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spk04: Welcome to BIOCEP's KOL webinar. All participants will be in list-only mode. You may submit online questions at any time today using the window on the webcast. Please note, this event is being recorded. I would now like to turn the conference over to Jody Kane. Please go ahead.
spk05: This is Jody Kane with LHA. Thank you all for joining us today. During this webinar, management will be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Overlooking statements include all statements that are not historical facts and generally can be identified by terms such as anticipates, estimates, believes, could, expects, intends, may, plans, potential, predicts, projects, should, will, would, or the negative of those terms. Forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause actual results, performance, or achievements to be materially different from those statements, as well as performance or achievements that are implied by forward-looking statements. In particular, there is significant uncertainty about the duration, severity, and contemplated impact of the COVID-19 pandemic. This means results could change at any time. And the contemplated impact of COVID-19 on BIOSEP's operations, financial results, and outlook is the best estimate based on the information for today's discussion. For details about these risks, please see the company's SEC filings. The content of this webinar contains time-sensitive information that is accurate only as of today, April 8, 2021. Except as required by law, BioCEP disclaims any obligation to publicly update or revise any information to reflect events or circumstances that occur after this event. Now I'd like to turn the webinar over to BioCEP's Director of Clinical and Translational Affairs, Dr. Barbara Blau. Barbara?
spk06: Thank you, Jody, for the introduction. My name is Barbara Blau. I'd like to welcome you to the BioCept Neuro-Oncology KOL webinar. I am pleased to introduce today's presenters. Joining me from BioCept are Michael Null, President and CEO, Dr. Michael Dugan, Senior Vice President, Chief Medical Officer, and Medical Director. It is my great pleasure to introduce to you our featured speakers. Joining us are Dr. Amir Azadi, who is a medical oncologist specializing in the neuro-oncology and assistant professor in the Department of Neurology at the Barrow Neurological Institute. Dr. Nicholas Blondin, who is assistant professor of Clinical Neurology at the Yale School of Medicine, and Dr. Priya Kumthaker, who is a UCNS certified neuro-oncologist from Northwestern University. Dr. Kumthaker serves in leadership roles with the National Clinical Trials Network and was named the Alliance for Clinical Trials National Executive Officer of Neuro-Oncology in 2016. Dr. Coomptaker is serving as the principal investigator for BioCEP's 4C registry study. And with that introduction, I would like to turn the webinar over to Michael Nall. Michael?
spk02: Thank you, Barbara, and thank you to everyone for joining us today. As well as our presenters, we very much appreciate your support. We're excited to get this important information out. Now, you notice the inside on the screen right now, which is an important new brand we have for the product we're talking about, which is our ability to capture cells and cerebral spinal fluid. So more to come on that in the coming weeks, but this is the first time folks are seeing that today. So go ahead to the next slide, Jody. I think we can go on from there. So at BioCept, we're focused on high unmet clinical needs, and these are critical decision points that affect patient outcomes. You know, folks know us because our long-term strategy is in oncology, and today we're going to learn about how we're helping patients with advanced cancers that are suspected of or have spread to the central nervous system and the brain. Now, many folks know BioCept as well because we do a lot of COVID testing. In fact, We've done over 300,000 patient samples just since June alone. But our core strategy was and remains oncology, and specifically now in this focus in cerebral spinal fluid and with our CNSide product. Now, BioSept is in liquid biopsy, which is a very large market, in fact, $17 billion. And that sounds huge, but if you think about it, every cancer – every patient diagnosed with cancer needs some level of genomic profiling. Traditionally, that's only been done on tissue biopsies once or maybe twice in a patient care continuum. Now with liquid biopsies, whether it be in blood or cerebral spinal fluid, as you hear about today, This can be done over and over. You can see how this can become and is becoming a very large market. Now, BioSept has unique technology that we've got patented that helps to inform clinical decision. And this is based on our ability to capture and analyze both intact tumor cells found in blood or in the cerebral spinal fluid, as well as cell-free material, such as what's called ctDNA and ctRNA. We do this testing in our own lab in San Diego. And most of our tests during the market is what we call lab-developed tests, which is the most common way tests come on the market in the U.S. However, we do have a regulatory path and hopefully high-value reimbursement in our future with our CNSide product. Next slide, Jody. So this high unmet need we focus on in these patients with see inside is when cancer has progressed. And in fact, 10 to 30% of patients diagnosed with cancer, unfortunately will have their cancer progressed to the central nervous system or brain. This is over 200,000 patients per year. And almost 100,000 of those are just in lung and breast cancer. The two first tumor histologies that BioSept has validated clinically in our lab. Now, this is a growing opportunity, and as you're going to hear today from our illustrious collaborators that we have here presenting, is there's help for these patients. Historically, these patients may have been sent to hospice, but between what these folks are doing now, there's treatments, and it's important to be able to identify these treatments, and you'll learn more about that today. Now, as I mentioned, this leverages our patented and proprietary cell capture and analysis system. And that's the critical point, the ability to capture these cells out of CSF in a much more sensitive way than the current standard of care. Now, the early data we generated has proven just that, that we're able to capture cells not only more frequently versus the standard of care cytology, but also in a quantitative fashion, which makes the test see inside ideal for monitoring. As you're hearing today, we have very strong KOL interest. In fact, we have our tests being used now in over two dozen of the leading academic institutions in the United States. And our goal is to get into guidelines to have see inside become the standard of care. And in fact, the existing guidelines point for the need for this. So that's enough from here for me today. You're going to hear from folks that are much more qualified than I to explain all this. And we'll start with Dr. Michael Dugan, who's our CMO and medical director. Mike?
