Hello, my name is Jamshid Nadahi. It is my pleasure to present to you an overview of F18 fluoroperidazepate myocardial perfusion imaging. This is a myocardial perfusion tracer that was recently introduced for clinical use after FDA approval, and I will go ahead and give you a summary of what has been published on this tracer and where it fits in clinical practice. Before we begin, I would like to show you my disclosures. These are related to GE Healthcare, which is the sponsor of this study. I've been the principal investigator of phase 1, 2, and 3 clinical trials of this tracer. I've received the research grant from GE Healthcare. I've been a member of the scientific advisory committee and the chair of the publication committee. The objectives of my presentation are to review F18 fluoroperidazepate attributes and clinical value based on published clinical trials, and then to describe opportunities and challenges for incorporating F18 fluoroperidazepate into clinical practice. First, I would like to share with you a timeline of FDA approval myocardial perfusion tracers and conclude that the excitement that we have in the field of nucleic cardiology for approval of this tracer relates to the fact that for the past so many years, several decades, there has not been a new myocardial perfusion tracer introduced in our field. When we go back to 1977, when thallium-201 was introduced as a myocardial perfusion tracer, as you know, it is currently not available and is not used. Then in 1989, rubidium-AD2 was approved by the FDA as the first pet myocardial perfusion imaging, and then it was followed by approval of technetium sestamib in 1991 and technetium tetraphosmin in 1996, and subsequently, N13 ammonia was approved in 2000. So as you note from this slide, rubidium-AD2 was approved prior to the most commonly used SPECT tracers such as sestamib and tetraphosmin, but when you look at the current number of U.S. procedures that are done annually, we see a major discrepancy that sestamib and tetraphosmin, these technetium-99M SPECT tracers, are used in the range of about approximately 6 million studies per year in the United States, but rubidium-AD2 that was approved prior to these SPECT tracers is only used at 200,000 studies per year in the United States. We believe that this discrepancy is mainly related to availability of rubidium-AD2 for clinical use that I will be elaborating on as we go on. Here is the chemical structure of F18 floperidaz. It is a mitochondrial complex I inhibitor, therefore it attaches to mitochondria avidly, and as we know, the myocardium is a mitochondria-rich organ, so it would be a perfect target for attachment of this tracer to the myocardium and for myocardial perfusion imaging purposes. So the excitement about F18 floperidaz comes from two aspects of this, or two characteristics of this tracer. Number one relates to the label, the F18 label, that has a long half-life of 109 minutes. What it does, it allows production and distribution of the floperidaz by the existing network of regional cyclotrons as a unit dose, unlike rubidium-AD2 that would require a fixed overhead of approximately half a million dollars a year for having access to a generator for clinical use. But here you can order it as a unit dose. It is very similar to FDG that is currently used for myocardial viability and cancer diagnosis, and the same network of regional cyclotrons that are available for FDG will ultimately be available for distribution of this tracer. The second attribute that relates to the long half-life of F18 is the ability to use this tracer in conjunction with treadmill exercise testing. The limitation of PET currently for use in conjunction with treadmill exercise is that the very short half-life of the current tracers such as rubidium and N13 ammonia does not allow injection at peak exercise and then waiting for a period of approximately 10 minutes for the recovery and moving the patient under the camera because by then the tracer has been decayed and the myocardium will not show very clearly on the images. However, here with F18 fluoropyridaz, the F18 allows a persistent uptake in the myocardium by the time that the patient completes the treadmill test and moves under the camera. The second group of attributes of this tracer is related or the second group of advantages, clinical advantages, are related to a higher myocardial extraction fraction, a shorter positron range of fluoropyridaz that allows better image resolution and higher defect contrast, better tracking of flow across broader flow range than other agents, better detection mild perfusion defects and better quantification of myocardial blood flow especially on a segmental basis. So here I'm reviewing again the existing PET tracers oxygen 15 water that is not approved by the FDA but N13 ammonia rubidium 82 that are approved by the FDA and you can see that their half-lives are very short and therefore they will require an on-site cyclotron in case of N13 ammonia. A few studies have shown that if a cyclotron center is in the vicinity of the imaging center it can produce the tracer and then deliver within 10-15 minutes to the site and still it is possible to do imaging without having a on-site cyclotron but overall the majority of use of N13 ammonia is based on centers that have an on-site cyclotron. With rubidium it requires a generator as I said earlier that basically is associated with a fixed overhead of approximately half a million dollars a year regardless of how many studies you do but with F18 fluoropyridaz because of the long half-life regional cyclotrons can be used for its production and distribution. Then with respect to the high extraction fraction that results in better defect diagnosis or better defect contrast I have this example from one of the trials is a patient with left anterior