Good afternoon, and welcome to the Biora Therapeutics KOL event. At this time, all attendees are in a listen-only mode. A question -and -answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the Biora website following the conclusion of the event. I'd now like to turn the call over to Dr. Ariella Kelman, Chief Medical Officer at Biora Therapeutics. Please go ahead, Ariella. Thanks very much, Taryn. It's a pleasure to be here with all of you today. We are pleased today to present our phase I clinical trial results from our NaviCap platform program, BT-600, a combination product of liquid tofacitinib delivered via the NaviCap platform. With no further ado, I would like to turn it over to Dr. Bruce Sands. Thanks very much. Thank you so much, Ariella. It's a pleasure to be here with you. These are forward-looking statements. I'm Bruce Sands. I'm the Chief of the Division of Gastroenterology at the Mount Sinai Health System in New York, and it's my pleasure to introduce you to some of the concepts of unmet needs in patients with ulcerative colitis. We'll start by describing what the condition actually is. The clinical presentation of ulcerative colitis can be conceived of as the location of inflammation within the large bowel. The disease is thought to progress distally in the rectum and involve more and more of the large bowel to eventually, in many patients, involve pancolitis. The symptoms can be different according to the extent of disease. On the left-hand side, you see extent one, which is proctitis. The symptoms there uniformly include rectal bleeding, as well as often tenesmus and urgency, though not necessarily diarrhea in some patients, and this would represent something between 30% and 60% of patients. Another 16%-45% of patients, depending on the data source, would have what would be called distal colitis, or we might call it left-sided colitis. This is disease or inflammation up to the splenic flexure, and in addition to rectal bleeding, you'll have looser bowel movements or diarrhea, abdominal cramping, and a variety of other potentially constitutional symptoms in some cases. But the constitutional symptoms become really prominent in patients with more extensive pancolitis. That means involving the entire large bowel, and that should be E3, not E1, in that part of the slide. Essentially, those patients may have symptoms of fatigue, fever, other things layered on in terms of severity. Now, it's always a bad thing when a patient initially has proctitis or more limited colitis and then extends their disease to involve more and more of the colon. That is known to be a bad prognostic factor for subsequent outcomes. We can also talk about what the disease is. In the left-hand side, you see normal colon. This is a biopsy taken somewhere in the colon. You see the lacy pattern of the goblet cells, which produce mucus, which is a protective factor for the surface of the colon. It's a very large surface area to defend from possible pathogens and invaders. So it would be normal to see inflammation in response, for example, to Salmonella or Shigella. But what we see in ulcerative colitis is an idiopathic inflammation that can be more and more severe. In the biopsy, on the upper left-hand side of the panel of four, you see inactive chronic colitis. This is bowel that has evidence of prior inflammation but is now mostly healed. You see branching of the crypts and dilation of the crypts, but there is not an inflammatory infiltrate of any sort other than normal physiologic amount of infiltrate. On the upper right-hand side, you see mildly active chronic colitis, characteristic of mild ulcerative colitis, and the characteristic there is a neutrophilic infiltrate and often what are called crypt abscesses that will occur, but this is involving the lamina propria and the epithelium. In the lower left-hand side, you see more moderately active chronic colitis. You see there are more blue cells packed into the mucosa, and then surely here you see evidence of some crypt abscesses, where the neutrophils are actually migrating into the epithelium, and that is a part of the disease process. And finally, on the lower left-hand side, you see frank ulceration, denudation of the epithelium, and the mucosa is packed with these inflammatory cells, plasmacytic infiltrate, lymphoplasmacytes, and neutrophils, which are the hallmark of the inflammation. But I think the thing you can take away from this appearance is the disease really is in the surface of the large bowel. That is where the disease is confined to. It doesn't involve the small bowel. It doesn't really extend much more deeply, except maybe in extremely severe cases. It's also worth noting that this is a high -impact condition. It's estimated that something like 1.5 million patients are affected by ulcerative colitis in the United States. There are at least an equal number in Western Europe and many more in other parts of the world. And in fact, if you look at epidemiologic trends across the world, the incidence of ulcerative colitis, and in fact, IBD in general, is rising across the globe, including places that previously had very low rates of incidence, such as Eastern Asia, China, India, these sorts of places are seeing a dramatic rise in the incidence rates. So it is estimated by the 2030s, this will be something of a global epidemic. And the disease has a great impact on the individuals who are affected. Many patients feel their condition actually controls their lives, and this is responded to in a positive way more often in patients with ulcerative colitis than, for example, other conditions like asthma or migraine or rheumatoid arthritis. On the