So good morning, everybody. Apologies again for the technical difficulties we’ve been having this morning. We’re we’re in the process of switching over from GoToMeeting to Zoom. So hopefully, these problems will be a thing of the past. The next time we do one of these.

So again, good morning, and and welcome to I Select deep dive webinar series. My name is Tom Bun. I’m an associate I’m the I Select Ventures team, and I’m excited to walk you through today’s presentation and findings.

For those new to these webinars, Iselect is an early stage or capital firm in Saint Louis, Missouri, focused primarily on early stage companies in healthcare and agriculture.

At I Select, we are privileged to live at the forefront of innovation. Seeing emerging problems, solutions, and macro trends at the beginning before they make their way into popular culture. We use these webinars not only as a way for us better engage with and understand new science and technology, but also to engage with the experts and entrepreneurs who are driving change and innovation in their respective fields.

One such topic that we’ve been researching is early stage cancer screening and diagnostics, particularly using blood as the medium to detect cancerous tumors.

For almost every type of cancer, early detection drastically improves outcomes. For this reason, I think, cheap, noninvasive and effective ways to detect cancer at the early stage, that you have most important students.

Before we get started, if you process comments, we are not soliciting investment or giving investment advice. In any way whatsoever. This presentation is general industry research based on publicly available information.

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So without further delay, let’s get into the presentation So we’re gonna be talking about blood based cancer diagnostics then.

We’re gonna start with some guest intros. I want you to have five people, gentlemen on the line today who are experts in the fields.

All five of them have have forgotten more about blood based screening and diagnostics than I know. So I will refer to them for for a lot of insights into questions that may come up.

So we’ll introduce them, then then we’ll go into the overview kinda why we’re framing this problem, why we’re interested in the problem, kind of the state of cancer in the diagnostics industry twenty nineteen.

We’re gonna look at a few technologies, you know, means of discovering cancer throughout the continuum of cancer life.

A couple of companies that we have with us today who are going to explain to everybody their ways, their unique ways in technologies and how they’re doing this. And finally, we’re gonna try and pull it up together, pull it all together in a a piece of slide where we talk about some risks and areas of investment. That I think we should be interested in as a firm. So, hopefully, again, it’s a it’s a more conversation than a model up and get rid of them.

So R naught, do you mind giving a brief background intro on on who you are and what you’re doing at fleetwood?

Yes. Good morning, everybody. My name is Arnon Chase. I see that we have three Israeli names here in this in this audio slash speakers. So yeah. This is we’ll we’ll capture basically all your attention today. I’m the CEO of Cleveland Diagnostics, which is a company that cofounded with Cleveland Clinic to commercialize develop and commercialize a a new technology that is specifically adaptable at looking at cancer at early stages And in blood, of course, with some of the particular characteristics, I think, that would fit very well the business proposition.

Actually, I’m I’m going to stop now, but if it’s okay, I noticed that in the overview, I do have some general context for the entire field that issues that have nothing to do with our company. But where does the entire field is is being approached currently by by the leaders in the field. And I would like to, actually, to have a moment then. But I’ll I’ll quit right now and let the next person.

Great. Thank you, Warren. Jira, do you mind giving a brief intro?

You are are you there?

Luis. There we go. This Luis Nunez from IV Diagnostics.

We’re an Indiana company focused on metastatic breast circulating tumor cells and we’re we’re advancing it significantly in the steel. So we have a huge interest in the the blood assays.

Great. Thanks, Luis. Did I hear your on the line as well?

Do you remember from SAVastil?

He might be on mute. Jira, let me know if you can hear us. We’ll move along to Paul. Paul is a friend of the fund I put Jack of all diagnostics trades as his as his title. Because you go to his LinkedIn. It’s about a mile long So Paul forgive me for being not as precise as I’d like to be in your title. But, hopefully, you can tell everybody a little bit about your background now.

Sure.

I did notice that that was interesting. So my background is I’m a physician scientist field is infectious diseases, and I’ve been in the in vitro diagnostic field for over over twenty five years. Hello?

Sorry.

Go ahead, Paul. Okay.

Both start up and around company.

And, presently, a partner in a number of the recent friends here in Saint Louis.

And we have our own strong best that I’m a complete bioler that I’m a vampire guy. Focused on IVD diagnostics.

So can you hear me now?

Yep. Jira, is that you? Yeah. That’s me.

Yeah. I put it on mute, and then the machine has been crazy. But, anyway, My name is Gios David Dobis. I’m the CEO of Savison.

We are a a liquid biopsy, you know, immuno metabolism platform.

We are situated both in the US and in Israel. I love in Israel.

This is a technology that we license from Tel Aviv University.

And I will share with you a little more about this this platform.

Great. Thank you, Yora. Yep.

Bob. Do you mind giving a brief overview?

Sure. I’m Bob Puscus with Trackxon. We’re here in Saint Louis.

We do more traditional studies of proteins and enzyme activities in blood.

