Natera, Inc. Q4 FY2022 Earnings Call

Welcome to Natera's financial results conference call for the fourth quarter of 2022. Please proceed.

Thanks, operator. Good afternoon. Thank you for joining our conference call to discuss the results of our fourth quarter of 2022. On the line, I'm joined by Steve Chapman, our CEO; Solomon Moshkevich, General Manager of Oncology; and John Fesko, Chief Business Officer. 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 this call will also be available at investor.natera.com. 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, opportunities and strategies and expectations for various current and future products, including product capabilities, expected release dates, reimbursement leverage and related effects on our financial and operating results. We caution you that such statements reflect our best judgment 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 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 28, 2023. 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 we'll 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.

Thanks, Mike. We had a great year in 2022, both in terms of commercial execution and achieving key milestones. We processed 2.1 million tests, which is year-on-year growth of 32%. Revenues were $820.2 million for the full year, $40 million higher than the midpoint of our initial 2022 guidance, up 31% from 2021 and up 37% when excluding the one-time QIAGEN revenue. Business momentum continued in Q4 with volume growth of 28% and product revenue growth of 28% year-over-year, even off a bigger base and with a difficult year-over-year growth comparison after a very strong Q4 2021. We performed 196,000 oncology tests in 2022, representing growth of 158% with 64,000 tests performed in Q4. This demonstrates continued strong sequential growth of 21%, or an increase of 11,000 units versus Q3 of 2022. We estimate that now more than 30% of oncologists in the United States are ordering Signatera. We've achieved several key milestones even since our presentation at the JPMorgan conference earlier this year. First, we were very pleased to see our prospective multisite CIRCULATE study published in January on the cover of Nature Medicine, which gives you some sense of excitement that the data is generating in the field. Consistent with our earlier publications in both colorectal cancer and other tumor types, the data showed strong, predictive and prognostic value of Signatera 18 months out post-surgery. Solomon will dive deeper into these topics later in the call. Second, we received confirmation from MolDx that Signatera had met coverage requirements for adjuvant and recurrence monitoring in patients with Stage IIb or higher breast cancer across all subtypes. We estimate that Stage IIb and higher population could represent roughly 1 million tests per year, and breast cancer patients already account for a growing portion of our Signatera volume. In addition to the current coverage, we've got a pipeline of data designed to further highlight Signatera's utility and expand coverage in breast cancer. In fact, we expect to publish two large-scale breast cancer studies this year, each with approximately 1,000 plasma samples. In women's health, we were very encouraged to see the American College of Medical Genetics issue updated guidance to include a recommendation that all pregnant individuals be offered screening for 22q deletion syndrome. ACMG's guideline referenced the strong 22q performance results achieved in the SMART study, and we hope to see action by other medical societies later this year as they digest and incorporate the findings of that study. We were also pleased to see another guideline adoption for expanded carrier screening as the National Society of Genetic Counselors recently offered a very strong endorsement. We will get into this in more detail later in the call. In Oregon Health, the International Society for Heart and Lung Transplantation issued new guidelines recognizing the value of donor-derived cell-free DNA with a Class 1 Level B recommendation. We continue to work towards Medicare coverage for our Prospera heart test. In addition to heart, we eagerly await the publication of our perspective real-world RenaCARE study, which evaluated Renasight in chronic kidney disease patients. We expect that study to publish in the first half of this year. Moving to 2023 guidance. We are setting our initial 2023 revenue guidance in a range of $980 million to $1 billion. We expect to generate this continued top line momentum even as we reduce operating expenses from 2022 levels and dramatically reduce our cash burn. I'm really pleased to inform everyone that we will be guiding to a cash burn reduction of roughly $150 million compared to 2022, and we are reiterating our path to hitting a cash flow breakeven quarter in 2024. As we mentioned previously, we've included about $5 million of annual expense all in for early cancer detection in our budget. This doesn't include the cost of a new PMA level prospective study, which we estimate would be about $30 million over two years, if required. As we said before, we're awaiting the results of our proof-of-concept study and further feedback from the FDA on the trial. Once we have the results and feedback in hand, we can then decide whether it's necessary to pull the trigger on a stepped-up level of investment. It goes without saying we wouldn't do that without having very favorable results from the proof-of-concept study. Finally, we are very pleased to announce the appointment of Ruth Williams-Brinkley to our Board of Directors. Ruth is a seasoned health care executive with three decades of industry experience. She currently serves as President of Kaiser Permanente Health Plan of the Mid-Atlantic states, where she oversees regional operations. She also held leadership roles at large health systems earlier in her career. We are thrilled to welcome Ruth to the Board, and we look forward to working with her. Okay. Great. Let's get into more details on the next slide. In 2022, we processed approximately 2.1 million tests, a 32% increase over a very strong 2021 growth year. This represents strong traction across the businesses, and I think we are well positioned for continued growth. I'm going to start off talking about women's health. Today, we estimate that roughly half of the eligible patients in the United States are getting NIPT. While that underlying market continues to grow, we've continued to consolidate market share. As we've also discussed, guideline adoption for 22q and expanded carrier screening are additional opportunities to further expand access and help more patients. And we are pleased to see recent traction in both areas. Let me turn it over to John, our Chief Business Officer, to discuss some of the latest updates on these topics.

