Navidea Biopharmaceuticals' (NAVB) CEO Michael Goldberg on Investor Briefing on Sentinel Lymph Node Biopsy in Head & Neck Cancers (Transcript)

Navidea Biopharmaceuticals, Inc. (NYSEMKT:NAVB)

Investor Briefing on Sentinel Lymph Node Biopsy in Head & Neck Cancers Conference Call

July 8, 2014, 08:00 AM ET


Stephen Lai - Associate Professor, Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center

Michael Goldberg - Interim Chief Executive Officer

Tom Tulip - President and Chief Business Officer.


Andrew McDonald - Managing Director, LifeSci Advisors

Andrew McDonald - Managing Director, LifeSci Advisors

I guess we go ahead and get started this morning. Good morning, everyone. My name is Andrew McDonald from LifeSci Advisors. Thank you all for joining us for this investor briefing focused on the use of Lymphoseek in head and neck cancers. We are fortunate enough today to have Dr. Stephen Lai join us. Dr. Lai is an Associate Professor in the Department of Head and Neck Surgery at the University of Texas M. D. Anderson Cancer Center and a board-certified head and neck cancer surgeon. Dr. Lai received his undergrad degree from Stanford University and his medical and doctorate degrees from The University of California, San Francisco. He performed his residency at The University of Pennsylvania and completed his fellowship in oncologic head and neck/cranial base surgery at The University of Pittsburgh School of Medicine. His clinical expertise is in head and neck cancers with special emphasis on thyroid and parathyroid disease, salivary gland neoplasms, conservation laryngeal surgery and oral cavity cancer. We appreciate you, the audience, joining us this morning, including those of you on the webcast.

Our agenda for this morning is fairly straightforward. We're going to start off with Dr. Lai's presentation, after which Dr. Goldberg, Interim CEO of Navidea, will make some remarks, and then we'll open up the session for Q&A. And we hope you find this morning's briefing informative. Thank you.

Stephen Lai

Well, thank you very much. I appreciate the opportunity to talk about clinical utility of Lymphoseek in head and neck cancers. So when I talk about oral cavity cancers or head and neck cancers in general, really where we're thinking about sentinel lymph node biopsy primarily are where there is currently evidence is really in oral cavity cancers. Oral cavity cancers represent somewhere about 30% to 40% of all head and neck cancers or squamous cell carcinomas of the head and neck. And the oral cavity, of course, includes the oral tongue, the floor of mouth, the hard palate, retromolar trigone, the buccal or cheek mucosa, the gingiva around the teeth and also the lips.

I'm going to talk about management of oral cavity cancer today with regard to the lymphatics or the lymph nodes. And you can see the diagram here on the right-hand side that shows sort of the lymphatic node chain, and then in the lower right-hand corner here, how we've broken down the neck sort of anatomically into levels, the one being sort of submental or submandibular area, two, three and four being the jugulodigastric chain. And it's really sort 1, 2 and 3 that are primarily involved in oral cavity cancer to a much lower incidence or extent here in level four and very rarely here in the posterior neck in level five.

So to understand the evolution of head and neck cancer management or oral cavity cancer management and nodal status, you have to understand the prognostic significance of nodal status. And certainly disease related survival drops significantly when cancer spreads to the regional lymph nodes. And here you can see sort of oral cavity and for oropharynx, so including tonsil and the posterior pharynx and the base of tongue. About a third of these cases show up localized, so it's only in the primary region. And so you can see five-year survival there is actually pretty good in the 80%, 85% range. About half of these patients, though, are showing up with regional disease also, so disease at the primary tumor site and then also in the regional in the cervical lymphatics. And those patients, you can see then their five-survival actually drops and in some cases almost drops in half.

Now the significance of nodal status is shown in the AJCC TNM or the sort of tumor, node and met cancer staging system, because any type of nodal disease or even N1 disease is staged then as Stage III disease. And all of these and nodal status is clearly important discussing not only surgical treatment, but then also adjuvant therapies such as radiation or chemotherapy. Despite clinical and radiographic examination, about 20% to 40% of clinically node-negative necks will still harbor pathologic disease. And the real challenge is how to identify those patients and how to treat those patients appropriately.

And so in head and neck surgery, the issue of N0 neck management has really been sort of a debate between elective neck dissection, which is systematic removal of lymph nodes from the one side of the neck that's usually the same side as that of the tumor, and that's really become a critical component for standard treatment versus potentially watchful waiting where you treat the primary tumor side and then you watch the N0 neck. And if disease develops, then you treat the neck at that time.

Now different pros and cons to elective neck dissection versus watchful waiting include that elective neck dissection gives you diagnostic information or the pathologic specimen to actually confirm what you found radiographically and clinically than it may even in the case of a true N0 neck actually be therapeutic. And again, as I mentioned, it can guide then whether or not you get additional radiation or chemotherapy treatment after surgery. Now the issue, though, of course is if you use that number about 20% to 40% that you may end up overtreating about 80% of those patients. So the great majority of these patients are coming up with N0 with truly pathologic N0 necks. And then of course the extent of this dissection still remains an active area of discussion.

Now in the watchful waiting side, you avoid the morbidity of neck dissections, so the potential effects to the nerves that affect the shoulder, the scar and sort of cosmetic effects that may occur with a neck dissection and then also any potential nerve or vascular injury that could occur. But the other thing that it does really depend on also is it depends on the patient for returning for regular follow-up. And what's come out of the literature is that when we go to a watchful waiting sort of model that unfortunately extracapsular spread is more common in salvaged necks. And then there is also the potential to develop unresectable disease. So in the sort of early decades of this discussion, the literature actually reported that there was only about 40% to 50% salvage rate in about 30% of the necks that would eventually become positive. And so the head and neck surgery field really moved away from watchful waiting to more of an elective neck dissection approach.

And so currently, elective neck dissection is the gold standard for staging and treatment for the clinically-negative or N0 neck for oral cavity squamous cell carcinoma. But as I already mentioned, there is sort of the potential here that about 75% of these patients with the N0 neck can potentially be sort of overtreated. And why we arrived at 20% is not only the sort of actual incidence of oral cavity squamous cell cancers, but we also, through our decision analysis in the field, decided that if there is a 20% risk, then that risk is sufficient for wanting to go ahead and doing elective neck dissection.

So what we're here to talk about today is potentially the advantages of sentinel lymph node versus elective neck dissection in the management of the clinically N0 neck for patients with neck cancers. And of course sentinel lymph node biopsy is well established for breast cancer and for melanoma and it may serve again as an effective alternative to elective neck dissection. And so some of the advantages, of course, or the sort of roll for sentinel lymph node biopsy include the really targeted removal and assessment of the highest risk nodes or the first-echelon nodes that may harbor the occult metastases in that clinically N0 neck. Again, as you would also potentially decrease surgical morbidity, because you're not doing a comprehensive neck dissection, the other thing is that it may account for unexpected patterns of lymphatic drainage, and I'll go over some of those examples in a moment.

