Welcome everyone to Natera's 2024 Fourth Quarter Financial Results Conference Call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a Q&A session. [Operator Instructions] As a reminder, this conference call is being recorded today, February 27, 2025. I would now like to hand the call over to Mr. Michael Brophy, Chief Financial Officer. Please go ahead, sir.

Thanks, operator. Good afternoon. Thank you for joining our conference call to discuss the results of our fourth quarter of 2024. On the line, I'm joined by Steve Chapman, our CEO; Solomon Moshkevich, President, Clinical Diagnostics; John Fesko, President and Chief Business Officer; and Alexey Aleshin, General Manager of Oncology. Today's conference call is being broadcast live via webcast. We will be referring to a slide presentation that has been posted to investor.natera.com. A replay of the call will also be posted to our IR site as soon as it's available. Starting on Slide 2, during the course of this conference call, we will make forward-looking statements regarding future events and our anticipated future performance such as our operational and financial outlook and projections, our assumptions for that outlook, market size, partnerships, clinical studies, expected results, opportunities and strategies and expectations for various current and future products, including product capabilities, expected release dates, reimbursement coverage and related effects on our financial and operating results. We caution you that such statements reflect our best judgement based on factors currently known to us and that actual events or results could differ materially. Please refer to the documents we file from time to time with the SEC, including our most recent Form 10-K or 10-Q and the Form 8-K filed with today's press release. Those documents identify important risks and other factors that may cause our actual results to differ materially from those contained in or suggested by the forward-looking statements. Forward-looking statements made during the call are being made as of today, February 27, 2025. If this call is replayed or reviewed after today, the information presented during the call may not contain current or accurate information. Natera disclaims any obligation to update or revise any forward-looking statements. We will provide guidance on today's call, but will not provide any further guidance or updates on our performance during the quarter unless we do so in a public forum. We will quote a number of numeric or growth changes as we discuss our financial performance, and unless otherwise noted, each such reference represents a year-on-year comparison. And now, I'd like to turn the call over to Steve. Steve?

Thanks, Mike. Let's get to the highlights on the next slide. 2024 was a transformational year for Natera, and I think the Q4 results demonstrate that we ended the year with a lot of momentum coming into 2025. Revenues in the quarter were $476 million, up 53% year-on-year and $4 million above our January pre-announcement of $472 million. Volumes were up 26% compared to Q4 of last year and included an excellent showing for Signatera unit growth. I'm pleased to report that gross margins in the quarter were 63%, which is significantly above the 51% we posted just one year ago, and highlights the progress we made on both COGS and realized pricing in 2024. Finally, we generated roughly $46 million of cash flow in Q4, wrapping up the full-year with about $86 million in total cash flow generation. On top of the financials, we discussed a series of milestones across the business in the last few months. We announced our innovation roadmap and shared several impressive datasets at the ASCO GI Conference in January. Most notably, we announced the 80702 data in colorectal cancer that underscores the predictive abilities of Signatera. We also had our first readout in early cancer detection and we are excited to share some additional data on that program on today's call. In women's health, the Green Journal published our clinical validation study for our fetal RhD test, which demonstrated excellent test results. We also have two meaningful novel studies coming down in organ health later this year that we look forward to discussing today. We are also pleased to see NCCN strengthen its position on cell-free DNA testing across several tumor types as well as an expansion of the Medicare coverage for patients with Stage 1 through 3 lung cancer. This makes Signatera more…

Thanks, Steve. Within our core business, we have a significant potential opportunity to unlock reimbursement from test volumes that were already running, and we've had several promising wins on this front recently. Many of you have seen that we secured a strong increase in our Medicare ADLT rate this year, which was driven by strong pricing achieved in our commercial contracts. Steve also touched on the new MolDX decision to cover Signatera and NSCLC. Based on the written requirements of the ADLT regulations, we believe no other MRD test is eligible to receive ADLT status unless they obtain FDA approval. We are also now seeing formal policies from commercial health plans announcing coverage for state-mandated biomarker legislation. Effective January 1, 2025, a leading benefits management company who supports a large number of health plans across the country published a formal policy detailing cancer biomarker mandates across 20 different states. Additionally, a top five national health plan updated their own medical policy in Q4 to reference state coverage mandates. Additional plans have also begun coverage and we are hopeful that others will follow suit. I will caution that we still expect ASP improvements from biomarker laws to flow in gradually over time, but these are early wins that we can build on. Within our women's health business, we also saw numerous plans to add policy coverage for expanded carrier screening, including a large national payer and several large Blue's plans. We also saw the first meaningful Medicaid coverage in expanded carrier screening with a published policy in one of the largest state Medicaid programs. Many other states have added expanded carrier codes to their fee schedules. We are excited about the momentum we're seeing here. Steve touched on the time and investment we've put into our operations to get reimbursed for…