Thanks, Steve. In December, the American College of Medical Genetics published a practice guideline that recommended offering noninvasive prenatal screening of 22q deletion syndrome to all patients. The guideline specifically referenced the SNP-based screening method Natera developed and profiled in our 20,000-patient SMART study, which published last year in the American Journal of Obstetrics and Gynecology. 22q deletion syndrome is the most common microdeletion syndrome in humans, affecting about one in 15 live births. It's more common than other genetic conditions recommended for routine screening such as trisomy 18, trisomy 13, cystic fibrosis, and spinal muscular atrophy. 22q deletion syndrome is a leading cause of congenital heart defects, palate issues, immunodeficiencies, endocrine dysfunction, and neurological issues. Patients born with 22q deletion syndrome may be very challenging to diagnose, with a median age of diagnosis at 4.7 years after seeing on average seven different clinical specialties prior to molecular diagnosis. Treatment with calcium from birth can prevent seizures and brain damage caused by hypocalcemia. In our SMART study, we saw 83% sensitivity in a 0.05% false positive rate, resulting in a very high positive predictive value of 53%. We're excited about the momentum created by the publication of SMART and ACMG's new recommendation that all patients be offered 22q deletion syndrome screening. We believe that 22q deletion screening will be a significant differentiator for Natera. Because Natera runs targeted sequencing of SNPs and we can differentiate maternal from fetal DNA, we can cost-effectively sequence at a much deeper level across the 22q region versus labs simply doing massively parallel signature sequencing. These differences contribute to our high sensitivity, specificity, and PPV. Additionally, today, most labs only touched for 22q deletions above 2.5 megabases. This is a major limitation because 41% of high-risk 22q results in our SMART study were below 2.5 megabases. Natera is not limited in this way. Finally, we've created a significant competitive lead with our published data. To our knowledge, Natera is the only lab that's published a multisite prospective study of 22q screening with genetic confirmation in the majority of subjects. The SMART study took seven years to complete and publish and will likely never be done again. To our knowledge, there are no other prospective trials ongoing, in which cases data lead will persist for a long time. We think these significant performance differences will be important to physicians, especially given there is no guideline recommending 22q be offered to all pregnant women. We believe physicians will place more value on 22q performance going forward. These differentiators may also be important for health plans as we start to see coverage come into place as we believe will happen. It's possible that payers will limit their coverage to only those 22q tests that have been validated to their standards. Beyond NIPT, we're also seeing guidelines change for expanded carrier screening. Earlier this month, the National Society of Genetic Counselors published a practice guideline to recommend expanded carrier screening be made available to all individuals considering reproduction. This follows a recommendation from ACMG in 2021 that expanded carrier screening should be offered to all pregnant patients. We're also seeing these guideline changes lead to medical policy changes at health plans. In fact, just this month, one large benefit manager that covers 15% of commercial covered lives introduced a new policy that supports the use of expanded carrier screening. There is still work to be done here, but the fact that we are now seeing progress is important. Okay. I'll turn it back to Steve to discuss organ health.

Great. Thanks, John. Our initiatives in organ health are going well. We continue to benefit from the publication of the large-scale multisite prospective Trifecta study in kidney transplant, which came out last fall. The results of that trial were excellent and appear to have been well received by the community. In heart transplant, we are excited for the readout of the independent academically led DTRT study. In DTRT, investigators tested greater than 450 plasma samples from greater than 150 heart transplant recipients across seven top academic sites with biopsy match samples and clinical follow-up of up to 3.5 years. We believe this is one of the most significant trials to date in the field, and we look forward to the results being published soon. Our momentum in heart is timely because ISHLT, the main governing body, just updated its guidelines to include donor-derived cell-free DNA testing for surveillance in heart transplant recipients. I also mentioned Renasight at the top of the call. As a reminder, Renasight is our genetic test for patients that have been previously diagnosed with chronic kidney disease. The test can determine whether they may have a genetic cause of their chronic kidney disease. We think there are more than 1 million newly diagnosed patients per year and about 37 million patients living with chronic kidney disease. With more than 10% of the population in the United States having CKD and being eligible for testing, we think this is one of the largest areas of health care that can be improved with genetic testing. Three years ago, we worked with the world's leading investigators from Columbia, Yale, UPenn, UPMC, NYU, Mayo Clinic, and Cleveland Clinic to design the definitive RenaCARE study. We completed enrollment in RenaCARE in August, having enrolled more than 1,600 patients from over 30 centers. The study is designed to assess how Renasight's genetic findings may impact the clinical management of patient care. As the results readout, it's important to put them in context. I think hereditary cancer is an instructive comparison. In a large study of nearly 3,000 cancer patients published in JAMA Oncology, 13.3% of patients had a pathogenic germline variant indicating hereditary cancer. And of those patients with a high variant, 28.2% had resulting treatment modifications. As RenaCARE readout, we will be looking at the same metrics: what fraction of the study participants have a pathogenic variant associated with their CKD and what fraction of the positive patients' treatment was modified after the pathogenic variant was discovered with the Renasight panel. We think the RenaCARE study could position us for guideline inclusion in the future. This is a very large opportunity, and we already have a distribution channel in place through our existing nephrology call point. Stay tuned for more updates on this important opportunity. With that, I will now turn it over to Solomon to review our oncology results in more detail.