spk08: Thanks, Mike. We're going to give a brief overview of our CNSide technology, as well as discuss briefly the concept of tumor cells in the cerebral spinal fluid. Our technology was developed to look for cells and DNA that was sloughed from tumors into the bloodstream. And this has commonly been called circulating tumor cells or circulating DNA and RNA. And that's a very interesting phenomenon that can occur in tumors of a variety of stages. But as a fairly later manifestation of many of the cancers, these cells can work their way into the cerebral spinal fluid through an organ known as the saccori plexus, which generates much of the cerebral spinal fluid surrounding the brain. Next slide. This sack of fluid kind of cushions the brain against impact and provides an environment that's somewhat distinct, fairly quite distinct from the bloodstream. There's about 150 cc's of fluid here surrounding the brain and the brain stem and the spinal cord. And you can see the choroid plexus is a little structure of blood vessels inside the lateral ventricles on each side of the brain. Next. When tumor cells work their way into this space, it can be very hard to diagnose clinically. And although this is a fairly, it can be seen fairly commonly in cancers late in the development of the cancer, it's actually not well recognized. In radiologic, the image you see on the left is probably from an autopsy slide. The one, because you don't usually biopsy this sort of scenario, unless there's a distinct lesion. The image on the right is a radiologic image of the spinal cord. And you can see these tiny white streaks along the lining of the spinal cord with the vertebral bodies to the left of the spinal cord. and other bone and soft tissue to the right of the spinal cord. This is actually a very obvious manifestation of the disease, but it's often much less obvious than this. And it creates a situation which is very difficult to diagnose and difficult to follow treatment response radiologically. Next. I'll let Dr. I'm going to describe this in more detail, but clearly we can impact the survival of these patients. Next. And in order to work up these patients, what they currently rely upon is a clinical examination of the patient, which is often manifest as very non-localized or symptoms that aren't specific to a particular part of the brain, maybe fatigue or headache. And they use radiologic imaging, as I said, not very sensitive to early changes, and cytology, a technique where the cells are collected from the CSF via a lumbar puncture. This technique is fairly poor in terms of reproducibility. It lacks a very high cellular yield. It's usually very what we call posicellular or low cellularity. And hence, it lacks sensitivity and is typically reported in a fairly subjective manner as just positive or negative. Reflecting the limitations of cytology, the NCCN guidelines currently say that lumbar puncture may be attempted up to three times to establish a diagnosis, and that involves sticking a needle into the intervertebral space here between L3 and L4, these lumbar vertebrae, and obstructing a little bit of fluid through this needle, which drips out into a little tube held up against the end of this right there. Next. In some preliminary studies that we performed or feasibility studies we performed in collaboration with a pharma trial that was done a few years ago, we found that our test was able to identify cells in the cerebral spinal fluid of these patients with suspected leptomeningeal disease more frequently than cytology. And these are limited numbers of patients, but the results were quite promising. And it also demonstrated that a number of the cytology results whereas we were typically getting much higher cell counts on the left side here, where we're positive. Next. Cytology prep's also not standardized. They collect the fluid, they spin it down in a centrifuge, they use a filter paper on the back of this, as in the lower pictures there, to sort of absorb some of the extra fluid, and what's left on the slide is then captured and stained and looked at under a microscope. but it's not really captured by any specific means. It's just basically aired right on the slide, and then the cells can become detached as they do the staining and so forth. Next. In contrast with our method, we take tumor cells in the fluid, and we label them with an antibody cocktail that consists of these various antibodies, Epchem, TROP2, HER2, EGFR, and others that are specific to epithelial antigens on the surface of the cell, as well as some of the zincomole antigens. And what that helps with is then we can label the cells with a cocktail, an antibody cocktail to a variety of antigens, do a secondary label with a secondary label of antibodies that has a biotin attached to it. And the biotin is a molecule that can stick to streptavidin, which is another molecule used to line the inside of our microfluidic chambers. When the cells are placed into this chamber and flow through here, the cells stick to the inside of it. And this becomes like a microscopic slide with the cells affixed inside the chamber. And we can use digital imaging to look at the cells. And we also label the cells with a variety of markers that give us specific information about the presence or absence of these, the presence or absence of lymphocytic markers, which we would exclude. These are white blood cells that show up in some small numbers in the CSF. We would exclude those. And then we'd also find things like epithelial markers like cytokeratin. We can tell nucleated cells versus debris by the use of a nuclear stain. And then we can do other specific stains for particular markers of interest like PD-L1, which is used for immunology therapy. Next. Next. The secret to our success is really this tube in the center, which allows us to collect the fluid and ship it for up to four days, stabilizing the cells and also the DNA and RNA that are found inside the liquid within the cerebral spinal fluid. On the left side sort of highlights that workflow that I just illustrated and then shows what we get from that, which is inside the chamber where those cells are locked in next to all these little pegs. We can image that with the fluorescence microscopy. and an automated image scanner to look for markers like cytokeratin, which are specific to epithelial cells that derive from outside the brain. And then we can also look for specific chromosomal aberrations like FISH probes that look for genes of interest to see whether they're present or absent. And we can see oftentimes many numbers of these probes, which indicates cells themselves have become abnormal in terms of their genetic content. And then on the right side, you can see we can do more specific analysis of the molecular defects that are often seen in cancers, such as EGFR in lung cancer or BRAF in melanoma. And we can also do even next generation sequencing on these, the DNA and RNA that are found in the supernatant or the fluid part of the CSF after the cells are isolated.