descending coronary disease. As you can see on the technetium 99m spec images on the stress and the rest study there is a mild defect in the distal anterior wall that appears to be reversible so this study was interpreted as probably abnormal with a very mild defect in the distal anterior wall and maybe the enter apical region but the same patient who was imaged with F18 fluoropyridaz the following day under the same stress condition that was pharmacologic stress you can see that the defect is much more pronounced it is clearly visualized in the left anterior descending coronary artery territory and also if you pay attention to the rest of the image you can see the left atrium actually showing behind the left ventricle and this is not unusual because of a high image resolution with this tracer we often see structures such as the atria on on the image and we always see the right ventricle with this tracer. I'd like to review different phases of trials that we have gone through and the conclusions from these trials in phase one two studies were performed and the publications are listed here one was injection of fluoropyridaz at rest looking at the safety dosimetry and biodistribution and then was injection of F18 fluoropyridaz during pharmacologic or exercise treadmill injection and that again safety of this tracer and dosimetry and biodistribution were evaluated both of these studies concluded that the that the tracer is safe and well tolerated dosimetry is acceptable and based on these findings clinical imaging protocols were developed so again to summarize the results of these two phase two phase one studies that the safety was shown and after injection at rest kidneys received the largest mean absorbed dose following the followed by the myocardium this is the resting injection but the maximum injection dose was determined to be about 20.5 millicuries after injection at peak exercise or pharmacologic stress the myocardium was the largest was the highest had the highest activity or received the largest mean absorbed dose and the maximum dose that may be administrated without exceeding one rem of effective dose was determined to be 19 millicuries for exercise and 15 millicuries for pharmacologic stress so based on these results the maximum injected dose for a rest stress imaging protocol was established to be 14 millicuries and as I will be showing you different protocols basically give a less than 14 millicuries to patients here is the protocol for doing same day rest pharmacologic stress imaging the protocol is similar to what we have been doing with technetium SPECT imaging or technetium 99m labeled tracers that we give a low dose for resting imaging and a high dose for stress imaging the low dose in this case is anywhere between 2.5 to 3 millicuries and followed by resting imaging we do the resting imaging with a dynamic mode initially and then continuing the static acquisition and then with the regalesson injection we give approximately 2 to 3 times the dose of 6 to 6.5 millicuries and again followed by while the patient is under the camera and therefore dynamic imaging is followed by static imaging there is a 15 minute waiting period between the two studies in order to minimize the spillover of activity from the rest image to the stress image because of a longer half-life of f18 however by changing the dose ratio to something like 3 to 1 or 4 to 1 and staying within a 14 millicury limit we can actually truncate this time period and be able to do rest and stress imaging back to back and therefore the protocol would take approximately half an hour to complete this is the protocol for same day rest and treadmill exercise imaging the dose ratio is different in this protocol we suggest 3 or 4 to 1 dose ratio between the stress image and the rest image and the reason for that is that the myocardial optic of fluoropyridase and for that matter all perfusion tracers with exercise treadmill are lower in terms of suv compared to pharmacologic stress and because of a lower suv of the myocardium we have to give a larger dose in order to maintain a minimal spillover of activity to the stress image here the recommendation for waiting between the rest and stress imaging is a one hour so after the 15 minutes of acquisition after resting injection we wait about 45 minutes and then we proceed to treadmill exercise imaging and injection of the tracer at peak stress the phase 2 trial was examining in a small group of patients with coronary artery disease and normal patients which are low likelihood patients a total of 142 patients looking at the diagnostic performance of f18 fluoropyridase and this was published in journal of american college of cardiology in 2013 and then we moved on to the phase 3 trials and the phase 3 trials were both published also in the journal of american college of cardiology the first one in 2020 and the second one in 2023 there are some differences between these two trials but in general fda requires that two phase 3 trials are done to show that the results are consistent the aims of the second phase 3 trial which we call it a pivotal trial for fluoropyridase and that was the basis of the fda approval the aims are shown on this slide that the primary endpoint was to look at the diagnostic efficacy sensitivity and specificity of fluoropyridase for the detection of significant coronary artery disease that was defined by greater than or equal to 50 coronary narrowing as defined or as determined by quantitative invasive coronary angiography secondary endpoints were to compare fluoropyridase PET with technetium labeled technetium 99 and labeled SPECT tracers in the detection of coronary artery disease the entire group as a key secondary endpoint then in the subgroup of women patients with a body mass index of 30 or greater and in diabetic patients and then