Thanks, John, and good afternoon, everyone. First, I would like to provide an update from the women's health side on our non-invasive fetal RhD test, where we're continuing to see growing demand and adoption. We were pleased to see the publication of our clinical validation study in the Journal of Obstetrics and Gynecology in November. This was the largest study of its kind performed in the U.S. to-date. It demonstrated excellent performance with sensitivity of 100% and specificity of 99.3%. The study provides compelling scientific evidence on the ability of our test to identify fetal RhD status and demonstrate the potential to assist patients and clinicians in the prevention and management of RhD alloimmunization. Thanks to the growing base of evidence, together with guidelines from ACOG supporting the use of fetal RHD testing in certain patients. Adoption among eligible patients has been strong, and we were pleased to see commercial coverage initiated by one of the largest payers in the country. This new policy, which became effective last month, expands access to fetal RhD testing that can significantly improve precision medicine during pregnancy. Building on this successful launch from last year, we look forward to additional product and future announcements later this year in women's health. Transitioning now to organ health, I want to share some details on two unique studies on Prospera that we expect to readout in the coming months, and we believe will have a meaningful impact on the field. The first is the PEDAL study, which is a first of its kind respective clinical trial of kidney transplant patients, that is designed to evaluate the dynamics of donor DNA monitoring during treatment of a rejection event. This is similar to the cancer setting, where circulating tumor DNA monitoring with Signatera for immunotherapy response has become an…

Thanks, Solomon. I want to start by highlighting the CALGB/SWOG 80702 study, the results of which were presented in an oral session at this year's ASCO GI Conference. Signatera was utilized to examine in a pre-specified manner, the tumor and plasma from around 1,000 Stage 3 colorectal cancer patients in this randomized cohort. The results found that in Signatera positive patients, the addition of celecoxib to standard adjuvant chemotherapy resulted in a three year DFS improvement and a reduction in all-cause mortality of over 40%. Signatera negative patients by contrast had no significant improvement in overall survival from receiving celecoxib. The results were very well received by the scientific and clinical community with multiple leading GI oncologists already telling us that they have started discussing celecoxib with their Stage 3 patients who test Signatera positive. This also represents another major proof point along with the IMvigor010 data in bladder cancer published back in 2021 that Signatera can be predictive of therapy benefit across multiple cancer types and drug classes. We look forward to publishing the study later this year. We expect 2025 to be a pivotal year for oncology business with multiple significant clinical readouts as well as expansion of our product portfolio. Before reviewing our new product launches, I wanted to spend a minute discussing the underlying technology that powers and differentiates our MRD product offerings. Over the past 15 years, Natera has developed, patented and optimized a multiplex PCR NGS technology that allows for deep and targeted detection of tumor-derived mutations in plasma, resulting in exquisite sensitivity and specificity while controlling COGS. While our technology can multiplex thousands of targets simultaneously as we do with Panorama NIPT, for example, we believe the best approach for tumor-informed MRD detection is to select a targeted set of the highest-quality clonal…

Thank you, Alex. As we previously shared at JPMorgan, we presented our first prospective validation of our ECD technology showing 95% sensitivity and 91% specificity with minimal degradation of performance in the asymptomatic screen detected population. We continue to make rapid progress on this program, and I'm happy to announce that we've confirmed our CRC sensitivity in another independent data set where the majority of patients were Stage 1 and 2. We are encouraged by these results in CRC and look forward to reporting it in a more definitive study later this year for the PROCEED trial. The big announcement for today is the readout of our prospective advanced adenoma trial. As a reminder, we've collected roughly 3,000 patients using a protocol similar to what we would use in an FDA-enabling trial. All samples were asymptomatic patients and collected prior to a screening colonoscopy. We're pleased to report that in the patients analyzed for the study, we found an 18% sensitivity for advanced adenoma with a specificity of 91%. Because of the manner in which these samples were collected, we don't expect to see the type of performance degradation that's been observed in other ECD trials. Based on the excellent results in CRC in advanced adenoma, we decided to kick-off the FDA-enabling FIND study, which is expected to enroll over the next 18 months. The PROCEED study has allowed us the opportunity to better estimate both the possible enrollment rate and the cost of the definitive study. We believe this improves the chances for executing the study on schedule and within budgeted costs. This is already baked into our guidance for the year and has limited impact on our cash trajectory. Finally, as we look at the overall opportunity, we're pleased to see the Medicare rate confirmed at $920 and given that we will seek FDA approval for this test, we believe ADLT pricing at a higher level is possible. This elevates the opportunity for Natera, which is exciting given our mission to help as many patients as possible. For distribution, we're considering partnering with a national distributor or using our direct sales channel or a combination of both. Directly, we believe today, we are already covering nearly all female patients through our OBGYN channel in all major hospital systems through our strategic accounts team. We can augment this with sales reps in select markets for a solid distribution strategy. We also think the idea of partnering is enticing as well, either as a standalone strategy or alongside our direct team. In either case, we can do this without significantly impacting our operating expenses. With that, I'll pass it back to Mike to review the financials. Mike?

