From Science to Clinical Utility: Cxbladder Detect - Bladder Cancer Detection for Patients Who Present with Hematuria - Tamer Aboushwareb, Neal Shore & Josh Meeks

November 21, 2022

Tamer Aboushwareb, Vice President of Medical Affairs, Pacific Edge, Ltd provides an overview of the Cxbladder Detect urine-based cancer diagnostic test and is joined by Neal Shore and Josh Meeks for a discussion on the clinical implications of the use of this test which is designed for high-risk patients who present with hematuria. Cxbladder is a suite of non-invasive, urine-based laboratory tests that measure the gene expression levels of five biomarkers in urine that effectively rule out or detect the presence of bladder cancer. The Cxbladder Detect test is used by treating clinicians to inform a bladder cancer diagnosis when combined with other tests in a urological evaluation for patients with a greater risk of bladder cancer.

Biographies:

Tamer Aboushwareb, MD, PhD, Vice President of Medical Affairs, Pacific Edge, Ltd. USA, Winston-Salem, NC

Joshua Meeks, MD, PhD, Edward M. Schaeffer, Professor of Urology, Associate Professor of Urology and Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL

Neal D. Shore, MD, FACS is the Medical Director for the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina


Read the Full Video Transcript

Tamer Aboushwareb: Good evening everyone, and thank you Dr. Shore and Dr. Meeks for being here with us. My name is Tamer Aboushwareb. I am the VP of Medical Affairs at Pacific Edge Diagnostics, and we're here today to discuss our product, the Cxbladder Detect, which is indicated for patients with hematuria. As you may all know, the hematuria evaluation and bladder cancer management present a significant clinical and financial challenge in the United States and all over the world. Almost 7 million people present with hematuria every year, and as you can see, almost 81,000 of those are diagnosed for with urothelial cancer every year. The cost to the system is around $5 billion, which makes it one of the most costly cancers in the world. Pacific Edge Diagnostics started in 2001, and the goal of our company is really to deliver actionable results that can contribute to clinically meaningful difference in cancer diagnosis.

The way we do this is by innovating and finding solutions for diagnosis and monitoring of bladder cancer. As you can see, our company started in New Zealand in 2001 specializing in innovative genomic cancer diagnostic tests. Our US headquarters and proprietary CLIA/CAP accredited laboratory was established in Hershey, Pennsylvania in 2011. We commercially launched our proprietary urine-based genomic messenger RNA biomarker test for bladder cancer, which is the Cxbladder in 2013, and we got approval from the New York Department of Health in 2017. Since then, our test has been validated in over 20 peer-reviewed publications for bladder cancer detection and surveillance, and since launch, over 85,000 Cxbladder tests have been performed for more than 2000 clinicians in the United States. We've launched our Cxbladder in-home sampling kit in 2020, and we have obtained Medicare coverage in July 2020. To give you a very quick overview of our test and what it entails, our test measures the gene expression of levels of five biomarkers.

As you can see, the four on top are involved in varying aspects of cell growth, division and proliferation. Those markers are expressed in a lot of different cancers. However, they are preferentially expressed in bladder cancer, and that's why they were chosen for our test. The fifth marker, the CXCR2 has a high expression in inflammation, and the reason we added this marker to our assay is to differentiate between true bladder cancer and inflammatory markers that sometimes can cause a false positive. When this particular marker is high, our tests will not be performed, and we are able to differentiate between cancer and just inflammation. As you can see, hematuria evaluation of bladder cancer management present a diagnostic challenge and some concerns. The challenges of diagnosing bladder cancer is that there is no single diagnostic test that is perfect. The majority of patients won't have UC.

We already know that, but many tests have a very high false negative rate, and could miss tumors as well. The Blue Light cystoscopy introduction in the recent years made it that it's more accurate than white light to detect CIS and other smaller tumors, but it also has the same false positive rate of white light cystoscopy. The other part of this is that it's not readily available. Not every site has it, and it can cause workflow challenge. As we also know, atypical and equivocal results presents a diagnostic dilemma. So, when you have a cytology or a [inaudible 00:04:00] then you have a typical or an equivocal result. Sometimes you don't know what to do with this patient. We obviously don't want to miss a tumor, especially insidious and CIS and upper tract tumors, and false positive results lead sometimes to unnecessary procedures. I can't say we can completely eradicate false positives.

That is almost an impossibility, but we can certainly try to reduce it to the most likely tumors. What is the ideal adjunct? Our goal here is to try to see if our test can truly be the ideal adjunct for your practice, and the characteristic of ideal adjunct in our mind is it's a purely objective test. There is no subjective reads. It has a very high specificity and positive predictive value to accurately identify these patients, and also has a very high sensitivity and negative predictive value. So, you are confident that if you decide to avoid cystoscopy for a patient, that patient will most likely not have a tumor. It has to be proven effective and accurately adjudicating a typical and equivocal results, and it's non-invasive, that only requires small amount of urine. As added benefits, it can improve confidence and remove doubt in unresolved hematuria workup, and it's covered by Medicare.