And then the other thing for pathologists is rather than looking at potentially 25, 35 lymph nodes from an elective neck dissection and having to look at each one of those lymph nodes, you can actually focus your analysis on a single lymph node. So you can actually sub-section across the entire lymph node looking for potential microscopic disease rather than what's typically done when you have 25, 35 lymph nodes, which is you may only take one or two cross-sections through a lymph node and you could potentially miss small deposits of disease in that scenario.

I'll show you an example. This is a sentinel lymph node mapping using sulphur colloid. This is a planar image and then these are SPECT/CTs where the lymphoscintigraphy has actually been fused to the CT image. So you're provided with anatomic localization. And you can see where, in this particular patient, with an ear or (inaudible) melanoma may have sentinel lymph nodes that show up here lower in the neck. This was a patient, about of us at my institution still use blue dye for melanoma. The rest of us actually just use the radiotracer agent. And so here you can see the blue dye being injected, the excision site here on the primary, and then I show you that you can see a little bit here the blue dye has actually travelled to the node. And then so intraoperatively you're using a gamma probe to actually identify where that node is. You see the SPECT/CT to provide you some guidance to where you're actually going to dissect that node out from. And then I show you the node here. And this is the actual count level for this particular node. I want you to kind of just keep this number in mind, because I'm going to show you an example with actually lymphocyte in a couple of minutes.

That was an example in melanoma. But sentinel lymph node biopsy for oral cavity cancers or in head and neck cancer has actually been more widely studied and even adopted in Europe. And there are a couple of prospective studies, but a lot of the literature is actually retrospective and small case series reports. In the United States in 2010, Dr. Civantos and group using sort of multi-institutional ACOSOG trial Z-0360 reported looking at 140 patients for oral cavity squamous cell carcinoma. The sizes were small. They were T1, T2. And they used radiolabel sulfur colloid. And you can see that they had a sensitivity here of about 90%, a false negative rate that was close to 10% and a predictive value of about 96%. And in the US, this was the first prospective trial that had been done to even at look at feasibility of doing sentinel lymph node biopsy and the feasibility of actually the study as a multi-institutional trial.

In Europe, the study where they actually looked at five-year follow-up, there were about 134 patients. They used something called Nanocoll. It's also a radiocolloid and they also used blue dye at the time. Again, sensitivity of about 91%. And negative predictive value here, there was a mixed number. And I bring up the issue of floor of mouth, because the floor of mouth, which is under the tongue, sits in relative proximity to the level 1 nymph nodes. And so there are some thoughts that actually sensitivity in that area and also negative predictive value are affected by that anatomy. And you can see that the numbers are lower here, 80% for floor of mouth and 88% for negative predictive value in this particular study.

And so sensitivity and negative predictive value are clearly negatively impacted as particular with the anatomic location of the floor of mouth. In this study by Dr. Civantos, there were some suggestions that sort of experienced surgeons were better at doing this procedure than inexperienced surgeons and then also that larger tumors may also contribute to some of the negative impact. We'll get in all of that in just a moment here.

I talk about those things in this context, because the current agent that's available is the technetium 99 labeled sulfur colloid. It's a relatively large particle size, about 200 nanometers when filtered. And what we notice about it is it actually has relatively slow injection site clearance and that slow injection site clearance may then contribute to what's called the shine-through effect or a shine-through phenomenon. And that's where the delineation of the lymph nodes is made difficult, because of the increased radioactivity at the injection site. And again, when you have an injection site that's the floor of mouth and you potentially have a first-echelon lymph node in that level 1 area, you may be masked by the overwhelming signal at that primary tumor site. The other sort of feature is that there is a lack of specificity. Because this is a sulfur colloid, it actually just passively flows through the lymphatic channels and it doesn't actually target specifically to the lymph nodes.

And so of course you talk about what might be an ideal agent for radiotracer agent for lymphatic node mapping and you want something that would rapidly clear from the injection site, so to decrease shine-through, and then something that has specificity or that may be targeted to a receptor and that would potentially increase the uptake and retention in the tissue of interest into the sentinel lymph node and then also then provide some flexibility with the timing of the imaging and the potential surgery, and in that case potentially same day or next day imaging and surgery schedules.

And so we'll talk about Lymphoseek today. And it was already approved for breast and melanoma and then the sNDA approval for head and neck very recently. And what's nice about this particular agent, again, it's got the site that binds the technetium. And then it has these mannose moieties along its dextran backbone. But the mannose moieties are nice, because they will actually bind to CD206, which is present on dendritic cells and macrophages within the lymph nodes. And so this actually allows then the receptor targeting. And then the 7 nanometer diameter, we think, allows for rapid clearance from the primary site. So it can potentially improve sort of not masking lymph nodes that are in high-risk areas.

And so the trial that's been completed and that we're in the midst of trying to publish is this Phase III prospective open-labeled multi-center study of Lymphoseek, comparing sentinel lymph node status relative to the status of non-sentinel lymph nodes within an elective neck dissection specimen. So a little bit of details about the study design and methods. I know there is a lot of text here. First, it's really again multi-center open-labeled non-randomized single arm with in-patient trial. And the patients were sort of oral cavity or cutaneous lesions that were T1 through T4 that are N0 clinically and radiographically. And I'll go through these details a little bit more here in this flow diagram.

So again, here it's T1 through T4. And the reason we included the T3 and the T4 lesions is that those patients were going to get elective node dissections anyway, so we could still compare their sentinel lymph nodes with the actual total neck contents for those particular patients. In the patients that were injected the probably the same day as surgery, everyone received the same physical amount of tilmanocept. But the patients who were injected the same day received a 0.5 millicurie label, whereas those injected the day prior were actually injected with 2.0 millicuries. And this was actually up to the particular institution how they wanted to inject the patient except for those patients with floor of mouth tumors. And the floor of mouth tumor patients, they were injected the prior day to surgery. And that was again to try to give additional for clearance from the primary tumor site, so that there wouldn't be a shine-through effect.

Now all the patients received imaging in the form of either planar imaging or SPECT/CT. And then they went to surgery to have the primary tumor removed. They had the sentinel lymph node mapping and then biopsy performed, as you would in a sentinel lymph node. And then we went ahead and did the elective neck dissection on top of that. And then the pathology was evaluated not only at each institution, but then the slides were also then sent to a central pathology core for additional confirmation.