Great. Thanks, Steve. The first slide is just a summary of our Q4 financials. If you look at the year-on-year change column to the right, you'll get a sense of the progress we made across every metric of the business. As Steve covered at the top of the call, the large increase in revenues with even faster growth in gross margins moved the P&L to a different level in 2024. Even as we made substantial investments in future growth, our loss per share narrowed significantly and we generated a meaningful amount of cash. You'll recall that we retired the convertible notes early in Q4, so that leaves us with just under $1 billion in cash and effectively no debt on the balance sheet aside from the relationship line-of-credit from UBS. Okay. Let's get to the 2025 guidance on the next slide. Steve touched on the revenue guide at the top of the call. We are pleased to be guiding to $1.87 billion to $1.95 billion in revenues to start the year off. Our base assumption for this guide is really just having the positive trends we've been seeing in the last few quarters continue rolling into 2025. That means steady volume growth and stable ASPs in women's health, continued market share capture and end-market growth in organ health and of course, we expect Signatera to continue to grow sequentially. We've also obviously seen Signatera clinical volume now grow consistently above the 8,000 to 10,000 sequential unit growth threshold we've previously set as a target. The guide presumes we will modestly outpace that 8,000 to 10,000 level in 2025. The guide does not attempt to forecast any revenue true-ups. While we think the true-ups represent good execution on cash collections, the fact that they can be lumpy and unpredictable means that…

[Operator Instructions] We'll go to Doug Schenkel, Wolfe Research.

Hi, good afternoon and thank you for taking my questions. I think a couple of questions on following-up on your prepared remarks. So, Steve, in your prepared remarks, you talked about, I think it was the ability to double Signatera revenue at the current level of volume over the next few years. Just maybe dumbing it down for me as a math person, cutting through all of that, does that mean that you would expect to potentially get Signatera ASPs up to around $2,000 over the balance of the decade? And then I guess one for Solomon. You talked about the rationale behind why more targeted approaches have resonated on the clinical side with Signatera. Obviously, that continues to resonate. That said, some pharmaceutical companies have indicated they want a broader panel. How is the introduction of your genome-based products resonating with pharmaceutical and biotech customers in the early going and how is that factored into guidance? Thank you.

Yes, thanks, Doug. This is Steve. So yes, just first on the ASP around the revenue per test, I think the idea is today, there's a significant number of tests that we process where we don't get paid by the insurance companies. And that's sort of baked into the average ASP that we share you guys when we're talking about ASPs. So as time goes on, as we get more coverage policies in place for things like expanded carrier screening, other tumor types, commercial coverage for Signatera, we think we could see the revenue per test effectively double as we start to get paid for some of the tests that we run today that are already baked into our COGS, we're not getting paid on. And so that the comment I made was more general about the business overall, but it also really does hold true for Signatera, and I think your math is sort of reasonable as you sort of look out into the future. Then on - I'll briefly comment on the genome side and then turn it over to Solomon. Certainly, there's some interest from pharma and in a select areas, some clinical providers. I think the product has been received very well, largely with the idea of kind of clinical - using it for clinical research. But at this point, doctor - if the doctor wants a genome, pharma company wants a genome, we have it available and the product performs exceptionally well. So we're excited about it. Solomon, you want to make any further comments?

Sure. Yes. I'll add that there are situations where we do research projects with pharmaceutical companies or academic consortia where they seek to answer more translational or researchy questions of interest. And we routinely run custom versions of our technology that can include hundreds of targets, if that's something that the customer wants. And generally, we think about building a product for the clinical setting that's going to become a workhorse and highly scalable and also cost-efficient. So I think that's where you're seeing attractive levels of adoption in the clinical setting. So we do think about these - the end products a little bit differently for those different settings. But the underlying core technology leveraging multiplex PCR, we think provides the advantages across both of those settings depending on the application type. And increasingly, we're able to add more services and more genomic insights from our analysis of the tissue, whether that's with a genome or an exome and from the normal DNA and being able to run additional side assays like RNA sequencing, for example. So there's a lot that we're able to do. Hopefully, that answers the question.

Yes, that was great. Thank you, guys.

The next question is Rachel Vatnsdal, JPMorgan.

Perfect. Thank you. Good afternoon to you guys, and thanks for taking the questions. First up here, just on Signatera, if we look at the volume growth that you saw throughout 2024, you did roughly 14,000 sequential unit growth throughout last year. You said you're going to do above that 8,000 to 10,000 per quarter or sequential per quarter in 2025. But can you just give us some more color on how much above you could do versus that 8,000 to 10,000 kind of like the old long-term plan that you guys had? And then could it be something in that range of 14,000 like we saw last year? And then I have a follow-up as well.