Obviously, you don't want to have your patient responsible for anything. We have added in-home sampling that provides a solution for patients with travel challenges. Our main validation result for the detect test, this is the O'Sullivan result. The purpose of this was to establish the performance characteristics of the Cxbladder in the detection of bladder cancer, and simultaneously compare the results of our test to results of cytoscopy cytology, NMP Bladder Check and NMP22. ELISA. 485 patients with hematuria were included. All patients received cytoscopy and histopathology to confirm or rule out disease. It's important to know that in this particular case, atypical psychology was considered positive. So, the results of cytology that you're seeing included the sensitivity, included the positive that were actually atypical cytology. As you can see, Cxbladder across the board performed better than all other markers, specifically in the TA and higher tumors, of course. In the TA, although our sensitivity was 68%, it was way higher, almost double the sensitive cytology, and NMP22, NMP22 ELISA, Bladder Check analyzer, and in everything else, we were almost 100%.

As you can see, in high grade tumor specifically, our sensitivity was 97%. For upper tract tumors, which we didn't have a lot in this, but we detected all of them. The overall sensitivity of the test was 82%, and the specificity was 85% at the lower cut point. We had another study to evaluate the Cxbladder in adjudication of atypical cytology and equivocal cystoscopy. In this particular study, 18% of cytology samples were classified as atypical by local cytology. The Cxbladder correctly adjudicated all 153 cytology atypical results. There was no false negatives. 47 of the 153 cytology atypical results were correctly ruled out by Cxbladder, and that Cxbladder correctly adjudicated 14 samples with atypical cytology and equivocal cystoscopy. Two of those samples were missed by cystoscopy and cytology, T1 and CIS tumors.

In conclusion, the Cxbladder can correctly adjudicate patients with urethral cancer, among those with atypical cytology and equivocal cystoscopy and Cxbladder can outperform cytology to accurately identify patients who do not have urothelial cancer. The last thing I want to mention today is our in-home sampling kit, which proved utility during the COVID-19 pandemic and beyond. Since we've introduced this kit, it's really, really made it easy for compliance for these patients, non-muscle invasive inpatient monitoring or in hematuria patients. The in-home sampling improved the clinic and procedure workflow through the identification of low probability patients versus standard clinical protocol, and it can clarify equivocal hematuria workups. The nice thing about this is that you can send these kits to the patient way ahead of the office visit, get the result, and then make your decision based on the test results. Thank you.

Neal Shore: So, Tamer, that was a great overview. I love that you brought up our European Urology paper from 2019. Proud to be an author on that with the lead author was Badri Konety and Karim Kader, Sima Porten, Sia Daneshmand and Yair Lotan were on that paper too. It's a really nice paper in 2019, European Urology, and I think as you point out, this really basically demonstrated the utility of using Cxbladder and helping us avoid unnecessary cystoscopies, and certainly adjudicating very accurately on atypical cytology. I think this is the kind of data and the fact that we've had this experience that is going to have implication once we become more and more involved in value-based care. I know we oftentimes hear that the cystoscope is the urologist's stethoscope, but I think more and more if we could be confident in a biomarker that helps us safely not miss a significant bladder cancer, CIS in particular, high-grade disease, then we're really following that lofty mantra value-based care.

So, I think it's great. Then the other thing I just wanted to add is during the height of the pandemic, we were using this home- based delivery system, which was great, because we had patients who couldn't get in. We had our own staffing shortages. We had patients who were very at-risk, who had risk for not only bladder cancer but were immunocompromised, and being able to mail them Cxbladder was really very nice, really created some tremendous efficiencies. But let me stop there, Josh, and what are some of your thoughts? You've spent so much of your career analyzing the biomarkers.

Joshua Meeks: I agree completely. I think the pandemic really changed how we approach these biomarkers, and more and more we felt we had a ... I wouldn't say have to have a reason for a patient to come in for a procedure, but there's a lot of folks that it is a lot to come into a metropolitan area, and a lot of exposure risk, and being able to send that to their house and get results back that would say there is a reason for you to come in. Your test is positive or looks good. It doesn't have to be that you switch to all biomarker, and they never come in for a scope again. But I think what we've tried to do is integrate it into followup so that maybe they're alternating biomarker and cystoscopy or especially again for folks who had just have a hard time coming in, even though the risks but the pandemic are less now, I think it's an alternative for patients, and it makes it very easy for followup for folks.

I think the more experience we've had with it, the more we feel confident that if that test is positive, you're, good chance you're going to find something, and you can trust the negative test. So, I've really used it for that, and then I've had folks that have been, had positive hematuria evaluations based on gross hematuria or microscopic hematuria that's recurrent, and you just don't know. They're too ill to go to the OR they kind of want a secondary screen, and I think this either reassures the primary care doc, myself as well as the patient that either they need to go forward with a cystoscopy in the office or we can continue to watch things. So, those are really where we've used it.