So the study objectives and some of these numbers you've already seen for the other two prospective studies. The primary objective was looking at the false negative rate. So again comparing sentinel lymph node status relative to the pathology status of the non-sentinel lymph nodes. And then secondary, one was to look at what is your detection rate, so how many sentinel lymph nodes you're actually finding in these patients. And then second, as related to false negative rate, once you have the data for that, to look at then sensitivity, negative predictive value and then overall accuracy for the agent. And of course as with the Phase I and Phase II studies to continue to look at safety profile, again there were overall no serious adverse events described for this agent.

So the actual patient demographics, the first thing to note here is that there were 85 patients enrolled into the study. And I'll come back to this issue in a couple of minutes. The actual age, about 60, and then so basically demonstrating that it was the right age, predominantly male population, which is also consistent for oral cavity cancers. And then sort of ethnic demographics all sort of line up with a typical head and neck cancer cohort.

Now we included cutaneous lesions also, but you can see that almost 93% of the lesions were intraoral. And as with the other studies, the great majority of these were either in the tongue or in the floor of mouth. And this floor of mouth population, you can see there were about 20 patients in that particular group. We also included, as I mentioned to you earlier, the T3 and T4 populations. Now you're going to expect a higher sort of metastases rate for these patients and potentially even a higher occult metastases rate. But you can see that again the great of majority of these patients, about 85% of patients still were in the T1, T2 range.

So the actual detection rate, so of 85 that were enrolled, 83 patients were actually injected, imaged and then had surgery. And at least one sentinel lymph node was identified and removed in 81 patients. So you had a lymph node identification rate of 97.6%.

So the actual false negative rate, so one sort of clarification I always like to point out is, yes, this is a Phase III clinical trial. Now typically in a Phase III clinical trial, people talk about, well, there is a treatment arm and there is a control arm, so what is your actual control arm? And while that applies to a therapeutic Phase III clinical trial, this is a diagnostic Phase III clinical trial. And it was designated a diagnostic Phase III clinical trial by the FDA. And so when you're looking at a diagnostic agent, you preset a statistical criteria that serves then as your basis of comparison. And so the pre-specified statistical endpoint was that you end up with a false negative rate of less than 14%. And that number was determined via met analysis by the trial designers and it was determined that in the literature, the false negative rate was around 14%.

And what you can see here is that in the study, there were 38 true positives and only one false negative. So actually the false negative rate was 2.56%. And so you had actually met the pre-specified statistical endpoint of less than 14% with a p value that's 0.02, so statistically significant in that regard. And then it had a sensitivity of 97.4%. And so when you then look at negative predictive value, again you're talking about true negatives over the false negative and true negative, and you can see that the negative predictive value here was really quite good at 97.8%. And then the actual accuracy, so true positives and true negatives, you can see the overall accuracy was 98.8%.

Now I want to come to this particular comparison. You have to be very careful when you're comparing clinical trials to each other, but I think that you can do it as long as you're clear on what you're doing the comparison relative to. So I think when you talk about the ACOSOG trial and then you talk about the NEO3-06 trial, a lot of people talk about, well, there were 140 patients enrolled in the ACOSOG trial and there were only 83 patients enrolled in the NEO3-06. Well, the NEO3-06 trial had built into the trial design that at 39 path positive patients, there had already been pre-specified analysis point where they were going to look at the data. And it was originally thought that 39 path positive patients, you probably have 114, 115 patients actually enrolled with a rate of about 30% where you were going to find that actual number. Well, when the data safety committee actually met and reviewed the data and noted that there were no adverse events and noted that they had already met the statistical criteria with regard to the false negative rate, it seemed reasonable to terminate the NEO3-06 trial at that point.

Now the basis for comparison isn't the number of total evaluable patients, 83 versus 140. It's actually the number of path positive patients, because this is the basis for your false negative rate. And so if you look, the false negative rate of 0.98% or 9.8% for the ACOSOG trial versus the NEO3-06 trial, which is about 2.5%, and then the confidence intervals, the p value is quite significant that these two false negative rates are different from each other. And then if you actually do again the comparison to the pre-specified statistical endpoint for the 306 trial, you can see again that 0.02 value for the false negative rate here for 306 for tilmanocept as compared to the 9.8%, which is not statistically significantly different from that false negative rate of 14%. And so I think in that way, as long as you're clear on the caveats, it is reasonable to do a comparison of the outcomes of these two populations.

So the other point that's notable out of this particular study is detection rates by day of surgery. So there were some institutions, they did the injection, the imaging the day of the actual procedure. There were some institutions that did it the day before. There were some that did it in a mixed group. And again, all the floor of mouth cancers had to be done the day before. And what's notable here is that there really is no difference observed between when you do the days of surgery. And again, there was only one false negative patient out of the entire population and it was actually a buccal lesion, not a floor of mouth lesion. And there were actually two patients with no sentinel lymph nodes identified.

Now what I wanted to show you is since it has been approved for melanoma, I've actually adopted using tilmanocept for sentinel lymph node mapping. And so you can see again the SPECT/CTs or the fusion images, the axial images and the coronal images showing where these lymph nodes show up. And then intraoperatively, you can see the incision points, the actual gamma probe being inserted here to look for the radioactivity. I show this particular image just to show people what it looks like when you're actually intraoperatively mapping the lymph nodes. The other thing I also like to show is that this little item here that's in the covering is actually the collimator for the probe. So typically with the radiotracer like sulfur colloid, you have a collimator that's on the tip of the probe, because it actually narrows the field that you're looking for radioactivity. And so you actually have to remove this for Lymphoseek or for tilmanocept. And I'll show you why in just a second here.

You can actually see then we dissect out the particular lymph node. We sort of draw the entire line of where neck dissection would be. And then you can see we draw the little hash marks where we actually are going to make our incision for the actual sentinel lymph node biopsy. And then basically what we do is remove the incision pocket over to identify the first lymph node and then we move the incision pocket posteriorly to find the second lymph node. And then you see the lymph node is dissected out here and then you can actually see the lymph nodes here on top of the probe. Now a few minutes ago when I showed you the sulfur colloid, you saw the number was like 2,227. And here the numbers for the actual lymph nodes are 69 and 49. And what's interesting here and it's difficult to actually quantify in a study per se, but once you start to use Lymphoseek for a while and if you've had some experience with the sulfur colloid is the signal to noise ratio is really substantially, I think at least qualitatively, is better for Lymphoseek than it was for the radio label sulfur colloid. And the reason is that your numbers, while lower, are very specific to the target. And that's part of the reason we have to take this collimator off, because virtually the background around this is virtually zero.

Now if you're using sulfur colloid, at least in our institution, you'll end up with a background that's in the several hundreds. And then you'll end up with a signal that's like a couple of thousand. But your signal to noise ratio then is much lower relative to what it is here. And I think that it actually helps with the speed with which you can identify the particular sentinel lymph nodes of interest.