right-hand side, you can see that patients worry about the long-term effects of the disease. The disease makes life much more stressful for them. It's an embarrassing condition. It affects their bowel movements. People are, in our society, much more prone to talk about their sex lives than they are about their bowel habits, so it is quite embarrassing. Many patients are depressed or anxious, so this has an enormous impact on the individual and, in fact, on their families as well. Despite many advances in the treatment of ulcerative colitis, we still have a very large therapeutic gap. Here you see an array of what are called advanced therapies for the treatment of ulcerative colitis, starting on top with the S1P receptor modulators in yellow. Etrasimod, recently approved, ozanimod, approved just a few years ago, and you can see that gap is rather large on the left-hand side, and we're talking about clinical remission during induction. This is short-term clinical remission. If we turn to the best agents that we have, things like, the JAK inhibitors, especially upadacitinib, or we look at infliximab, one of our oldest advanced therapies, anti-TNF antibody. We see maybe better efficacy, but we're still leaving many patients behind who are not achieving, out-and-out clinical remission during induction, and this is just induction. The story is even worse if you consider maintenance of induction or maintenance of that effect over the course of a year or subsequent years. You see many people who respond or remit actually lose their response or remission over the course of time. So all of this is to say that despite many different, newly approved agents over the last 25, 28 years, there still is room for improvement, and many of these agents also have, issues with safety. For example, the JAK inhibitors, of course, have a black box warning, as do the anti-TNFs. The JAK inhibitors, in particular, can't even be used in the U.S. until a patient has failed a TNF inhibitor. So there's a huge unmet need in ulcerative colitis, and there is a desire, because this is a colonic disease, and the disease is superficial in the mucosa, to target the disease anatomically and topically, and that this perhaps, has the promise of improving, both efficacy and patient outcomes. The challenges really are that there's difficulty in achieving sufficient drug activity at the site of disease. All these drugs, even if they're given orally, are absorbed pretty much in the small bowel and have systemic effects, and then make their way to the large bowel, where they have very specific effects on the ulcerative colitis itself. So the potential solution there could be localized delivery, which could increase drug activity at the site of disease, which is, after all, accessible, and that should correlate with improved outcomes. The second issue is there's systemic toxicity, which may occur in relation to the systemic nature of exposure with any of these medications. Some are, of course, safer than others. It's unfortunately, the fact that the more effective therapies are also the ones which have more issues with adverse events. So the hope is that with targeted topical delivery, you could reduce systemic uptake and reduce the toxicity and adverse events. And finally, the world of IBD, because of the limitations of efficacy that I remarked upon before, we are all turning to the notion of combination therapy, that we're not going to overcome this therapeutic plateau with one single agent, but more likely, we will achieve that by combining different agents. But if we're going to do that, we need agents with very limited toxicity. And again, this topical targeted delivery could help us achieve that goal as well. So NaviCap, as you're going to hear, does achieve that targeted oral delivery. It's anatomically targeted toward delivery of an agent in the large bowel, where topical application of the drug will have an impact. So instead of the conventional means of oral delivery, which is basically ingestion of a capsule or maybe injection, where the drug is absorbed systemically, and then eventually makes its way to the colon, NaviCap is really being taken orally, but it's really delivery from lumen into the tissue of the colon, and from there, to a smaller extent, to the blood. So this achieves tissue exposure through topical delivery, but lowers systemic exposure to the drug, and that's the promise of NaviCap that you're going to hear about here. And with that, I'm happy to turn this over to Ariella. Thanks. Thanks very much, Bruce, As Bruce just told you, NaviCap is our oral delivery platform, which has been programmed to deliver drug directly to the colon. Here's a picture of it here, and it's a convenient oral capsule. It's approximately the size of a fish oil pill, and it's an electromechanical device, which uses what we call GIT rac auto location technology, dependent on changes in light reflection throughout the various anatomic segments of the GI t ract. It thereby enables targeted delivery directly to the colon, and we have tested that in both fasted as well as fed states. This is true also regardless of level of GI motility or other physiologic states, such as differences in pH. Does not depend on those. And this enables targeted drug delivery, using a formulation method designed to coat the length of the colon and minimizing systemic uptake. Today, we're going to discuss our phase I clinical trial, which evaluated the safety and PK or pharmacokinetics of BT-600, our drug device combination of NaviCap and tofacitinib in healthy participants. This was a study of 48 healthy participants. We had a single ascending dose portion