Yes, thanks for the question. So I'll let Mike comment a little bit on the guide, but first, I'll just say we're very underpenetrated. This is a very large market. We generated over 100 peer-reviewed papers, and we're seeing very significant interest from physicians and that interest is accelerating as we generate data like the 702 study that really provides an actionable predictive use case for the product. So as we said in the prepared remarks, Q1 volume growth in Signatera is looking to be one of the best quarters that we've ever had in the history of the company. So we're feeling very good about volume growth in Signatera. Mike, do you want to comment on sort of how we do the guide?

The guide, I mean we covered the philosophy kind of in detail in the prepared remarks. So the guide presumes that we can do better than the 8,000 to 10,000. It's not necessarily anchored at 14,000. It's going to be - it wouldn't surprise me if you just look at last year, averaging out, you're kind of in that, 13,000, 14,000 range, but obviously and you had 15,000, you got 11,000. It wouldn't surprise me if you have those types of kind of typical fluctuations through the course of the quarters and that's really more driven by just different numbers of receiving days that are available to you in a given quarter. So I think the spirit of the guide is that the momentum continues and it's a strong but still an achievable target as a starting point for the guide for the year.

Great. Thanks for that color. Then I just wanted to dig into the concept of true-ups here as well. So you mentioned that you're not including true-ups within the current guide for 2025. You've also talked about how the magnitude of those true-ups are going to come down as you guys continue to do better on collections and have more visibility in that. So could you just level set for us, what should we expect in terms of that true-up on getting more standard as we go forward in the trajectory there over the next few years? Thanks.

Yes. I mean, I think Mike, you take it.

Yes, I mean the goal for the true-up - the reason why we have true-ups is that the historical cash collections are exceeding the historical accruals. And as we get history with better and better cash collections per test, obviously, the accrual increases in sympathy, okay? And so invariably that's going - the change in the ASPs in these products is going to moderate. And when it does for a period of time, you'll have the - you'll have the true-ups kind of decline kind of on a glide slope. So I do think that they'll kind of moderate over time back to kind of what we saw historically, which was sort of like a $5 million kind of true-up number every quarter. The reason why we don't guide to it though is that that's hard to predict quarter-to-quarter. So I'll just give you an example. I mean, we're working very hard to win appeals on cases that we ran in the fourth quarter of 2023. So we've already kind of collected 100% of the revenue that we needed to collect for 2023, Q4. But if we win more of those appeals, if the cash arrives in Q1 or arrives in Q2, then we'll book revenue in that period. So fully expect it to be lumpy, but you've seen the ASPs go up quite a bit. And I expect over time on average those to moderate down on a more or less linear glide slope.

Next up from Morgan Stanley is Tejas Savant.

Hi guys, good evening, and thanks for the time here. Just to start, maybe one for Alex here. I know in the deck you talked about the number of targets only being one variable impacting tumor-informed MRD assay performance. But how many markers do you anticipate tracking for your personalized whole-genome panels at 16 like the current version of Signatera? And how did you think about that choice in terms of COGS considerations versus optimizing for perhaps higher sensitivity? And can you just share some early color on feedback from the oncologist community?

Yes, let me make a couple of comments and then throw it over to Alex. So yes, on the genome product, we're tracking 64 variants. And remember, we're using the same multiplex PCR NGS approach that we use with the 16 variant assay. So the philosophy is to go extremely deep at a very highly curated targeted set of variants. And we think that's the best approach. We could do 2000 variants. We can do - we actually do 30,000 variants in a single reaction when we run certain tests. We do that all the time in the laboratory. But we chose specifically to do 16, and now in this case of genome, 64 because we think that's the right approach where you're optimizing sensitivity and specificity. And I think that's proving to be the right decision. If you look at our clinical performance data, you look at our very strong data that we published for recurrence monitoring, it's really good. So this looks like to be the right approach and we're excited about it. Alex, do you want to comment further?

Yes. Maybe just one or two quick points. I think the first is, we've seen really very positive and very strong feedback with this launch, both from the broader academic community, the consortia community as well as the pharma community. So we're very pleased with that. And now the way we think about it, as Steve mentioned, is there's a few factors that go into asset performance. Number of variants is just one of many. So error model is super important, the quality of the variant selected and then the ability to sequence and call those variants very, very deeply. And I think when we did the math, 16 was really kind of the optimal number for exome. And kind of when we did the math for genome, I think at least initially the number is 64 that kind of optimizes performance kind of across those metrics, while kind of keeping COGS contained.

