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How Cell-free DNA Testing is Revolutionizing Care
Episode

Paul Billings, Chief Medical Officer and Senior Vice President of Medical Affairs at Natera

How Cell-free DNA Testing is Revolutionizing Care

In this episode, we are privileged to feature the amazing Dr. Paul Billings. Paul is the Chief Medical Officer and Senior Vice president of Medical Affairs for Natera. Natera is a global leader in cell-free (cfDNA) testing with a focus on women’s health, oncology, and organ health. The company is an expert at the process and measurement of cell-free DNA and at providing that in context with genetic information as well. 

Dr. Billings educates us on cell-free (cfDNA) testing. He discusses how his company develops millions of testing opportunities in genetics that have given them incredible expertise in measuring very small amounts of cell-free DNA. He shares how Natera has developed a series of products to cast light on things like the health of a fetus, recurrence of cancer, and health of an organ transplant. Dr.l also shares his hypothesis on how a drug post organ transplant is working through constant monitoring of cfDNA. He talks about the three indications Natera is working on, providing clear explanations of how they add enormous value to genetics and healthcare, and specific examples of how Natera works. There are so many things to learn from this insightful and exciting conversation with Paul, so please tune in!

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How Cell-free DNA Testing is Revolutionizing Care

About Paul Billings

Dr. Paul Billings is the Chief Medical Officer and Senior Vice president of Medical Affairs for Natera. He became The CMO and Senior Vice President in 2018. He’s a board-certified internist and clinical geneticist who also holds a Ph.D. in immunology from Harvard University. His thesis advisor was Dr. Baruch Benessere, who subsequently received the Nobel Prize in Medicine. Prior to joining Natera, Dr Billings was the chairman of Biological Dynamics, a revolutionary molecular measurement platform. Previously, he served as a partner in the diagnostic medicine consultancy the Bethesda group and the managing director of the Bethesda group Fund. Early in his career, he was a Senior Vice President and Senior Physician at Laboratory Corporation of America, Chief Medical Officer at Life Technologies, and later the clinical division of Thermo Fisher Scientific. He’s an expert in precision medicine diagnostics, particularly in oncology, transplantation, and women’s health. He earned his M.D. from also Harvard University

How Cell-free DNA Testing is Revolutionizing Care with Paul Billings, Chief Medical Officer and Senior Vice president of Medical Affairs at Natera: Audio automatically transcribed by Sonix

How Cell-free DNA Testing is Revolutionizing Care with Paul Billings, Chief Medical Officer and Senior Vice president of Medical Affairs at Natera: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.

Saul Marquez:
Hey Outcomes Rocket Nation! Saul Marquez here. I want to talk to you about Natera, a leader in personalized genetic testing and diagnostics that is transforming how we make critical health care decisions. Natera is revolutionizing the standard of medical care with next generation cell free DNA testing. Its non-invasive blood tests provide critical health insights to improve outcomes and enable earlier and more targeted interventions that lead to longer, healthier lives. Be sure to check out Natera to learn more. That’s Natera, NATERA.com to learn more.

Saul Marquez:
Hey everybody, Saul Marquez with the Outcomes Rocket. Such a pleasure to have you here today on this amazing series with Natera. Today I have the pleasure of hosting the amazing Dr. Paul Billings. He is the Chief Medical Officer and Senior Vice president of Medical Affairs for Natera. He became The CMO and Senior Vice President in 2018. He’s a board-certified internist and clinical geneticist who also holds a Ph.D. in immunology from Harvard University. His thesis advisor was Dr. Baruch Benessere, who subsequently received the Nobel Prize in Medicine. Prior to joining Natera, Dr Billings was the chairman of Biological Dynamics, a revolutionary molecular measurement platform. Previously, he served as a partner in the diagnostic medicine consultancy the Bethesda group and the managing director of the Bethesda group Fund. Early in his career, he was a Senior Vice President and Senior Physician at Laboratory Corporation of America, Chief Medical Officer at Life Technologies, and later the clinical division of Thermo Fisher Scientific. He’s an expert in precision medicine diagnostics, particularly in pncology, transplantation, and women’s health, which is a lot of what will be covering here today. He earned his M.D. from also Harvard University, and without further ado, Dr. Billings, such a pleasure to have you here today.

Dr. Paul Billings:
Oh, thanks. I’m happy to be here and to shed some light on what Natera is up to.

Saul Marquez:
Yeah, thank you. And you guys a are up to some fascinating work, so why don’t we just start off with a brief Introduction to Natera? Tell us a little bit about what you guys do with the cfDNA space and what makes you different?