spk04: Next.
spk08: So what we're trying to do with the test is address three critical questions. Is there tumor? Is there a target? Or is there a trend? And in this first case presentation, you can see with the presence of epithelial cells expressing cytokeratin, the green marker, plus these abnormal chromosomes, this is not a normal cell. This is indicative of central nervous system involvement by metastatic cancer. And the patient has a history of lung cancer, but had an inconclusive cytology. Next. The next question we can address is, is there a target, something that can be used for targeted therapies? And this case illustrates HER2 new amplification within tumor cells from a patient with breast cancer. And you can see a large number of amplified HER2 new, which is the reddish magenta color probe versus the small green dots, which are the probes that are for the chromosome on which that gene is located on chromosome 17. And when those ratios get way out of whack like that. We say that's pertunive amplification, which is a bad feature. It usually confers a growth advantage to these cells, and they're more easily gaining access into places like the central nervous system or other metastatic sites. However, there are therapies available that can impact these cells, as in this case.
spk04: Next.
spk08: We also can derive the cerebral spinal fluid from a device called an Amaya reservoir, which was developed and usually used for the application of intrathecal therapy into the cerebral spinal fluid. This would either be chemotherapy that reduces the systemic side effects or targeted therapies or molecules too big to cross the blood-brain barrier. And we can also use this to, or the clinicians can also use this to extract the cerebral spinal fluid, which can be used for serial monitoring of the CSF tumor cells and the CT DNA and RNA. Answering the question, is there a trend? Next. So I'll turn it over to Dr. Nicholas Blondin, who's going to highlight his experience with the test, in particular, answering these questions.
spk07: Dr. Blondin? Thank you. Thank you so much, Dr. Dugan. Good morning, everyone. I'm Dr. Nicholas Blondin. I'm a neurologist and neuro-oncologist at the Yale Cancer Center in Connecticut. I've been using the BioSept CN side platform for management of my leptomeningeal metastasis patients, and I'd like to share this case of a patient of mine that really has benefited from this technology. This patient is a 49-year-old woman who has a BRCA2 mutation, and she was initially diagnosed with an ERPR-positive HER2-negative breast cancer in 2015. She was treated with a number of lines of therapy by one of my medical oncology colleagues, and she has had systemic progressions of disease, including diffuse bone metastasis in 2018, and generally she had been responding to different lines of systemic therapy. However, in September of 2020, she developed seizures, which were concerning for a suspected CNS metastasis. An MRI of the brain was done in early October, demonstrating leptomeningeal enhancement covering the right cerebral hemisphere and also the cerebellum. And this was suggestive of leptomeningeal metastasis. Subsequently, a lumbar puncture was done, confirming an elevated number of nucleated cells and a positive hospital cytology test. The BioSept-CN side test confirmed a high number of CSF tumor cells, and importantly, they were noted to be negative for HER2 expression. That was consistent with her known systemic breast cancer. So at that point, she had neurological disabilities, including headaches, dizziness, significant back pain, and seizures had occurred. And so we discussed whether this was an advanced complication of her disease. So treatment options could include palliative care with a hospice program, whole brain radiation therapy. However, that's known to have pretty substantial neurological toxicities, or intrathecal chemotherapy via anomalia reservoir. And she opted for the intrathecal chemotherapy approach. So she underwent placement of the Omaya reservoir in late October and intrathecal chemotherapy with methotrexate was initiated. Next slide, please. So in conjunction with her intrathecal chemotherapy treatments, I performed CSF analysis from the Omaya reservoir sample over time. and found that there was significantly improved sensitivity in the CSF tumor cell detection by the CN side test compared to hospital cytology. As you can see in the chart, the hospital cytology actually turned negative following initiation of methotrexate. However, with the CN side test, I was able to know that the CSF remained positive, which is what I expected, but the CSF tumor cell count was markedly decreasing over time. Next slide, please. And so following the initiation of intrathecal chemotherapy in late October, there was a significant decrease in the number of CSF tumor cells. I was able to see this trend and measure the treatment response using the Biocept C-inside test. And I treated her with methotrexate twice weekly in the month of November and then weekly in the month of December and then suspended further treatments. And I'm now monitoring the CSF approximately once per month with the C-inside. Clinically, she has had marked improvement. She had no further seizures after treatment was started, and symptoms of headaches, dizziness, and back pain all had resolved by late November. And fortunately, she remains neurologically intact. She's now about six months after diagnosis of her leptomeningeal metastasis, and she does continue on to systemic therapy. So I'm quite pleased with the outcome of treatment for this patient and plan to continue utilizing the CN side test to monitor her CSF. And we could reinitiate intrathecal chemotherapy in the future if there appears to be increasing numbers of CSF tumor cells in the future. All right. With that, I think I'll turn back to Dr. Dugan and our next presenter.