Now one other feature that I wanted to sort of mention about sentinel lymph node mapping and its utility in oral cavity cancers is an example here of one of the patients that was actually on the study. This is a 69-year-old patient. He had a left tongue cancer that was a T2. So it's greater than 2 centimeters and less than 4 centimeters in size. This patient was injected 24 hours prior to the surgery. And on his SPECT/CT imaging, you can see that he actually had lymph nodes that appeared both on the left and the right-hand side. And I'll show you this image. You can see it rotating here on the room. I'm not sure about the actual webcast. But you can see that the tongue tumor here is on the left-hand side. He's got two lymph nodes that are lighting up on the left-hand side and one node that's lighting up here on the right-hand side. And again, this is a clinically, no negative neck. So radiographically and by physical exam, you don't know that there is any disease there. But what's interesting and while you would think that on a left to lateral tongue, the primarily would flow to the left side of the neck, on this patient and in a subset of patients, there is actual flow to the (inaudible) that you otherwise wouldn't pick up.

So for this patient, intraoperatively we went ahead and took out both of the lymph nodes on the left-hand side and we took out the lymph node on the right-hand side. Now given the sort of decision treaty at the time, we knew we would go ahead and do the entire elective neck dissection on the left-hand side and we elected just to see what the sentinel lymph nodes show on the right-hand side. Now interestingly, all of the sentinel lymph nodes turned out to be positive. So he actually had occult spread of the disease to his right neck that otherwise would not have been detected. And so this altered not only his intraoperative surgery, but then also adjusted his adjuvant treatment or his closed op radiation, because the radiation to the right neck, which initially would have been thought to be N0 or negative, would have received a lower dose than what it did actually receive once we knew that there was positive disease in that neck.

And then the last case, I just want to show you is with the rising incidents of oropharyngeal cancer that may be related to HPV, we're seeing a lot more patients relatively young, male and female and involving small lesions that we're finding. And in this particular patient, you can see just a little heterogeneity here. She had a posterior pharyngeal wall tumor. And so we were able to actually remove this particular tumor using transoral robotic surgery. Now we removed the tumor, but with oropharynx cancer, you're concerned about disease potentially spreading to the neck. And so I show you right now what's sort of standard of care. And the standard of care is we did the CT scan, ruled out that there was any neck disease. We went ahead and did an ultrasound and we would have done a fine-needle aspiration biopsy if there was potentially any disease present here, but we didn't see any disease in the ultrasound. And so we went ahead, removed her disease and now we're just observing her, because she had otherwise pathology that didn't indication that she needed any additional adjuvant therapy.

But you can imaging in this particular scenario, potentially removing a disease potentially surgically, potentially with the robot and then going ahead with a patient who has already been injected to be mapping their sentinel lymph node to be able to identify those lymph nodes in this particular tumor sub-site for potentially harboring occult disease. And so in conclusion, I think there really are sentinel lymph node biopsy opportunities in head and neck. I think the oral cavity is continuing to be developed and needs to continue to be studied. Then the literature is already well established for melanoma and can continue to be expanded for head and neck sub-sites. There's cutaneous squamous cell carcinoma that can be aggressive and high risk. And those tumors need to be identified and may also benefit from sentinel lymph node mapping. And then of course that last example I gave you, which is the orophaynx potentially doing sentinel lymph node mapping in conjunction with the robotic surgery resection of the primary tumor sites.

And so in conclusion, I'd just draw you back to the Phase III clinical trial that there were high rates of identification of the sentinel lymph nodes that there was quite low false negative rate of 2.56% that met the statistically predefined endpoint. There was high observed sensitivity. Negative predictive value was good and then as was the accuracy. And that you could use tilmanocept really to help predict pathologic nodal status in head and neck cancers, including the floor of mouth and that this really forms the basis for doing additional studies on sentinel lymph node biopsy in the head and neck. And again, that there was really excellent observed tolerance and no adverse safety events in the study.

And with that, I also want to thank the other investigators who led their particular sites for the NEO-306 trial. Thank you very much.

Michael Goldberg

Okay. Thank you very much. I think that was a tremendous presentation. And hopefully, what we ought to learn from this is the complexity and the depth of the data that we've been able to generate up till now with Lymphoseek is surgery and changing surgeons' opinions is a very, very complex business and it requires really, really good data. And I think Dr. Lai and the team that worked with him did a really, really excellent job, doing very, very, very careful work to, I think, really move the ball forward and introduce a product that is going to have tremendous benefits for patients not just in head and neck, but as we'll talk about, I think, allowing this important agent to be available for surgeons in multiple indications.

So before I make just a few comments and then open this up to Q&A, I will make some forward-looking statements, and I ask you to look at our regulatory filings and anything about Lymphoseek is all available in our website. So now that we have this product approved in United States, we think it dramatically adds to and expands our ability from a commercial enterprise to talk about and introduce this product more broadly. As you know, we have about a year ago got an approval for lymphatic mapping in breast and melanoma, and this is the first sentinel node agent.

And what's interesting and what attracted us way back to investing in Navidea was the fact that we knew that physicians all over the world were using lymphatic mapping agents that were not approved for sentinel node, for which data was interesting, but no real good, clean data, no data specifically for sentinel node mapping of the quality that Dr. Lai and his colleagues generated for us on sentinel node. But people knew the importance of identifying lymph nodes and hopefully trying to find that sentinel node and trying to better stage tumors. So we got interested in this product. We were interested in it, because we felt that a specialized purpose-filled product like Lymphoseek would be a major advance in light of the fact that surgeons all over the world were trying to do the best they could to properly stage their tumors. And we thought that this agent would advance the field.

So clearly, we've put a plan in place and the team, way before I got involved, put a very, very aggressive plan in place to stepwise develop this product where it was currently being used to go after what we would consider the low-hanging fruit and get this product both approved and then to be the first specialized product that was now approved for lymphatic mapping and sentinel node mapping.

The first approval, as I said, which was the first lymphatic mapping agent approved in over 30 years. So up until now, again people were using all kinds of different agents in the United States, blue dye and sulfur colloid overseas. Other agents, all of them have their pros and cons. None of them have the qualities that Lymphoseek has. And very, very importantly and I think from a commercial perspective and our ability to now talk about this in a much more fine tuned fashion is our ability to talk about this as a sentinel node mapping agent. Remember, for years people have been using lymphatic mapping, but really what they're hoping for was to identify the sentinel node. Now for the first time, we have data that clearly shows that we can not only identify the sentinel node, but we can go through the rigors of the regulatory process and get something approved for sentinel node mapping.

And for those who follow this company, you've seen this slide many times before, but from the perspective of Navidea, the company, I think it's very important that we understand the components of what we have. We now have an agent that's approved, that has the ability to get through the regulatory hurdles, which is a very, very, very difficult process, as well as to generate the data in a multi-center Phase III study to give us powerful statistical significance for its intended use, but as well we've shown that it's safe and we've been able to overcome all of the CMC sections, which for many, many drugs or potential drugs is a thing that enables that product not to get to market, even though sometimes the drug will have interesting safety and efficacy features, because of CMC issues, these products do not get approved.