We have a core of proteins that allow us to look at a number of cancers. And I’ll talk more about that later.

Thank you, Bob.

And Frank, feel free to give a brief background about yourself as well. I know we used to cover what you guys are generally up to, but would love to hear your background.

So this is Bob. Did you want me to do that?

No. Not, Bob. Frank, Frank might not be with us. Frank from IV diagnostics.

That’s alright. We’ll we’ll keep moving on. Luis told us about what we’re up to.

Sure. Sure.

Currently, we’re we’re developing a a CTC assay or we’ve developed CPC assay taking it through clinical studies.

Trying to enter the market.

And this is for metastatic breast cancer.

We were able to monitor the breast cancer progression and related to different, you know, medical treatments either chemotherapy or even immunotherapy.

So that’s one product that we’re currently in the market, and we’re trying to go global with that. We’re also in in a non invasive device to monitor the circulating tumor cell in humans without a blood ass a withdrawal. So that’s sort of our status of where we’re at.

Fantastic.

Okay. Well, we’ll we’ll move move along. I’m gonna talk a little bit about the background here, which we can short circuit a little bit given how how many people know how pressing a problem with tumors.

But so cancer in twenty nineteen is Snapchat.

As many people know, new cancer diagnoses are expected to rise by seventy percent in the next two decades.

Fourteen million new cases per year to twenty two million. As an economic organization.

But interestingly, overall rate of cancer deaths in the U. S. Has actually fallen by twenty five percent since its peak in nineteen ninety one was translating about two point four million lives today.

But however, improved treatments are likely not the reason why. The likely reasons why are that a reduction of smoking and improvements and screening. Have led to thirty six percent fewer deaths for some of the most common cancers such as lung, or rectal, breast, and prostate.

In fact, cancer death rates now are not all that different from the nineteen thirties before they started to rise very quickly with you know, millions of people smoking cigarettes.

So cancer drug cost despite, you know, deaths falling by twenty five percent are still projected to exceed a hundred and fifty billion by next year.

And interestingly, a new method most of the r and d within oncology and and cancer research are largely focused on treating the worst cases. So if you think about the last cell of cancer versus the first cell of cancer.

You know, a lot of money is being spent on later stage immunotherapies for patients with pretty sort lifespan left.

So I think all in all, there needs to be a paradigm shift for switching from the last cell patients to the first cell patients because we can ultimately save more people with that approach.

As it says here, the estimated cost savings from early diagnosis adds up to over twenty six billion dollars a year. Which is more than any other new approach to problems.

So using these or or going off the early diagnosis liquid biopsies are are one way to do it. They’re less invasive. They’re more easily repeatable, potentially more accurate than biopsy.

Currently, the liquid biopsy market is estimated about thirty two point six billion.

And they really do have a lot of different functionality. So they can monitor cancer development.

They can track response to treatments.

They can be a surveillance surveillance method for high risk patients. And increasingly, and eventually there, they’re gonna be, you know, early stage screening methods and and diagnosis methods as well.

So just to put two numbers, what I I tried to put a narrative form in the last slide, the benefits of early detection. This comes from Cleveland Diagnostics website. Zoren on. Thank you for that. This shows the survival percentage with stage of diagnosis.

So as you can see, my point in the last slide was earlier diagnosis stage lives.

This slide shows it in states, especially for very deadly diseases. Prostate colon breast cancer. There’s a very high survivability if you catch the disease in the early to the mid stage.

And it there’s a precipitous drop off after the mid stage.

Interesting also to point out that the idea of early detection is not that new. In fact, I read something that at far back in nineteen o seven, there was a British physician named Charles Child, who’s the author of the control of scours observed cancer itself is not incurable. It is the look it it is the delay that makes it so and push for a public campaign for early intervention.

So we are now kinda still echoing this Charles child’s words with how we’re attempting to change the paradigm and and cancer screening and detection to death.

So the problem with today’s detection, you’re really trading off high invasiveness and high accuracy, or low invasiveness and low accuracy.

So colonoscopy, for instance, a a very invasive procedure you get very high sensitivity.

Another blood test, for instance, the c a one twenty five, which is the cancer antigen for ovarian cancer. You only have fifty percent sensitivity in in the early stages.

That jumps in some of the later stages, but you’re sacrificing as it stands low invasiveness and low accuracy as opposed to high accuracy of the more invasive methods.

So detection with blood markers and imaging, for example mammograms and CT scans, They work well after significant growth for metastasis.

For instance, eighty one percent of pancreatic cancers haven’t metastasized at that detection.

Imaging modalities. They only detect tumors of significant mass, and they provide no information on molecular makeup. Which ultimately requires biopsies to get a better understanding of of what the cancer is.

These biopsies themselves don’t capture the the heterogeneous of tumors.

In twenty to fifty percent of cases, there’s insufficient tumor material for conclusive analysis.

Read that up to twenty five percent of lung cancer biopsy fail to obtain enough tissue for a sample.