spk08: Thank you, Dr. Blondin. Next is Dr. Amir Azadi from Barrow Neurological Institute in Phoenix. Dr. Azadi?
spk03: Good morning. Hi, this is Dr. Amir Azadi. I'm one of the neuro-oncologists at Barrow Neurological Institute in Phoenix. And thank you, everyone. I wanted to share my own experience regarding a couple of patients that I used the BICEPT in terms of diagnosis and treatment follow-up, which we found to be very interesting. So the first case is a 45 years old woman. She was very functional. with a very good performance status. She initially diagnosed with breast cancer, HER2 positive back in 2014, and she received treatment under care of one of our oncologist colleague in town in 2016. She had brain, liver, and bone metastases. And she had treatment with radiosurgery to the lesion and changed systemic treatment with anti-HER2 target treatments. In June 2019, unfortunately, she has developed some neurological findings, including numbness in right leg, weakness in her fingers on the right side, which... was suspicious for leptomeningeal involvement, brain involvement. We did MRI, which showed spine MRI finding suspicious for leptomeningeal disease. She had a very long tethering of thickness involvement in her spine from up at the cervical level down to the lumbar area, which we did test with cytology in the hospital. Cytology turned to be negative despite of positive radiologic finding, which at that point, we did not have the biocept available in our location, but we placed the OMIA reservoir, and we started treatment with IV Herceptin, which is anti-HER2 treatment. In April 2020, despite of repeated cytology being negative for her, we tested the BISF, the CN side test, and confirmed the positive circulating tumor cells with HER2 positive targets. which we continued the treatment, we trained the number of circulating tumor cells. She showed clinical improvement and showing to decrease circulating tumor cells by see inside test and her symptoms resolved accordingly. Next slide, please. And this is the time that we started following her circulating tumor cells back in April 2020. She showed a continuous decrease in her circulating tumor cells, continued treatment with Herceptin initially received every week. and then we tapered down to every three weeks, adjusted dose, and we finally been able to reach out to zero circulating tumor cells and complete resolution of her neurological symptoms. She is now very functional. She's able to go back to work and doing her normal daily activities. I am following her symptoms with physical examination, radiographic surveillance every two or three months, and do check her circling tumor cells every month, which still shows zero. Next slide, please. My second case, which is very interesting in term of finding by Biosep, she's a 57 years old woman, which she diagnosed with a stage four HER2 negative breast cancer. And on July 2020, she has developed a weakness in her lower extremities, had an MRI suspicious for a leptomeningeal involvement. She had a gain cytology tested on CSF, showed negative results despite of positive radiographic findings. She had a myoplast, and then we checked with bioseps inside testing, and she showed more than 4,500 circling tumor cells, including some portion of cells being HER2 positive. We started treatment for her with intrathecal treatment with topotecan. The reason we started topotecan because... she had methotrexate outside and she showed severe toxicities. We opted to choose topotecan in alternation with Herceptin by a similar Archangenti. She continued to show improvement in her symptoms. She was able to hike and do her daily activities and her circulating tumor cells continuously decreased. And the last two tests showed zero circulating tumor cells And she is completely asymptomatic in terms of neurologic findings. And she continues on systemic treatment with systemic NAD, no evidence of disease, and improvement of her neurologic symptoms. Next slide, please. And this is the trend from when we placed Amaya. We started intrathecal. treatment for her and shows significant decrease in her circling tumor cells and remaining stable with zero circling tumor cells. I still continue to do every month testing for her. Actually, she had a test yesterday. We're very excited to see the results and neurologically, she continues to show being stable and very functional. Next slide, please. Thank you so much. So I take over to Dr. Kumtaker.
