Hello, good morning, everyone. I'm Brian Cooley, Senior Vice President for Sorrento Therapeutics, and I head the Sofusa lymphatic drug development division. I want to thank everyone for joining us today for this webcast and the key opinion leader discussion panel on Empowering the Lymphatics. The goal for today's discussion is really to educate all of us on the potential benefits of lymphatic targeting using our Sofusa microneedle platform. Today's discussion will feature data released earlier this week at the American College of Rheumatology in Philadelphia. This 12-week open-label study demonstrated improved therapeutic outcomes in 10 of 10 patients switched from standard injections of the etanercept to Sofusa's lymphatic treatment, and that's at half the dose or less. So we believe this is quite remarkable and excited to share this with you. To help us interpret these findings, we're going to be joined today by a panel of experts. So we have Dr. Roel Querubin, who is the primary investigator for the study. We have Dr. Mike Royal, who's our Chief Medical Officer, and then also Dr. Russell Ross, who is the inventor of the Sofusa system. And with that, we thank you very much for your interest. That's enough for my introduction, and I will turn it over to our moderator, who's Dr. Chris Jeffers. He's the CEO for Hibiscus BioVentures. But thank you again, and Chris, I'll turn it over to you. Thanks, Brian. I appreciate it, and thanks for everybody for joining today to hear about these really exciting results. Let me give a little more introduction to our panel. We've got a really fantastic group of people. First is Dr. Roel Querubin. Dr. Querubin's a practicing rheumatologist at the Atlanta Research Center for Rheumatology and the Marietta Rheumatology Associates, and he focuses on the diagnosis and management of musculoskeletal diseases. He's got a particular interest in inflammatory arthropathies, which include connective tissue diseases. His clinical trial experience includes studies for therapies, including RA, systemic lupus, psoriatic arthritis, and ankylosing spondylitis. And he's written peer-reviewed articles for all the national rheumatology journals and presented at national meetings. Dr. Querubin got his MD at Medical College of Georgia, was an intern at Atlanta Medical Center in internal medicine, and then was a rheumatology fellow at Emory. So thank you, Dr. Querubin, for joining today. Dr. Rusty Ross or Russell Ross is the Chief Technology Officer of Sofusa. Dr. Ross was also the inventor of the Sofusa Lymphatic Delivery System and has really pioneered the early development of this work. He leads all the development and commercialization of novel lymphatic-directed therapies for RA and oncology, including melanoma and non-Hodgkin's lymphoma. Prior to being at Sorrento, Dr. Ross spent 20 years at Kimberly-Clark in several R&D leadership positions, both on the consumer and the professional businesses. He got his PhD from the University of Wisconsin and has been awarded over 73 patents and numerous peer-reviewed articles. Thanks, Rusty. Dr. Mike Royal is the Chief Medical Officer for Sorrento. Dr. Royal is a pharmaceutical executive with over 20 years of experience in clinical development and medical affairs. He was most recently the CMO of Connect Biopharma, and prior to that, at Concentric Analgesics. He came back to Sorrento, where he was previously the EVP of Clinical Development Reg Affairs in 2016, and he's board-certified in internal medicine, pain management, anesthesiology, and additional qualifications in pain management and legal medicine. He's had academic appointments at USUHS, at the University of Pittsburgh, University of Oklahoma, and University of California, San Diego. He has an MD from the University of Massachusetts, an MBA from New York University, and a JD from the University of Maryland. So thank you so much, Dr. Royal, for joining. And finally, our panelist was going to be Dr. Vibeke Strand, and Dr. Strand is the Adjunct Clinical Professor of the Division of Immunology and Rheumatology at Stanford University. Prior to that, she was at UCSF for 12 years and has been a leading clinical investigator in rheumatology and autoimmune. Unfortunately, Dr. Strand has had a health emergency today and won't be able to join us, so we will endeavor to carry on without her. So with that, welcome to everyone else. And what I thought we would do first is just talk a little bit about the unmet need here and sort of the reason for a lot of the development that has undergone in this program. And I'll direct this question to Dr. Querubin. From the perspective of a practitioner, what do you think are the most significant unmet needs in RA right now? Thanks, Chris. Thanks for having me, and yeah, I think the general agreement, the general consensus in the rheumatology field is the greatest unmet need would be, especially in the developed world, managing patients who are refractory to available treatments. Refractory meaning refractory standard of care, typically one or more TNF therapies, and then if unresponsive to those, attempts to use different mechanisms: T-cell therapy, B-cell therapy, interleukin therapy, small molecule therapy, but typically refractory initially to TNFs, so that's exciting from our standpoint to see that through this lymphatics delivery that there may be more effective response without actually requiring a change of classes or even without requiring a change of therapy, so just a change from maybe subcu or IV to lymphatics delivery. What is currently the standard of care on patients that aren't well controlled on subcutaneous anti-TNF therapy? For TNFs, it can be one of two things. You can actually stay with the TNF, and if it's something like Remicade, you can actually titrate the dose of Remicade to response. You can go from three milligrams, five, seven, 10 milligrams. So one of those TNFs that Remicade you can titrate. If they fail one TNF, you can actually use a second TNF. And studies have shown that despite using the same class, you can actually stick with that class, and you'll see a response to TNFs. Then after, say, two or three different TNFs, we do consider switching mechanism of action. When you do, I mean, what are the issues that you find when you're associated with sort of changing from one biologic to another, from one class to another? Are there any specific issues you're trying to solve for? are no specific issues as far as changing from one class to another. The main concern would be that if they've been on a previous DMARD, and that's a negative predictor of response to another biologic, there's no specific concern about changing TNF to another class or another mechanism. But each mechanism has certain side effects that you have to balance in association with the profile of the patient. Some mechanisms have unique risks. TNFs have heart failure risks, non-melanoma skin cancer risks, maybe potential solid tumor risks. So if you have a patient with those histories, you'd avoid TNFs. If you have a history of, say, DVT clots, heart attack, strokes, multiple cardiovascular