Great. So we'll kick it off. Dan Brennan, Tools Diagnostics Analyst here at TD Cowen. Pleased to be joining the stage here with management from Guardant. We have Helmy Eltoukhy, Co-CEO, and Mike Bell, Chief Financial Officer. I'll look at my email here. Feel free to send questions. We have a long list. Maybe just starting off, guys, you just reported the fourth quarter. Just kinda wondering, you know, what would you call out stood out from the quarter, and kinda how do you feel about the 2024 outlook for Guardant?
Yeah. No, we've felt we had broad-based strength across the business. Clinical volumes were good. I think we closed the year out really nicely. Biopharma volumes, as we typically see in Q4, were very strong. We had an excellent year, I mean, 25%-26% year-over-year revenue growth, really firing on all cylinders, from what we could see. And I think it's a great setup for 2024. We achieved our goals in terms of EMR integrations. We think we built a lot in terms of infrastructure in 2023 that we have yet to capitalize on, and we think will be catalysts for 2024 growth. We have ASP improvements that are baked in in terms of Medicare, and then hopefully some tailwinds from the commercial payer side. International is nicely teed up with really great traction in Japan and the U.K.
Great. Maybe Mike or Helmy, you know, just in terms of the guide, 16%-19% year-over-year growth with clinical revenues growing at least 20%, and you've got these ASPs increasing on Guardant 360. So when we do the math, like, we come up with kind of a low- to mid-teens volume growth for Guardant 360, which seems like a big deceleration yet. Wouldn't expect, like, that would happen. So maybe could, could, could you walk through the key underpinnings of that 16%-19%, and is anything with our math right, and are you just baking in conservatism in volumes, or, you know, maybe something's going on in the market?
Yeah. I mean, I think on the clinical revenue, you know, our guide sort of implies a 20%+ growth on the clinical side. And yes, we've got the ASP uplifts. You know, there's a lot within that clinical revenue because there's Guardant 360 in the U.S. There's Guardant 360 international, especially in Japan and the U.K. We've got Tissue Next in there. We've got Reveal. So there's a multitude of products there. And so, you know, we're not sort of backing into every growth driver. I think one thing that's important with Guardant 360, you know, last year, particularly in the first half, we had the ESR1 approval, which almost overnight doubled our Guardant3 60 breast volume in the U.S.
And so, you know, there's a bit of a difficult comment that we've got to get over in the first half of the year. So, you know, maybe that's impacting a little bit the year-over-year growth trajectory on Guardant360. But nevertheless, I think across all products, and in all markets, you know, we're expecting to see good, strong growth. We should expect to see sequential growth each quarter. So again, as Helmy said, I think, you know, we're set up for a strong 2024.
Great. I'm gonna hit some questions on screening, and then we're gonna jump back into the base business and MRD and international. But just, you know, in terms of screening, obviously on the Q4 call, you know, AmirAli talked about, you know, listen, if the test program doesn't meet certain hurdles, you know, there will be no Shield. You guys are convicted on the program, but, you know, it has been, you know, a key point of debate, if you will, on the stock. Maybe can you just comment further on this staged approach to your commitment to Shield? And as we look out over the course of 2024, like, what are the criteria, sales, volume targets, FDA, you know, things like that, that need to be met? Otherwise, you know, you eventually could decide maybe to step away.
Yeah. You know, there's nothing specific I would say we would step away. And it and, you know, I don't think that's our intention. I think what AmirAli really is talking about is, yeah, if this FDA process was a total failure, then of course we're not gonna carry on regardless and, and, you know, burn $200 million a year with a product that's not gonna make an impact in the market. So I think, you know, it's something we're looking at very closely. We're planning for success. When we talked about the maximum $200 million burn in 2024, that's, you know, assuming a timely FDA approval and that we're gonna do a full-blown launch and that everything's going well.
And I think, you know, I think the message is that $200 million's our, our maximum. If the product isn't gonna have the commercial traction that we expect, then we're gonna be able to, you know, manage that manage that burn down, and we're gonna do it we're gonna manage the business accordingly. And, so I think, you know, we're not we're not we don't wanna set any specific metrics and say, you know, if, if this happens, we're gonna do this. I think let's, let's see what happens with the FDA approval. But at this moment in time, we're, we're planning for success, and we're expecting approval this year and to, to launch in 2024.