spk01: Thanks, Dr. Azadi. My name is Dr. Priya Kumtaker. I'm a neuro-oncologist also at Northwestern. And like Drs. Blondin and Azadi, I've had, you know, the opportunity to use the Biosip platform in my leptomeningeal patients. What I'll do, though, is I think that they've illustrated some really great stories of how this has been helpful in their patient population. What I really wanted to do today was to tell you a little bit about the clinical trial work that I've done in this setting and let you kind of update you on this data, as well as let you know what our shortcomings have been in the treatment space that were really revealed by our clinical trials. So This is sort of a busy slide that I'll unpack with you all. Dr. Dugan introduced this earlier, but essentially what this slide shows that the bottom two columns, the bottom two rows here represent our historical controls for leptomeningeal disease. So to give you an idea, leptomeningeal disease, when first diagnosed in the breast cancer population, and very similar in other solid tumors, what we're looking at from the time of diagnosis is about a three-month overall survival. So certainly an area that we need to do a lot of work in. The top two rows here show... two clinical trials that myself and our group ran in the leptomeningeal setting. The first is with the drug called ANG1005. And in that study, which we published this past year in Clinical Cancer Research, we had, from the time of registration onto study, patients living after treatment for a total of about eight months. And in our intrathecal trastuzumab study, which has been published in abstract format and is pending right now in full manuscript format, had an overall survival of about 12 months. And these survival estimates of eight months and 12 months are actually from the time of entry into clinical trial and not from the time of actual diagnosis. So Little bit apples to oranges in these survival comparisons. But really what I wanted to illustrate is that we're working on the therapies through clinical trials to really advance this field. And we're seeing, one, more patients being diagnosed with leptomeningeal disease. We're seeing more patients being diagnosed and living hopefully longer with these new therapies that we're introducing. So for the first study, we are actually in the process of opening the phase three in the registrational studies, specifically in the leptomeningeal space. And intrathecal trastuzumab, we're also looking at larger studies in this space as well. And what we can see, again, improvement from historic controls to what we saw in this study. But when we looked a little further, next slide, please. When I looked a little deeper in this, we're looking at PFS or progression-free survival versus OS or overall survival. And I call this my dirty laundry slide, right? Because typically PFS, really goes in line with overall survival, particularly in diseases like leptomeningeal diseases, where patients who are going on study don't typically go on to receive a multitude of other treatments. For many of these patients, this was their last tumor-directed therapy. And what we see here in both of our studies was this distinct disparity between progression-free survival and overall survival. Interestingly, both studies had very similar progression-free survival at 2.8 months, and that was drastically different than the median overall survival. And so there's something missing there from a diagnostic component that we see with this survival disparity between progression-free survival and overall survival. Next slide, please. So let's take a step back and look at how do we measure response currently? And Dr. Dugan touched on some of these photos, but I'll walk us through this. So the three basic components of diagnosis in the leptomeningeal space currently is radiographic, clinical, and cytologic. So radiographic, let's just take a moment to look at, you see these two pictures here, and these are post-contrast imaging of the brain axial imaging. Then the second one is sagittal images of the spinal cord. And I know that I don't think I can show you with my pointer here, but you can see for the brain along, you see these white streaks along the cerebellar foliar, kind of the wrinkles of the cerebellum, as well as here in the temporal lobe. And it really just looks like somebody maybe took a highlighter to it. It's very thin, radiographic, representation of leptomeningeal disease. And same with the spinal cord. So on the right here, you see the spinal cord. And again, looks like kind of a white line or white highlighter, very narrowly drawn on almost to the spinal cord that represents a leptomeningeal disease. And the reason I wanted to show you the actual pictures is that to illustrate how difficult this is to follow radiographically. You know, this is not a solid tumor mass like a glioblastoma or a liver met where you can really get great bidimensional results. measurements. It's not really how leptomeningeal works, just given the biology of it and the distribution. So we can see it radiographically, but not the best thing to follow in terms of imaging. And the second is clinically. So we know that clinically that patients have specific leptomeningeal disease-related symptoms. So these are often things like cranial nerve deficits, spinal nerve deficits. And while, yes, we can follow these, they're not quite objective, and they're often impacted by a lot of different functions. So whether it's dosing of steroids, whether it's systemic disease or cancer that's elsewhere in the body, these clinical side effects and these clinical symptoms can be impacted by other factors happening with the patient. So it doesn't make it a solid goalpost to really chase after in terms of measuring disease response in leptomeningeal disease. And then lastly, CSF cytology. So this is really what's considered the gold standard of care in leptomeningeal disease. But Mike sort of touched on this. Dr. Dugan touched on this earlier. And so, you know, there's a couple issues here with CSF sampling and CSF cytology. So for CSF cytology, the first issue is sample viability. These cells can often lyse if they're left to sit, let's say, for 30 minutes or longer. And the longer they go, the more without being properly preserved, they can actually lyse even further. So we have an issue with cell viability. And then even if you have a really great and viable sample and you traverse that first challenge of cell sample viability, we also have just poor sensitivity. You know, you saw the process that Dr. Dugan showed you that we look at for cytology. It's not a perfect process. And because of that, with the first lumbar puncture or first sampling of CSF, the sensitivity that we see you know, optimistically is maybe up to 60%, maybe at most two-thirds. So really poor sensitivity. And even if you do up to three consecutive samples of that CSF through a