What we now have is a product that's been proven to be safe and effective for an indication. And the backbone, we believe, and as we've begun to talk about a lot in the recent past, is the ability of this agent to be used more broadly. And having this agent available in the hands of surgeons will enable them to begin to explore much more broadly the use of this agent, just like surgeons have for the last 30-plus years used various lymphatic agents to explore sentinel node mapping and other indications, for which those products were useful.

In terms of the market, with the addition of head and neck, clearly we have an important market. The size of this market is indicated here. I want to really highlight on this slide the fact that we, in the US, tend to be a little bit prevential sometimes. But outside United States, there's a lot of good work being done and a lot of innovation and very high quality work as well. And what you see is in fact sentinel node mapping, lymphatic mapping is actually much more mature and progressed in Europe than it is in United States. And as we've been working and looking around the world to license the Lymphoseek product and developed it worldwide, what we found is there's a tremendous amount of use of lymphatic agents and interest now in Lymphoseek, where physicians are using various lymphatic agents that are available, but not nearly legally. The quality of Lymphoseek for lots of different tumors, for lots of different indications that it is our goal to partner with them, explore those indications and try to cross-fertilize the use in terms of what we in the US are doing to teach the rest of the world and what they're doing to teach some of the surgeons here in the United States.

Just go back one more point, it's really interesting again, and this is what interested us when I first invested in the company was that people were doing about 200,000 procedures a year in United States with agents that were never proven, that were never approved, but the need and demand was so great for these agents that significant number of procedures were being done. Clearly now having gone through the regulatory process and proving the efficacy and safety of our product makes us very, very confident that this product will not only dramatically take over the existing approved markets, but has the potential in the hands of surgeons all over the world to dramatically the expand the use of lymphatic and sentinel node mapping.

And to give you some numbers, and this is the incidents of these tumors around the world, and again there is a big paper that came out very recently out of Europe in prostate cancer. There is a lot of interesting work with colorectal cancer, lots of different problems, not necessarily the same issues. People don't know necessarily where lymphatic drainages in some of the tumors. Lots of work in terms of making decisions on how deeply to probe and how far to look to properly stage these tumors. So there is a lot of work, a lot of effort and a lot of expense around the world looking at properly staging tumors. And we believe hopefully with the soon to be introduced product in Europe and with developments around the world that this agent will be explored and used and data will be generated that'll enable us to go after and help in proper staging of many, if not most, of the solid tumors.

So we're very excited that Lymphoseek is out there, that we now have the first sentinel node label. And we are highly confident that as this product gets more and more exposure, surgeons around the world will explore the use of this product, just as they have for the last 30 years using inferior products to try to determine how best to stage their patients.

As you know, we have a partnership with Cardinal Health. Cardinal Health in the United States is the leading radiopharmaceutical company. Again, around the world, things are different. In the US, radiopharmaceuticals for most institutions are prepared at a radiopharmacy and then delivered to the hospital in a just-in-time method for use in the surgery. Outside the United States and in fact that some of the large hospitals in the United States, they do their own labeling. It's a different business, which is why we're pursuing different types of partnerships around the world and working with Cardinal and on our own to try to go after all the hospitals that are doing solid tumor surgery to make sure we get this on formulary and available in physicians' hands, not just to use it in breast melanoma and head and neck, but a physicians are interested, obviously it's up to them, they can explore for anything they'd like.

So what are our efforts to further develop this product? The sales of this product have been growing nicely. It's a very complex sale. Many, many people are involved. You've got the radiopharmacists. You've got the surgeon. You've got the medical oncologists. Different institutions have different political natures and it's very, very complex, but we've actually made some really, I think, remarkable progress and we're seeing nice growth month-over-month. We'll be reporting our quarterly numbers relatively soon. And we're excited by the potential of this product. We think this product can be and should be the state-of-the-art in solid tumor surgery and we fully expect that over time this will be the standard of care.

So we have another PDUFA date coming up in October, which will give us a broader approval to make it easier to dose the patients for doing both same-day and now a day before surgery. We're looking at many avenues to improve and extend the clinical use of this product. So we're looking, as we've indicated, in solid tumors like colorectal cancer and we're talking to people and exploring, prostate cancers and gynecological cancers and a whole host of other solid tumors. We're looking to further develop the comparative data. Dr. Lai presented the comparison between our Phase III results with head and neck and the published head and neck studies. We're looking to expand that to further show both the qualitative and quantitative differences of Lymphoseek versus sulfur colloid in the US and other agents around the world. And we're looking to take the data that we've generated and hopefully create treatment guidelines that include the use of Lymphoseek in certain key tumors based on the data that we've generated.

As I indicated, we're looking to launch this product overseas. We've got a pending European approval and partnership. And we have discussions ongoing around the world. Obviously from a commercial perspective, that's important, but just as important as it for the revenues that we can generate the ability to cross-fertilize, how it's used, how lymphatic agent and sentinel node mapping is being used around the world can help us in marketing and developing interest through publications and through further work with this product to generate interest in United States and around the world, so that physicians have the best agent to go after solid tumor staging.

We've also got a major effort ongoing to build awareness and interest in Lymphoseek here in the United States. So initially through Cardinal, we were focusing on the radiopharmaceutical operations within the hospitals. We're now increasing our focus on the surgeons. So first we push. Now we're going to go for a pull. Cardinal has learned a lot in the first year of launching this product and they have developed some further incentives for their own sales force to increase and improve their efforts. With the sentinel node label, obviously that gives us tremendous messaging advantages that we didn't have, that we now have in terms of our ability to talk about this product.

And we have announced, as you know, that we're looking for a new CEO for the company whose job will be to bring that additional sales and marketing expertise that the company did not have. So we have a great team, a great effort, a great partnership ongoing. But as we're looking to expand this product and expand it as broadly and as quickly as we can, our focus has been and will be enhanced on the accelerating sales of Lymphoseek in the US and around the world.

I can't not speak about really the breadth and the depth of this product in terms of what it is beyond just Lymphoseek. As you all know and as Dr. Lai indicated, you got to look at this agent and realize that its target is something that has tremendous, tremendous potential. And the target is not just for sentinel node mapping and I say that not to minimize. The market for sentinel node mapping is enormous and I believe it's a critical piece in the future of cancer staging and will be a very, very important product. And as indicated, as an organization, that is our primary focus is to continue the increase in the sales and the penetration of Lymphoseek on a global basis.