risk factors, then you may consider avoiding certain mechanisms like JAK inhibitors. If you have a history of, say, GI disease with diverticulitis, concomitant NSAIDs, steroids, then you would avoid a certain class such as interleukin-6 antibody therapy. If you have a history of cancer, in general, you avoid all biologics except potentially Rituxan. So it's not necessarily about the risk of switching. It's more about the risk of each medication and profile with the patient. Maybe I'll direct this next question to Doctors Ross and Royal in terms of the drug development side. I mean, where do you see the most exciting new developments on the horizon in RA? I mean, what sort of opportunities do you see coming down the pipe? Well, obviously. I'm sorry. Can you hear me now? We can, yes. Okay. You know, the most exciting development is coming up with ways of continuing to improve patients' lives while using alternate methods of delivery like the lymphatic delivery. The ability to take people who were previously poorly responsive to treatment, such as etanercept, and then being able to recoup them and get them to be responsive while using a much lower dose is pretty significant, I believe. I mean, not only in terms of the fact that you can turn poor responders into now being good responders, but also doing it at half the dose, which is a considerable savings not only for the patients, but for the payers. I think this is something that is pretty significant now because you have the ability to fully use the benefit of a TNF- alpha type drug without having to go on to yet another medication and again and again to go on to switch and maybe even go off to immunomodulators prematurely. I think this is pretty compelling at this point. Yeah. And back to Dr. Querubin. I mean, in terms of response rates on your TNFs, you talked earlier about refractory patients. I mean, what are the normal response rates on TNF therapy, and what is the sort of incidence of a refractory patient? For response rates, I guess, first of all, there's multiple classes, like we said, T-cell, B-cell, and such. Of all these classes, I think up to 80%-90% of patients are initially treated with a TNF as the first-line biologic, and that's after like a conventional synthetic DMARD, and of these 80%-90%, I would say if we're looking at what's called ACR responses, there's an ACR20, 20% response, ACR50 and ACR70, 50% and 70% response. Significant clinical response, I would say, is more of an ACR50 response, so of these patients that start the TNF, I'd say maybe one-third reach an ACR50 score. Maybe I'll direct this to Rusty. I mean, what have you seen recently, both from ACR and others, in terms of new approaches that you think might be attractive for future development? Yeah, no, I think the exciting things that are going on right now in autoimmune and RA is that we're starting to understand more the role of your immune system in this disease in terms of the pathology of this disease. As we increase that understanding, now you're going to start to see more therapies like Sofusa, which are trying to treat that disease by delivering therapies to the lymph nodes. As we go from there, right now, as we look out in the future, more out in the future, right, it's now that we're going to be treating the disease potentially more through the lymphatics. There's other targets on B-cells and T-cells that may be able to have a lot more effect in terms of reducing the pain that these patients are feeling. Rusty, just to stick with you for a second on that. I mean, what is the role of the lymphatics in RA specifically, and how much work has been done on that? Also in other autoimmune diseases, what do we understand about the role of the lymphatics in those diseases? Yeah, I mean, we've been in the last 10, 15 years, the role of lymphatics and autoimmune has been quite substantial. And what people have been able to identify the last 10 years of the role of the lymphatics is that these overexpressions of certain cytokines like TNF, they're getting into your lymph nodes and your lymphatic system. And so one implication for that is it can affect your lymphatic function. So one way to characterize the lymphatic function is in terms of how well it's pumping or moving interstitial fluid through their system and back to the circulation. And we've seen with these autoimmune disorders that you see an impairment in that lymphatic function. In addition to just the impairment in lymphatic function, RA also can cause unwanted immune reactions in the lymph nodes. So maybe causing some type of B-cell reaction or higher levels of T-cells or lower levels of effector T-cells. So this is becoming a really exciting space to work in because we can take this knowledge that we've developed from some systemic therapies and our knowledge of lymphatics to actually start to develop much better solutions to helping people deal with this disease. That's great. And just maybe one last question for Dr. Royal. I mean, obviously, this is a new paradigm in terms of intralymphatic delivery, and there's going to be new issues with the FDA regarding the concentration of these drugs in the lymphatics versus the systemic circulation. What are your current thoughts about the potential risks and benefits of that sort of preferential uptake by the lymphatics? I think largely with lymphatic delivery, you're using a lower dose than the approved dose that may be administered through other methodologies such as intravenous or subcutaneous, etc. From a safety perspective, you're pretty well covered. The fact is that your total exposure is going to be far less. There doesn't appear to be any additional risk by giving it lymphatically as opposed to subcutaneously, where there may be some uptake within both the bloodstream and the lymphatic system, or from intravenous administration where you're getting very high immediate blood levels and a far greater exposure than the lymphatics. I think from a safety perspective, generally, the doses are going to be lower. FDA would like the potential for delivering efficacious doses without having to go to very high doses where safety is always a concern. So I think this is the ability to fully optimize efficacy with lower doses, I think, is kind of a no-brainer from the FDA's perspective. With that, I think it would be great to see the data. Brian, I'll hand it back over to you to talk through that. Yeah, thank you, Chris. Yeah, so I'm going to give a brief introduction here to the business unit of Sofusa and the technology, and then turn it over to Dr. Ross to go through our first human proof-of-concept data. But our vision for the Sofusa team that's based in Atlanta is to help healthcare professionals improve the lives of people with cancer and autoimmune disease. So we're excited to share this data with you today. We have some forward-looking statements that talk about risks and uncertainties in presenting this data. This presentation and webcast will all be available on our website following the webcast. So like I said, I'll give an introduction to the technology, turn it over to Rusty