Dr. Paul Billings:
Well, so Natera is probably the world’s leader in the commercialization and use of cell free DNA to improve medical care. We’ve developed over millions of testing opportunities, both deep expertise in genetics, in nucleic acid biology, but also in the preparation of samples for cell free DNA analysis and for their analysis after testing the bioinformatics. And that’s really given us incredible expertise in measuring very small amounts of cell free DNA. And in addition, quantifying those small amounts. You know, often cell free DNA in whether you measure it in blood or in other kinds of fluids, it’s mixtures. There’s normal and abnormal cell free DNA in there, so you need to be able to identify very small amounts. And so we’ve developed a series of products that use our expertise in cell free DNA and in the measurement of those small amounts to cast light, let’s say, on the health of a fetus or on the recurrence of a cancer or on the health of an organ transplant. And that’s one set of things. And then in addition, because we are a genetics company, we’ve also developed markers and panels which allow us to get deeper prior to germ line. We call it, you know, prior genetic knowledge about, let’s say, the fetus or a patient who might be at risk for cancer or a patient who might be experiencing early stages of kidney disease. And we would like to know what, what the cause of that kidney disease is. So the company is expert at the process and measurement of cell free DNA and at providing that in context with genetic information as well.

Saul Marquez:
That’s just fascinating. And so, you know, I want to take a minute here, Dr. Billings to level set with the audience. There’s an opportunity for education. When I was first learning about Natera and cell free DNA, it was a great experience, an opportunity to learn what exactly was cell free DNA. So can you tell us what cell free DNA is? How is it different from normal DNA?

Dr. Paul Billings:
Sure. So basically, all the trillions of cells you have in your body have DNA, and DNA is the information by which a cell knows how to do what it’s supposed to do and exist in your body. DNA has a half life like everything else in our body. It leaves, it dies. The cell that contains it dies. And that DNA then is extruded into the fluid around the cell and eventually into the bloodstream. And that becomes what we typically talk about as cell free DNA. We’re usually talking about a measurement in the blood of DNA that has left cells. Now that’s that cell death can be the causes the DNA to be extruded from the cell and enter the bloodstream. That can be a normal process. Cells have, you know, a half life and they die after a while. Or it can be a pathological process. Right? It can be because there’s an infection in that tissue or because there’s a tumor in that tissue and there’s inflammation and that inflammation can cause the cell death. So cell free DNA is either the normal product of cells just dying as as our body cycles through its its birth of cells and its death of cells, or it can be associated with a pathological process and that can be inflammation, infection, cancer or a bunch of things autoimmune diseases. So now one question you might ask is is the cell free DNA that’s produced by normal processes different from the cell free DNA that’s produced by pathological processes? And the answer is we don’t have a complete answer. There’s a good deal of overlap, but the size of the cell free DNA, the size of the fragments, the modification of those fragments, which we call epigenomics, if they can be different. So we might be able to clearly distinguish pathological cell free DNA from normal cell free DNA. There are other ways that we can tell, and just by the amount of this cell free DNA or the species of cell free DNA that we detect sometimes that helps. But it’s first blush is a measurement of the turnover or the death of cells that we’re interested in. And that’s really what makes it interesting. And if we can target what cell free DNA we’re looking at, whether it’s let’s say the fetus, or let’s say a tumor, we can say something about how those cells in that fetus or how those cells in that tumor are behaving now. The advantage of cell free DNA is that a lot of that information we used to have to get by sticking needles in or extracting lots, you know, doing pathological sampling of that target. Now we can do that just by a blood sample. So it’s wonderfully non-invasive. We can do multiple time shots so we can tell, well, is that process getting worse? Is it getting better? Are more cells dying or more cells staying the same? And we can, even as I have said in the beginning, we can quantify that number, that amount of cell free DNA and that trend, whether it’s going up or down or staying the same. That can be informative in management for instance, as we give drugs to patients to common infection or treat a cancer or avoid or rejecting organ rejection of an organ. We can measure whether those drugs are working or not. By the quantification and track that and hopefully make that more precise and give people just exactly the right dose that treats them, but doesn’t give them side effects. So that’s that’s all, you know, that’s the kind of ideal use of cell free DNA. There are a couple of other properties in cell free DNA that make it. It’s hard to find it comes in mixtures that can be very small amounts. It’s rather short lived. Cell free DNA, you know, fours to a day or two for most cell free DNA to exist in the blood. That’s a problem. And the informatics, the back end analyzing because DNA, you know, there are lots of bases in DNA, so the fragments have lots of components to it. And analyzing that complexity requires a lot of informatics power on the back end as you as you sequence the DNA from the cell free component.