lumbar puncture, you still reach this ceiling of a 90% sensitivity, which for our patients with diseases like this is really truly not good enough for future studies and for future treatments for our patients. Next slide. Next slide. So how can we improve upon this and what's missing? So the first three pictures I have here, you know, we see the imaging, cytology, and clinical exam, which, as I've mentioned, is our standard of care currently for measurement of leptomeningeal disease longitudinally. And we want to take these current measurements and have concurrent correlations of these tests with quantitative measurements of treatment response, because our current three modalities are not quantitative. And this is where C-INSIDE enters the picture. It allows that quantitative measurement of treatment response As Dr. Blondin and Dr. Azadi have nicely laid out in their case presentations, they were able to quantitatively see how these patients responded to treatment, when they needed to change treatment, and what that response was in a more concrete, objective, and quantitative manner. Next slide. What we're proposing is basically a multi-tiered clinical trial strategy for see inside and target selector. So we want to establish the see inside and target selector technology. We're going to use it for a few different things. And again, Dr. Dugan touched on this. The first is we clearly have an unmet need for clinical and reliable clinical diagnostic tools. Neuro-oncologists, the three on this call and others that you will speak to, will uniformly agree that our clinical diagnostic tools are not dependable, they're not reproducible, and we need to have improvement upon this to really make clinical decisions and have a clinical standard of care that's viable for diagnoses. Secondly, and very importantly, and you saw many examples of this in these case presentations, we need a treatment response monitoring tool. This is something that's much more reliable than radiologic and cytologic imaging or cytologic studies. You saw with the imaging, it's not very efficient and not practical to measure in a two- or three-dimensional format any of the radiographic findings that we see in leptomeningeal disease. And then cytology, besides just that it is black and white, positive or negative, we don't have a quantitative measurement of it. And in and of itself, it's not reliable with poor sensitivity. So we need a better diagnostic tool. We need a better response tool. And importantly, this see inside and target selector technology can help us with things beyond even what we expect of current diagnostics. And by that specifically, I mean the ability to select the right treatment You know, I didn't present any of my patient slides today because we have some great case presentations today, but I have actually used the BICEP technology to be able to select the right treatment for my patients. There are several biomarkers for targeted therapy that we can get from a liquid biopsy format in the CSF, saving patients' biopsies in other areas. And we also know this idea of branched evolution that's been well documented and published showing that the molecular breakdown of CNS disease or brain and CSF disease can be different than that of a patient's systemic or body disease. So I've had at least one or two patients who were HER2 negative breast cancer, for example, in their systemic disease, and then found to be HER2 positive with their CSF. And so for that reason, we were then able to institute other therapies that were successfully by the patient and then also had response to, and we were able to do that all because we were able to select the right treatment because of the specific biomarkers we found. So the first two solve a problem that we know exists, and really the preferred selection of treatment is solving an additional problem that we know exists but we didn't think was possible to even solve with the current diagnostic systems. It would also be great as a prognostication assay to guide therapy choices. So, for example, what kind of radiation might be helpful, whether or not we should target the CNS in our therapies. If we determine that these technologies can prognosticate who might go on to develop brain metastases, can really change the playing field in being able to, one, guide our patients from a prognostic standpoint, and two, in selection of the right therapies based on those prognoses. And lastly, it can be a means to distinguish tumor progression on therapies. In the CNS world, both in brain metastases, CNS, any CNS metastases, as well as in primary brain tumors, we often struggle with this idea of pseudoprogression or changes on scans because of radiation changes. And so if we have a an established method to distinguish between true tumor progression and a treatment effect can be, again, very impactful for patient outcome as well as patient treatment selection. Next slide. So how do we plan on answering these questions? So we're proposing this 4C registry study and establishing CNC inside as a diagnostic and treatment response monitoring test. So this nicely graphically represents the three questions that we, the three broader questions that we hope to answer. So as I mentioned, is there tumor? So the diagnostic perspective. And beyond is there tumor, what is the quantitative presence of that tumor and how is it changing over time, which sort of leads us into, is there a trend? So if we're following trends as we're determining whether a patient stays on treatment, comes off treatment, or changes treatment, that trend is really critical for us as a clinician to decide next steps in treatment. And then very importantly also, is there a target? So could that target be different than what we find in the body? And are we opening more doors to allow for better opportunities of treatment for our patients by discovering targets in the CNS, knowing that they can sometimes be a little different than targets that we find for the same patient in their body disease? So where does the 4C come from? It would probably create 16Cs because we're going to be looking at so many different factors in this registry, but really the prime pillars of this are CSF tumor cells and cell-free DNA versus standard of care, which is including kind of what we call ICE, so the imaging cytology and the exam. Next slide. So lastly, what do we want this for? We really see as clinicians and as a clinical trialist, I see CNSide as a way to improve diagnosis and monitoring of CNS involvement in a patient population that represents a really high unmet need and really a population that's just growing as we're improving upon systemic therapies, we're just seeing leptomeningeal disease grow and grow. And we want to leverage Bioscept's core technology and improve upon existing standard of care. So I'll stop there. Turn it over. I don't know who I'm turning. I think I'm turning it over to Dr. Blau.