for the poster presentation, which was just presented at ACR. And then we're going to open it up for additional questions from the moderator and also questions from the audience. Please feel free to submit your questions. Let me get to the next slide. Yep, and that's just me. I've already done the introduction of myself, but I lead the Sofusa division and also work in drug delivery and diagnostics and connected health for Sorrento. As Chris mentioned, looking at this slide of who are we, right? Basically, Sorrento was founded back in 2009, over 800 employees, and it was really founded by Dr. Henry Ji on this proprietary G-MAB library. This G-MAB library is really an engine that powers a lot of the platform technologies that have been developed or acquired by Sorrento over time. In Atlanta, our focus is on the lymphatic Sofusa platform. The platform was actually acquired from Kimberly-Clark back in 2018, proprietary drug delivery system. A lot of development of the device itself was done at Kimberly-Clark, and then Sorrento has really taken over the clinical and regulatory and product development as we move to the next phase. Kimberly-Clark wasn't necessarily the best company to move into clinical development and to become a pharma company as they focus on things like Huggies and Kleenex. But in Atlanta, we are really now a fully integrated operation in terms of device development, manufacturing. We also have a preclinical animal lab and clinical operations to be able to support studies for Sorrento or for potential partners. So looking at the Sorrento and the Sofusa pipeline, Sorrento has a very robust pipeline focused in three areas: in COVID-19, oncology, and non-opioid pain. We actually had a big event last week where Henry Ji and Jaisim Shah, the CEO for Scilex, rang the bell at NASDAQ as we spun out the non-opioid pain business under a separate ticker symbol, SCLX. This is a nice example, I think, of Sorrento's optionality to take a very robust pipeline and platforms and be able to monetize these assets, and from a Sofusa pipeline perspective, we've now got multiple programs. We're going to focus on the anti-TNF or the etenircept program today, but we also have a program going on at City of Hope in cutaneous T-cell lymphoma. That study is just now enrolling, and then we have also a research collaboration with Mayo Clinic where we have just some fantastic researchers helping us look at and explore other indications and other pathways like melanoma and in-transit metastases with different checkpoint inhibitors. So it really highlights hopefully what our clinical development strategy is, which is to first test Sofusa in small proof of concept studies with well-characterized mechanisms, high levels of unmet need, and big markets. And with that, we believe we can significantly de-risk and streamline our path to market by doing these small proof of concepts and then where you see really good results, being able to advance those quickly. And our regulatory strategy on these programs is to develop these as combination products. We also envision partnering in addition to the Sofusa and Sorrento pipeline in order to maximize the potential of this platform across the patent-protected lifecycle. So getting a little bit into the lymphatics and the technology, and then Rusty will talk about a lot more. But there have been many attempts to try to target drugs in the lymphatics, like Rusty and Mike and Dr. Querubin mentioned. There's been a lot of development and better understanding of the lymphatics, and whether it's direct lymphatic injections, liposomes, albumin nanoparticles, there have been ways to try to get into the lymphatics, but it's difficult, right? If you look at the structure of the skin, you've got the epidermis, you've got the inner dermal layer and the subcutaneous layer. Our first line of defense is really at that epidermal dermal boundary where you have these highly fenestrated and permeable lymphatic capillaries and also dendritic cells. So it's been very difficult to inject. If you inject subcutaneous or IV, you're getting a big bolus into the systemic circulation, but not very much lymphatically. And with our system, we believe we're able to get better exposure to the immune targets, which we believe, as Mike said, that we'll be able to get an improved therapeutic response potentially even with less drug. So in addition to what I mentioned in our pipeline, we're focused on oncology and autoimmune initially, but there's also a number of pathologies that are known to be linked to the lymphatics. Indeed, I was reading an article from Washington University. They recently published the link between the lymphatics and to amyloid beta and the clearing of plaques in Alzheimer's, and that there may be some relation to lymphatic flow and function. In addition, we've developed a Sofusa lymphatic injection device for vaccine. It's a small injection device that delivers to the lymphatics, and we've demonstrated we can get better cellular immunity at one-tenth of the dose in our animal models. So there's other opportunities beyond just oncology and autoimmune that are somewhat untapped relative to what we might be able to do with targeted lymphatic delivery. So now, what's our solution, right? And today, we'll focus on RA. But the solution is really a microneedle system, and microneedles have been around for a long time, right? So what's unique about this microneedle platform? It's really the placement of the needles, the nanostructured covering over the needles or draping, and the microfluidics. So if you look at the slide, we basically have very precise microneedles that only penetrate the skin about 180 microns. And so with that, they don't get to the nerve endings. It's a virtual pain-free experience. But more importantly, you're able to place those microneedles just above the porous and fenestrated lymphatic capillaries. The second thing that's really the secret to Sofusa is the nano-topography. These nanostructures, and this was what was discovered by Rusty, are these nanostructures have a very unique ability to be able to open up tight junctions in the skin and facilitate transcellular and paracellular transport. The microneedles serve two purposes. They flow the drug towards the lymphatic capillaries, but they also are able to facilitate better absorption and paracellular and transcellular transport through the skin, which you're not able to do typically with large molecules. We'll show you some data on that. Then finally, the microfluidics, right? We have microfluidic channels that it's very important with Sofusa. You have a slow, what I call soft infusion for Sofusa, where you're able to get a constant flow into the lymphatic capillary. It's very important to get the drug consistent flow rates across the entire microneedle array of 324 microneedles. And so the microfluidics help to do that. And all of that is part of our patent estate. So now, here on slide 10, I mean, on the left, you basically see what I was describing, the importance of placement to enhance large molecule transport through the skin. The