Got it. That's helpful. And Mike, a quick follow-up on the guide for you. So first, how are you thinking about any potential benefit from the NovaSeq X transition? And second, on the Medicare lung reimbursement for Signatera, any color you can share in terms of payer mix, Medicare versus commercial in non-small cell lung? And how many deaths will be covered in the surveillance setting?

Yes. Let me comment on...

Go ahead.

Sorry, we're - sorry. Yes, let me comment on lung, Mike, and then you can maybe jump in on the COGS projects that we've executed on. But obviously, we're really positive on lung. We're seeing a lot of interest there from providers. That's an area where historically, we did really well engaging with the KOLs and some of the top centers, but we weren't reimbursed. So it wasn't necessarily, I think, the first thing that our sales representatives and medical team were talking about when they were out in the field. But nevertheless, we still have a lot of volume coming through. There's a lot of interest. So this is a big opportunity for us as we look at just the number of patients that are diagnosed, I think the clinical importance of this type of testing and the value that we can provide from surveillance. So I think this represents a new vector of growth for Natera that could potentially even help us push significantly past maybe some of the record volume quarters that we saw in 2024. Mike, do you want to talk on COGS projects?

Yes. So just versus we're on lung, I mean, I think the Medicare mix is going to be broadly similar to the average that we see kind of across the business there. So I do think it will be kind of a - kind of a contributor as the - similar to the rest of the tumor types. There's not like a very meaningful SKU, I think within that Medicare mix. And similarly, I mean, I presume that there will be - now that we have the coverage, we'll go back and just confirm on the pricing decisions with MolDx, but I think it's safe to presume that the similar kind of setup in terms of a bundle pricing would be would be the standard there for the adjuvant setting. In terms of the COGS project, yes, I mean we definitely we're going to have some improvements to COGS. I think here in '25 and that's part of the guide and that's part of the kind of the gross margin improvement that's contemplated in the guide is pretty meaningful gross margin improvement versus the underlying 59% we just posted in Q4. I think Steve's comments in the prepared remarks were more - it used to be up until the middle of last year, it was really like the overwhelming thrust of the R&D effort was - we were forced to kind of prioritize just getting these COGS projects out the door and now we can be a lot more nimble and focused on some interesting product launches and features and data sets. So it's a much more kind of balanced portfolio.

Got it. Appreciate the color, guys. Thank you.

The next question is Tycho Peterson, Jefferies.

Hi, this is Noah on for Tycho. Thanks for taking our questions. I wanted to start by asking about the 702 study and particularly interested in what the initial reaction has been like there? Anything you would point out as an indicator that this will lead to broader use from clinicians.

Yes, thanks for the question. So I guess I'll make a comment and then maybe hand it over to Alex or Solomon, if they want to comment further. But anytime you have something like this that's very actionable for the doctors, there's going to be significant interest, particularly when it has that predictive impact as well. And I can just say from my view, coming out of the conference, one of the leading colorectal physicians came up and said, hey look, I've already started prescribing celecoxib in my practice to MRD-positive patients based on this data. So I think to hear that really gave us confidence that this is very important and it's going to change practice. So Alex or Solomon, you guys want to comment further?

No. I think the initial feedback is overwhelmingly positive. I think there's also additional data that was presented at ASCO GI about the benefit of Aspirin in some early-stage colorectal cancer patients. I think that further kind of reinforced this concept that COGS inhibition, especially when biomarker directed can be very, very impactful for these patients. And just to put this in the context, there's not been a new therapeutic development in the adjuvant management of colon cancer for over 20 years since the MOSAIC study. So I think because of this, I think patient advocacy groups, physicians, I think there's just broad excitement across the board. And we'll see how this translates into further guideline changes. We can't predict that, but you're looking kind of forward to see what the NCCM committee kind of may weigh in, on this data.

I'd just - from my side.

That's helpful. Thanks. And then one more from us. On MRD, obviously, a number of competitors will be launching in the next year or so, just wondering what your competitive strategy is in order to try to maintain the market-leading position there. Thanks.

Yes. So there's always been competitors coming in. I think a couple of them have sort of been enjoying because of our IP position. But for the last couple of years, there's been competitors selling MRD testing in the marketplace clinically. So we feel like we're in a good position. You have to just do the fundamental things. You have to deliver high quality clinical data. You have to have an amazing customer experience, you have to have a strong medical and commercial team, and we're continuing to do that. The other area of focus is innovation. And I think we're in a very strong position because we're able to invest very significantly in R&D. And you can see we're not burning cash. We're cash flow positive. We're at one of the highest levels of R&D spend that we've been at, and that's because we think there's a lot of opportunities for product line extensions, product line enhancements, new versions of products and most importantly, big large scale market moving clinical trials. So we're doing all those things and we think we're doing the right things. But look, competition is a good thing too. It's great to see that this market is very meaningful and that it's growing. And I mean it's what like 3% penetrated or something like that. So this is probably the largest molecular diagnostic opportunity in the history of oncology molecular diagnostics. So certainly, there's going to be a lot of competitors coming in.