Mm-hmm. And then maybe just hitting the AdCom a little bit. Obviously, you got delayed, and you know, you indicated you couldn't fill this or the FDA—excuse me—couldn't fill the seats. It's just the feedback is, "Wow, this is such a seminal event," or, "It's such a big new product." It would just seem kind of odd that they couldn't fill a seat. Just again, any more color, just how we should think about or investors think about this push out in the AdCom timing?
Yeah. From what we understand, this particular committee hasn't been called for a PMA review for many years, and so those seats hadn't been filled. I think 5 out of 10 were filled. They have certain requirements in terms of number of filled positions for PMA review. And so, yeah, that was the main reason. I think the FDA is making good progress in terms of filling those seats. And I think the important thing to note is this doesn't change that a lot of time is for the review period. And so the AdCom, even if it's pushed out, you know, doesn't delay the final FDA approval or, you know, at least decision for the device. And so, yeah, it's unfortunate it got pushed out, but it doesn't really impact the overall timeline in any way.
You know, in terms of questions, I guess we'll get that a few days before possibly. But, like, will adherence, you think, be something that gets discussed? Just like obviously, they'll look at the data. They'll look at the, you know, kind of the, you know, the endpoints and how you did. But just what are some of the areas you think could come up on the AdCom?
Yeah. I mean, I think we don't know all the specifics yet, but I would say the two general areas that, you know, we think would be under consideration from previous AdComs would be sort of the design of the study, looking at the data, quality of the data, as well as the label considerations in terms of first line and second line.
Mm-hmm. So maybe on that, you guys were pretty confident on the call that even if it was second line, it still could be a really material opportunity. Just obviously, there is a very large unscreened opportunity. So how do you think about a second-line label? I know the way Amir or you guys described it on the call, it wouldn't really have an impact. Just, is that what your market intelligence says? 'Cause there's probably some concern if it was second line, it could really limit the opportunity.
Yeah. I mean, we, we are selling the LDT as a second-line device right now, and we're seeing metrics that are frankly off the charts in terms of physician depth and, you know, excitement for ordering. And I think the, the big thing that you need to keep in mind is that colonoscopy sets on a separate sort of pedestal on its own. And once a patient's refused a, a colonoscopy, then the physician is thinking, "How do I get this patient screened by whatever means is possible, whatever you know, whatever it takes?"
And so that's why FIT is still used. It's still the most used test per year, from an annual volume point of view. And it's why we know that Shield will do really well regardless of, of the label consideration. Obviously, we're still pushing towards first line. I wanna make that clear. We think certainly in the first, you know, half a decade of trajectory, the first five years, it probably doesn't make too much of a difference in terms of uptake, of the device.
Mm-hmm. And, you know, we expect there'll be a, you know, big readout from a competitor soon, although timelines have slipped a little bit. And it's certainly that day or whenever it comes up, there'll be a lot of questions depending on how the data looks versus the competitor profile. If for some reason that data looks a lot better than yours, just I don't know. Like, again, hard to forecast what that could be, but if it's materially better, does that influence at all kinda how you guys are planning to go to market, or just any color on the competitive impact?
Okay. I think when we lay out a plan that there's gonna be essentially continuous improvement of the of the device, we have a V2 that is ready to go, that is, you know, I think substantially better in terms of performance, from V1, at least in the initial data sets. And so, you know, we have a roadmap by which we believe we can remain competitive, you know, in terms of the, the probable possibilities in terms of where competitors may, may read out. But right now, we're the only game in town. We feel very confident in terms of our probably one-plus-year head start and first-mover advantage. And so but all of these all of these variables, as they play out, are going to essentially inform our investment thesis in Shield.
Obviously, if we don't get an approval or the landscape changes from a competitive point of view in a way that we haven't foreseen, all of that is gonna inform sort of the investment thesis, and we'll make decisions accordingly. We're not gonna waste money where it doesn't make sense. We are, you know, trying to be, as we always have been, judicious stewards of the capital that we've raised.
Maybe final question would be just, can you remind us, you know, at your investor day, you laid out a five-year target on Shield. Just, you know, how would you know, back to this gated idea, any sense of, like, how the uptake would be? Is it linear? Obviously, it probably starts slower. And then B, just on USPSTF, like, do you think the 13% AA detection, given the other profile of, you know, 83% and 90%, do you think that clears the USPSTF hurdle?