Thanks, Steve. In the past few months, we made great progress in oncology. The big stories today are volume growth, colorectal data publication, and Medicare coverage in breast cancer. We've observed excellent volume growth and adoption since our launch in 2019. At the end of Q3, we had communicated our expectation to deliver more than 185,000 units in 2022. And as you can see, we've exceeded expectations with 196,000. This growth is driven by new patients, follow-on tests for existing patients, and new ordering providers. Steve mentioned that more than 30% of oncologists in the U.S. are now ordering Signatera. When combined with strong volume growth, I think this shows that Signatera is rapidly becoming part of the standard of care in the United States, helping many patients gain reassurance when their testing is back negative or to get an early chance at intervention when the test is positive. In terms of volume mix, the way to think about it is that roughly 60% to 65% of the volume is from colorectal, bladder, and immunotherapy monitoring. And now adding breast cancer to that list makes about 80%. As a reminder, our reimbursement today is largely driven by Medicare, and we are making progress with commercial plans as well. We've gotten to this point because of our core technology and the magnitude of the clinical unmet need, but also because we've been able to scale the lab and build an industry-leading medical and commercial team with reimbursement momentum and advanced diagnostic lab test status based on strong evidence of clinical validity and utility across disease types. We believe Natera benefits from an important first-mover advantage in the MRD field. We think a Signatera patient with an existing personalized assay is unlikely to switch to another MRD test. That has a ripple effect. Since our ordering providers will usually have a cohort of existing Signatera patients who are doing ongoing monitoring with regular blood draws, it makes it more challenging to bring another MRD lab into the physician's practice, which creates a unique competitive advantage unseen in the clinical lab industry. Another significant competitive advantage is in data generation, where we started working back in 2015. We now have roughly 40 peer-reviewed Signatera publications across more than two dozen cancer types. I think the fact that we've been able to generate consistently excellent results across tumor types gives us confidence in the eventual pan-cancer adoption and reimbursement for Signatera. Let's turn now to our progress in colorectal cancer. In mid-January, we announced the publication of our CIRCULATE study in the journal Nature Medicine, featuring 18 months of clinical follow-up across over 1,000 patients. The study demonstrated strong performance for Signatera with a presurgical detection rate of 95.9% in Stage II and III colorectal patients. In addition, we showed the strong predictive benefits of Signatera in CRC, where Signatera positive patients benefited significantly from adjuvant chemotherapy, whereas Signatera negative patients did not. We think this has significant implications for CRC patients, many of whom today do not get the chemotherapy they need or others who may be treated unnecessarily. The key distinction here is the prospective nature of the study with physicians and patients receiving results in real-time and also the predictive element, which takes the evidence beyond sensitivity and specificity into improved outcomes. This raises the evidence bar for the whole field, and it strengthens the utility of Signatera in colorectal cancer. We expect that it will help us reach the next level in physician adoption as well as influencing the NCCN Guidelines Committee. We are still anticipating an updated NCCN guideline in the near future since it has not yet been published from the annual committee meeting in August of 2022. Given the timing of our publication this January, we do not know if the evidence will have been incorporated by the NCCN committee in this round. In that case, we expect it would be considered in the next round. Also, the CIRCULATE trial is ongoing with future readouts expected to strengthen the evidence further, including from the two randomized arms, Altera and VEGA. To step back for a minute, our journey in colorectal cancer creates a replicable road map for Signatera adoption in new indications. First, the biobank cohort that confirmed clinical validity and enabled Medicare coverage and initial adoption, then the prospective trials, partnered either with pharma or academic consortia that drive more definitive evidence with an aim to change guidelines. We plan to repeat that journey in bladder cancer, immunotherapy monitoring, and breast cancer. The MolDx decision to cover Signatera in breast cancer is the latest example of this model at work. Signatera was approved for coverage in advanced breast cancer patients for both adjuvant and recurrence monitoring across all disease types. Given the number of people suffering from breast cancer in the U.S., we view Medicare coverage as a critical milestone. Looking at the addressable market, there are approximately 290,000 newly diagnosed breast cancer patients every year with approximately 25% to 30% of these patients with resectable Stage IIb and higher. For this patient population, we estimate an addressable market of approximately 1 million tests, and we see potential opportunities to expand our coverage in the future into the neoadjuvant setting and earlier stages of disease. Steve mentioned that a meaningful chunk of our existing Signatera clinical volumes, approximately 15%, are already coming from breast cancer patients. This is an early sign of the strong demand from patients and physicians to inform difficult treatment decisions and better monitor their disease. Many of our strongest testimonials come from patients with breast cancer, including one that was featured on Good Morning America. The breast cancer community is highly organized and self-empowered, making this an indication where we see patients voting with their feet. We're looking forward to growing rapidly in breast cancer as we expand our commercial effort and deliver more data from our clinical pipeline. This coverage decision expands our reimbursed addressable market to approximately 3.5 million tests per year. In 2023, we will be focusing our team on growth in CRC and breast cancer as well as bladder cancer and immunotherapy monitoring, publishing new evidence and translating it into expanded coverage and adoption. Our clinical data pipeline remains strong with this slide showing some key highlights. During Q4, we continued our progress with peer-reviewed publications in gastroesophageal and anal cancers, along with the key publication of our CIRCULATE study. We also had a good data set in melanoma that was accepted for publication. And at key medical conferences, we presented new data in colon, esophagogastric, anal, and neoadjuvant breast cancer. At the same time, we remain focused on our Phase III studies and our CDX partnerships in colorectal, bladder, and breast cancers. Now I'd like to hand it over to Mike to cover the financials.