But that being said, this platform is of tremendous value to us. And what we believe we have is a product that's FDA approved that shows that this is a safe and effective product at targeting this CD206 target. And as we've indicated before, this is a very, very important target. And we have the ability, as we demonstrated in the nature piece last year and a lot of work that we'll be presenting shortly that by adding a different reporter, and a reporter could be an imaging agent or it could be a therapeutic agent, to this backbone targeted as it is to this target opens up tremendous opportunities for some massive, massive market opportunities.

So as I indicated, this publication was sort of our unveiling of the potential outside of sentinel node mapping for where this target can be used and for where we've generated some data with collaborators. The markets are enormous. And the potential both on the diagnostic side and the therapeutic side are extremely largely even compared to what we believe is a very large market for Lymphoseek. The point here is this targeted platform, which is now FDA approved and which has been demonstrated to be very effective at targeting this specific target has only begun to scratch the surface of the potential for its use in both diagnostic and therapeutic applications. And we've organized the company around the premise that our resources and our skills first and foremost are going to be focused on improving and getting Lymphoseek sales towards generating a substantial cash flow and continuing the development of these products initially through non-dilutive means and ultimately hopefully out of the cash flow generated out of the Lymphoseek sales.

So with that, I think you could see that if you consider Lymphoseek as the backbone, manocept as the entity, the potential here is enormous. Clearly, the focus is we have a FDA approved commercial product that stands alone. There's nothing else like it. The target that we've proven ourselves against is a target that has many, many applications beyond just sentinel node mapping. This is proven. This is demonstrated, not by us, but by others that this is a really, really set of targets. I say set of targets, because it goes after multiple diseases, although it really is exactly the same target. Lots and lots of great work has been done on the CD206 entity, and this agent is an excellent agent that is now FDA approved based on its ability to show it can safely and effectively target CD206.

So you can see here what we have. Obviously something like rheumatoid arthritis, which is the largest drug category in the world is something that could be very, very exciting for us. We've shown that we can differentiate osteoarthritis from rheumatoid arthritis. When you think about the drug companies and the need to get with a disease modifying agent, earlier diagnosis, so that you can begin treatment earlier, where you can modify the disease so that the joint will be less damaged, if not maybe not damaged at all, the potential applications for this are enormous. To both diagnose the diseases earlier and to provide alternate treatments is very, very valuable. And stay tuned, there'll be a lot more to talk about this over the coming weeks to months.

Okay, so very, very quickly just to summarize then, I believe this is my last slide. Then we'll open up to Q&A. We've had a pretty exciting last few months. Obviously the entire foundation is built on our ability to target this really, really important target CD206. Lymphoseek is the first manifestation. Lymphoseek is manocept targeted to CD206, linked to a reporter, which is a technetium 99. We've shown that we can add isotopes. We can add different isotopes. We can add fluorescent probes. We can add chemotherapeutic drugs. And the product goes where it's supposed to go and behaves as it's supposed to go. So this is a delivery vehicle to this target and we're only limited by our imagination into how we can apply this target.

What we have upcoming in sNDA, as I indicated, further evidence of the utility of Lymphoseek, not just how well it works, but how easy it is and how it falls better into the dosing requirements of given hospitals. We're expecting and EMA approval shortly of the breast melanoma and head and neck indications and then the launch in Europe to follow. Multiple international Lymphoseek partnerships, we're going to look to take advantage of what we learned in United States, but as well understand the differences, the cultural and operational differences of hospitals and radiopharmaceutical products outside the United States and tailor our partnerships to meet those needs. And then we will be looking to have some clinical studies initiated in two very interesting indications, Kaposi's sarcoma, a cancer, and rheumatoid arthritis, a very, very important, very, very large market opportunity. And we have some very exciting clinical and academic collaborations that we should be in a position to announce as well, which further shows the expansive nature of this critically important agent.

So with that, I thank all of you for your attention and those on the web. We will have question and answer, I guess, just from the audience here.

Question-and-Answer Session

Unidentified Analyst

Could you give us an approximation of what you think the average realization will be under normal conditions as opposed to clinical conditions for a patient?

Michael Goldberg

I didn't understand the question.

Unidentified Analyst

Typically, what will it cost to an ordinary patient after the clinical and after it's been distributed in the US per injection?

Michael Goldberg

I think we have announced that this is covered by CMS. It doesn't cost to patient anything.

Unidentified Analyst

Well, after that in ordinary practice?

Michael Goldberg

This is part of the surgical procedure. It doesn't cost them anything.

Unidentified Analyst

Per injection?

Michael Goldberg

Oh, what we realize?

Unidentified Analyst


Michael Goldberg

Currently, Cardinal prices about $300 a dose. And we've indicated we get about half of that.

Unidentified Analyst

So marketing strategy, you used the phrase worldwide a number of times. What are you doing outside the United States to advance the usage of the drug? And also, if you don't mind, where are you on your CEO hire?

Michael Goldberg

So in terms of outside the United States, we have announced a European partner that is in the process of being closed. The relationship closed. That really is much more dependent on getting the European approval, which we indicated we expect shortly. I don't know what that means in Europe, but shortly.

Unidentified Analyst

After the August period?

Michael Goldberg

I don't think anything happens from now until the end of August. So I'm no expert. You can probe Tom. He is much more up to speed on those details, but I don't count anything at this stage in Europe until at least September, but we're told relatively shortly. And then we have the partnership and then we'll have the launch. We've indicated that we don't expect anything to occur until 2015 and it takes some time to launch. It's a process. We have other collaborations in development outside of Europe and the United States. I think we've announced some work already that we've delivered some product to the Middle East and there'll be other announcements. Stay tuned.

In terms of the CEO search, as you know, I'm not getting paid for this. I enjoy it, but I've got other things on my plate. My primary focus is to bring in a really experienced executive who has got hands-on experience developing a drug that got an indication and expanding it. It's complicated. It's difficult. The regulatory people back at Navidea don't even like when I discuss this. But at the end of the day, this industry is rife with indications where products get approved for one indication. We seek counsel all the time for small indication and then get used more broadly. There're not a lot of market there, but there are ways to improve awareness and get people to use it. So Dr. Lai indicated when I was talking to him, once it's on formulary, once people are aware, if you are a doctor who wants to provide the best care for your patients, if it's available, you may want to use it. I mean doctors always talk about, oh, I need evidence-based, show me the data. And then you ask him, but you've been using this product for ever and no one ever did the study. The studies that were done were not really that compelling. Well, it's the best I've got, so I'm using it.

So our objective is to show them that this special purpose product, well, not yet approved for that indication, we will try to generate the data and try to get it approved as broadly as we can, but meanwhile your patient is going to wait 10, 15 years for the definitive studies with the outcomes and everything to come out. Do you want to withhold this? Do you have enough evidence? What more evidence can we give you to make you want to use this product? So that's an experience set that I surely don't have. And nothing negative about the people who are running Navidea, Mark Pykett and others who I was instrumental in bringing on, they're great at what they do and getting this to the level it's at, getting those to neuro products which we're going to partner, which are phenomenal products which you've gotten into Phase III testing, wonderful, wonderful programs, but you know what, we better spend the $60 million on improving Lymphoseek sales and building a manocept pipeline than on taking those products. I'd rather get a royalty and make sure those products get to the market sooner.