Saul Marquez:
That’s super fascinating, Dr. Billings, and very helpful. So folks, cell free DNA is just one of those markers. Would you call it a marker?

Dr. Paul Billings:
Absolutely.

Saul Marquez:
Right? Yeah.

Dr. Paul Billings:
It’s a biomarker.

Saul Marquez:
It’s a biomarker in the blood, the byproduct of a dead cell, normal death or through pathological reasons. But it’s tough to gather. And so Natera has special algorithms, special tools to be able to pull this and understand. One example that you use, Dr Billings that really intrigued was around if a drug post organ transplant is working. And so the drug then would a higher quantity of cell free DNA signal that it’s not because more cells are dying? Or is it the opposite?

Dr. Paul Billings:
Well, we’re actively pursuing clinical research on this topic, and it’s not one hundred percent resolved, but the hypothesis is that the donor cell free DNA, the donor organ, is different from the recipient’s cell free DNA that we know for sure. And we can detect that difference very, very sensitively and specifically so we can make a very quantitative and specific determination of donor derived cell free DNA that’s being shed by, let’s say, the transplanted kidney or the transplanted heart or the transplanted lung. We can detect that. And the idea is that if, let’s say that is being shed because the kidney is being rejected by the recipient and we’re using immunosuppressive drugs to quiet that rejection that the amount of cell free DNA being extruded by that rejecting Kidney, we can detect with our Prospera assay and very sensitively track that. And if the suppression is working, it should go down. Right? There should be less cell death and less cell free donor derived cell free DNA. If, on the other hand, the immunosuppressant drugs are not working, we would see the same or more cell free DNA release. And the idea is that those drugs, for example, have side effects. One of the important side effects of chronic immunosuppression. For instanc is cancer. Patients who receive transplants and on immunosuppressive drugs have a higher incidence of cancer. And the thought is that if we can reduce those drugs just to the right amount so we don’t get rejection, but we don’t over immunosuppressed them, we could reduce the incidence of cancer. And that’s a goal of ours, in our research and in our development. We’d like to offer that to the transplant community, across many organs, actually.

Saul Marquez:
Wow. Super interesting. So my understanding is there’s three different indications that you guys are working on with the cell free DNA tests. Talk to us about those.It’s Signatera, Prospera, Panorama. Talk to us about what these all do and what they mean.