needles just penetrate the epidermis and then slowly infuse at a constant flow gradient over these highly fenestrated capillaries. And with that, we believe we're able to get, or we know we're able to get much higher concentrations in the lymphatics. And then on the right, this is one of our early publications, which demonstrates the impact of the nano-topography on absorption. So if you look at the chart, the dark black line is undraped microneedles. So you see a very low serum concentration with undraped needles. However, the dotted line needles that are draped with our nano-topography show a tenfold increase in area under the curve and serum concentration. So that impact is significant of the nanostructures coming in contact with the live skin cells in the epidermis, activating cellular pathways and really remodels tight junctions. You can see the pictures down there at the bottom where you get a disruption and a changing of the tight junctions in the epidermis. But this process is reversible. So when you remove that, the skin basically goes back to normal. So that's a little bit on how the technology works. But now for the so what, right? And Rusty will go through the clinical data with etanercept, but I wanted to share with you this biodistribution study that we did also with etanercept. We basically radio-labeled etanercept in this Sprague- Dawley rat model. What we were able to do is look at the biodistribution and look at organ concentrations over time. So as you see on the chart on the left, the concentration of etanercept in lymph nodes with IV, subcutaneous, and even intradermal injections is quite small. But with Sofusa, after just a one-hour infusion, we see a 40-fold increase in lymph node concentrations. And that's at 12 hours after a one-hour infusion. And then you still see significantly higher concentrations at 36 hours. So that really gives us a reason to believe around why we might get better exposure to drug targets in the lymph nodes and a better response rate. And then on the right, you see the biodistribution in other organ systems, right? So the off-target organs or other organ systems, you actually have a lower concentration versus the systemic delivery of IV infusion. And so this data gives us hope that we may be able to get lower side effects, potentially a lower dose without some of the off-target organ side effects that you see sometimes with these biologic drugs. So pictures and graphs are nice, but videos are worth a thousand tables and charts. So we have now done multiple imaging studies with indocyanine green and near-infrared fluorescent imaging. And so the chart on the left basically shows a woman where we're able to put the device onto her arm, and you can see the axillary lymph node there lit up in green. And then this lady on the right, she had the device on her leg, and you can see the Sofusa device there. And I'm going to go to the next slide because this is where we have a video, and you'll actually be able to see the pumping, right? You can see the device down there at the bottom. And there you can see the lymphatic pumping of the indocyanine green traveling up through the lymphatic capillaries into the axillary lymph nodes. And you'll also see a lymphatic capillary along the back of the leg. Imagine now that you have etanercept and you're delivering this through the lymphatic capillaries at a constant flow rate over an hour. You're getting very good exposure to those draining lymph nodes. With that, in summary, we basically see with the Sofusa system a biodistribution advantage and the ability to target lymph nodes. We also have, we won't cover it in this webcast, but we have a lot of preclinical data on antitumor efficacy, reduced metastases, and we're just starting our first human proof of concepts in cancer. And then Rusty is going to talk more about items three, four, and five, the improved therapeutic response, reduced dose, and the lymphatic flow and function. And as a nice benefit, this is a virtually pain-free infusion for patients, and we've developed not only a wearable device for the clinic to do infusions, but also an all-in-one wearable that you can use at home. So with that, I'm going to turn things over to Dr. Ross, and he will go through the ACR poster presentation and more details on the phase one clinical study. All right. Thank you, Brian. Really excited to present this data today to really show the first kind of proof of concept study, what the advantages are of delivering a therapy to the lymphatics and the draining lymph nodes that's involved in the disease and the benefits that has for treating inflammatory diseases like rheumatoid arthritis where the immune system is highly upregulated. So do I move these slides or just click next? Okay. Sorry. All right. So the study that we're going to present today is a 10-person open-label study that we did in rheumatoid arthritis patients. And the patients, the inclusion-exclusion criteria that we use to select these patients is we pick patients that were currently on etanercept and that they had to be on etanercept for more than 12 weeks subcutaneously and that they were exhibiting an inadequate response. What we mean by an inadequate response is that they were still, by measurements, DAS measurements, exhibiting moderate to severe disease activity. What we did in the study is on the first day of treatment, we switched the patients from 50 milligrams subcutaneous weekly dose to 25 milligrams of etanercept that were delivered over an hour using the Sofusa nano-topography microneedle device. Now, if you look at the population of the patients that were in this study, the median time that they had been on etanercept before they entered the study was approximately about a year. The minimum patient time was about six months. We had a couple of patients that were almost out to 10 years being on subcutaneous injections with etanercept. Why are we developing lymphatic treatments for RA? The heart of this is that if you look at the pathology of rheumatoid arthritis, it's really an inflammatory disease. It's an upregulation of your immune system, and it results in a variety of different cytokines and other immune cells ending up in the joints and the synovial area. As a result of that, it causes swelling and causes pain. As I mentioned earlier, it also has had some downstream effects in terms of how the lymphatic functions. The best way to kind of measure how the lymphatic functions is to look at pumping rates. You also see when you're impairing the lymphatics that it causes other rashes and possibly lymphedema and other comorbidities. It just made sense to try to say, "Okay, we're treating inflammatory disease systemically with subcutaneous or IV," that it might make sense to actually try to get these therapies where they might do the most good. That is to move it into the lymphatics. This is then observed that flares are related to lymphatics. This was why we're developing these treatments. How did we run the study? From a methods perspective, we delivered 25 milligrams of etanercept using the Sofusa device over approximately