in addition we looked at the safety of fluoropyridase that was the common theme in all the trials that we had to repeatedly look at the safety and tolerability of the tracer here are the key results from this pivotal trial looking at the area under the curve in the ROC curve for PET shown in green and for SPECT shown in red in the overall patients of 578 patients you see a significantly better area under the curve for PET as compared to SPECT meaning that the diagnostic performance was superior to SPECT when we go to the subgroup of women 188 patients you can see that again the difference is there significant between the two PET in green and SPECT in red in patients with a BMI of greater than or equal to 30 but 298 patients in this study again there was the diagnostic performance of PET shown in green was superior and statistically significant as compared to SPECT shown in red and also in diabetic patients 194 patients again we could see that the diagnostic performance of PET was superior to SPECT here we're looking at some of the other secondary endpoints and I would like to focus on the lower panel the upper panel summarizes what we just talked about but the lower panel is comparing PET in yellow or gold color compared to SPECT in blue and here we're looking at image quality which is defined as the percent of the studies that were graded by the panel of independent blinded observers as being excellent and here you can see that for both rest and stress imaging by pharmacologic stress or exercise fluoropyridaz was superior to SPECT and then diagnostic certainty was also evaluated which was defined as the percent of the studies that were interpreted by the blinded panel as being definitely normal or definitely abnormal and they were much higher percentage by PET as compared to SPECT meaning that in the SPECT category more studies were considered to be equivocal or probably normal or probably abnormal so the certainty was not as high as we see with PET imaging and an important result from this trial was the difference in radiation exposure to the patient that with SPECT the radiation exposure was 12.4 millisieverts but with PET was half of that 6.3 millisieverts We have conducted some internal studies that this radiation dose can be actually reduced further to somewhere less than three millisieverts of radiation to the patient with different processing and acquisition protocols. Here's an example of a patient with left main disease taken from the first phase 3 trial. It comes from the publication in JAC in 2020. It shows that this patient on biospec imaging had a completely normal study, was interpreted as definitely normal by the panel of blinded observers. However, the same patient with floor period as PET shows definite and clear-cut perfusion defects in the anterior wall, anterolateral wall, and apex that corresponds to the distribution of the left main and was the patient was therefore correctly identified as having left main disease as opposed to spec that the disease was missed and it was falsely negative. Here is another example comparing floor period as PET with technetium 99m SPECT. First, we are looking at the SPECT imaging. These are the selected slices in the short axis, horizontal long axis, and vertical long axis at stress and rest, and the study was considered to be normal by the panel of blinded observers. This patient in fact had significant right coronary artery disease, and the study was then considered to be falsely negative by SPECT. Now going to the PET study, you can see clearly a very distinct perfusion defect in the inferior and infrared septal region of the left ventricle that is reversible on the resting study. Therefore, this study was correctly identified as a true positive for presence of right coronary artery disease. One of the attributes obviously of this imaging protocol is that you can look at the function, but the function is at peak stress unlike SPECT imaging that it is anywhere up to 45 minutes after injection of the tracer. This is actually right at peak stress, and you can see that there is wall motion abnormality corresponding to the distribution of the right coronary in the inferior and infrared septal region. However, if you look at the SPECT image, you can see that on the stress study there is normal contraction of the left ventricle in the inferior wall, the territory of the right coronary artery. So therefore, the study was falsely negative for both perfusion and function. Now we go to another case example of a 74-year-old male with a body mass index of 34 who underwent treadmill exercise testing. By quantitative coronary angiography, the patient had 52% proximal LAD disease, 52% middle AD disease, and 79% distal disease. Again on the SPECT image, the study was considered to be normal by the panel of blinded observers, so this was a false negative study for this patient. However, what the FLIR-PIR does study, you can see a clear-cut defect in the region of the apex that corresponds to the distal LAD territory, so the PET study was a true positive study. Here is an example of a patient, a 64-year-old female with a body mass index of 52 who underwent pharmacologic stress testing. By quantitative coronary angiography, the patient had only 35% proximal LAD, so therefore was considered to be a normal study. The SPECT study shows that there are defects in the inferior left ventricular region that appears reversible, also in the apical region that is reversible, and in the distal inferior wall that is also reversible. So the study was determined to be a false positive study, most likely due to the patient's high BMI and multiple attenuation artifacts. However, the PET study was entirely normal. Please pay attention to the inferior wall that is entirely normal in this study, and the study was a true negative study by