So all this is is the reason why we’re we’re starting to look more into in blood based cancer diagnostics here. And I think, in in general, the scientific community as well, which we’ll talk about as made evidence by some companies in the field. But blood based cancer diagnostics be they predictive and prognostic or prognostic, have the ability to be kind of the holy grail.

So not a treatment or a therapy. But can still drastically improve outcomes by finding by finding cancers at their earliest stage, and we can still respond very effectively.

To the r naught’s point as well, two thirds of cancers caught early are curable.

So needless to say very, very important to to focus our efforts on where we can find cancers earlier and and how we can almost most judiciously respond to them as we do find them.

So this graphic shows kind of where we are from cancer screening and and where we’re going.

So right now, we’re largely at one Oregon at a time detection.

The universal screening, which may come from from blood or a liquid biopsy, could be simultaneous or multi organ detection.

The current method excludes most cancer types. The universal method could potentially include many cancers or all cancers. We have folks on the phone today, who are going after eight cancers, I believe.

Multiple modalities goes to a single medium or or one modality.

And inefficient and costly goes to very highly efficient non invasive non invasive, potentially very cost savings.

So I I know we have some experts on the phone, but I know many of our listeners are not experts. Just a very quick primer on sensitivity versus specificity as we’ll be using that a little bit more in in the rest of the slides.

But these two statistical definitions are far down the baseline. One zero one for understanding if the test is is good or not. So sensitivity ultimately refers to the percent of patients with a disease who test positive. So a one hundred percent sensitive test means that the test correctly identifies every person who has the target disease.

Specificicity on the other hand shows that the percent of percentage of patients with a disease you test negative.

So the test’s correct leg identifies every person who does not have the target.

So it’s important to keep in mind here. Actually, we’ve heard the disease.

What that? Just a small correction. Percent of the patient without the disease, namely negative who tests negative. That’s specificity. What you read is one minus specificity, but doesn’t matter. It’s the idea is the same.

Got it. Thank you. That’s why we have you on the call.

So these these statistical markers matter when you’re especially as you’re talking about different types of of screening and and where along the value chain a specific test is going to to take place, for for instance, a screening test, you want very highly sensitive yet low specificity. So that correlates to not many false negatives. You don’t want people who are positive to go and and falsely be described as negative.

And then you’re okay with some false positives because we’ll be you’ll go to, you know, the next line of defense in the in the screening process, and and they will be they’ll realize that they do not have the disease.

So we’ll talk a little bit more about sensitivity and specificity as it relates to some other drugs under development, but wanted to give that that very brief background.

Nice job.

Thank you.

So as far as what we’re going to be looking at from some of the companies on the phone today, These liquid biopsies use analytes or biomarkers to detect cancer.

In this case, we’re talking about blood. But in the blood are, you know, many different things, many different dead cells, living cell DNA from the body goes to circulate around the body. And using blood, you can have access to many of these important markets of disease.

So we’re gonna look we’re gonna talk about CTCs first.

IV diagnostics, again, is focusing on on CTCs.

But CTCs are really cancer cells that detach from a primary tumor and travel through the bloodstream or hepatic system to other parts of the body.

So here’s a a little diagram of it.

But really, CTCs are the root cause of metastatic cancer. When cancer cells shed from a tumor, they can travel to other areas of the body through the bloodstream or the limb lymph system.

And according to the American Cancer Society about one third of patients with cancer have metastases detected at the time of the first diagnosis.

So metastatic cancer refers to cancer that begins in the primary site and spread to spread to other part of the device.

So circulating tumor cells or CTCs, are are implicated heavily in that process.

So I’d love for for Frank or Luis to talk a little bit more about maybe the importance of CT and how an in vivo method of detecting and monitoring CTCs would be would be a a game game changer.

Yes. In respect to to how we’ve done it and what we see is resolved, but monitoring CTC can allow physicians to use it as a tool I need to process overall for our purchase of products and sell my product, press cancel.

It only takes about the maybe two hours two hours and a half of preparation.

Once you they’re the Luvs sample and get the serum and and it’s all ready to go and pick it up fifteen minutes to add this video. Look ticometer. So the the process overall is very rapid. So, you know, decisions could get information in respect to how effective their treatment’s becoming we’ve observed that he has a certain genetic cancer some patients do not respond as effectively to their treatment and in risk state, we could monitor the the the numbers of circulating tumor cells to relate that to treatment effect So we believe that this is something that’s not just for metastatically, or patients that are in remission, but we believe that it could apply for for other applications, which we’re pursuing at this time other lung other cancers like lung cancer correct answer.

Where we could be that specific to target these cells and and provide information to the to the physician to make the decision fast and treatment.

Great.

And, Luis, can you talk a little bit about where you are on the regulatory pathway?

Yes. We we’ve we we’re currently, you know, definitely the test is available as a clear laboratory, meaning that that’s not an FDA approved, but as we gain more results more clinical results, we’ll go for for five ten k and for the FDA approved product hook. We we are currently do not have a large amount of, you know, clinical data. You know, we only have plus the conversation.