one and a quarter hours. The delivery rate out of the device was around 0.4 ml per hour. Before we treated the patients, we also collected some information on the lymphatic function using the indocyanine green dye delivered with the same device in the same location that we were doing the dosing. And then taking a movie of the pumping of the indocyanine green in those patients and recorded it for 10 minutes. And then over those 10 minutes, we would go back to the video and determine what the pumping rate was. And that pump rate was how we were going to assess the lymphatic function. So from a protocol perspective, we were after, firstly, safety and pilot efficacy. But the other aspects of what we were interested in understanding was the implications of dose and dose frequency on the response. So the way the study was set up is that on week zero, the patients would come in, and we started them on half dose. So right now, etanercept is prescribed at 50 milligrams weekly. We came in and delivered 25 milligrams weekly for 12 weeks. We put this device on the patient's arm, dorsal side of their arm between their wrist and elbow, and we treated them for 12 weeks. Now, if they responded by having approximately a response that's about 0.6 ULR better than where they came in, what we did was then switch them to an extension of another 12 weeks where they would go from weekly to biweekly. They also could stay on weekly depending on how they responded. The big thing about moving into extension A also was during those first 12 weeks, they didn't see a dose escalation. We had built into that first 12 weeks that if they were not responding, we could have went to 50 milligrams. But we saw everybody responding at 25 milligrams, and so they moved into biweekly or weekly. And then, of course, if they continued to respond on biweekly, they could go into an extension to every month. And if they were continuing to respond at weekly in extension A, they could move into biweekly. And what you see on the right is out of the 10 patients, none of the 10 patients went to 50 milligrams, as I mentioned. And in extension A, we had eight of those patients move into biweekly, and we had two of those patients stay on weekly. And then as we switched them to monthly, we saw four patients make it through monthly, and the other five after biweekly did not proceed to monthly. Now, we still have one patient on monthly dosing, so that's why there's only N equals 4. That will be N equals 5 as we get through the study. But what we see here, and we're still evaluating, we haven't closed out the study yet. So we do see that there is a frequency dependence in this dosing. And depending on probably how well this drug works with that particular patient, they could go out to monthly dosing. And if you look at that, that's basically going from a 50 milligram dose down to a 12.5 milligram dose, which is really good from a safety to efficacy benefit. All right. Based on that, I'll go through some of the top-line data. And in this study, we looked at all the DAS properties. We looked at tender joints, swollen joints, and DAS28-ESR and DAS28-CRP. And if you look on the right side, what you see is that we saw a 70% reduction in tender joints. And I'll show you the individual patient data of these averages on the next slide. We saw a 34% improvement in the DAS28-ESR. And we saw a 57% improvement in the physician's global assessment score. And what was really nice to see was that we saw a 62% reduction in the patient's pain scores and a 65% reduction in the patient global assessment. And what you see on the left is the actual averages with the individual patient data. And on the first graph is the disease activity score from week zero to week 12. And that's where we saw the 65% reduction, and that was a p-value less than 0.001 between week zero and week 12. And the patient's assessment of pain is in the next graph. You saw going from week zero to week 12, on average, we saw a 62% reduction, which was also a p-value less than 0.001. So this was a very significant change in pain and disease activity in this study for these 10 patients through the first 12 weeks and half the dose. So now, if you look at what we saw in the actual individual patients, because I think looking at this for this first study was a good way to do this, we saw in the tender joints a really significant drop in tender joints, as I mentioned. And in the swollen joints, we saw some patients that did have a dramatic decrease in swollen joint count. But we did see some patients that stayed, a couple of the patients that stayed relatively flat. And then in the disease activity in the DAS28-ESR, what you saw is that most of these patients had high disease activity when they came in. And all of them had a nice response. And pretty much every one of them went from a high disease activity to moderate. And we had several of the patients that went down into low, and we had a couple of patients that went down into remission. So those are the RA scores for the study. And what I want to show you now is what we saw with the lymphatic response. So what we did, what I'm going to show you is an example of how we characterize the lymphatic function changes that we saw in one of the patients. And I'll show you the summary data after this first example. But I'll show you the videos in a second. But at week zero on the first patient we had in the study, when we were delivering indocyanine green, we saw very little structure to the lymphatic vessels and a rather small observation of pumping rates. And I'll show that in the video. Do I start that, or? I'm not sure if the video is running. All right. Well, I'm just going to move to the next slide here. I apologize for that. So this is a little bit more of an upfront picture. So that really bright spot is where the Sofusa lymphatic delivery device is located. And you really don't see too much of the lymphatic vessels in this image at week zero prior to their first dose. And then on the next slide, you can see when at week six, as we delivered the indocyanine green, that you can now see this clarity. You can see the lymphatic vessels and the pump rates improve dramatically. To summarize this across all the patients, what we have here is on the left, I'm showing you where the device was located for both treatment and imaging and kind of a close-up of what the vessels look like when you're making the videos. Then we take a 10-minute video and we count the pump rates. On the right is what you see are the pumps per minute through week zero, week six, and week 12. What we see at baseline, what we saw was an average pump rate of around one pump per minute. As we move from week zero to week 12, the pump rate increased to 2.9. A pump rate of about around three at this location is a number that we have seen in other imaging studies in healthy volunteers. Over the course of 12 weeks and by delivering etanercept lymphatically, we saw a significant improvement and almost a complete restoration of their lymphatic pump rates. In conclusion, we will say that the rheumatoid arthritis disease activity