The long-winded answer is we've got an executive search firm that's been hired. We've already gotten some resumes. And as soon as we can get that person, I of course would be the happiest of everybody.

Unidentified Analyst

You've talked about the data being (inaudible). Can you give more specificity around in terms of it's got a lot of indications, a lot of potential? What the capital cost would be? (inaudible).

Michael Goldberg

I think we're going very shortly, stay tuned. I'm not going to give obviously the details. It hasn't yet obviously been announced. But if you can hold that question and if you don't get the answer very soon, don't ask me to define very soon, but it's sooner than European approval. I think you'll see an example of that. And essentially what we have and the way we're looking at this, for example, is as I indicated, this could be used in therapeutics as well. So what we're looking to do is try to find opportunities where someone has an interest in both diagnostic and therapeutic. There're lots of therapeutics in inflammation and in cancer that work really well, but their safety index is not very, very good. So take a disease like rheumatoid arthritis. If you had to get the drug systemically, you're worried about liver enzymes. You've taken oral drug. It could elevate liver enzymes. A lot of great therapeutic products don't get to market, because their index is too small. There's just not enough room between safety and efficacy.

So now you take a product like this that can target the joint. So you have three rheumatoid arthritic joints. And the way you diagnose rheumatoid arthritis is there's a list of seven different things. And if you have four out of seven, you're diagnosed with rheumatoid arthritis. You don't really know you have it or you don't have it. If we can actually develop evidence that shows if this lights up, you've got rheumatoid arthritis. Firstly, you can start treatment much earlier. These DMARDs are really expensive. But getting patients on it earlier can really change the quality of life of the patient. So obviously those clients that people may be interested in funding this study, because they're the ones who would have the real benefit. If you've got a person with rheumatoid arthritis and you get him 15 years earlier on your agent, that's 15 years you wouldn't have had as a business. It helps the patient and helps the pharmaceutical company.

On the flip side is there're lots of companies out there that have these great products that just couldn't get regulatory approval and maybe just wouldn't even be effective enough because of the safety issues. But what if you can now target it to the joint. Say you bypass the liver, if that was the problem. You bypass the systemic effects, because we're now targeting that to the very elevated CD206 that exists in the joint. So there're some very interesting agents that people have developed and would want to target. And I think that could be again a concept that you can build around in terms of non-dilutive. Ultimately, yes, we would like to be the company that in-licenses compounds that we could apply to this scaffold and keep 100% of the rights. But what we're going to do is end up initially partnering with other companies who already have proprietary technologies or proprietary interest in the outcomes that we would benefit from.

Unidentified Analyst

Are you aware of any other compounds comparable to your agents developed by international companies or US-based companies?

Michael Goldberg

So there are many compounds outside of the United States that are being used for lymphatic mapping. Tom, are you aware of any other company developing in the United States or in Europe a sentinel node agent?

Tom Tulip

There certainly have been some abortive attempts, but at this point, there really are no other elements in the competitive space.

Michael Goldberg

So the answer to the question for those on the webcast who might not have heard Tom, there have been others who have tried, but they haven't been successful. And we're not aware of anyone else. And very, very importantly, if you look at the structure, and this is something that from my prior life when I was very involved in heparin, which is a glycosaminoglycan, for those of you who follow the industry, you know that the low molecular weight heparins had a very, very, very long extension period on their pens, because it's very, very hard to develop a competing product to that. The same thing with a drug like COPAXONE, it's a very difficult drug to make a generic copy of. So in addition to not being aware of any companies that are specifically now developing sentinel node agents, this backbone that we have is going to be very difficult for people to copy because of the same reasons that the heparins were difficult to copy.

The bad news is it took us a lot longer to get this approved in the United States and in Europe because of the complexity of the underlying agent. The good news, now that we have it approved, this is going to be very, very difficult for generics to copy. And I believe that will give us a much better and longer proprietary position. We have a strong proprietary position, but I do think this will be very difficult to copy for others. And I think that will give us an extra level and an extra duration of IP protection or know-how protection going forward, because it will be very hard to make a generic copy of this agent.

Unidentified Analyst

Can I ask a question about Dr. Lai? Without making you a spokesperson for Navidea, I just wonder if you could talk us through the formulary approval process. It's basically the first part of my question just in terms of timing, level of evidence, the formulary the committee needed in order to put Lymphoseek on formulary. And I have a follow-up question about your surgical colleagues.

Michael Goldberg

I don't know a lot of the inter-workings of the regulatory process. I worked with my nuclear medicine colleagues actually. And once we had actually heard that the breast and melanoma indication had been given by the FDA, that was the threshold that we knew would be the minimum threshold to bring it on board for the committee. So in our particular institution, that can take anywhere from about three to six months to bring on board. Given that we were already using it in a trial and we already had some procedures to bring it in, because we were using it in the oral cavity trial, the nuclear medicine group already had some familiarity with it. And so we were actually able to bring it in, in about three months. So for an institution like mine, that's actually pretty good.

Unidentified Analyst

And then secondly just regarding your surgical colleagues, I'm just wondering when you speak with them, what are some of the barriers to a more rapid adoption? I mean this drug has superior properties. It's not more expensive. Is it because, as Michael Goldberg said, the long-term outcome that is not there yet? I'm just wondering why isn't surgical morbidity a big part of the discussion, et cetera?

Michael Goldberg

I would first say that medical field in general were not necessarily the fastest are far as technology adapters. I mean you look at the state of electronic medical records in the field and you can understand. In the complex medicolegal arena that we're in, sometimes there's familiarity with an old procedure, sort of provide some expertise and it's something that you're comfortable with and it's something that can sort of withstand legal test of standard of care. Sometimes that's what's more difficult to overcome than actually what maybe clear technological advantages. I will say that some of my younger colleagues, my trainees, residents and fellows are actually the people who have actually been in cases with me whether it was during the clinical trial or now as I do melanoma cases, they're the people who sort of now get to see cases being done by my colleagues with sulfur colloid and then by myself. And they can actually see the actual difference between the two. So those are people who now are graduating from our program, going to other places and potentially trying to bring Lymphoseek to those institutions too. So I think really it has to get into the hands of the surgeons to actually try the product.

I also think the research, as far as the outcomes, is really critical too. I know we talk a lot about evidence-based research, but I do think it really is an important piece in the marketing process to medical care providers.

Unidentified Analyst

Just one additional anecdote. You had indicated to me that when you were originally approached to participate in the Phase III, just tell us how long it took just to get through that process?