But in more of it will be required for the FDA approval. But at this point, we can, you know, sell the product by, like, we need to leave a lab or hospital that they could use to lose. And we’ve done that already with Yeah. And we’re pursuing another other organization around the the country, and we have distributors that are specific we could get to agreement.

I think that’s what we’re pursuing. We just started. We could start our clinical studies in, you know, sometimes late summer. So now we’re kinda ramping up in in the cell.

Failed of the Bella Act.

And so we yeah. The Bella Ashley heard the those standard is the self search that we we’re competitive, but we see our our assay as must simpler, much cheaper and very rapid compared to and the accuracy, of course, is that Sydney is it’s higher. We have less loss positive for breast cancer. But we’ve also evaluated clinically this velocity for other other types of cancers, and we’re pursuing, for example, lung cancer with a Chinese group. So there’s a lot of interest in in gabbing and assay that hits us that could bring some information for physicians to make decisions on. Treatment.

Right. Thank you, David.

Appreciate that.

No problem.

So that’s a great represent represent representative company focusing on CTCs.

Moving down to the the second item I had in the first list, which is circulating tumor DNA, CT DNA.

Kind of related. These are small pieces of cell free DNA. They’re about a hundred times more abundant than CTCs.

We have known that their they’ve been in abundance in in blood for several decades, but but recently, the speedy next gen sequencing technologies have been able to distinguish low levels of them in in the total cell free DNA shed by all cells. So recently, there’s been a a surge of investment and r and d work and to try to leverage the information in the circulating tumor DNA DNA pieces to find cancer. And there have been several notable companies that have been that have been doing that. Grill is perhaps the best known They have a next gen sequencing blood test for detecting multiple cancer types by analyzing this CT DNA methylation patterns.

So they spun out of the the next gen sequencing company, Illumina, in twenty sixteen, and they’ve raised a whopping one point five billion dollars since So they started looking for cancer associated mutations in CT DNA.

But recent studies have shown that even non malignant cells can accumulate clonal mutations, and therefore cause false positives and a lot of the work they were doing with the the CT DNA.

So now they’re actually looking at how at the methylation signatures and how they attach to the CTDNF.

So this, according to the CEO, could be actually more beneficial than looking at kind of the traditional CT DNA.

Because for a particular region of the genome being investigated, the DNA would typically harbor just two or three mutations of interest. Whereas he says that methylation tags are much more abundant and in the hundreds of thousands of methylation tags in the same segment of the genome.

So their sequencing database of cancer and non cancer methylation signatures covers about thirty million methylation sites across the genome.

So it’s supposed to be able to indicate the presence or absence of cancer, and they can also provide insights into the tissue of origin of any cancer that is detected.

Tom, is that gonna be used just for detection of the cancer? Or is it also gonna guide treatment and be something that they use to understand the right way to approach treating the cancer. My understanding, it’s gonna be a screening test. Just the screening test? Do you wanna some on the on the phone have another perspective as to use cases for Grille’s technology.

It is gonna be early detection. They started as an early detection company and not necessarily in the liquid biopsy.

Standard context, which is to customize targeted therapies and such, which is a much smaller market once you’ve been identified.

But I think that they really got stuck. They have a lot of money, so they’ll unstuck get get themselves unstuck. No question about it. But The main problem that Grail has is is simply the cost, because they’re doing something that’s called deep read, which in simple English means that their cost of good is extremely high sequencing. And even if it goes down, it’s still gonna be very high because they they have to look at so many of those methylation pieces, if you think. So they so they if you look really at the data that they have, they’re the thirty four percent that’s showing right now, the seventy seven.

By by definition, they wanna work called state one, state two cancers. And by definition, they have very low sensitivity there. So, they’ll have to reinvent something.

Yep.

Great.

Thank you for that.

Moving on to the next company here, garden health.

So they have a commercially available circulating tumor DNA test. Of seventy three gene panel to guide the treatment selection for non small cell lung cancer.

So Mike to your point, this is this one is is a we’ll have a later stage in the in the value chain of cancer diagnostics more all along the lines of treatment selection.

They also do have a screening technology in development.

They will they’ll be starting their pivotal perspective screening study from what I understand and colorectal cancers, and they’ll recruit ten thousand patients with average risk of developing the d disease.

So they they have a commercially available test right now for for lung cancer.

They have a commercially available five hundred gene panel for drug development. And then in development are these early stage detection in screening methods.

Then Thrive earlier detection. You may have heard of CancerSeq. CancerSeq is their main product They have a multi analyte test that combines mutations in CTDNA at nineteen hundred low locot with measurements of protein biomarkers to diagnose eight common cancers.

Recently, in earlier this summer, they they published data in a retrospective study with about a thousand patients, which with confirmed non metastatic cancer.