Great. Thanks, Solomon. The next slide just summarizes our 2022 performance and financials. Steve covered the revenue and growth rates, and we feel like we are in a great position to continue driving growth, given our leadership position in several large and underpenetrated areas of care. I would just note that the growth comparison versus 2021 is a little skewed against us because you'll recall in 2021, we had the onetime revenue recognition of close to $29 million from the wind down of our QIAGEN partnership that Steve alluded to. That also affects the comparison on gross margins, which were a little elevated in 2021 with QIAGEN and other revenue true-ups. And of course, we've described how headwinds in germline ASPs, the California P&S program and growth in Signatera clinical volumes would temporarily pressure margins as we sought to expand reimbursement. Operating expenses landed in line with our original guide from this time last year, and our ending cash balance is in line with our expectations. Okay. Let's get into the guide. As Steve mentioned, we are guiding $980 million to $1 billion in revenue for 2023. This will require us to continue to deliver strong volume growth across all of our focus areas but include some caution on advancing average selling prices. As we've described in the past, we feel like we can make meaningful progress on ASPs just through execution in women's health and the natural evolution of our volume mix for Signatera clinical volumes. And we've included modest progress on these fronts in the guide. We are also including a very modest benefit from the recent breast cancer coverage decision. And I expect we will be able to give more details on the impact of breast cancer coverage once we gain more experience with the reimbursement. In addition to those efforts, we have the three major guidelines that can really change our reimbursement profile with 22q and expanded carrier screening in women's health, and ACCN guidelines in colorectal cancer. Consistent with our typical approach, we haven't included any potential impact from these guideline changes in our forecast just because we don't control the outcome or the timing. We are taking a similarly cautious line on gross margins. This guide essentially presumes limited progress on reimbursement and hitting our COGS projects this year. Over the longer term, guideline inclusion and continued study reimbursement execution would give us clear line of sight to gross margin in the mid-50s and beyond just as we have described in the past. Okay. On this slide, I want to spend a bit more time on OpEx and the cash burn guidance. You'll note that despite guiding to continued growth, we expect to see operating expenses to decline by roughly $45 million this year versus 2022. As Steve described, we've built strong leadership positions in each of our areas of focus that can now drive substantial future growth without continuing to increase operating expenses. Many of you will recall that we've executed this playbook once before when we pledged to get to cash flow breakeven in our women's health business by the middle of 2021. In that instance, we spent years building a commercial channel, running large clinical trials, improving product performance while executing large COGS reduction projects and investing in a user experience platform that could scale with large volume increases. We then held our women's health-related expenses stable as the big trials concluded. While the volumes continue to pour in, we met our 2021 guideline. We've now established strong leadership positions in our newer areas of focus. And this year, we can start to demonstrate the same operating leverage. As a result, we expect our cash burn to decline by roughly $150 million this year alone. We've already demonstrated meaningful reductions in quarterly cash burn over the course of 2022, where we burned approximately $160 million in Q1 of '22, and now we're at roughly half that amount in Q4. We've also been making good progress in collecting on some of the accounts receivable generated during the rapid growth we experienced last year. I called out roughly $50 million in cash collection backlog in Q3, and we estimate we've collected about $40 million of that cash to date. DSOs also declined modestly in Q4 despite continued strong sequential revenue and volume growth. And we've put a lot of muscle behind accelerating our Signatera reimbursement processes recently. We think all this progress puts us in a good position to pursue the cash flow breakeven target we set last year. If we get good news on any of the three guidelines I mentioned, we fully expect to reach a cash flow breakeven quarter in mid-2024 as we've previously described. If we are delayed with those guidelines, we still think we are in a great position to hit the goal when you cost discipline. So we expect our existing cash balance will allow us to meet the current objectives ahead of us. So we are very pleased to share these results with you today. And now let me hand the call over to the operator for questions.