And the next question is Puneet Souda, Leerink Partners.

Yes, Hi guys. Thanks for the questions here. Maybe first one on the cadence, can you remind us maybe, Mike, how should we think about growth through the year? You have a number of drivers, obviously, data reading out, products launching and on top of that, John talked about a number of ASP drivers. So just trying to understand how to think about Q1 and the cadence through the year? And the gross margin lift that you have in the guide was also strong. So just is that largely ASP or how much sort of COGS reduction are you thinking about? Again, you know, looking at both oncology and women's health? And I have a follow-up.

Yes, Mike.

Yes. Thanks. Yes, I think the - it's a good question on the cadence. Typically, the women's health business, I actually think that we will return to our normal form there where Q1 is a very strong quarter for women's health. Just seasonally Q2 tends to be softer and then you kind of return to kind of Q1 levels and beyond in Q3 and Q4. Last year, the cards were kind of scrambled a little bit just because we did - we added those Invitae units and that was kind of straddled between Q1 and Q2. So you didn't quite see that trend in the financials this year, but this is a pretty clean year from adds as far as that's concerned. So I think women's health return to kind of the normal seasonality we've seen over the last decade. Signatera and Prospera, we haven't - there's not really a seasonal component there other than the dynamic that I mentioned earlier in the call, which is just, hey, number of receiving days will vary. And we're to scale, particularly in Signatera wherever you're receiving days is worth a lot of units and so you just got to keep that in mind. So holidays, will impact you. But that's the main for us. It's kind of Q1 bigger because of women's health, Q2 softer because again, seasonality in women's health and then kind of return to form in the second half of the year and not much seasonality in the organ health and Signatera. And sorry...

Gross margin?

Yes. So yes, I agree with you. I mean, look the - I think that's important to think about the gross margins. The guidance actually it does imply a very bullish outlook as it relates to kind of continued gross margin improvement. And I do think as Tejas asked, there are some thoughts projects that we are going to deliver in '25 that I think will be useful. We're also just going to get some benefits on the COGS side just from the scale efficiencies as you kind of grow units the way that we're growing them, you do get kind of - you do get a linear benefit to all the facilities and all the equipment and the people and things like that, and we're getting more and more efficient there. So that's a component of it. I do think that weighting them, there's more of a weighting toward benefits in ASPs. So that's kind of the continued growth in the Signatera ASP and also just steady execution kind of women's health ASPs kind of continuing on where we left them in Q4 and then annualize them for a full-year would get you a strong uplift. But that does leave you room for upside and John kind of alluded to some of the potential sources of upside we have, particularly in women's health ASPs.

Got it. And then if I could, I'll try my best with this question on NCCN, but we're also getting questions on the advanced adenoma data that you provided in the slide deck. So NCCN, ctDNA is prognostic, but not predictive. And then they also said ctDNA is not recommended for surveillance. I appreciate the Merkel cell support that you're getting there. But could you elaborate on the oncologists feedback? And one side, there's the traction with payers potentially. But on the other side, the - there's also the offset maybe in the community setting, they might - I mean, the oncologists are still going to be looking for NCCN. So maybe just help us understand - capture the NCCN and how we're thinking about that. And just on advanced adenoma, why should we not see any degradation there? Thank you so much.

Yes. Let me just comment briefly and then maybe Alex, you can make a couple of comments on advanced adenoma. But on NCCN, it's being received very positively. There's been a lot of - a lot of good feedback on the calls that we've done and meetings we've had over the last two weeks. I think certainly adjuvant was an enhancement. And as Solomon pointed out in the prepared remarks, some of the data that I think is very meaningful, like for example, the 702 couldn't be considered where maybe you would have received that predictive claim. But certainly that's an enhancement. And on surveillance, it's - we think it's sort of just administrative language cleanup. That's kind of some of the feedback we've been getting as there was no real intention there and that makes sense and that's kind of in line with what we're hearing out in the field as well. So we don't think it will have any impact. There's also great surveillance data. I mean INTERCEPT, which is more and more people are talking about that now out of MD Anderson, very significant trial. And then the BESPOKE study was received very positively at ASCO GI and so certainly, we think that's going to have an impact as well. But I would say net NCCN readout was very positive for us. And then on advanced adenoma, I'll turn it over to Alex on advanced adenoma. Alex?