Cancer seek achieved detection rates from sixty nine to ninety eight percent with ninety nine percent specificity across five cancers, which were over e, liver, stomach, pancreas, and esophagus.

All of all of which, by the way, there are no screening tests available for right now. In a machine learning based algorithm, localized to tumors to two and atomic site in a median eighty three percent of patients and do a single organ in a median sixty three percent of patients.

So this is another predominantly screening test. I’m not I’m not exactly sure when they’re gonna be starting prospective studies.

I know Grail will be starting them next year in in Garden as well. But it seems like cancer or seek is is also on the press business card.

Some full time looking studies.

There’s just a couple points about circulating tumor DNA. We can fly past it for most of time. I know there are a few more entrepreneurs who would like to speak. But the point is here that there are a lot of applications for CTDNET.

You can get prognosis determination.

You can monitor ongoing treatment for a suite of therapeutics being used for cancer patients. You can select the right treatment.

You can get tumor size and disease burden that’s more on the the screening size.

And you and you can detect in asymptomatic individuals.

So, again, this this biomarker, if you will, as applications across kinda the continuum of of cancer care all the way from screening to maintenance.

So switching gears into protein.

Bob alluded to what he was doing earlier. Bob, would you mind telling us a little bit more about traction and and kinda where you guys are and and what the next steps are?

Sure.

We have a modest goal, which is to cure cancer.

It’s a bold thing to say, but what we’re doing is developing a a cancer guidance system that is applicable in all the three key points finding it and you can’t cure it unless you can find it.

Hearing it, we can help assess which therapeutics might be used and best and prove it, which is always what a patient wants to know, is it gone?

So, we do this by looking at proteins in the blood, we look at the activity of some proteins. And some are auto antibodies. Two different categories.

And as it turns out, this group that we’ve developed is Very special. Normally, if you’re gonna look at a cancer, you develop a set of biomarkers and that’s it for that cancer.

Then if you want to look at a second channel, you need a second set of biomarkers.

In our case though, we get patterns from our biomarkers that the small group, we look at eighteen parameters.

And one pattern will be distinctive for a particular cancer Another pattern set will be distinctive for another cancer. So, we can look at large number of different cancers. We have looked at about a dozen different ones at this point.

Our initial focus is going to be on the screening side.

Initially, on rule out tests that are done after traditional screening tests. So, for example, after a mammogram, they’re positive, but most of them are false positives. So you could run one of our tests and for ninety percent of the women that were positive, we would say they could just go home and there is no cancer there to be found. The rest would follow in the normal path and get a confirmation of cancer. We can do the same kind of thing for lung cancer.

And in addition to that, we can go on the other side and do what would be a prescreened.

So, screened specifically for lung cancer, screened specifically for breast cancer before ballooned as the cat scans for lung or mammograms for breast cancer. And we talked about screening for multiple cancers. This is something we’ve looked at from the very beginning, that was our idea was to look at multiple cancers. And once Grail and the others had come out with their information, we thought we should check and see how we did it compared to them. And we actually did very well.

Our sensitivities are in the 90s, for the cancers that we’ve looked at, specificity are in the mid-80s to high-90s.

And So rather than try to look at eight to twenty cancers, which has been the goal for Thrive and grail, we said we’d pick something a little more modest and look at five.

So we’re looking at breast cancer, lung cancer, and that non small cell and small cell can differentiate those two, colorectal and ovarian cancer.

And so Those are the ones that we’ve looked at, and we do very well detecting them. And the next piece is, can you tell which one it is? And yes, we can do that very effectively. We’ve developed a particular algorithm that allows us to do that, and we can specify for the ones where we’ve detected the cancer, ninety seven percent of the time, which cancer it is. So we’re moving forward on advancing that one.

When we detect these cancers, it’s not just one pattern for one cancer.

Cancer may have four or five or six different patterns, and we believe that those also will have some utility in helping identify which therapeutic might be best used.

We’ve also used the fact that there are these multiple patterns to identify, for example, in lung cancer, which lung cancer is in the lips. And which would be aggressive.

And the estimate is that about twenty percent of lung cancers would be indolent and that’s precisely what we find with one of our patterns.

And then treatment assessment, we’ve we’ve done some instances where we’ve looked at the patients that have had surgery, prostate cancer, patient, for example. And we know that after surgery, the patterns that we find are gone.

And except for cases where the prostate cancer is metastatic. And in those cases, the cancer patterns still exist.

So we can, we think, give an idea that cancer is gone.

Inversely, when it returns, the pattern would expect to come back. And then one other thing that happens with epidemics sometimes is that the cancer will actually change. And since we have multiple patterns that we find for cancer, we may be able to see when that happens as well as treatment.

So altogether, this comprises for us a cancer guidance system that would be a value for the three key steps, which is screening, identifying and monitoring therapeutics and proving it’s gone.

Great, Bob. Thank you for that.

We have another company doing something similar. They’re looking at kind of protein structure as as as opposed to which proteins are are being manifest.