Our first question will come from Tejas Savant with Morgan Stanley.

So just a couple of quick follow-ups here, Mike, for you. Can you talk in a little bit more detail about the Signatera breast coverage decision in terms of both the near-term impact? I know there's some chance of a look-back payment. And obviously, you've cited about 15% of your current volume that comes from breast. So just curious as to some specifics around the contribution there from Signatera, perhaps in the back half of the year here. And then my second follow-up is on the gross margin trajectory. I totally understand a bunch of puts and takes here based upon the ASP recovery, reproductive health, and some of the other sort of non-covered indications for Signatera that you guys are making a commercial push in. But any color on the sequential trajectory on gross margins through the year would be helpful as well.

Tejas, thank you for your questions. I’ll start with your last one. Yes, I believe your inference is correct. I expect the gross margin trajectory to improve throughout the year based on the variables we've discussed. We'll have more time for reimbursement from Signatera, the mix will evolve, and we can continue to enhance our average selling prices in Signatera. Additionally, our projects in the women's health channel will have more time to yield results as the year progresses. So, I anticipate a steady progression in margins. Regarding the breast cancer contribution, we were excited to receive the positive decision from MolDx. Given the recent timing, we took a cautious approach in estimating its contribution to our guidance. We need to engage with Noridian for details on pricing, which will follow the usual timeline. This will provide us with clarity on the projected contributions throughout the year, likely with a back-end weighting. Another important factor is the volume in breast cancer cases, which Steve mentioned. We have seen organic growth in breast cancer volume through our channels, and with this coverage decision, there’s potential for significant expansion in reimbursed volumes. We need time to execute this before including it in our guidance. Lastly, regarding look-back payments, I do expect some. Typically, coverage decisions are effective from the submission date to MolDx, so there could be look-back payments from last year. We will update you once we have more clarity on that. Steve, do you have any additional comments on this question?

No, I think you thoroughly covered things. Thanks, Mike.

Your next question comes from the line of Julia Qin with JPMorgan.

So just a follow-up on the gross margin guidance. I mean, looking at the 41% to 44% versus your mid-50% gross margin target somewhere in '24, do you see any, obviously, understanding that guideline is a big moving piece to that. But how much of that growth improvement is dependent on the guideline and the revenue inflection? And how much of that is kind of more within your control, like the lowering sequencing costs and lab operations? And then if the guidelines do not materialize before mid-2024, what kind of levers or where do you see flexibility to further take down costs? And then I have a follow-up.

Yes, Mike, let me first comment on some of these cost of goods sold projects. We've done a good job over the years of consolidating our resources for these major cost reduction initiatives. These projects are quite straightforward; they involve transitioning to the NovaSeq from the NextSeq, for instance, or increasing capacity in certain facilities. They are not technically complex, and we have high confidence in achieving our goals. We have several significant cost reduction projects that will constitute a large portion of what we are presenting in our future guidance. Mike, would you like to elaborate on the margin progression?

Yes. No, I think that's a good lead-in, Steve. I mean, I think there's a lot of that margin progression that is just clearly within our control. I mean, you touched on the COGS project. I think on the ASP front, I mean we also talked in detail about the evolution that we expect to see in Signatera ASPs. Just as a reminder, we've already kind of seen a real sea change in Signatera ASPs from launch to now, which is ASPs were in the mid-400s as we started, and now they're kind of in the mid-700s. And that continue to evolve in our favor just based on mix and increasing the reimbursement we're seeing from Medicare and also expanding some commercial coverage as well. So I think those are all levers that are in our favor. And then I think the other part of this in terms of levers that we can pull, I mean, you see us pulling some of these levers right now. And that is just kind of the leverage we can get on our operating expense base. So I think this, our ability to continue to drive revenues on the current platform, I think, is simplified by the cash burn guide. And I think that in the event that guidelines are delayed, I don't think that means that they're permanently delayed. I think that means we can still get them. And we've got scope for us, I think, just to meet our goals with continuing OpEx discipline, as we talked about in the prepared remarks.