Tamer Aboushwareb: That's great to know, to hear as well, and thank you very much for your confidence in our product. I guess one of the questions that I wanted to ask both of you is really when you, you've obviously both had experience with the product, with the test, and used it a lot, but what is more important to you for a hematuria evaluation patient? Is it the negative? Is it the true negatives or is the true positives? Because obviously, our test has been optimized to do a little bit of both, but as we move forward, we are, we're working on producing more tests, and we're working on improving our current tests. So, one of the things that would be beneficial for us as a company as well to understand what is the more important? Is it the negative predictive value or the predictive value?

Neal Shore: Well, we want it all, right? We want a test that's 100% accurate. You said in the beginning there Tamer, and rightfully so, there's no test that's perfect. I think not only with the caveat of the concern about a medical legal claimant and so NPV tends to be king. If we have a test then I can tell a patient, "Look this, it's so accurate and telling me you don't have a high-grade cancer, a TAG-3 or CIS, and I can avoid a cystoscopy, and let's face it, the vast, vast, overwhelming majority of microhematuria is essentially idiopathic or not malignancy related. So, having that NPV is really fantastic. But at the same time, we do have patients who present with positive disease, and so the greater the degree of accuracy the better. But Josh, how do you educate residents and fellows about biomarkers?

Joshua Meeks: It depends on the population of what I want. So, if it's someone that you're, you've never diagnosed, then obviously you're looking for something that's, you're going to get rid of, like you said, the false positive rate. You want to be able to rule those folks out. The rate of cancer in someone with microhematuria can be less than 1%, depending on their risk status or it can be as high as up to 10 to 25% if they have gross hematuria. So, that spectrum is so broad, and if you look at how all of our guidelines are written, we use microhematuria UA because it's got a very high sensitivity, you're not going to miss many patients. But the problem is there's a lot of unneeded work that goes into those folks. So, I think looking for something in the middle for people that you would love to have a test that is somewhere between a urinalysis and a CT urogram and a cystoscopy and it kind of fits into that.

So, that's where the screening is for the people with cancer. Again, you don't want to miss anything, and I have some folks that would love to stop cystoscopy, but I think there's a comfort that comes along with that, of having a scope. Even though you tell them it's been five years, let's start, probably don't need to see me next year. This is a great way to say, look, everybody, there's an answer. It's not a, we didn't look. It's we looked, and we feel confident that it's okay to miss this year. So, I think there's a lot of applications and again, the more folks get these opportunities to use them, I think the more comfortable they'll feel.

Tamer Aboushwareb: That's great to hear. Thank you very much. We are definitely working very hard in our company to improve our test, our offerings, and we are focusing on both sides. I mean, I think it would be great to have the perfect test. That would be amazing. But I think our most focus right now is really on the negative predictive value to make sure that if we tell you that the patient is negative, we are confident to the utmost that it is negative. So far, most of our studies, and I don't know if the studies that I showed you and others, we've only missed low-grade tumors. Our test hasn't missed high-grade tumors. So, our high-grade negative predictive value is extremely, extremely high, which should give you and others that are using the test confidence that you're not missing one of those tumors. If you do miss, very, very few that you miss will be low-grade tumors that you will probably see in the future, and wouldn't cause a lot of damage for the patient.

Joshua Meeks: I've been impressed by the turnaround time. Do you have an idea of what you shoot for? Because I think usually our office will order it's a home test, and then I get something that comes into my inbox with the result. I feel like that's pretty quick. Do you have any idea what that timeframe looks like?

Tamer Aboushwareb: Our target turnaround time is between seven and 14 days. However, we tend to, we try to make it earlier than that. So, our average turnaround time is about eight to nine days, but we just, because we never know that the workload and so forth with the lab, occasionally it'll take the two weeks, but generally it'll take between seven and nine days.

Joshua Meeks: I definitely, from a consumer side, I would say that usually within two weeks, by the time we've ordered a test, I've gotten a result back from you. So, I think that's the reality.

Tamer Aboushwareb: Yeah, yeah. Our maximum is the 14 days.

Neal Shore: When we were doing a lot of this mail, the home mailing, and with telehealth it was sort of ideal. To Josh's point, we would send, either the kit would be sent directly to the patient's home. We know when they received it. I shouldn't say we. My team would know, and we'd schedule the telehealth two weeks later, and it was invariably we had the results to go over with the patient. It was remarkably efficient. I think efficiency is going to be a big thing moving forward as we all realize person power, shortage of physicians, expanding aged population at risk of bladder cancer, and hematuria evaluations, both gross and microscopic. Then the value-based proposition and throughput, it really makes for a good opportunity for incorporating the strategy.

Tamer Aboushwareb: I completely agree. Well, thank you both very much for your attendance today and input. I really, really appreciate it, and we will be talking again soon. Thank you.

Joshua Meeks: Thank you.

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