Thanks, Steve. Puneet, I think this is our first readout. I think what makes us more comfortable to really think that we're minimizing the chance for degradation as much as possible is that, these are samples that are collected prospectively, colonoscopy matched in the screening population, kind of really following the same ethos as our prospective FDA enabling study that Steve announced that we're launching shortly. And again, this is the first of what we hope to be multiple readouts also for advanced adenoma. I think we're planning an additional readout later this year, again, following the same ethos of only running prospectively collected colonoscopy matched samples following a very similar protocol to the FDA study. And the good news is that, we still have a little bit more time before the algorithm has to be completely locked, right? So we do also think there could be room for further improvement beyond the number that we initially read out. So those are the things we're doing to try to minimize the chance of degradation as much as possible.

Got it. Helpful. Thank you.

Next up is Catherine Schulte, Baird.

Hi guys, thanks for the questions. Maybe first on biomarker bills. Is there any way to frame what your success rates have been in getting paid in those states to date? How has that evolved once the bill becomes effective? And then I know you aren't baking anything into guidance, but how do you think those success rates could realistically evolve over the course of the year?

Yes, that's a good question. So I think the outlook on biomarker is positive and it's great to see that we're seeing, I think the first signs of the ship turning here. So let me turn it over to John Fesko to talk just briefly on what's happening there.

Thanks, Steve. Catherine, we've been cautious on the impact of biomarkers because we didn't know the pace at which it would flow through, and it's taken a little longer than we had hoped for. But with these formal publications, we think that creates ammunition to go press other plans. And we have heard from other plans that they want to come into compliance with the law. So we think that we will see conservative positive improvement over the course of this year and next year.

Okay. And then maybe on R&D, just given the magnitude of the increase you're calling for this year, can you just talk through the spend buckets within that oncology versus women's health versus early detection? How much is the FDA enabling study? And then just how should we be thinking about R&D growth over the next couple of years or where that might settle out as a percent of revenue over time?

Yes. Just make one more comment on the biomarker bill. I mean this goes back to - this goes back to, I think Doug's question at the beginning around our prepared comments that level the revenue per test. So biomarker bill is a great example because today we'll receive a test from a commercial payer and a lot of times they don't pay us. And this is an opportunity as the biomarker bill comes in where we can actually get paid on some of the tests that we're already running. So not only are we accelerating volume growth as time goes on by getting things like lung coverage in place and just the MRD market evolving, but we also have this impact of accelerating ASP that's happening over time. And the biomarker bill is very significant opportunity for us. R&D, so yes, sorry, I just had to remember what the second question was. Yes, on the R&D side, look, the vast majority of the R&D is going to be on MRD. And that's clinical trials and that's product line extensions, product line enhancements, that's COGS and scaling related projects and that's UX related projects. When you look at other areas of the business, certainly, we think women's health and organ health are very important. We've got some pretty exciting launches happening there with those businesses in the future. But and also some great clinical studies as we went over PEDAL and DEFINE. These are really the first time - these specific things have ever been studied in this very rigorous prospective manner. I mean, we think they can be very meaningful for the field. But yes, the main focus is MRD in oncology, and we think we think that's where we should be putting our investment now. Of course, the ECD opportunity, although traditionally, our investment there has been very targeted, and we'll continue with that philosophy. Now we're launching the FDA-enabling study. That's already worked into the budget, already worked into the guidance for the year, but there will be some spend there. And we think that that's warranted given what we think is really, really strong performance on the ECD product. And given the ASP, I think the $900 plus Medicare clinical fee schedule rate plus the opportunity to have an ADLT rate that could be in the $1,500 range. I think that that's actually - that makes it a very significant opportunity for Natera. And given our ability to develop these types of work through the regulatory framework or historical success with distribution and actually the built-in channel that we already have for distribution, we think we can be a very major player in that space, and we think we can do it without really significantly increasing the operating expenses and have a very high gross margin product. So certainly, that's worth investing and that's why we're putting money behind that.

Great. Thank you.

Up next is Daniel Brennan, TD Cowen.

Great, thanks. Thanks for the questions. Maybe just starting on price, Mike, just kind of walk us through, I think you said women's health price is flat in '25. So kind of what are you assuming on Signatera? And if you could let us know kind of on commercial payers, just what's the progress been there and kind of what are you baking in implied in that price for '25 of commercial payers? And then I had a follow-up.

Yes, Mike, you want to take that?

Yes, go ahead. Thanks. Thanks for the question. So yes, just on Signatera, we just expect kind of steady kind of continued improvement in the ASPs. Women's health, as you mentioned, is stable. What's going to drive the improvement in Signatera at least in the base model? It's just going to be continued execution on reimbursement for our Medicare Advantage volumes for coverage services. So that's been an important driver for Signatera ASPs over the last 12 to 18 months is kind of getting Medicare Advantage reimbursement from the 20% range to now kind of in the 60%, high-60s range. And so we're going to make steady improvement on that. We fully expect in '25 and that's what gives us confidence actually guide to improving Signatera ASPs in the year. And then I'd just highlight again, I mean the women's health ASPs have been really strong. We've been very encouraged by the results we've got from all the hard work there. So that's certainly a potential source of upside if we can continue to see improved ASPs, particularly in expanded carrier screening, that would represent upside to what we've guided today.