So instead of that, they’re looking at kind of how the proteins change in the presence or in the absence of cancer. And we have Cleveland diagnostic books if I can change the slide.

Tell a little bit more about that that approach.

Are you not either? Yes. Yeah. Thanks. And actually, I wanted to I’ll talk a few a few moments about what we do. I think it’s really important to add few words on on context. I think that understanding that this particular field should be in viewed together with cancer as an industry.

And if you think of cancer as a disease, you missed the whole point. Because the entire approach to this disease has been marked only by, as we said before, let’s basically, the old American way, it’s the high noon, you know, we’ll simply pull the gun at high noon and shoot cancer straight in the in the head. And that has been the approach that finally, I think would allow diagnostics to to really claim it’s it’s rightful right foot place, and the CAR T, in the last bio, for example, conference, the largest conference biotechnology. The entire story was how do we convince Medicare to pay a million dollars to cure somebody with CAR T.

You know, as soon as you have that and you multiplied by late stage cancers, you realize that the solution has to come from somewhere else. So I think that it’s I’ll call it the golden age of diagnostics is coming, and I think that we we are glad to be able to provide solutions there. The other thing that we we were just in a big panel with, together with people like, from Grale, and Intel and cancer Institute and others.

And we simply brought the point that none of us would be able to provide the answer.

You know, us as a company in a sense. So anybody else who provides a single technology would not be able to answer all aspects, because it is really a workup. It is starting from different level of sensitivity and specificity. It vary all the way from early detection in which sensitivities is paramount and down to sort of, let’s call it the diagnosis, the pre biopsy.

In which we’re talking about high specificity.

So, you have to think about it. The last point or the last two points is really, really important.

Is is the first thing is cost. Because we are diagnostics. We are not CAR T. We’ll have to be in the dollar range, especially if we’re working on you know, an early detection. So when somebody like Grail, with all due respect coming in and saying that they have early detection, but it costs five hundred dollars they’re not doing error detection. This is just not gonna be happening.

So And again, you have to look simply relative cost structure of doing deep sequencing versus, you know, versus simpler, maybe DNA approaches versus looking at proteins that are traditionally In the lab has been two dollars range kind of for in Eliza, which is a standard when looking at how much of specific protein exists.

And the last thing that I want to say is something that appears to us as we get into the market or near the market, is how important it is from the lab workflow. The last thing you want to do is go to a lab director and say, here is an instrument that does x y z.

They hate it. They have to maintain it. They have to they have to service it. They have to run calibration every day on it.

I mean, small things like that. So, you have to think when you provide a solution on all of those things together, and then realize that your solution has to fit exactly this, this work up that I just described. Finally, we had in this little panel. We had even Intel.

Everybody’s talking about machine learning and such.

And they’re simply looking at asymptomatic people in the population, reading very, very large datasets that includes conventional read reads of all the lab, all the lab results of everybody. And, trying to see whether can actually identify people early on so they could go then into our test. And I think that they could be also an integral part of the whole thing.

Alright. So this is kind of my my my preamble to what I wanted to say in the next thirty two minutes. So our approach is to simply look at, do you have cancer or not and not whether you will have cancer, which is a traditional DNA approach not the liquid the current liquid biopsy, of course.

When a protein changed in shape, and we can calibrate it against proteins made in cancer cells versus proteins that may be normal cells, I can get basically any protein biomarker and make it into high specificity. So you read before there was a name, cancer antigen one hundred and twenty five or PSA, which many of you on the on the call should probably get.

And you can ask yourself, well, why aren’t they working? We are not working because they’re not specific for cancer. So, that’s really what we do. We take everything that is known that runs already in the lab, and we make it cancer specific.

And we already proved it. So we ran at least a thousand patients today against biopsies in two large multi center prospective clinical studies that were published already. Our cost basis is of what you see on the right is basically in the dollar range. So we fit very nicely in the early detection.

The first test that would fit this this paradigm of simply making known protein biomarkers better, is PSA, and it’s gonna be called ISO PSA.

That that we have our key opinion leaders are from Cleveland Clinic and Johns Hopkins and everybody else.

And it’s been, again, validated already. We got we just got FDA breakthrough designation this month. Or last months, I guess.

And you can see the rest of the of the timeline. The key thing is probably next summer, it’s going to be approved by a PMA, which is really the long way that the FDA approves. But because we are breakthrough, we have a lot of things that allows us to get near that than other in our conversation with FDA things are much, much quicker. And finally, we’re working also with CMS to get national coverage on these two.

Yes. We do like everybody else that we’re on the call. We’re also working on test, we already have data on our ability to do that. Namely, one blood test would tell you a little bit better about which organ, the cancer may come with, and it’s not really difficult.

Because those changes that we see in protein biomarker to the structure of proteins are generic to cancer and not to the tissue.

So but, again, we also work on specific things that would work well together with current modalities for example, in breast cancer, you have mammography.

