making sure that everyone who is eligible for screening finds a solution that works best for them.

Paul, would you ever see a day -- I'm jumping in with a question for Paul. Paul, would you ever see a day where you would screen people age 40 once over a 5-year interval or something like that in order to appropriately utilize resources in that age group.

I think we have to get smarter. Right now, we tend to say, here's a strategy and treat it as that's the only strategy. That's the only 1 that patient will pursue. I think we've now got a blend of effective visualization options, stool-based options. Others that are on the radar screen. And I think we need to understand, based on the performance, based on the willingness to repeat screening based on the interval that is recommended what is the best combination of those factors that's going to allow people to really avoid dying of a preventable disease.

Your next question comes from the line of Daniel Leonard with UBS.

I get to follow Kevin Conroy in the question queue. I like it. I'm trying to reconcile the comments on the increased incidence of cancer in that 40 to 44 year old age group and the medical rationale for screening in that age group with the fact there weren't any cases of cancer and BLUE-C in that age group, and there was only 1 in that 40 to 49 age group. Can you help me better understand that?

Why don't I take a stab at this and then pass along to Paul. So if -- although the prevalence of disease is lower in the younger age group, if you detect somebody Stage 1 at age 40 and successfully treat that patient you are gaining in the models maybe 40 or 50 years life years gained, compare that to somebody age 80 who is detected with Stage 1 through screening, maybe you are gaining several years of life years in the model. So although the prevalence is lower, the life year gain impact is significantly higher. And that's the way these models work. And I think just from a real-world perspective, people in their 40s who are struck with this disease frequently have families, they have jobs. They are very active in terms of generating economic activity and the screening models don't take into account that. And if you looked at this from a societal basis, these are the age of the highest and greatest productivity in our society, and we're losing people and we're losing people at an alarming rate. I don't know, Paul, if you have anything to add?

That's all true, Kevin and well said. The other way that I would maybe think of it, Daniel, is that typically when groups report incidence rates, mortality rates, they would say x number per 100,000. And if you look at that x number in the younger populations, it's lower than it is in older populations. Colorectal cancer risk does increase with age. What's happening now that we don't fully understand is that x is now becoming 2x in some populations. So the rate per 100,000 or the rate within that younger population is growing in a way that we're not seeing in the older populations. We're actually seeing in some older populations, rates are going down because of the impact of screening. But we're not seeing the same trends in the younger audiences even though the number per 100,000 might be lower.

That's helpful clarification, I appreciate that.

Kevin, if I can add something real quick. If you look at the advanced precancerous lesions where there's a larger end the Cologuard Plus outperformed FIT dramatically in the same way it outperformed it for cancer. So even when there's a limited number of cases, Cologuard plus outperforms.

Appreciate that. Can I just...

Go ahead.

Oh no. Kevin, if you have -- if you want to [ Cokes ] Jorge into a collaboration, I'll...

My question will come after yours, Dan. But I do have a question for Jorge afterwards.

All right. Well, Mizone related. It follows up to Vijay's question from earlier on your market research, Kevin. You mentioned that 2/3 of those surveyed are going to increase usage based on the data. Is there anything you could share regarding magnitude of increased usage that you came across in your work?

I can't. I was just about to say a lot then. No, I think -- no, I can't share any more of that research sitting here today. We can get into that in the future. One of the things that we're seeing, though, is just as time goes on, more and more GIs are comfortable with Cologuard, and I think they'll be even more comfortable with Cologuard Plus. When you improved the specificity as much as we've improved here, they're going to become even more comfortable with that. So this just builds over time. It takes a long time to change medical practice, especially in a primary care setting. And I think Cologuard is building a momentum that is unstoppable. And with this new higher bar that we've achieved, I think that will continue. So my follow-up to Jorge and then, Dan, if you have another question, but Jorge, you haven't really had a chance to talk much. And this is an innovation that is probably a decade in development from the early research. I'd just ask you, what are you most proud of? And what is the team most proud of in -- today with this publication?