and lymphatic function were improved in all moderate to severely active RA patients with an inadequate response to 50 milligrams subcu when switched to lymphatic treatment of etanercept at 25 milligrams. From a safety perspective, the lymphatic treatments were well tolerated. We did not have any serious adverse events. We only had mild erythema and some pinpoint blood drops at the application site on some of the patients. We did have one patient exhibit a rash once out of 22 treatments that did resolve. This patient did have rashes with etanercept prior to coming into the study, and we really think that this data is underscoring the importance of directing TNF inhibitors local, regionally via lymphatics and drain lymph nodes in the treatment of RA, so with that, I think we'll move on to Brian to the Q&A. Rusty, before you go on to that, you alternated arms, didn't you, during the study for infusion? Oh, that's correct. That's correct. So I forgot to mention that. Thanks, Mike. So yeah, so every week, we would switch the device from the left to right arm. Okay. So now let's maybe move, Chris, to our discussion and more questions from the audience. Yep. Can you hear me, Warren? Yes. Can you hear me? Okay. Good. Sorry. So let me start. We've got a few questions from the audience, but let me start with just a few general questions. And we'll start with Dr. Querubin. I'd be interested to hear your impressions of the results and your immediate thoughts. I'm very impressed with the results. These patients were moderately to severely active rheumatoid patients. We were using DAS scores. DAS scores meaning if you use a score less than 2.6, that's remission, and mild activity 2.6- 3.2 or so, then severe being 5.2. All of our patients were above 3.2 and several greater than 5.2 DAS scores. These were difficult-to-control patients that have taken the standard dosing of Enbrel with continued disease activity. All showed response to DAS scores, joint counts, pain scales, global scores, and all completed that initial 12-week treatment period with no dropouts based upon effectiveness or side effects. Then through the 24 and 36 week extensions, we decreased the frequencies to every two to four weeks. Most completed those, maybe half completed up to the 36-week extension with sustained improvement. So very impressive for initially 50% of the standard Enbrel dose. And then, like Rusty said, down to even 12% of the standard dose. So impressive results. Given that the Enbrel was only delivered in the arms of these patients in alternating arms, were the improvements that you saw only related to sort of the arms and peripheral in just the arms, or did you see more systemic effects? We saw improvements, yeah. It was delivered to the arms, and we alternated arms, but we saw improvements symmetrically, even though it was delivered alternating arms. And we saw improvements in the lower limbs as well. So more systemic improvements rather than just isolated to that site where it was infused. So yeah, excellent systemic response. Who do you think are the primary patient population that you think this therapy would be most appropriate for? I think it's good for most of our patients. So I think it's good for patients that required this higher dose Enbrel, and you give them a lower dose with similar or improved response. For some patients, you can actually, like we said, reduce the frequency to even up to every four weeks of a medication that was delivered initially every week. And then patients that have these fears of needles or infusions and such would benefit with those patients as well. So I think for many of these patients. So if I understand, you would consider this for first-line treatment as well as for refractory patients as well? Most certainly, yes. Most certainly. Great. Just a couple of questions from the audience as well. And I'll direct this, I guess, to Brian. The regulatory pathway for this, is this a device, a drug, a biologic, a combo? What is the regulatory path for this product? Brian, I can't hear you. I'm not sure if you're speaking or. Yeah. Yes, I was. Can you hear me now? There we go. Yep. I can. I was on mute. Yeah. So the regulatory path. So basically, because of the change in safety, efficacy, and dosing, right, we're pursuing as primary a combination product route, right? I mean, with the change in dosing, this is something that's well beyond a convenience. And so with that, we think the way to develop it and the initial discussions we've had with the FDA are to develop it as a combination product. We are planning now with this data to have discussions with the FDA in the first quarter of next year and present some of this in pre-submission meetings to get advice on the design and the best way to streamline. I mean, one thing to me that's exciting about this data, I mean, getting 10 out of 10 patients to respond is remarkable in any pharmaceutical study. And it's not that we're always going to have 100%, right? I'm sure there'll be some that may not. But what this means is the powering for the study. We may not have to do a really large study. And we're going to take that to the FDA and get advice on what's the best path to develop TNF- alpha from the Sorrento pipeline, PD-1, and move those forward as quickly as possible. So Brian, just while I've got you here, one other question that's various versions of what you're coming in. So the infusion rate on this was approximately 75 minutes, as I understand it. Can you speak to that as where you feel that's going to in terms of the inconvenience of that as opposed to an injector and sort of what the current thought is on that? Yeah. I mean, I think it's a great point and a great question. I mean, people are used now to giving biologics very quickly as injections. So I'll answer that in a couple of ways. So one is, if it's not working, right, you need to try something different, right? So for refractory patients, I think it's pretty clear. Yes, this is longer than a 10-second injection, but doing an auto injector is not trivial, right? There's a lot of instructions and things that you have to do with that. And so we've actually developed a device. The device you saw pictures of was called the DoseConnect device. And that's being used in the clinic specifically for clinical trials because we can very easily change the dose. You don't have to develop and test a completely new dose and container closure. So it's much quicker and much more efficient to use that pump. But the pump and a 75-minute infusion in the clinic is not how we envision this being used. We've developed another device, which Rusty showed a picture of, which is called the DoseDisc. And the key to lymphatic targeting is you're not going to do it in five to 10 seconds, right? It is going to take an hour, maybe two hours. It depends on the dose. But we've developed an all-in-one wearable, which actually is very similar to other wearables that are being used in the market today, right? There's products like Repatha and the Onpro device that are used currently to deliver large volumes of biologics. Now, we're going