Dr. Paul Billings:
Okay, so let’s start with Signatera. Signatera is our cancer monitoring test, our molecular residual disease test, and it’s unique because it’s personalized for everyone’s cancer. That is, it’s not a fixed panel. We create a new panel each time we receive tissue or a sample of a tumor, and that test that we create, that personalized test is highly sensitive and highly specific for that tumor, and for recurrences of that tumor. So one of the things that we’re engaged in studies at all levels with individual investigators, with drug companies, with consortia all over the world. One of the most exciting ones, which we have an initial report recently of is the circulate trial.That’s actually a global trial, but they’ve reported it initially initial sample in our Japanese collaboration. And what we showed in that is that in colorectal cancer, where if you have stage two or stage three colorectal cancer, you have it surgically removed and thus we can make our Signatera test at that time. It’s really often unclear whether you need more treatment or not. That is, and the treatment can be quite prolonged. Many months of treatment and the treatment, of course, has toxicities, which are very, very unpleasant. So if you’re cured with that surgery, you’d really want to know that because you would avoid further treatment. What we’ve shown is that in good number of patients now, I think it’s over a thousand patients so far, there’ll be more to come, if you are negative on our test after the surgical procedure, you are not going to reoccur so we can avoid unnecessary adjunctive chemotherapy in those patients who have a negative recurrence, a negative finding on the Signatera test. The other interesting thing about that study is that because we take tissue from that thousand patients or more, we sequenced that and looked at the mutations in those cancers. And it turns out that a lot of those cancers share mutations of three percent. I think or so share several mutations. And so if you had a panel, you’d have not very good sensitivity and specificity if you use the panel on those patients. So the extra sensitivity and specificity that allows us to make these very accurate predictions in the colorectal cancers are because we sequence each tumor and create a unique test for each patient. And that’s an important finding. There are some competitors of ours who are using fixed panels, and we believe that there’s increasing evidence that the sensitivity and specificity for cancer decision making is much better if you use our approach. Now for Prospera, Prospera is our test for organ rejection in kidney transplants and then most recently in heart and soon in lung transplants, in kidney transplants. Over the last year or so, we’ve seen lots of patients with COVID infections and kidney transplants with other kinds of complicating infections or disorders. And the problem with co-illnesses, other factors is they can raise the background cell free DNA, they can raise the recipient’s cell free DNA, and that can artificially impact how we measure the difference between donor derived cell free DNA and recipient cell free DNA and can give you, for instance, potentially false negative results. So in response to that observation and those clinical samples coming in, we’ve made a new way of analyzing the data, which allows us to quantify the donor derived cell free DNA directly. So historically, we expressed it as a ratio, and we said that if you were above one percent donor drive cell free DNA, you were at risk for rejection. If you were less than one percent, you were not as much at risk for rejection. Now we have that measurement, but we also have a direct quantification, the number of donor derived molecules. And it turns out that if we look at that number, there are some cases where the ratio doesn’t help or maybe falsely gives you a sense of security while the absolute number actually says that there is something bad happening at the level of that kidney and that quantification, and we think this will be true in heart and in and lung as well, that quantification will give us an extra level of precision, extra liberal predictability about whether a pathological or important process, particularly rejection is going on at the level of the organ. Finally, in Panorama, Panorama is our test which measures cell free DNA in a pregnant woman and allows us to measure the fetal component of the cell free DNA of a pregnant woman. And it gives us insight into the fetus. Now what we’ve shown we’ve just completed in our reporting now a twenty thousand pregnancy global study of pregnant women. It was four prospective study and we’ve had a number of amazing results. One is that Panorama very accurately can identify fetuses that have trisomy twenty one or Down syndrome, trisomy 18 and 13, which are other common chromosomal variations which can impact the fetus very significantly. We can identify sex chromosome changes in the fetus not uncommonly. You can have a male with more than one X or more than one Y. With women. You can have a situation where they only have one x instead of two, and those are not uncommon fetal malformations, which can impact the outcome of that pregnancy. We can sex the pregnancy. We can tell very accurately what the sex of that. So we’ve done that we’ve shown and that’s going to be very important in general screening. But we’ve also shown that the Panorama test gives us insight into what are called micro deletion syndromes, which actually are as common in pregnancies in the United States as things like cystic fibrosis, which is, you know, often people know lots about cystic fibrosis. They don’t really have ever heard of these micro deletions. But there is common in aggregate as something like six cystic fibrosis,. And we can measure those micro deletion syndromes, the common forms of microdeletions very accurately with our panorama test. So, you know, are this large prospective study is demonstrated an enormous amount of value to the way we do, and it’s a unique way that we do the panorama test this fetal cell free DNA analysis. And you know, we’re doing other kinds of analysis on the data that we have. We have other projects underway. Cell free DNA of the way we do it is very good at, for instance, analyzing differences between twins. You know, you can have fraternal twins or you can have identical twins, and the risks in those pregnancies are different. Fraternal twins tend to do better than identical twins in terms of pregnancy outcomes, so we can tell interested families and their care providers about that. And it may actually be that the amount of cell free DNA that the fetus puts out is in itself a risk factor or a can be helpful in identifying pregnancies that are going to have a problem in the second or third trimester of pregnancy or who are going to do fine. And we’re analyzing that as well. So, you know, we’re doing a lot of things with our Panorama, which is our fetal test, our Prospera, which is our organ rejection and organ health test. And with Signatera, which is our tumor monitoring test. We’re going to do some new things in the future where cell free DNA can be used for infectious disease diagnosis, for instance, and we’re pursuing new kinds of infectious disease testing using cell free DNA where that cell free DNA is actually coming from the pathogen, the the bacteria or the virus, or the fungi, which is in the recipient’s body. So we’re doing some work on that and other ways that we can get information and value from the measurement of cell free DNA.

Saul Marquez:
Yeah. Dr Billings, super stimulating and you know, on this last one that you mentioned, so infectious diseases. What’s the benefit of that? So you get the data, you get the cell free DNA and what do you learn and what can you action based off that?

Dr. Paul Billings:
I mean, you can ask whether it is simply an infection that’s causing an elevation cell free DNA or a new type of cell free DNA? Or is it both rejection and infection or cancer and infection? Or, frankly, is the fact that we have very low cell free DNA from the fetus, which is a worrisome sign that if you have too low, if the fetus is not producing the normal amount, it’s producing too little. That’s a worrisome sign. Is that potentially because there’s a co-infection or which could be treated and then the fetus would take off and be back to a normal level? Or is it independent of the health of the fetus? So and for instance, let me give you one more example. When you do lung transplantation, lungs, you know that’s a big operation. You’re replacing someone’s lungs and the lungs are in connection to the outside world. So lungs are frequently full of infective particles, whether they be viruses or bacteria or whatever. When you start to have problems with a transplanted lung, you often have both infection problems, as well as immunological rejection problems. Having a robust cell free DNA test that could help us sort that out would be enormously helpful to the people treating those patients. That’s the target.