Yes, I'm happy having you and Paul do also talking, by the way. So I think what I would say to the team is most proud of is the fact that it is clearly a much better test and in doing so, we also improved the efficiency of the test with improvements in chemistry, automation, workflow and the elimination of markers. So we've made the test a lot more efficient. And we've been able to increase, for example, lab capacity by about 40% with Cologuard Plus. So there are so many things to talk about, but it's a very short call.

But I interjected, Dan, do you have anything else?

Oh no, thank you. And Kevin, sorry to interrupt your follow-up question to Jorge, I'm good.

Your next question comes from the line of Subbu Nambi with Guggenheim.

Sorry for the background. Was there any feedback from reviewers on a head-to-head comparison with Cologuard instead of FIT. And then could you also provide any commentary on the sensitivity by stage within Cologuard and NextGen Cologuard?

So the first question, we designed the study to compare Cologuard 2.0 to the FIT test in a separate study previously published, we compared the performance of Cologuard and Cologuard Plus. And there was a significant difference there. We did not run all 20,000 -- or any of the 20,000 samples on Cologuard that, I guess, is a possibility down the road, but that was just not part of our plan. And Paul, do you want to take the second part of the question?

Sure. So I think the question was cancer sensitivity by stage. And we did show the overall colorectal cancer sensitivity, the Stage 1 through 3 sensitivity. We showed the individual stage sensitivity in the paper in a graph, but happy to walk through those numbers for Stage 1 sensitivity was 87%. Stage 2 was 94%, Stage 3, 97% and Stage 4 100%. As I mentioned earlier, the unstaged 4 cases 100% pickup with Cologuard Plus as well. For those who are looking at the DeeP-C data, the sensitivity point estimates for that Stage 1 set do differ between DeeP-C and BLUE-C. As Kevin just pointed out, we didn't directly compare in the BLUE-C study, Cologuard and Cologuard Plus. But we have done that in a different sample set of archived specimens from DeeP-C, and we've shown that there is no difference by stage detection with respect to the 2 assays. I do want to point out the confidence intervals overlap between the point estimates for Stage 1 in the DeeP-C and the BLUE-C. So there is no statistically significant difference between the 2 assay versions. And lastly, and I think importantly, in these different populations where we have to make sure that we aren't trying to over interpret the data. But when you look within the BLUE-C study, Cologuard Plus outperformed the same independent FIT by a wider margin. Again, demonstrating and supporting that the Cologuard Plus assay has better characteristics, better performance characteristics than the current Cologuard test.

Subbu, you didn't ask, but I think it's really relevant for the conversation here. For the independent FIT test in BLUE-C, the stage-by-stage sensitivity were Stage 1, 50%, Stage 2, 78%, Stage 3, 71%, Stage 4, 83%. And I think as Paul said earlier, the on-stage fits on 75% for an overall sensitivity of the independent of 67%. So Cologuard Plus did meaningfully outperform broadly across all the relevant sensitivities.

And I believe Jorge wants to add a comment.

Yes. Because at this point, I want to make sure we completely are clear. So BLUE-C was not designed as a comparator to Cologuard -- between Cologuard and Cologuard Plus. However, the confidence intervals and specificity do not overlap between DeeP-C and BLUE-C, Cologuard versus Cologuard Plus, but there are 2 separate studies. So that's the point. The other is that we did compare head-to-head in DeeP-C samples, which were over 7,600 samples in that study. And Stage 1, 2, 3 and 4 were equivalent between both. We saw an improvement in APL sensitivity across all categories. Category 2.1, 2.2, 2.3, 2.4, and specificity was also higher for Cologuard plus than Cologuard in that study. That is under review and will -- and that data has been shown at conferences.

I think -- are there any other questions? I'd just like to thank one more time the Exact Sciences team that's responsible for potentially bringing this incredible new innovation to physicians, to patients potentially all over the world and also to all of the patients and clinical sites that participated in this study. We can't advance innovations without the participations of patients and health care providers. So we appreciate that greatly. Thank you all, and we're happy to take individual questions later. You can reach out to the team, and we look forward to our next earnings call. Thank you.

This concludes today's call. You may now disconnect.