spk06: To me. Yeah. Thank you, Dr. Kunteker. Thank you, everybody, for these great presentations. Now I am opening it up to the Q&A session and wanted to read out the first question. And I think this one will be good for Dr. Dugan. How does our technology differ from... Dr. Dugan?
spk08: Yeah, Barbara, can you repeat? You cut out for a little bit, so I'm not sure anybody heard you. How does our technology differ from
spk06: Competitive technologies.
spk08: Yes. There have been some other attempts to look at these cells via different means. We've adapted technology that was developed for the identification of circulating tumor cells, and there are other circulating tumor cell platforms that have been used. However, we believe that DARS is the only one that we've really gathered a large amount of data with regard to this and are trying to work in a more specific directed way in this fashion. The cytology methods, as described, vary tremendously. And the concept that I described earlier about the cells being unique, being in the CSF, it lends itself to this technology because the cells accumulate in larger numbers. And we believe that with our labeling, our antibody labeling, our antibodies cell labeled capture method, and our imaging method, we offer a unique solution.
spk06: Great. Then the next question I think are really great for our clinicians in today's meeting. And the question there is, is there a circumstance under which you would envision using both cytology and see and cite in combination? Or should we think about the opportunity to use one versus the other? So let's start with Dr. Blondink.
spk07: All right, thank you, Barbara. As I demonstrated in my presentation, our cytology results are often inconclusive or can be non-diagnostic. And it's due to these factors that Dr. Kupthakar mentioned that the cells may be poorly preserved. And in my experience, the BioSTEP assay is much more helpful for determining really Is tumor present? Are tumor cells present? And then the molecular biomarkers, you know, which can be tested with the Bioset platform is also extremely useful in terms of treating patients clinically. Her two positive breast cancer patients could be treated with trastuzumab. Her two negative patients would not be expected to respond to that drug and so should be treated with other drugs such as methotrexate or topotecan.
spk06: Great.
spk03: Dr. Ajayi? Sure. I would say, I mean, there are a few situations that we might not be able to completely confirm radiographically. This is the leptomeningeal disease from the cancer or maybe infection, which cytology might be helpful in those situations to do other staining. But in terms of Confirmation of leptomeningeal disease, I think, would be more informative in term of diagnosis. As we said, the cytology sensitivity test is not that great with a lot of possible repeat needed in that case. And with one bicep test, we can confirm the disease and the tumor burden And also, the behavior and molecular profiling of the tumor would be very informative in terms of how to treat, what to treat, and treatment follow-up. And I think, I mean, if we reach the point that we can use radiographic in conjunctive with see inside, would be optimal.
spk06: Dr. Kunteka?
spk01: Yeah, I think the points, I think just to kind of get to the meat of it, what I would say is if we can demonstrate superior sensitivity and specificity in solid tumor as compared to cytology, I think that this can trump all of cytology. I cannot think of a situation clinically where I would want to use cytology over the CNSide platform once validated. So I think it could work. truly cannibalize it. And I think the one exception that might be true, and it would be sort of a stretch, would be potentially in the liquid tumor space where we're still needing to do routine flow cytometry, perhaps. But I think even then there is room to be fully trumped by this technology.
spk06: Great. Yeah, that's great. So the next question will go to Dr. Dugan, and that is, what is the specific plan or strategy to present this platform to oncologists and make it truly a new standard of care in the testing strategy?
spk08: Thanks, Barbara. Just to touch on what Dr. Kumpiker mentioned, Um, we do think there are significant advantages of sensitivity, even in the, um, non-solid tumors like leukemias and lymphomas where flow psychometry has, you know, you need hundreds of thousands of cells to really properly work those up by flow psychometry or millions of cells. It would be the ideal. And because for each marker, you want thousands and thousands of cells. We can do the markers with just a few hundred cells or a few dozen cells, which is a pretty striking difference in sensitivity. I mean, I think our clinical strategy is pretty well laid out, as she mentioned. We want to just establish its performance relative to the other modalities. We want to see how it performs in terms of informing the therapy choices and the response to therapy. And then I think we can pursue a broader strategy where we add on additional markers and additional tumor types like primary brain tumors and the leukemia and lymphomas, which we're working on in a research setting, but we'd like to see if we could develop those as viable commercial assays in concert with clinical trials that would establish their use.
spk06: Thank you, Dr. Dugan. Then there was another question related to this. What are the strategies to reach out and help as many patients as possible? And I think to see this question is, you know, a patient is seen by a medical oncologist and at one point seen by a neuro-oncologist. So how do we reach out to as many patients as possible? I would say Dr. Koonteker.