Yes. And just to be clear, we don't need any of those guidelines to come in to get to that 50% margin target.

Got it. Super helpful. And then one more on the women's health side if I may. It seems like between microdeletion, ECS, and MRD, microdeletion is the nearest term in terms of when we can expect guidelines. You mentioned in your prepared remarks that the evidence is strongest for 22q. So the guideline and subsequent payer coverage is limited to 22q, how much ASP lift can we expect to see for your women's health volume?

Yes, I'll take that. So 22q, I think, is really the whole ball game for microdeletion testing. So when we actually led the coding submission to the AMA, which started, I think, in 2017, the code was growing in 2019. And today, the pricing that we have in payer contracts with CMS is for 22q. Other deletions are included, but 22q is sort of the base microdeletion that's part of that infrastructure. So the pricing from payers will be the same, whether it's 22q or whether it's a broad microdeletion. We think 22q is where most of the interest is as we go forward. And I think that's where the guidelines are going to be focused. And we've got a lot of differentiators. I mean, I know John sort of highlighted some of those, but these differentiators really make a big difference, both with physicians and we think also with payers. And I think it's going to be interesting to see how this pans out in the future. I also mentioned on expanded carrier screening. So today, we have a good guideline in place from NSGC. There's a strong guideline from ACMG. And the ACMG guideline is actually pretty strong. We think it's, in fact, supportive of expanded carrier screening. And that's one of the reasons why you're seeing payers starting to issue positive coverage policies. So we mentioned on the call that one of the lab benefit managers that covers 15% of all the commercial covered lives in the United States just last week issued a positive guideline for expanded carrier screening. And so that's new incremental upside that's not in the model. And I think, as Mike mentioned, your product mix is sort of one of the reasons why you've seen the slight reduction in margin recently. Some of that comes from us making a proactive decision to take on some of the low-margin business as they went out of business. And we thought that, that was a good idea to do because we knew that these guidelines were coming, and it turns out that was the right decision. Now we've seen since they went out of business and we picked up a significant chunk of that volume, we've seen this big lab benefit management company, they'll come out and say they're going to be covering expanded carrier screening. We've seen the NSGC guidelines come out. So I think that was the right decision to temporarily take on a larger book of expanded carrier screening volume, have a slight reduction in the overall margin, but know that the guidelines are coming, and we're going to be able to collect on that in the future.

Your next question will come from the line of Puneet Souda with SVB Securities.

So first one on Signatera. Can you just clarify what contribution from biopharma versus clinical in the volumes that you saw in the year? And then I have a few follow-ups.

Yes. Overwhelming contribution from the clinical versus the pharma, as you'd expect. But Solomon, go ahead. Do you want to comment?

I think that was Steve. Steve, did you want to comment?

No, I was just going to say if you want to make any more color on that, go ahead.

Yes. Look, the major accelerating growth we're seeing right now is from the clinical business for multiple reasons I reviewed during my remarks. Pharma business is looking steady. And we've got a pretty strong pipeline as well, both have retrospective studies as well as new prospective trials. And we remain committed to our Phase III and companion diagnostic partnerships as well.

Okay. Got it. Helpful. And then maybe for Solomon as well and trying to understand the overall TAM that is accessible and inaccessible at this point for Signatera, given that you already are in breast, and congrats on that. CRC already IO monitoring, the indications are expanding. So maybe talk to us as to the tumor-informed approach with the tissue. How much of that $20 billion or so market can you capture? And sort of what portion of the market remains sort of inaccessible because it's the tissue-based approach?

Sure. Thanks for the question. I don't think of major portions of the market being inaccessible because of a tissue-informed approach. I think the tissue-informed approach gives an advantage in terms of a single product that can be applied pan-cancer and across stages of disease. And I think that's how we're seeing the story play out. So to your question of penetration of the TAM, breast cancer was a really significant milestone for us, given how many patients are out there suffering from breast cancer or who are breast cancer survivors. 3.5 million tests per year now addressable and covered by Medicare is very significant. So in terms of growth, there are multiple additional indications that we see for opportunity to expand coverage with Medicare. But I think at this point, in addition to that, we're really focused on expanding the private coverage for the indications that you already saw on the slide in colorectal cancer, bladder, breast cancer, and immunotherapy monitoring. So I think there's a ton of growth on the table from those four categories and from growing to new ones where we've shown several studies that have good validity evidence in other GI cancers in the neoadjuvant setting for breast cancer and more. Hopefully, that answers your question.

Yes, that's very helpful, Solomon. Last one for Mike if I may. Mike, the carrier testing market saw an exit from one of your competitors. So wondering sort of how are you thinking about that volume, some of that volume coming to Natera. And then could you talk to us about commercial pricing in that market? And how should we think about the ASPs in that market in '23 and beyond?