Mammography has been said before, it’s not specific enough. Well, you could run it before mammography altogether with mammography. Memography is one hundred and twenty five dollars reimbursement. You run another fifty dollar test, and voila, you get yourself basically something that’s very, very specific.

And and does not require a specific biopsy to be, you know, and three weeks of wait for a nervous patient. The other one, of course, is even bigger lung cancer, which is basically half of the, half of the world outside the U. S. Smoked at one time And the only way that the only modality that you can, that you can look at patients today is something that’s called low dose CT, or spiral CT, but that has at least ninety six percent ninety six percent false positive. So, they simply wait long enough but at that point, most of the cancer are stage four. So, again, if you would generate a blood test that could work in tandem with with this load of OCT, and to follow-up a high risk patient that is that is the right way. And the final thing that I wanted to say and find and I said that I guess a couple of times already is there are some cancers that I don’t think that we’ll ever be able to find early enough.

Everybody knows about pancreatic and ovarian and all of that. I can, move anyone that is interested with one page, why it would be impossible to find them, find those cancers early.

Is strictly speaking something that’s called in statistics. There is a part that’s called bayesian statistics that simply said at if the prevalence of the disease in that population is low enough, you’ll never be able to get it. Because you’ll generate enough false positive that would make the test useless as far as the application in the field.

So, I think that we have to focus on the big ones, indeed, and we have to work together.

And we have to work even with virtual screening early on. But I think that this is really the golden age of diagnostics that it’s coming upon us, and we are all good to be a part of it.

Thank you, Arnan. Very fascinating stuff you’re working on.

We have Savacel here who’s taking a a completely different approach. They’re looking at the immunomatabolism and biomarkers that come from the immune system as a as a means to detect cancer and location.

Do you your you are are you still with us? I’m still and and I like to be in the golden age.

Yeah. Thank you for the previous speaker.

Savicelli is a unique platform in this space.

We are we are focused really on early detection.

We are doing it by measuring the metabolic state of the immune system.

Up to now, this rapidly emerging field of immunometabolism was focused on therapeutics.

And we are using it in diagnostics.

I won’t go you already gave the market size I would just say that we are projected we are we are focused on early detection.

Because of our methodology, we have a unique capability for early detection.

And we already spoke about some alternative sequencing based liquid biopsies, and the difficulty that they have in terms of stage one and stage two detection.

So disease intrusion and cell malfunction, malform, they include cancer, and they are detected first with the immune system.

And the the immune system energizes, they do what you call a metabolic shift in order to get rid of the body of the in order to have an effective function and get rid of the cancer.

And this it turns out that this metabolic function modulate cell, fate, and function, and thus dictate or influence immune response.

They’ve done experiments where they show that if you don’t allow the immune cells to to do a metabolic shift by blocking the glycolysis, T cells can can divide, and they can survive.

But they cannot mature into an effect of t cell and secret cytokine of chemicals.

So what we measure in a sense is with the we measure the differential metabolic responses of the immune system.

And thus enable us to do early detection.

Savicel demonstrated compelling proof of concept study. We published it in cancer immunology and immunotherapy.

And we yielded ninety one percent sensitivity, eighty percent specificity.

The important part is that our ability to detect stage one is as good as later stages. So very similar sensitivity in detecting any of these cancers.

What we have is a very broad platform.

It has the ability to extend beyond cancer and other cancers, of course, to autoimmune diseases.

I think, you know, if I could add just to what a previous speaker spoke about the importance of cost and all this stuff that and selecting the right cancers to to work on, It’s also important to select the cancers, especially for smaller companies that already have approved that LED detection does save lives. So what you don’t want to do is do very long studies to show So so that you save life by detecting early detection.

But our results were strong.

And again, back to the broad platform, we could do autoimmune diseases.

We can do treatment monitor and your therapy selection.

In this case, we have some unique capability that are really in the space of immunotherapy.

Because a lot a lot of immune therapies, what they’re trying to do in effect is change, modify the metabolic function of the immune system, Casing point is some something like KEYruda, where with their antibody anti PD one, They’re trying to the the the t cells when they express a lot of PD-one marker on the cells. They don’t mature into an effect or t cell, and the candida is an antibody, reverses that. So people are working in this whole area of the metabolic change of the immune system, and we can play all the we are focused initially on the cancer Specifically, we have a product in lung and in breast.

Our initial indication is to be a tool like other people spoke to assist in the diagnosis of indeterminate nodules identified by imaging.

We have a unique and growing patent to state.

So we have patents granted in the US, EU, China, Japan and other countries.

And of course, we have an experienced team.

And our core competence is in immuno metabolism.

On the one hand, which is a subsection of immunology and in software and analytics, which we are doing also in house.

Again, we we are planning to do to start with a clear, followed by an FDA, similar to what’s what was stated earlier.

Great, you are. Thank you for that. Thank you. We’re at the top of the hour or the bottom of the hour now. Totally understand if anyone needs to drop off. I’m gonna go through a few more slides. I would love to have your comments and questions.