to be able to cut the dose, so that's going to make it more convenient. Potentially, we can reduce the dose frequency. That's going to make it more convenient, and then you'll have this all-in-one wearable that's Bluetooth-enabled that's going to be able to be used, whether it's once a week or once a month. We think that's going to be a very convenient alternative. You'll have to wear it for an hour or two, but the precedent is out there, and there's a lot of products that are moving that direction anyway. Brian, while I've got you, I'm just going to, as a former lawyer, I'm going to keep you on the stand here for a couple of other questions coming in. The maximum volume that you can deliver with either the DoseConnect or the DoseDisc, can you talk just to that a little bit? Yeah, I can. And Rusty can speak more to it. But basically, the DoseConnect, there's really no limit to the volume that we can deliver. And I think the other thing to recognize is autoimmune is very different than oncology, right? I mean, most oncology infusions are given in an infusion clinic. So the work that we're doing with Mayo Clinic, with City of Hope, we could envision that DoseConnect being an option to be able to deliver in the clinic. But for the, and remind me, Chris, what was the question again? Oh, the volume, right? The volume. Maximum volume. Yeah. Yeah, the maximum volume. And the DoseDisc, I mean, right now, we have designed for a 1.5 ml cartridge and a 2.5 ml cartridge. But those can be adjusted if needed. As we look at the potential to be able to reduce the dose, we think most all medicines will be able to be delivered with the 1.5 ml cartridge. Great. Thanks. I'll take you out the hot seat now. Rusty, this one's another question from the audience. And I'm going to give you this in two parts if you can address both. The first is, what are the drugs do you think are really suitable for lymphatic delivery, and what do you think the next step is there? And then secondly, can you also address, when you do that, those that you think are most appropriate for home delivery? And is that really what you're thinking, or those that would largely be administered at home? Yeah. So I mean, as we look at what would be appropriate drugs for treating lymphatics, right, you're looking at stuff that would go after TNF or other cytokines, right? There's IL-17, IL-6, anything that could go after reducing the overexpressed cytokines that occur in inflammatory reaction. But now, as I mentioned earlier, right, part of what's happening when these types of cytokines and other compounds are draining into the lymph nodes where you have a lot of B-cell, T-cell education going on, I think another big step is to start looking at things that may block certain B-cell pathways. It could be BAFF or APRIL or RANKL. There's several different B-cell pathways that lead to additional information, as well as stuff on T-cells, right? PD-1, CTLA-4 may be another good target for rheumatoid arthritis. And there's some precedent of that. As I think we continue to learn more about how these immune cells in the lymph nodes are contributing to the pathology of rheumatoid arthritis, there probably is even going to be more targets that might make a lot more sense than the ones that we're focusing on right now. Well, and related to that, and again, a question from the audience is, I mean, what are the current studies that are in development for RA by Sorrento with this device? And then second, what are your plans on other autoimmune indications that you might go after next? Do you want me to take that, or? Either you, I would assume either you or Mike, either one. I mean, obviously, psoriasis would be a great place for us to also go after, right? I mean, this would also be a big opportunity, right? I mean, this lymphatic benefit to inflammatory diseases might be a real interesting option even for lupus, right? So if you start looking at the list, right, you could go down to that. And we are right now doing some work in psoriasis. Great. Chris? Yeah, Brian? Yes. Yeah, just to add to that, I mean, I think if you think about the Sorrento pipeline and then the potential partnered pipeline, right? So I think right now in rheumatoid arthritis, we have the best data around TNF- alpha. So that's what we're developing currently with Sorrento. I think as we look at some of the other antibodies with the G-MAB library, I mean, we've got infinite possibilities there. And I think we'll be looking for what are the areas that we want to build, not just clinical capability, but also commercial capability. And I think with rheumatoid arthritis, we've got Scilex in the pain area. Currently, I think that's one that commercially makes a lot of sense. And I think we'll continue, as Rusty says and Mike has many thoughts on where we might be able to go with other mechanisms and other indications. But what we would do with that is look at the preclinical models and look where we're really getting the most differentiation in the highest unmet need areas. So it's a bit of a wishy-washy answer. We're going to focus on TNF- alpha right now, but we are going to really use this to learn and explore some of the other areas. And we'll develop the most promising ones with the Sorrento pipeline, and we'll be open to partnering discussions for those that may have expertise in some of the other areas like psoriasis or lupus. All right. Yeah, the really. I'm going to. Sorry. I'm sorry. Sorry, Mike. The potential really interesting opportunities are for superficial tumors like melanoma. We're starting up a study with Mayo on that. There's also sort of really wild potential to deliver cellular therapies targeting, say, melanoma or even oncolytic viruses that could be delivered through this pathway. Lymphatic delivery is sort of a new area that people are thinking about as a way to fully tap into the efficacy potential of any product, and so these are pretty cool things to consider rather than just dumping everything in intravenously or subcutaneously or however. Perhaps there's an alternate delivery mechanism that may fully tap into the efficacious potential of any product, and so we'll be looking at all of those things in time as we work with Brian and Rusty on these things, and Mike, on a related question to that, do you see this as improving treatment to the sentinel lymph nodes? I'm sorry. I had some background noise. Could you restate that? Sure. Do you see this as improving the treatment to the sentinel lymph nodes? I think clearly there is that going on, but there's also the possibility that you're getting fully activating any product that's delivered lymphatically that can then have a systemic effect. We've known for a long time that a vaccine delivered lymphatically can produce the same efficacy response as an intramuscular vaccine at a lower dose. I mean, I myself participated in this study with the hepatitis vaccine a long time ago where they were trying to do intradermal with a needle rather than sub-Q, and the results were definitely in favor of an intradermal approach, but as many people who have tried to do