Yeah. I mean, from the trajectory, yeah, at our investor day, we laid out that by 2028, you know, we'd expect to be at least 1 million tests a year, $500 million in revenue. So nothing's changed from that perspective. I don't think, you know, we're not considering giving sort of year-by-year, blow-by-blow accounts of the volume. But I think, yeah, we're feeling confident about that. Again, that assumes that there's competition coming in the market. It does assume that we get USPSTF in the guidelines in 2026. So, you know, those assumptions are baked in there. Yeah, I mean, that's the current plan.
Yeah. And in terms of the performance of the device, I mean, I think we are fairly confident that it should get a positive review by USPSTF. I think compliance and adherence is an important part of the equation. It's been called out in the last review cycle in terms of compliance and adherence being an issue with the current modalities. And the models that we have really show that it makes a substantial difference in terms of this particular device, Shield, at 83%, 90% 83% sensitivity, 90% specificity, and high compliance, that it'll essentially move the needle quite considerably over the current landscape in terms of detection of CRCs and quality sort of life years gained.
Great. Well, maybe switching over to the base business, you know, with on the clinical side, you know, clinical therapy selection business is $400 million-plus, growing 30% the last few years. Just what's the penetration like here, and kinda what are the bigger opportunities as you look ahead, like, 2024?
Yeah. We think there continues to be a really nice setup. Obviously, we saw with ESR1 that as new therapeutic options get launched into the market, there's substantial step-ups in terms of penetration and different tumor types. And so we think that theme will continue to evolve as more drugs get approved. Right now, we think the penetration's around maybe 20%-30% of, you know, Guardant360 in the sort of one test per patient sort of setting. Much lower and then that's in the major cancer types, much lower in the sort of long tail of, you know, 47-50 cancers. And what we're seeing, though, is that the breast and lung guidelines this year have been updated to put liquid on equal footing with tissue, which is really a fantastic development.
The lung guidelines go so far as to recommend simultaneous or concurrent testing of both upfront. Breast guidelines talk about reflexing to other if one is negative. And so you're seeing this essentially quasi-doubling of the potential market when you take tissue and liquid together upfront. And this is without considering the number of times a patient will have to get a genotype because that initial drug fails. Every progression, a patient's gonna need another drug. The fact that the drugs are getting better, that patients are living longer, I think bodes well for the increasing opportunities that exist in the market.
And then finally, we think application of therapy selection is gonna happen earlier and earlier in terms of patient journey. Right now, it's really confined to the metastatic and stage III setting, but we think ultimately, as you start moving targeted therapies, immunotherapies, towards the adjuvant setting, yeah, it'll, it'll, you know, further expand the market quite considerably.
Just on the kinda simultaneous use testing, that's something we heard as well. What's the average number of tests today that you see per patient? And given those guideline updates, where does coverage stand, either from a commercial standpoint or a Medicare standpoint?
Yeah. I mean, the average number is still closer to one than, you know, two. Very much closer to one. So that's why it's a sort of big opportunity that's still ahead of us. In terms of reimbursement, because we've taken, I think, a very conscientious approach of essentially requiring a follow-up with the physician if, if they want a reflex to another test, we've, we've had relatively good success from a reimbursement point of view.
But, like, was it something that Medicare would make a NCD on, local coverage decision, and then I guess commercial just happens piecemeal, right? Like, just in terms of 'cause you mean we had actually reached out as we did our diligence for ahead of this report we did last year. And we, you know, feedback we got, like, "Oh, what's the clinical utility of testing, you know, simultaneously?" Just wondering kinda how we think about Medicare.
Yeah. I mean, right now, it really depends on the policy, but there are certain provisions where if you have two different tests, you can have both of them covered. It just, yeah, depends on the specifics, which MAC you're in, and whether you qualify under the NCD or not. So, but yeah, we feel very good in terms of where we stand.
And international, you talked about it on the call. You know, you kinda gave some stats on Japan in particular, but you got U.K., you've got India, you've got, you know, China. Just kinda walk through, like, how, how big is that business today, and are we at a point over the next year or two or three that it could become materially bigger?