As we as we continue to go through those. But again, if you have to drop off, no problem.

So wanted to touch on some recent deal activity.

As venture capitalists, we are interested in kind of price and valuation and enterprise value of these companies as they mature and go into either the public markets or get acquired by, you know, a larger diagnostic company.

And there are three kind of big deals that that have happened in the last couple of months, actually. One called adaptive biotechnologies which we talked about a little. They raised three hundred million dollars in an initial public offering, valuing them at two point three two billion dollars as of June of this year.

That market value has gone up significantly since then. They’re now working about three point seven billion. And they raised four hundred and twenty million in venture funding.

Freedom is is a still a start up, still a private company.

They’ve raised about a hundred and sixty million dollars in their most recent series b.

That was read led by Polaris Partners in RA Capital. But they got a lot of participation from kind of the blue chip venture funds in this space. So Google Ventures, Roche, Kaiser Perminente, data collective and injuries in Horowitz all all participate in in what freedom is doing. And to my knowledge, you’re it sounds like frenome is focusing on amino metabolism, analytes as well, which at least a part would be a good amount for you.

But moving on to Frive, Thriveory is a very big series a in May of twenty nineteen, hundred and ten million dollars at a fifty five million dollar pre money.

That was led by third rock and cross the exact site is prohibited.

Thrive is is starting to do some work in colorectal cancer. So it’s interesting that exact science has participated as exact sciences.

It’s the company behind Colvard. You’ve probably seen those commercials about the answer screening test where you they mail you a kit and you mail them your food. And they tell you whether or not you likely have colon cancer. So no surprise there that they’re interested in in other ways of assessing, you know, early risk of cancer.

And all in all, you know, this shows me that demand is there. The market is pretty frothy for this type of this type of technology that is obviously very needed in the realm of cancer care.

So moving on to to my final slide, a lot of these are kind of rhetorical questions. I would love to get your your comments on them. So where I think we should consider investment.

Again, the highest clinical need appears to be in screening.

We need early decisions on on screening, diagnosing, and monitoring.

Diagnosing seems like will always be checked by a I know I don’t hear you, Tom. Are you still on?

Yeah. Tongman, I can’t hear him either.

Can’t hear here either.

Yeah. Perhaps, we should all just chime in. This is a discussion slide I presume this is Arnan. So whoever wants say something about this and other.

I think I made my piece already in my when I when I spoke about how we see at least whether, you know, what should we what should we do? And in my book is is never to think that we’re the only company in the world and simply to understand really our role and place in this in this spectrum of that is called the diagnostics. And and work well with each other. You know, we don’t own the whole space, and we don’t have the only solution in the world. And I think that the entire field, especially complex disease such as cancer, know, you have to look at that as a as a as a continuum.

And then the other point that I really wanted to ask others, how do they see themselves as feeding into the reimbursement and, you know, and the cost of the test by itself, the cost of goods, and the simplicity of running into the lab. All the practical questions that make something that looks great in the research stage succeed or not.

Well, I think it depends on the also on the cancer and the cost associated with all these false positive and unnecessary invasive procedures, which cost the healthcare a lot of system, a lot of money, the healthcare system. So I think in a lot of cases, then the amount of money that you save, and somebody also mentioned the idea of the treatment So I think the money that you save by unnecessary invasive procedure to diagnose is one major cost saving to the health care and it can be also in the billions.

And I think that if you detect early, you’re saving very expensive treatment cost So I think that indeed it’s us like the age of diagnosis is coming, and I think it can absorb some cost if if if it generates significant. At least you if you choose initially the kind of cancers that have the have the most amount of saving associated with that. Yeah. I I think that we we hit upon an area here that Tom didn’t touch on, but I think Arnan, you you you mentioned. And that is you you can talk about the cost savings, but you also have to be aware of the problem of false positives. And and there’s a blurring that goes on between early detection screening and diagnosis. These are all different different things, because the patient comes in with a different pretest probability.

And we talk about specificity, but what we really need to talk about is positive predictive value. And so as the prevalence goes down, a number of false positives goes up, that begets more invasive testing, which costs the system. So that’s gonna be the biggest hurdle for these tests.

Is using them appropriately for patients with the highest pretest probability.

And somebody mentioned, and I I really think that an area that needs a lot of more more intensive investigation. And that is using AI to choose which patients to use the test on so that you got the highest pretest probability going into the test and the lowest number of of of false positives. And and I think that’s an area that will help us a lot, not to use these tests on all comers as they as they come in the door.

And and I think there’s a continuum from asymptomatic patients that have no reason to think they have cancer, but they might all the way to patients with stage four and obvious cancer when they’re imaging studies.

We need to be able to use the each test is going to have to be used appropriately of depending on the test utility, taking into account the likelihood that the patient might have the disease. I mean, people forget that a ninety percent specificity translates into many, many more false positives, than true positives if the prevalence or the pretest probability is very low.

Thanks.