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Yair Lotan: Thank you for joining me. Today, I'm going to speak to you a little bit about a multicenter randomized trial that was performed, to compare the Cxbladder Triage to cystoscopy in patients with microhematuria. This study was known as the STRATA trial. It was a safe testing of risk for asymptomatic microscopic hematuria trial. And I'm presenting it on behalf of my co-authors. And this was a multicenter study that was funded by Pacific Edge. And I should note, that I'm a consultant for Pacific Edge.

So we all know that microhematuria is a very common condition in adults. There are approximately 7 million patients with microhematuria annually in the United States. The biggest concern for patients with microhematuria is cancer. And we know that bladder cancer is present, but the incidence is low in referred populations, maybe have around one to 5%. And when you look at the entire population of the United States with microhematuria, the fact is, many patients aren't referred, and the overall rate of cancer is even lower. There are also some other cancers like kidney cancer, prostate cancer, and benign conditions, such as kidney stones, et cetera, that can also contribute to microhematuria.

The problem that we have is that most patients with microhematuria are not evaluated, or even referred to urology. And of those that are evaluated, there are a large proportion of unnecessary cystoscopies, since the vast majority of patients don't have bladder cancer and don't need someone looking in their bladder.

The study hypothesis was, can we use an algorithm using a biomarker test with a high negative predictive value to safely rule out further evaluation of patients with lower risk, without impacting the likelihood of finding cancer? And this is an important goal, because it might be able to enrich patients who are referred, and also avoid unnecessary evaluation of patients who are at low risk.

So the primary objective was to use a prospective randomized control trial, and evaluate the rate of cystoscopy using standard of care, and comparing that to an alternative clinical pathway using the Cxbladder Triage test in patients with microscopic hematuria. The secondary objective was to evaluate the performance measures of the Cxbladder test in patients that were enrolled in the study, and had cystoscopy performed.

So the study designed was the following: patients with hematuria that were referred to urology provided a urine sample for a Cxbladder test. We then categorized patients based on risk of cancer. And I should note, that this is different than the current stratification, the AUA hematuria guidelines, primarily because the study started before the hematuria guidelines were developed. And so, there's some overlap in the lower risk group, between what we currently call low and intermediate patients with microhematuria. So the lower risk group was defined as anybody with 3 to 29 red blood cells, and a minimal smoking history, i.e., less than 10 pack years. And we did not use an age stratification. As you know, the AUA guidelines used 60 as an age to move you right to high risk. We didn't use that. The higher risk group had to have more than 30 red blood cells, or more than 10 pack years of smoking.

In the patients on the lower risk group, we randomized them to having a Cxbladder test versus standard of care, which was cystoscopy. And the patients who had the negative Cxbladder test were offered omission of cystoscopy with surveillance. The not lower risk tests were offered standard of care. We collected the Cxbladder test, but did not use it or provide it to the clinician or the patient for advisement.

We then recorded what patients decided to do and what outcomes were recorded. And then we subsequently reviewed records for follow-up, to see what other follow-up patients had, and also if there were any side effects or negative impacts.
For the lower risk group, which was the randomized group, we started off with 223 patients, but ended up with 135 patients that we could evaluate. In the test arm, there were 81 patients, and 54 patients in the control arm.

71 out of the 81 patients had a negative Cxbladder test, and of those, 57 did not undergo cystoscopy, 14 did. 10 patients had a positive Cxbladder test, and 8 out of 10 of those chose to have cystoscopy.

In the control arm, interestingly, though they were having standard of care, only 36 patients underwent cystoscopy, which was a little surprising. 18 patients did not have additional cystoscopy, after discussion with their provider.

This figure summarizes the rate of cystoscopy in both the lower risk, and in the not lower risk or higher risk group. You can see that in the not lower risk group, 82% of patients underwent cystoscopy. And the not lower risk group, only 43% of patients underwent cystoscopy. And specifically, if you look at the patients who were in the control arm versus the test arm, it was 67% in the control arm, 27% in the test arm, which was a 59% relative reduction in cystoscopy observed between the control and the test arm. And again, those patients who had a positive Cxbladder, 80% chose to undergo cystoscopy.

When we looked at Cxbladder performance, among all patients who had cystoscopy, it was 270 patients, including 22 who were found to have bladder cancer. The sensitivity was quite high, 90%. The specificity was also good overall, it was 56%, with a 99% negative predictive value. The positive predictive value was 15%. But this is not surprising, since only less than 10% of patients actually had bladder cancer in the entire cohort, which is pretty typical for a hematuria database. Importantly, in the not lower risk group, patients who were negative for Cxbladder, none of them were found to have bladder cancer. And in the positive, there was one patient who had bladder cancer. In the not lower risk group, obviously, a larger percentage of patients who had Cxbladder and positive were found to have cancer. There were two patients who had a negative Cxbladder. They both had low-grade non-invasive cancers.