FLIR-PIR-DAS-PET. We have performed several side studies related to different features of FLIR-PIR-DAS-PET. One of them that was done by Dr. Packard as a lead author and was published in the journal Nuclear Medicine in 2021 was to look at the influence of the left ventricular size in 755 patients that were part of the first phase 3 study, and he showed that in patients with LV volumes of less than 113, again PET was superior to SPECT, with the area under the care being significantly higher with PET compared to SPECT, while with the patients who had fairly large ventricles, the difference was not as dramatic, and in fact it did not reach statistical significance, meaning that one of the important, it basically points out that the reason that FLIR-PIR-DAS-PET does better than SPECT in these patients with smaller ventricles is because of its higher imaging character, higher image resolution that can detect smaller defects that become blurry with SPECT imaging, and it is independent of the patient's gender, it could be male patient or female patient when the patient is on the smaller size, and by that, by the virtue of that, the heart size is also smaller, then SPECT does not perform as well, even if you compare SPECT performance by itself in a small ventricle compared to a larger ventricle, you can see that the SPECT doesn't perform as well in the smaller ventricles, so this is one advantage that even in male patients who are smaller size and the heart is smaller, FLIR-PIR-DAS-PET will do better. Another important and exciting feature with PET imaging and with FLIR-PIR-DAS-PET is the ability to perform absolute quantitation of myocardial blood flow. The concept was proven in a very small group of patients in a publication in Journal of Nuclear Medicine in 2014 that showed that in patients with significant disease, shown in red bars, the resting flow is not much different than patients with less degree of stenosis or those with low likelihood of disease, but when we look at the stress flow, we can see that the stress flow is significantly lower, leading to a much lower coronary flow reserve or myocardial flow reserve as measured by this method. Also pay attention to the peak myocardial flow reserve and the peak flow rates that are higher than what we measure with rubidium, and that basically indicates that there is a more linear relationship between FLIR-PIR-DAS uptake and its relationship to flow as opposed to rubidium that has a role of phenomenon. The concept of quantitation, as you well know, is twofold. One is to do relative quantitation. I showed the results in a polar map fashion, and that has been validated not only by our group and published in the Journal of Nuclear Cardiology, but also it has been shown by other software manufacturers and groups of researchers from Michigan and from Cedars-Sinai. So therefore, this aspect of quantitation is available by all the three major manufacturers, software manufacturers. You can see in a patient with a normal distribution that there is no definite defect on the polar map, but in this patient with a defect in the lateral wall on visual analysis, there is a blackout region in the lateral wall that corresponds to it, and we can quantify the percent of the myocardium that is involved in this area. But the more important aspect of quantitation is to look at absolute quantitation and look at stress myocardial flow and myocardial and what we call myocardial flow reserve or MFR. And an important attribute of F18 FLIR-PIR-DAS is that because of its high image resolution, we can do the measurements on all the 17 myocardial segments accurately. So that we call segmental quantitation of myocardial flow. So in this study that was published in the European Journal of Cardiovascular Imaging in 2021, that was first authored by Dr. Packard from our group, we see that comparing the area under the curve when you have only perfusion quantitation, the relative quantitation, and the influence of adding segmental myocardial blood flow at stress or at a territory basis or MFR on a segmental basis. So you can see that there is a significant improvement, incremental information, by adding segmental stress myocardial blood flow and also segmental territory stress myocardial blood flow to the perfusion quantitation alone. But you can see that the other types of quantitation did not add as much information as you can get from either segmental or territorial stress myocardial blood flow. And that is in agreement with what has been published in the past that in absolute quantitation of myocardial blood flow, the information that is contained on the stress myocardial blood flow is superior to myocardial flow reserve. An important finding in our study was that when we look at patients with moderate disease between 50 to 69 percent, we can see that the improvement or the incremental information in segmental stress myocardial blood flow was much greater. You can see that the difference in the area under the curve is much more pronounced as opposed to what we saw in the entire population. And you can see again the message that there is significant improvement in performance in terms of diagnostic performance when we add either segmental or territorial stress myocardial blood flow to perfusion defect analysis alone. So I'd like to, in the last few slides, to summarize for you what I believe would be the opportunities for F18 fluopirates in the clinical arena. I would like to show you some statistics. There are 2,500 PET scanners in hospitals across the U.S. and they collectively do 2 million scans per year. But only out of these 2 million scans, only 7 percent are using rubidium. And that goes back again to what I said in the beginning, that the problem here is that the lab has to be either a very large volume lab so that the cost of generator is acceptable