Let me take that one, Mike. I previously mentioned that we observed the exit of a significant competitor. Natera has actually performed well and gained some of that business, particularly in carrier screening. While this business currently has relatively low margins, we believe there is an opportunity soon to significantly increase the average selling price of that incoming volume. Recently, a guideline on expanded carrier screening was released by NSGC, and a major benefit management company that covers 15% of commercial lives changed its coverage last week. Where coverage was previously not available, it now is. We see considerable potential, and I think our decision to pursue this business, despite its initial low margins, will prove to be the right choice. Mike, would you like to share further insights on the landscape?

No, I think that covers it well.

Your next question will come from the line of Max Masucci with Cowen and Company.

Congrats on another great year. So the five-year Signatera CRC surveillance periods is essentially pegged to prior recommendations for CEA testing. But in breast, the risk of recurrence varies by subtype. So just based on any conversations you've had with CMS or others, how are you thinking about the ideal surveillance period for Signatera breast? Is it more likely to be static, say, five years across all subtypes? Or could it vary by subtype?

Yes, let me add a couple of comments before you jump in. If you look back at the clinical trials we’ve conducted, we’ve completed about five years of follow-up on those patients. We are using that as a benchmark. We are still waiting for the final billing letter from MolDx, which will provide more details, but we are essentially referring back to what is in the clinical trial. Solomon?

Right. Yes. So just to echo Steve's comments, the conservative view is to look at what we presented in the paper, the trial that was published in Clinical Cancer Research, which had follow-up of up to five years and testing every six months. But to your question, Max, the patients are treated very differently depending on their disease subtype and their stage. So we know that if a patient, for example, with triple-negative breast cancer is going to recur, they tend to recur earlier post-surgery and post-definitive treatment compared to a HR-positive HER2-negative patient whose chance of recurrence is kind of steady over even more than five years up to ten years. And so we do expect to see some variation in the usage patterns across those subtypes. But I think it's still a little bit early days to see how that really plays out. And I think also, we're pretty pleased to see the initial uptake of Signatera in breast cancer as we mentioned, where really significant number of patients are just voting with their feet. And they want that information during the surveillance period, as well as to help inform some tough treatment decisions.

Certainly. I'd like to ask one more question. The Medicare coverage win for Signatera MIBC occurred in July. Did that coverage win lead to an increase in test ordering for Signatera IO? Additionally, considering the large number of newly diagnosed operable breast cancer patients each year, do you anticipate that the Medicare coverage win for Signatera breast will result in increased ordering of Signatera IO in 2023 and beyond?

Yes. Let me just comment there. So I think getting Medicare coverage, I think, definitely is an endorsement of the data. I mean, they do a very rigorous review. And I think it may not necessarily be that sort of coverage that triggers additional ordering, but I think it allows us to feel comfortable to have our medical affairs team out educating physicians and our commercial team out educating physicians very thoroughly about the indication. So when you look at muscle invasive bladder, I mean, we're seeing record numbers. When you look at IO, we're seeing record numbers and growth. And when you look at any indication that's come out and gotten coverage, that really has triggered, I think, additional education and medical education around the particular tumor type, which does result in increased utilization. So certainly, breast we're seeing really strong organic interest. But once we put the power of our team behind that as well to show the data and educate physicians on the studies that we've done, we think it's going to be powerful.

I wanted to add that we notice an interesting aspect regarding increased usage in immuno-oncology monitoring when coverage is established for conditions like bladder or breast cancer. Physicians often begin using the test for specific patient types and gradually recognize its broader benefits, leading to increased application across their practices. This trend occurs consistently. Additionally, in relation to an earlier question, the number of patients eligible for immunotherapy keeps rising as new trials from leading immune checkpoint inhibitor manufacturers report results, which further expands our eligible population with more patients receiving immunotherapy.

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

I guess first on the commercial payer side for Signatera, what are your expectations for 2023 if we just assume no NPCN guideline inclusion? Are there any other states that have or are working on legislation for covering genetic testing like Signatera, similar to what we saw in Louisiana last year?

Solomon, you want to take that?

Sure. There are four states that have already passed legislation, and many more are considering legislation in their state houses. We are actively monitoring this, although we don’t control it. However, we are part of many discussions. John and his team have done an excellent job educating lawmakers across all 50 states. We are seeing more progress with commercial payers as our evidence strengthens and the number of covered patients continues to rise. We expect to make some announcements this year regarding commercial coverage, and we hope to see further adoption of the biomarker legislation. John, do you want to add anything?

Thanks, Solomon. Just to expand, beyond Louisiana, legislation has passed in effect now in three other states, including Rhode Island, Illinois, Arizona. There's legislation pending in at least 15 states this year, championed by the American Cancer Society, including some big states like Texas, Florida, New York. So we actually feel quite confident about that, and it's great for patients. It's great for the space. And that's pushing commercial policy on the payer side as well.