So in conclusion, this was the first randomized controlled trial comparing a marker-based approach for evaluating hematuria with standard of care. And in this prospective study, the Cxbladder Triage, when used to inform decision on cystoscopy in patients with lower risk hematuria resulted in close to a 60% relative reduction in cystoscopy. The Cxbladder test was very accurate, with a sensitivity of 90% and a negative predictive value of 99%. And among those who had Cxbladder tests and follow-up, only one patient was subsequently found to have a bladder tumor one year later. And this was actually found because the patient converted from a negative Cxbladder test to a positive Cxbladder test, which then led to an evaluation finding that tumor. So this is an important metric that shows that if you use it in follow-up, you could detect cancers if they developed down the road.

Tamer Aboushwareb: Thank you, Dr. Lotan, very much for this great presentation. My name is Tamer Aboushwareb, I am the Chief Medical Officer for Pacific Edge Diagnostics, and I'm here today with Dr. Lotan. And after your presentation, Dr. Lotan, there were a couple of questions that we wanted to discuss with you. And one of the most important ones is, of course, what is your opinion on how to use these tests, the high negative predictive value test, appropriately in the microscopic hematuria evaluation of patients?

Yair Lotan: So I think it's an important question. So I think we need to take a step back, and ask how are we doing with hematuria evaluation in the US? And what I would argue is that we're doing quite poorly. Despite the fact that we evaluate it fairly commonly as urologists, the vast majority of patients with microhematuria are not seeing us at all. And when you look at bladder cancer diagnosis over the last 30, 40 years, we find that the stage of diagnosis has really not shifted at all. About a quarter of patients show up with muscle invasive disease, and 5% show up with metastatic disease.

And there have been several studies that have demonstrated, that if you can find the cancer earlier when patients have microscopic disease, rather than visualize when they have gross hematuria, when you can see it, that their stage of diagnosis is earlier. And so, there is a gap between patients coming to see urologists, and which patients get referred. And when they get referred, we know that women get referred in a delayed fashion, because people blame UTIs. But even a lot of men who have a smoking history and are elderly are not referred in a timely fashion.

So the real question is, should we continue to do what we're doing right now? Which is to wait for primary care physicians to refer patients in a relatively non-selective way. Or should we introduce a biomarker that might enrich the population for those most likely to have cancer, and also reduce the burden on patients who are at very low risk for disease? And so, I think we need a test similar to how PSA is being utilized. PSA is not a great analogy, because it actually performs quite a bit less accurately than the Cxbladder test and some other urine markers. It actually has a lower positive predictive value. It actually has a lower sensitivity and negative predictive value. But if we could have a test that a primary care physician could use in a patient with microhematuria, refer the positives for evaluation, and maybe avoid the negatives who are at low risk, especially if they have other clinical factors that would suggest that they're at low risk for bladder cancer, then I think that could significantly improve the way we evaluate patients currently.

Tamer Aboushwareb: That's a great answer. And that's basically what we in Pacific Edge, and maybe everybody in this field, is really trying to get to, where our test could be the platform that initiates the referral of the right patients to the urologist. But to do so, obviously, is not an easy task, which would shift the stratification, or the triaging of these patients into the primary care. So that brings me to my next question is, what do you think would be needed or necessary for that change to happen? In your mind, what type of information or data that would be necessary to change yours and other urologist minds to move into that area?

Yair Lotan: So I think it's interesting, because there's not an exact formula for what it would take to garner sufficient evidence. So for several decades that I've been involved in the field, company after company has basically taken patients with hematuria who were getting cystoscopy, ran their assay, demonstrated a very high sensitivity, a high negative predictive value, and yet, the field didn't change, and to say we should incorporate markers. The big criticism has always been, you need to demonstrate that this works within a practical randomized trial, and really, to alter clinical care.

So this is the first trial, and I think this is a very important step to show that if you have a patient with a negative marker, you can avoid cystoscopy. Now the natural criticism is, how do you know for sure they don't have cancer? And the answer to that is, you can't ask a patient who is relatively lower risk with clinical factors and has a negative marker to then do cystoscopy. They're not necessarily going to agree to that. And so, you can follow them for a period of time, and try to see if they develop bladder cancer or not. With the thought that bladder cancer, unlike many other cancers, usually present. So it's very rare to find bladder cancer on autopsy, that's unknown. And most of the time, patients become symptomatic.