and practical. But in general, a minority of the existing PET scanners do myocardial perfusion imaging. Therefore, by having a unit dose availability, a lot of these existing PET scanners can also get into the arena of doing myocardial perfusion imaging. And this percentage, I'm sure that will increase in the future. The clinical attributes are summarized here that we are dealing with as we compare F18 fluopirates with SPECT. We have a lower radiation dose to the patient, possibility of PET imaging in conjunction with treadmill exercise, higher sensitivity for detection of coronary artery disease and its extent, higher diagnostic performance in women, patients with BMI of greater than or equal to 30, and diabetics, better image quality, higher confidence of interpretation, and optimal connotation of segmental myocardial blood flow. What are the challenges for implementing F18 fluopirates in the clinical arena? First is physician training for interpretation of F18 fluopirates as images. So these images have a very high image contrast or image resolution as compared to what we are used to, either rubidium or technetium SPECT images. Therefore, the physicians need to be retrained to how to interpret defects in these. I'll give you one example. For instance, with F18 fluopirates, we often see apical thinning as an area of reduction of activity in the apex. And this is not commonly seen with SPECT or rubidium images. And this kind of reduction of activity in the apex may be misleading and they may be misinterpreted as being a definite defect. But by looking at these studies and proper training, we know that when we look at this type of defects in the apex and we see that contraction is entirely normal, this would represent apical thinning. That is only one example of what the training will include. The second challenge is that the time that is required for transitioning from SPECT to PET equipment. I did show in the previous slide that we think that the current PET equipment can be initially used to do fluopirates imaging, but most likely we will be exceeding the volume to the point that we need to get a dedicated PET scanner for cardiac imaging. And that would require to transition from SPECT imaging that is, as I said earlier, 5 to 6 million of these are done every year, to PET imaging that are currently only 200,000. And I suspect that by going through this process in the next few years, the number of PET studies will increase at the expense of SPECT studies for detection of disease. Another challenge is reducing radiation exposure to technologists and physicians during treadmill exercise injection of F18 fluopiridaz. Because of its high, being a PET tracer and having a high penetration, we are in the process of developing protocols to how to protect patients. We have not had any issues in terms of overexposure to technologists and physicians during our trials, but those were anecdotal cases. When we get to the point that 6 or 7 of these studies are done every day, then I think that we have to be able to protect the physicians and the technologists when they're performing exercise testing and injection of F18 fluopiridaz. Another challenge is the higher cost of a PET versus SPECT equipment. I know that there are designs of dedicated cardiac PET scanners that could be available at a fraction of the cost of a whole body PET scanner. And I think that that will close the gap in the price difference between PET and SPECT in the future. But I think that even now, when you do economical or financial analysis, you'll see that the purchase of a dedicated or a whole body PET scanner is justified for not only the clinical benefits that we get from F18 fluopiridaz compared to SPECT, but also that it would be a cost-effective approach. And reimbursement by private insurance companies has been a challenge for PET all along. It is interesting to note that even though rubidium has been approved in 1989 by the FDA, which goes back to three and a half decades, and also has been approved for use by Medicare, quite a few private insurance companies still consider the PET rubidium studies as being experimental or investigational. I think that that is unfortunately an excuse not to pay for it. But more and more, they're realizing that with the data coming out and the pressure from the patients and clinicians that PET is an acceptable modality with rubidium, and there are efforts ongoing to show the benefits of fluopiridaz as compared to SPECT to the private insurance companies and obtain approval for reimbursement. So the key points are summarized here that are a repetition of what I had said earlier, that it is a novel FDA-approved PET myocardial perfusion imaging agent that can be distributed as a unit dose and can be used in conjunction with terminal exercise testing. As compared to SPECT MPI, it has a higher diagnostic performance for overall detection of disease, and in patient subgroups such as females, obese patients, and also higher image quality, higher confidence of image interpretation, and lower radiation dose to patients. It allows segmental analysis of myocardial blood flow that improves detection of coronary artery disease as compared with perfusion defect analysis alone, and F18 fluopiridaz has the potential of becoming a game changer in the non-invasive evaluation of coronary artery disease. For your information, I've included several publications related to various clinical trials of this tracer and different publications and review articles here for your interest, and you're welcome to refer to the full article for more detail on what I just presented to you. Thank you very much for your attention.

F18 fluoroperidazepate

myocardial perfusion imaging

cardiac diagnostics

PET imaging

coronary artery disease

clinical trials

radiation exposure

diagnostic sensitivity