Great. And then maybe just a follow-up on lung. So can you just remind us of what percent of the lung indication you have today like wasn't covered by IO, so of the 200 plus 1,000 incidents, how many of those patients are already applicable for IO? So what's like the expansion that you see? And any other approvals we could expect this year with tumor types are kind of high on the list? Thank you.

Yes Solomon, you want to comment on sort of how things are parsed out between maybe the adjuvant indication in lung where we were already covering quite a few of the patients with IO monitoring and then what is this kind of very large surveillance opportunity that we just received coverage for?

Sure. Thank you. In lung cancer, immunotherapy is already very commonly prescribed even in early stages of disease. In many patients in the adjuvant setting in the early stages and some patients also in the neoadjuvant setting, so that's before surgery and some patients get both. So Signatera was already covered for immunotherapy monitoring in those patients, and that would be a single bundle payment of when a patient is starting monitoring for immunotherapy. The new coverage, it provides a - or the new Medicare determination provides coverage in the surveillance setting. So this is for patients who complete their definitive therapy, who will have no more evidence of disease and in line with NCCN recommendations for monitoring in the surveillance setting, Signatera can now be used as well and paid for by Medicare. So we think that's a big deal. We think it's in line with the evidence and in line with the opportunity for greatest impact for those patients. In terms of other disease types, we've published now in many additional cancer types. We have several submissions that are currently in progress and others that are being prepared that the draft off of the evidence that's been established and published. So looking forward to provide further updates there. And thanks for the question.

Great. Thank you.

The next question is Dan Leonard, UBS.

Great. Thank you for running along. I'll ask a two-parter on early cancer. First-off, can you clarify the timing? I think you mentioned 18-month trial. So does that mean we'll get data by the end of 2026 and you'd hope for a 2027 FDA approval, if all goes well? So that's the first part. And the second part, can you touch on the platform capability? Is this a platform where you could add other cancers as well on the same format or would any future multi-cancer offering via a different technology platform entirely?

Yes, it's a great question. So, yes, let me - I think the timing is probably about right. Alex or Solomon, if you want to provide any more specifics there, but I think roughly kind of in the right ballpark. The good news is with the trial, we set up this entire infrastructure of PROCEED study. So we already collected prospectively 3,000 samples there. We worked with different vendors to run the trial. And so we're basically just sort of flipping a switch and moving into the new trial with the same infrastructure. And I think that's going to allow us to get it done, I think quickly and efficiently. And as Alex said, we've learned a lot through I think the 3,000 patient PROCEED trial. On the platform that we built, I think you're exactly right. We spent two years building a discovery platform that allows us to identify novel markers and we're just sort of pumping new data through that and using that to design assays now and this sort of pan-cancer approach. Now we're still assessing our strategy for the next version of where we want to go after CRC. I mean, we think that the right approach is focusing on CRC initially. But certainly, as we said in tumor-naive MRD, we're already moving to other tumor types. And I think in the field of early cancer detection, there's going to be that opportunity to do the same thing based on the strength of the platform that we've built.

Thank you.

And next, we'll hear from Subbu Nambi, Guggenheim.

Hi, guys. Thank you for taking my question. I have two questions. One, could you elaborate on why you believe no one else will receive ADLD status. One could argue a first-in-class tumor naive test, for example. And then second, how much of an advantage is having a biobank with all the Signatera samples to develop in tumor-naive and screening tests that you just touched upon them.

So look, I think if you go through - I would just point you to go kind of go through the ADLT regulation. There's multiple tumor-naive MRD tests on the market and that's one of the disqualifiers for an ADLT without FDA approval. So I think there's several commercial CLIA-validated on-market tumor naive products and if you go through the specific legislation, you know that itself is a sort of disqualifier for a new ADLT approval. Now, of course, there's the FDA path, but that takes time. From a sample collection standpoint, I mean this is one of the real values of Natera and you start to see - remember, we've been at this since 2015, we started collecting biobanks, we started doing prospective clinical studies, we started collecting samples. So when it comes to launching new products in the MRD space or new versions of the product, we have a real advantage because we've published over 100 peer-reviewed papers and we have over 100 ongoing clinical trials and biobase studies that we're participating in. So we're in - like we said in tumor naive for colorectal, we already have a prospective 1,000 patient sample covering surveillance in the adjuvant setting. It's already running in the lab today. So I think that just gives you a sense of how quickly we can execute on things.

That's great. Thank you, guys.

And everyone, that does conclude our question-and-answer session, as well as our conference for today. We would like to thank you all for your participation. You may now disconnect.