So if you take patients and you follow them for a period of time, and they don't develop bladder cancer, and their marker is still negative, perhaps their imaging is negative, then you can feel pretty comfortable you didn't miss disease. And remember, the incidence is actually quite low overall, and you're even selecting patients at lower risk. And you're also identifying them with a negative marker, and they even have lower risk after that.

And so, I think the real question is, education first for primary care physicians, not just urologists, but the primary care physicians need to change their paradigm. And so, that's going to take a step. They're not used to doing that, but I think we need to offer it.

The second issue is perhaps a little bit more follow up, for people to recognize that it's hard to prove a negative, but you can follow these patients and show that you're not finding disease. But I don't think it's continuing to do more studies where everybody gets cystoscopy. I mean, there are thousands of patients who have had Cxbladder, and tens of thousands of patients who had other urine markers, that have all shown fairly consistently that if you are looking for good markers for disease, you'll be able to identify most of the patients with high grade disease, and maybe you'll miss a few patients with low grade disease, but those patients almost never progress and never metastasize.

Tamer Aboushwareb: Okay. Well that's definitely the way we believe as well. And I think, like you said, the field will need to move towards that. And hopefully this study that you presented, which is the first randomized clinical trial in that area, and other studies that our company and others will doing in the future, should hopefully push the field forward, and put that into perspective more for the urologist, as well as the primary care physicians.

So I guess my next question, and really the final question here is, where do you think this whole field should go from here? As you see, as you saw and you presented today, the urine marker, the Triage test, has a very high negative predictive value, although the positive predictive value, like you said, is not very high. What would be the next step? What would you believe to be the next generation test that could potentially be even a further step ahead? To push that field into exactly what you said, where all the classification happens at the primary care, and the urologist only gets the patients that need to be evaluated.

Yair Lotan: Right. So obviously, we think that the Cxbladder is an RNA panel, but even your company, and I've been involved with the research adding in DNA markers, like FGFR and TERT, which broaden the tests to detect more low grade tumors. And I think that's a step forward. Multiplex tests that look maybe at various different components of cancers will catch more of them. The truth is, that until the last hematuria guidelines, which I'm on, so I'll take equal credit and blame, was the first one to explore a risk stratification. And so, I doubt we have the perfect formula. A 60-year-old woman with 3 red blood cells is high risk. A 59-year-old man with 10 years of smoking and 10 red blood cells is intermediate risk. So are they equivalent? No. Men have bladder cancer four times more commonly.

So I think we will still need to work on the risk stratification. It's quite possible that a urine marker will work very well for patients in their 60s, with few red blood cells and a rare history of smoking. So I think further studies looking at where the markers would be optimally situated will be important as well. And I think time and some additional studies will help refine the process.

The goal is not actually to eliminate cystoscopy. And it's also not to be perfect. I think when I was training, used to be if you didn't have some evaluations for appendicitis that were occasionally negative means you weren't looking hard enough. Now, of course, I don't think they operate on every patients with appendicitis anymore. But the fact is, that we shouldn't have every cystoscopy positive for cancer. It means we're not scoping enough patients, and we're missing some smaller cancers. But what we should be doing is increasing the yield.

So if we do 100 cystoscopies, we shouldn't be happy that we find one or two cancers. We should hopefully hope that for every 100 cystoscopies we find 20 or 30 cancers. That still means 60 to 70, or 80% of patients are going to get cystoscopies that are negative, but those should be the highest risk. What troubles me, is that when I look at large data sets of who's getting evaluation, sure you're scoping people who are older male smokers more often than younger non-smoking women, but you're not scoping the majority of male older smokers. You're actually scoping the minority of each group. And what we really need to do is enrich for the highest risk groups, and I think the marker will actually help appropriately triage patients, so that a higher percentage of patients with cancer get scoped, and not get delay of diagnosis. And so I think there's a lot of room for improvement, and I think your markers really offer a non-invasive approach that will help us get where we need to go.

Tamer Aboushwareb: That's great, Dr. Lotan. Thank you very much for your time today. And we could not agree more. We truly believe that this marker and others will push this field forward, and hopefully will reduce the burden on patients, but at the same time, like you said, improve the yield of cystoscopies in the urology office, and improve cancer detection. Thank you very much again. And we appreciate your time, and look forward to the next time.

Yair Lotan: Thank you so much.