Yeah. It's still a very small portion of our overall volume right now, but we're seeing essentially the really nice inflection points. Essentially, inflection point for international volume, country by country, is uptake by the public healthcare systems in those countries. That's really when you get to the large sort of population explosions in terms of the use of the test and uptake of the test. And obviously, we got there in Japan last year with a reimbursement in, you know, late last year, and we're seeing really amazing uptake of that test. We think sometime this year, we may cross over to be the sort of number one-used liquid biopsy in Japan. And that's a market that at full scale is, you know, about half of the U.S. opportunity.
So it's a very large opportunity for us, an ASP that's similar to what we had last year for Guardant 360. U.K. also is a sizable opportunity. The NHS has essentially indicated that they would like to roll out liquid biopsy testing to almost all their lung cancer patients in England. And that's just the beginning. They're thinking about these tests for multiple other cancer types. And this is really the power of a blood-based methodology, especially in countries where essentially access to some of the specialty medical professions, like an interventional radiologist or a pathologist, may be more challenging.
And so this is really the beauty of these technologies, not just for therapy selection but MRD and eventually screening, is that we can really reshape the sort of medical landscape in many of these countries. And so that same playbook, we think will play out in multiple other countries around the world. The way I look at it is, something like, you know, 90%, 93% of all, like, cancer deaths happen outside of the U.S., and so the market is still very, very large,
Mm-hmm. And did you bake in, like, any way to quantify what's incorporated in 2024 guidance for, you know, Japan uptakes since that's the new one that's ramping?
No, no, I don't think no specific way to, to quantify Japan. And it'll still be relatively, you know, minimal of our total revenue. But, no, I think we still, like, excited. It could be a, a good opportunity, and maybe there's plenty of upside with, with Japan and, and also the U.K. in 2024.
So we hosted this panel yesterday, and one of the doctors on it was, you know, pretty constructive on, you know, the ESR1 opportunity, but more so from, like, some forthcoming trials. And you mentioned SERENA-6 from AstraZeneca, which is a different trial than the trial that you got approval for, for Orserdu or that the, the pharma company got approval for, for Orserdu. Maybe just speak to SERENA-6, like, what that trial entails. And, you know, this doctor basically said if it's successful, it could be a paradigm shift, and he could see sequentially using 7, 8 Guardant360 tests during the course of treatment. So it's very different. So maybe just give us some color on that, Helmy.
Yeah. No, that's an exciting, sort of trial that we're part of, with AstraZeneca. And, in that trial, what they're trying to do is essentially catch patients right when ESR1 emerges, as soon as it's detectable. And so the protocol for that study is testing these patients multiple times. I forget the interval, but, you know, quite, quite, quite a, sort of dense frequency of testing to be able to catch essentially that first emergence of ESR1 and then switch the therapy. And we think this is, a sort of a game changer in terms of really thinking about, you know, aggressive monitoring of patients from a genotyping perspective, rapid switching to next-generation drugs. And this is the first of, we think, many-type drugs that would, incorporate this paradigm. And obviously, it would mean a, pretty significant multiplier on available, sort of testing volumes, in, in the market.
Great. So maybe just on the competitive landscape, you know, we just hosted another large lab, and they're really excited for their liquid test. And I think a handful of the, the larger CLIA labs that are private, some of which, you know, are looking to come to market that, you know, they have launched or in the process of launching liquid tests. Just, just speak a little bit about from the competitive landscape and kind of either the moat or the position that you have. And do you guys envision, in terms of your guidance over the next couple of years, like, losing any share as these new players make a push?
No, I mean, we're always thinking about the market from a product-market fit point of view. Is our product one that is more desirable than, where the sort of puck is headed in terms of the competitors' tests? And we continue to believe even our current tests continue to have very desirable from a turnaround time. I mean, we're averaging four or five days now in terms of turnaround time for Guardant 360, which is just completely unmatched to anything in the market. Detection rates still much higher in terms of Guardant 360 versus other tests.
And then, you know, just the connectivity that we have from an EMR point of view, everything that we've invested in from a customer experience, the medical affairs sort of, you know, group that we have that is able to handhold physicians through the results interpretation, we rate number one in terms of, not only share of voice but, added value or perce-perception of added value from a sales rep and medical staff point of view, which is, you know, great to see. And then obviously, we have Smart Liquid Biopsy, you know, coming down the pike this year. And we think that's just gonna raise the bar. We're already seeing, almost every, you know, top academic center really excited to sort of, latch on and, be a part of this, revolution of, of liquid biopsy.