Okay. Super helpful. And then maybe one on early detection. When should we expect to hear the results from the proof-of-concept study and FDA feedback just to know the path forward for that program? Are those 2023 events?

Yes. They definitely will be. So I would say proof of concept will probably be like two phases. One will be a slightly smaller study. And then there'll be a follow-on study that has several hundred patients, which we hope to be able to announce the results from. I think those will definitely be '23 events. And then as far as the FDA goes, we do expect to get some additional feedback this year. We've already previously described some of the initial feedback. But I think the key right now is that the investment is low. We're keeping that stable at around $5 million a year. And we're in a position to crank that up on the back of very strong proof-of-concept results, which we hope to have.

Our next question will come from the line of Andrew Cooper with Raymond James.

Maybe to start, you've given in the past some metrics on sort of the California dynamics. Can you give us the latest and greatest there and sort of what the expectations assumed in the guide are for the status quo or potential outcome from some of the legal actions going on there?

Mike, do you want to take that?

Yes, to recap, there is now an injunction in place in California that allows us to offer Panorama to our customers, which is great. We have assumed that this will still be a significant challenge in 2023 regarding margins. However, I believe there is potential for improvement. As we move through the year, we will provide updates on the growing number of customers who will transition to Panorama over time. This situation is difficult to predict for various reasons, and we generally adopt a conservative approach in such cases. Therefore, we have modeled a very modest scenario that we hope to exceed.

Okay. Great. And then I want to focus maybe on one comment you made around the path to breakeven. I think you said we've done this before in women's health. So I guess does that lead us to believe when we think about some of these OpEx cuts that are coming, they're coming outside of women's health? Is there more meat on the bone there? Just how do we think about the actual dollar reductions and where some of those are actually stemming from and what they tell us about sort of the business and where you're going from that perspective.

Yes, let me share a few comments, and then you can jump in. We've been focused on running an efficient operation for quite some time. A significant portion of our spending in R&D has been directed towards clinical trials. As some of these studies begin to report results and trials conclude, we can expect a reduction in operating expenses. For example, the SMART study has cost us between $5 million and $10 million annually for seven years, but now that it has concluded and we have results, we will no longer need to invest in it. This highlights where we made the right investments, funded the trial, and now that the trial is complete, we can move forward. We are concentrating on efficiency and have achieved 40 publications, which took considerable effort across the board.

Okay. Great. Maybe one last one. Mike, you said I think, mid-700 ASP in the clinical side for Signatera. I think last quarter, you said over 750. So I just want to make sure kind of a trajectory there, and how you think about in the guide to the degree you can give a little bit more detail just the growth in covered indications, which just seems like you're certainly focusing on versus ancillary growth that you're happy to take, but in non-covered and sort of the margin dilutive side?

We had a strong quarter regarding the steady growth of clinical oncology ASP. I would say we're moving along smoothly. As we mentioned before, aside from the guidelines, factors such as volume mix, expansions in the covered universe, and fewer people in the bundle while more transition to the recurrence monitoring setting suggest a clear path for us to reach the 800s over the year, and it appears we are on track to achieve that.

Our final question will come from the line of Mark Massaro with BTIG.

Congrats on an excellent 2022. So you have a number of peer-reviewed publications. And I guess I'd be curious if it's reasonable to expect you to add a couple more Medicare coverage wins this year. Obviously, you have data for lung, esophageal, melanoma, head and neck, pancreatic, ovarian, but how should we think about the timing of potential Medicare coverage determinations? And roughly how many have been submitted to MolDx that we would be waiting on some type of decision?

Thank you, Mark. We have a consistent stream of submissions happening at any given time. While we won't disclose our specific strategy for competitive reasons, having 40 peer-reviewed publications is significant because coverage requires peer-reviewed data. We see this as a major advantage for Natera. Similarly, our ADLT status is unique; others cannot qualify for it without FDA approval, which is a challenging process for them. We view this as another strong reimbursement advantage. You can expect more updates this year as we navigate our submission pipeline, but we won't share our exact strategy for competitive reasons.

Yes. So I think we've always sort of said that we think that you really have to go indication by indication until you've hit a certain threshold. There's sort of a tipping point where it becomes more of a sort of a pan-cancer view. And I think we're really moving fast and getting through the indication-by-indication coverage. So I think we're doing a great job. We're delivering the evidence, and that's going to be the foundation for everything. The great thing about Signatera and the tumor-informed approach is that it's pan-cancer. We don't have to go out and kind of redesign the assay. We just run the same platform across all different tumor types, and I think that enables this path to pan-cancer. So stay tuned. I think it's possible there could be some momentum on pan-cancer in the future. But we're going to have to see how things pan out.

Ladies and gentlemen, that will conclude today's meeting. We thank you all for joining. You may now disconnect.