spk01: Sure. I mean, this is the perfect question to ask, you know, and I think the key is education, education, education, right? And I think in multifaceted approach of education. So that means in the neuro-on community, in the medical oncology community, and showing, you know, the ease of use and the superiority of the testing to this community, I think is the way to do it. You have already seen such a nice organic growth in the use of your test over the past year for the sheer fact that we've seen clinical utility of it. So these things spread organically and spread organically quite quickly with education to the community, and that'll happen.
spk06: Great. Thank you so much, Dr. Kuntekar. Then a question on the technology. Dr. Dugan, When we see a cell in our microfluidic chamber, how do we know it's a cancer cell and not a normal cell?
spk08: That's a great question, Barbara. The principal concept here and why we think the cerebral spinal fluid is such an ideal sample type for our technology is that usually you don't get epithelial cells floating around in the cerebral spinal fluid. It's usually a very there are very few cells there. In fact, it's very different from blood. Blood has millions of cells in a small thimble full of blood. Whereas the cerebral spinal fluid is closer to pond water. And with that concept in mind, when we identify the tumor cells, we have a very enriched sample that doesn't have a lot of background cells. And we can isolate those and characterize them quite well. Great. Thank you very much. Your question, I may have drifted off a little bit.
spk06: Yeah, I think that was pretty clear. Thank you. Then a question to our neuro-oncologists. Could you elaborate on how you think this technology can be used for other types of brain tumors than leptomeningeal brain tumors, starting with Dr. Blondin?
spk07: Thanks, Barbara. The CN side test is currently being used for breast cancer and non-small cell lung cancer, although other cancer types can certainly cause leptomeningeal metastasis. I'm actually personally treating patients with melanoma and renal cell carcinoma with leptomeningeal metastasis. So I think there will be an opportunity to expand into different tumor or cancer types for testing. And then with gliomas, like glioblastoma, it can disseminate through this BSF and cause a glioblastoma leptomeningeal metastasis, devastating complication of an already challenging disease. for which there really is no established effective treatments. So, I'm hopeful that we can get some better understanding of that disease or improve diagnosis of it in the future. The Biocept platform seems to be, in my opinion, a great platform for that.
spk06: Great. Thank you very much, Dr. Koentenker.
spk01: Yeah. I could do a whole hour on what else it could be used for because I do think that this could be such an impactful technology. So Dr. Blondin is exactly right. I think primary brain tumors, which is a whole other slew in and of itself, right, of diagnoses that we can use this on, would be critical to see if we can distinguish pseudotumor versus true tumor, look at progression, evaluate in the maintenance phase. But really the one word that I want to say that we could use along for all of these is prognostication and prevention, right? So 30% to 50% of HER2-positive brain tumors go on to systemic cancer, excuse me, go on to develop CNS disease, 30% to 50%. So if we could have a crystal ball test like this that could tell us who those patients are, imagine what kind of impact we could have. Similarly, triple negative breast cancer patients. So I'm talking about patients without known CNS disease. If we can predict who those patients are, imagine the impact that we can have. HER2 negative patients, triple negative patients, metastatic melanoma patients, where we see CNS metastases can occur in almost 50% of those patients. If we can use this test as our future predictor, the impact could be limitless in terms of survival, prognostication, decision-making, so prevention, I would say. And then in the maintenance therapy phase, so both for our primary tumors as well as for metastatic disease, we have these phases where we've done the radiation, we've given the treatment, patients are doing, quote, well, meaning the scans look good and they feel okay. But if we were able to have a system where we periodically, say once a month, arbitrarily I'm saying that, were evaluating their CSF, and we could have an early sign of when their disease is biologically changing to then start our therapies as early as possible to have the most impact, we could really change the disease course and disease modify for these patients as well. So that's as succinct as I can make it, but that answer could go on and on. The possibilities are truly limitless.
spk03: Nice. I think that all pointed was very great. I mean, I completely agree that we need to collect more data from other oncologists, other neuro oncologists for other diseases and look deeper to possible molecular findings. and other tumor cells to see if we can find, find any consistent trend to use for other type of cancer. I mean, uh, that's great that we have for breast cancer and lung cancer, but definitely the need for other type of cancer with all the terminational diseases, it's there. And Dr. Pumtaker's point regarding the prevention and diagnostic. I mean, there are many diseases that we have guideline for this disease, check the CSF and do this. And then, uh, follow the guidelines. So if we can prevent or predict the chance of involvement of the leptomeningeal can be detected sooner, it might prevent from a disaster of treatment and many, many, many, many damage or destroy our morbidities. I completely agree.
spk06: Great. Thank you, everybody. We unfortunately have reached our allotted time for this event. And I want to especially thank our presenters and everybody who joined this webinar today. For those whose questions were unable to answer because of the time limitation, we will absolutely follow up with you in the next few days. And just really thank you again and have a great day.
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