Stephen Lai

In the process of learning to do these clinical trials, we were the third institution to be approached about opening this trial at M.D. Anderson. We were actually the 15th center to actually get through our regulatory hurdles. So if you do that as a comparison, it took almost two years to open the trial. But despite that, we ended up being the second highest accrual and had the trial not stopped, had the early stopping point, we were on a trajectory to really open that up. That all being said, I do think clinical trials are important. We talk about potentially delaying getting these treatments to patients out there that it would benefit, but patients these days are very savvy consumers. You get a clinical trial out on the internet, you get it registered with People are going to find that trial and they're going to find the institutions where those trials are open, because they want these kinds of things. And so I think in some ways, it is very interesting, because we have used an off-label product for so long, but we now actually have an FDA approved labeled product to actually be doing these studies with or to be actually treating these patients with.

Michael Goldberg

But just to emphasize, it takes a long time before the product is approved, to get someone to get the leading institutions, I mean they're all evidence-based, they're all going through all these committees, everyone has their views. It's complex. And you think a leading institution like M.D. Anderson where they want to be at the cutting edge and everything else would jump at this. And yet, we see it took two years. It's our belief that now that this is FDA approved, now that we have a sentinel node label, now that we're going to be looking to do additional studies for additional indications, having this essentially good housekeeping seal of approval on the product that really differentiates us from everything else could enable us a quicker process. That being said, getting into the hospitals has been difficult. You got the quick early adopters. You got those who take some more time. But we're making progress. We're seeing the sales. We're seeing the ramp. We're seeing the daily doses going up significantly. And we think there'll be a point where this will be accepted. And if you're not providing this, you're going to be an outlier in your institution. And if I'm the medical oncologist looking for the best data to make the decision on how to treat my patient and I'm the insurance company and I'm deciding to spend $100,000 on some crazy therapy, I want to make sure it's the right therapy and the patient who's going to get the side effects from that we better be right.

And if we're not going to give that right therapy, we want to make sure that we did the right analysis. So there is a lot of competing forces. It's not going to be easy. It hasn't been easy. But I think it's actually been pretty remarkable how well we've done till now. And I'm very, very excited that now we have the sentinel node label, that will allow us a lot more access and a lot better penetration than we've had without the sentinel node label.

Unidentified Analyst

When do you think you might have some (inaudible) listings? And the second would be I'd love to hear your one or two favorite anecdotes of patients who did better on this new agent than they might have before.

Stephen Lai

I think the case study that I gave you is probably one of the most striking examples. This is our patient, and I'll give you a little comparison, because that patient, had we not detected a sentinel lymph node in his contralateral neck, probably would have recurred in about a four to five month range. We could have made a decision to go back and do an elective neck dissection. It would have delayed his treatment on the ipsilateral side already, because we knew the disease was there. So, we elected to just go ahead and treat him as if he had additional disease in that opposite side neck. So that's a different dose of radiation than if you are sort of treating for an elective dose. So it's a difference of between of about 50, 54 grey versus 60 to 66 grey. But that difference is enough to potentially stop positive disease there and eradicate it in that side.

That being said, we've had now cases more recently of patients who had contralateral neck disease and who have had disease that was truly negative on the ipsilateral side, so a right tongue, a right neck that had no disease present, clear margins, no perineural invasion. So in fact, those patients didn't receive any radiation at all. And then they had disease that actually grew quite rapidly in the opposite side. And I talked at the beginning about watchful waiting versus the elective node dissection. We ended up having a patient who on her contralateral neck ended up having disease that was so rapid that we couldn't do a selective neck dissection on her. We ended up actually having to do a radical neck dissection for her. It invaded into the muscle. It invaded into the nerve. But those are kinds of patients who probably might have benefited, because we don't have any clues or any biomarkers at this point to demonstrate who are the 8% to 10% to 12% of patients who are going to have contralateral flow in those particular patients.

The melanoma patients, that's a little harder. Because the indication has been relatively recent, we're in the process of following those patients out longitudinally and seeing how they're doing. But I've had patients now who actually have melanoma on the neck. And so if you imagine, it's not dissimilar to having a floor of mouth and then a level 1 lymph node. Now you've got a neck, skin melanoma and you've got lymph nodes that are actually highest at risk immediately under that lesion. And so we've noticed that with those particular patients, we're able to get clearance from that primary site, so that we can actually identify the lymph nodes that are immediately adjacent to it.

So those are the kinds of anecdotes that I can tell you. And that having done this procedure previously with sulfur colloid and now with Lymphoseek, those are kinds of differences that we're seeing when we're performing the procedure.

Michael Goldberg

And just one further comment more broadly. Dr. Lai showed this really interesting slide where the pathologist gets the lymph node and if you're getting 50 lymph nodes, how thick are the cuts you're going to take to look to see if there's microscopic spread or not depending, I guess, on how busy he is, he's going to make a decision. You talked to colorectal surgeons. You talked to prostate surgeons. One of the problems they have is, first of all, they don't even know which is the lymph node draining that bed. It could be as the same thing that head and neck, you have a tumor on your left lobe of your prostate, but it could actually drain to the right lymphatics. So one of the things is obviously one just showing what the lymphatic drainage is from the tumor site.

There's a big study just published out of France a few weeks ago with over 200 patients in prostate cancer. And they compared full pelvic dissection to extended pelvic dissection using the best available imaging agent that they had in Europe at the time. And what they showed was extended pelvic dissection is a lot safer and better than full pelvic dissection, even though the trauma and the complications are greater because there's a lot of tumor that you find in the extended that you don't find in just the full pelvic dissection. And at the same time, you're retrieving lots and lots of lymph nodes, how carefully you analyze them is all important. And very importantly, in this study, using the tracer, they had a 9% false negative rate, because in this case, they looked at the sentinel nodes and compared what the sentinel nodes said to the full and extended pelvic dissection. So, we don't have good agents until Lymphoseek. The agents that we have give information, but not enough information. And I think the benefit of Lymphoseek even where you're going to do a full dissection is to at least tell the pathologist, you know what, these four tumor beds, the sentinel node and each of those tumor beds do the best dissection. So that you do the finest dissection there and depending on what you see, you can decide to do the rest.

So there's lots and lots of interim steps that one could have. And going after the surgeon trying to provide them with the reasons why this agent should be tried. Remember, there's no real evidence base from most of what they're doing in this space, because these agents have not been studied that well. And where they've really been studied, they all fall short, because they're not designed properly. This agent has the chance and the opportunity and while we're waiting for the real evidence-based medicine, if you're the patient who is being treated, you want to get the best possible outcome you can. Today, we have a safe product and effective product. It's not that expensive. What's the downside?

Any other questions? So I thank all of you. And if you have anything private, we'll stick around for a few minutes. Thank you.

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