There's just no, no one has really had their hands in a real way in terms of deep, methylome data, epigenomics data in the cancer field. There's already been tantalizing studies, kind of one-off studies by different academics, you know, by us in terms of the power of that data and so, so sort of all the applications that can happen. You can have patients, that can be identified for PARP inhibitors that were missed before, for IO therapies that were missed, see subtype transitions in, in patients, see things that were only, detectable in tissue, in blood.
So this is really getting the sort of minds of these physicians really, kind of, going, really nicely. And, and so we think this will create a new cascade of adoption in terms of getting the academics back on board in a deeper and, more meaningful way. We think that'll essentially trickle back down to the community oncologists and sort of renew the cycle that we had in 2014 when we launched the first liquid biopsy.
When does that start, kind of Smart Liquid Biopsy clinical?
Yeah, you know, most things are ready to go. We're waiting for some of the sort of regulatory and reimbursement kind of approvals just to turn that on. But from a technological point of view, yeah, we're ready to turn that on.
Great. And then just on MRD, you discussed filing for CRC and breast, this year. Just, you know, I know you talked about on the Q4 call how you've been gating, you know, kinda the revenue or the or the volume there just given, you know, trying to manage profitability. Just give us a sense of, you know, what, what's the timing for filing and, and expected approval? And then in terms of publications, when, when do you think those would come out?
Yeah. So we've submitted our CRC surveillance data, you know, for publication. We'll see when that gets accepted. And once it is, we'll submit it to MolDX for reimbursement. So all things going well, it may happen, you know, sometime late this year, may push out to next year if we have to do a few rounds with MolDX. And breast is probably a quarter behind that timeline.
Mm-hmm. And, you know, just in terms of the profile, you know, it's always hard to, you know, you got longitudinal sensitivity, landmark sensitivity. How do you think the performance of your breast and colorectal cancer tests kinda line up with the market leader?
Yeah. We're very pleased where in terms of our the performances, we think it's in line, if not, you know, favorable in many ways. We're seeing that, like, when we work with pharma companies, and they're seeing the Smart Liquid Biopsy data now, they're really excited in terms of what this means. There's a lot of logistical challenges that many of them are seeing, especially in the clinical trials setting in terms of getting access to tissue and really being able to enroll the widest available population. And so having a blood-only solution that performs as well as we do has been really exciting. So we're seeing the sort of change in adoption, both on the clinical and the pharma sides.
Just kinda pivotal trials, are there any, like, large, you know, kinda drug-related outcome studies that we should be aware of, you know, similar, you know, kinda what the market leader is expecting this year?
Yeah. I think, later this year, we should have a final readout of PEGASUS. That's a interventional study. That's a utility study. And then, we have, you know, ACT-3, which may be sometime next year. And then we should have some sort of secondary endpoints from COSMOS potentially on a utility kind of point of view. And then further out, we have TRACC , which is a, I think, a nearly 2,000-patient study.
We're almost out of time here. A sec. But let me just get one question in from Mike. Mike, you know, the guide for 2024 seems, you know, 1%-3%, you know, I think, OpEx growth. Just kinda walk us through the leverage and the business model and just, you know, how we should think about that going forward.
Yeah. I think with therapy selection, there's a huge amount of leverage with the OpEx. You know, at the end of 2023, that business reached cash flow breakeven. And this year, it's gonna generate positive cash flow. You know, we've got a very stable R&D line now in therapy selection that enables us to innovate. We've built out a very strong commercial team on the oncology side. And so there's no heavy uplifts coming down the road for that. And G&A as well. You know, we're a mature company now, and we've built out a lot of that infrastructure. So I think on therapy selection, we can really continue to leverage. And we should expect, you know, OpEx to not have, again, large uplifts going forward.
Where we'll focus on OpEx, I think, is gonna be on the screening side. Obviously, we're gonna need to invest on the commercial side for the launch and ongoing. But, you know, we said many times, we're gonna manage the ramp-up on the commercial side with the stage gates. And we're gonna manage the net cash burn on screening to $200 million. So I think, again, you know, just a lot of leverage. We've built out a lot of things over many years. And so now's the time we can really start to sort of generate that leverage.
Great.