intradermal injections with a needle, it is really hard to keep it in the right place. And a microneedle array that is designed to do exactly that is far superior and less likely to deliver product somewhere where it's not supposed to be, largely typically subcutaneously when you try to do it with a needle. So I think this provides an opportunity to make patients happier because they're getting potentially lower amounts of drug and getting a better effect than what they may have gotten with the higher dose. And so you can get the benefit of a lower side effect profile with better efficacy. And patient satisfaction is important. I mean, the patients in the study really loved the way that it was delivered, relatively pain-free. I mean, sure, you had some very minor punctate-type bleeding, but compare that to a subcutaneous injection where everyone gets bleeding and discomfort, especially when you're trying to deliver more than a very tiny volume. So I think this has a definite role to play, whether it's a 505(b)(2) approach for an approved product or whether it's a drug-device combination for a new chemical entity, for example. All of these things are potentials. And eventually, you could even get the device approved for lymphatic delivery of any other drug given that potential as an approach to FDA. So there's a lot of potential with this product and the delivery mechanism completely untapped at this point, but we'll try to do our best to fill that basket with potential opportunities. Thanks, Mike. That's great. And actually, I think that's a good dovetail for a number of questions about the study for Dr. Querubin. And Dr. Querubin, I'll just start by dovetailing off of Mike's discussion of the patient response. What was your feedback on the patient experience or pain levels after the application that were reported by the patients? The main feedback regarding the application is that it was simple, very simple application. It was much better tolerated than injection therapy. No injection site pain, no fear of needles or sub-Q or IV access, and there was virtually, like you said previously, no significant infusion site pain. Some patients stated maybe pressure with application of the site, but no pain. Some patients had some redness at the infusion site, but it was transient, but overall, very happy with the experience. They were impressed with therapy. Like we said, it was just half a dose. Very impressive. So another question just from the audience, a few others here is, what were the characteristics of the patients that made it into Extension D or the monthly dosing regimen? Rusty, do you have those? Yeah. So they had to have a 0.6 or better response on their DAS28 score in order to move into the biweekly. And they could not lose that 0.6 change in their DAS28-ESR score on biweekly to move into their monthly. So if they started at 4.8, they on weekly got below 4.2 on DAS28, and they had to stay there or continue to prove to move into each extension. Great. And Rusty, while I've got you here, I'm going to give you one more question from the attendees. Do you have data comparing your one-hour sub-Q infusion to one-hour lymphatic delivery? No, I do not. I mean, the only data that the way we actually do that comparison is we've done it in animals where we would put the device on the back of, let's say, a Sprague-D awley rat. And we would look at the biodistribution from that, and we would do the sub-Q injection at that same point. Now, we have done a little bit trying to extend the duration of which we did that sub-Q. So I think we've done out to maybe 10-15 minutes with a needle that is in the subcutaneous. And you still don't get the lymphatic absorption results or the change in the arthritic paw swelling in rats. So been unsuccessful to this point with what I've described to you. And on that same point, Rusty, what was the serum PK for Sofusa compared to the PK of IV? So with the etanercept, we run about a 70% bioavailability, which, versus sub-Q, is actually a little bit better. We haven't analyzed the actual serum samples from the study yet at the different time points, but we do know the bioavailability is somewhere around 70%, 60%-70%. Great. And back to Dr. Querubin, a question here. So what explanation can you provide for why the patient showed an inadequate response to sub-Q injection from Enbrel, but then responded when it was delivered lymphatically? Per Rusty's presentation earlier, if you have inadequate concentrations of the biologic in the lymphatic system, it'll affect response. So if you go through, say, sub-Q or IV, it has to go through what's known as the first pass effect. Medications absorb through the circulatory system. Some of it's cleared through the liver kidneys. Some of it eventually gets to the circulation to the lymphatics. So Sofusa is directly absorbed, administered into the lymphatics, shown to have high concentration of the biologic where it's most effective in the lymph nodes. So better response lymphatically. That's great. And maybe just, Brian, I'm not sure if we have any additional questions. I don't think we have any more from the audience. Is that right? Okay. Well, thank you for all the panelists for your time. With that, I'll, yeah. Sorry, Rusty. Yeah. I just wanted to add to what Dr. Querubin said. So one other interesting element of this is if you looked at the health records of some of these patients, there was some speculation that ADAs were helping to contribute to the poor response of sub-Q. So what I thought was quite fascinating about that with some of these patients is they would still have had those ADAs most likely when they came into the study and they started to respond right away. So we are evaluating all that data on these patients. The analytics will come out, but it does appear that in some of these patients, that ADAs were part of it, and the lymphatic delivery didn't seem to be impaired by the fact that they did have high levels of ADAs when they came into the study. Great. Well, I don't think there's any additional questions. Again, thank you so much for the panelists for being involved and taking the time and for everybody for attending. With that, I'll turn it over to Brian maybe to wrap up, and Brian, I think you're on. Oops. Hope you're good now. Unmute me, please. There I am. Yeah. Well, thank you, Chris, for your participation and help in the moderation. Thanks to all the participants. We had over 50 participants, and hopefully this was interesting and helpful for everybody. Thanks also especially to Dr. Querubin. We also had a site in Houston, and so we're very appreciative to the patients and the investigators who have helped us uncover an important chapter in the Sofusa journey. So we were, I think, extremely motivated before to make this dream become a reality, and we're even more motivated now. So we're looking forward to a lot more. Stay tuned for data in not just rheumatoid arthritis and cancer, and we look forward to a lot more from the Sofusa team in Atlanta. So thanks, everybody, and everybody have a great rest of your day. Thank you. Thank you.