Saul Marquez:
Yeah. Thank you for connecting the dots there for us. I wasn’t connecting them. But now it just makes so much sense. It’s all interrelated.

Dr. Paul Billings:
Exactly.

Saul Marquez:
And yeah, yeah, it makes so much sense. Dr Billings. Wow. And then ultimately, we’re looking at it’s non-invasive. It’s real time. That’s right. And that’s the beauty of this whole thing. And what’s making the difference is how you guys are doing it. So I appreciate you sharing that. With all of this opportunity and fine tuning that you’re doing, it obviously comes with challenges as well. So talk to us a little bit about the challenges involved with with cell free DNA and the things that you guys are working on there.

Dr. Paul Billings:
So look, I mean, one is just getting more information, mining it for more information. What’s real, what’s useful to the health care system, what’s kind of interesting as a science project, but really not that useful. So that’s the first challenge. The second challenge is these are complex results that we measure in our Panorama and our Prosperity test. Thirteen thousand or more targets in each one of those assays and lots of targets in our Signatera assay as well. So interpreting that, knowing what’s real signal and what’s not real signal, that’s all needs constantly improvement of the algorithms of the informatics. In many cases, what Natera does and the test that I’ve talked about primarily today Prospera, Signatera and Panorama, they’re measurements of cell free DNA. But as I told you, we also measure germline changes and tissue specific changes as well genetic changes. Those can have implications for other people in the family. Right? I might measure your cancer risk, your your hereditary cancer risk, but that says something about your brothers and sisters and your kids and maybe your parents too, if they’re still alive. So I need to be able to transmit this information not only to you and to make it actionable, hopefully for you to prevent cancer or prevent kidney failure, or prevent a genetic disease in a potential fetus. But in addition, I may need to give that information to your sibs and your parents and to your children. And how we do that effectively is really important. Another problem is that these tests are complicated and and sometimes quite expensive to run. So how we get reimbursed by the health, how we get valued and reimbursed by the health care system and by the payers of health care, which are largely in most countries, the government with a swath of private third party payers and how they value both the predictive genetic testing as well as the at risk you’re at an at risk individual genetic testing that’s important for us to keep on working on and make it, you know, make it a possibility that a commercial company like ours can do this kind of testing. And then there are a whole slew of long term ethical issues around genetic testing and tests that involve DNA. You know, privacy, the prevention of people using this in a kind of a discriminatory manner because the field is so fast moving, how new information is incorporated with old testing and what are the responsibilities of the companies that do that and the providers, the docs who do it and the genetic counselors who are involved with the patients. All these things in many others, including the history of eugenics in the United States and around the world. That’s all relevant and important considerations, and we need to continue to educate and talk about limitations and talk about what else is needed in society to make genetic testing and genetic monitoring the optimal useful for those patients who need it and who want it. Those are challenges that we’re still working on.

Saul Marquez:
Some big ones, but you guys are definitely taking the the lead on both the challenges and opportunities. Dr. Billings, an incredible session today. I’ve got to tell you this is super educational, and I know that the listeners are wanting to figure out more. There’s a whole other topic to discuss here, and that’s the ethics of genetic testing. So we’ll open the loop for our next podcast. Folks, we’re going to be covering the ethics of genetic testing with Dr. Billings, so make sure you tune into that one. But for now, just want to give you a big thanks, Dr. Billings. This is just an incredible topic. Incredible work by Natera. Just want to thank you for today’s session.

Dr. Paul Billings:
Thanks for having me. A leader in personalized genetic testing, Natera combines its cell free DNA platform with cutting edge technology and a focus on real world data to transform what’s possible during people’s most critical health moments. Natera has applied its core technology to the areas of women’s health, oncology and organ health, helping millions of people manage their disease from a simple, non-invasive blood test. If you’re interested in learning more about how Natera is revolutionizing the standard of medical care, visit Natera.com. That’s NATERA.com.

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Things You’ll Learn

  • Cell-free DNA is short-lived. 
  • cfDNA is a biomarker, a byproduct of a dead cell, normal death or pathological reasons. 
  • Signatera is a cancer-monitoring test that is unique and personalized for everyone’s cancer. 
  • Prospera is a test for organ rejection in kidney and heart transplants. 
  • Prospera measures the cell-free DNA component of a pregnant woman and gives insight to the fetus. 
  • Fraternal twins tend to do better than identical twins in terms of pregnancy outcomes.

 

Resource

Learn more about Natera at https://www.natera.com/