as well as a multiple ascending dose portion. We studied 5 milligrams as well as 10 milligram daily dosing, unlike XELJANZ BID dosing, versus placebo. And in the single dose cohorts, we gave a single dose and followed patients out. In the multi-dose portion, we treated daily for seven days, and on the eighth day, we did a flexible sigmoidoscopy, so we were able to do tissue biopsies and to look at colon tissue concentrations as well as colon tissue histology for safety. I'm really pleased to report that we have met all trial objectives in this phase I study. We showed precise drug delivery to the colon with limited systemic exposure. The plasma PK profile was consistent with drug delivery in the colon. Tofacitinib was first detected in blood at approximately six hours, and that is specifically consistent with colonic delivery as opposed to upper GI tract delivery or systemic delivery, where you would see drug in blood much, much sooner, for example, at less than 30 minutes. Maximal blood levels of drug were three to four times lower than seen with XELJANZ, and we demonstrated the ability to deliver tofacitinib to the colon with overall lower systemic concentrations than seen with conventional oral delivery in both the SAD and MAD cohorts in this study. I'm also pleased to say that we did see evidence of pancolonic drug delivery. NaviCap delivers its payload in the proximal colon, and tofacitinib was detected across all biopsied regions in the distal colon across multiple sites. The delivery and distribution of tissue exposure was consistent with delivery to the entire colon. And, we have also done some modeling which projects tissue levels at or above the estimated IC90 or inhibitory concentration of the JAK/STAT pathway across all three biopsy sites through at least 16 hours. We also were able to study device function in this trial. After the NaviCaps were ingested and the subjects were dosed, they were collected, and the software was analyzed. We were able to show that over 95% of devices successfully detected colon entry, and that this correlated with pharmacokinetic data as well. Very importantly, the NaviCap, in combination with tofacitinib, was well tolerated by participants in both the SAD and MAD cohorts. We were quite pleased with the safety of daily administration. We saw a consistent drug release in the colon, bypassing the upper GI tract. As the NaviCap traverses through the GI tract, it makes calls, which we call S1, S2, S3, and S4 calls, as well as an S5 call outside the body. S4 call signifies that the NaviCap has detected colon entry, and we can see when S4 calls were made by analyzing the board inside of the NaviCap. Over 95% of devices successfully detected colon entry. There was no early drug release before colon entry, which we consider to be quite important and quite specific to the NaviCap and consistent with excellent, precise device performance. There was a very tight correlation between software device function and pharmacokinetic results, and data was consistent with those which we previously observed in four separate human device function studies, including in studies of in patients with ulcerative colitis as well as healthy volunteers. You can see that during the SAD portion, devices identified colon entry in 100% of the time, and during MAD, it was 96% of the time. The mean time of colon entry in hours after ingestion was about six hours, and the first time we saw drug and blood was about an hour later at about seven hours, and this is consistent with what we expect with normal GI physiology and what we've previously seen. The PK profile that we saw in plasma confirms lower systemic levels with three to four times lower Cmax than has been seen and published with XELJANZ. What you're looking at here is a single dose of pharmacokinetic plasma curves, the plasma concentration time curves, and we're showing it here for our phase I results with BT-600, and also for published results with XELJANZ of their single ascending dose study, also in healthy volunteers. It's very clear from these curves that we do see dose proportionality with 10 milligrams showing higher concentrations than five milligrams, and overall much lower concentrations than are seen at comparable doses with XELJANZ. You also see a blunted Cmax, as well as an overall wider curve, which is associated with a preferred therapeutic index, which is considered to be associated with potentially less toxicity. During the multi-ascending dose portion, when we delivered daily dosing for seven days, the pharmacokinetics were confirmed. And similar to what we saw in the SAD portion, the PK confirms, once again, colonic delivery with first drug in blood anywhere from six to eight hours, and overall low systemic exposure, compared to XELJANZ at similar doses. And this is true for the maximal concentration, or the Cmax, and also true for the overall AUC. These are characteristic and specific example, single -subject concentration time curves during the MAD portion, and the blue represents 10 milligrams, and the green represents five milligrams. And what you see is a very consistent PK profile with repeat doses. Once again, we're seeing dose-dependent, low systemic exposures, consistent dose on dose and timing, as well as levels consistent with colonic delivery. Moving on to our colon tissue data. What we're showing here is an example, a subject, and their plasma concentration profile for the final dose. The final dose is on day seven, and what we're showing here is our methodology for our biopsy. It is pretty unusual to do flexible sigmoidoscopies in healthy volunteer studies, but it was important to understand the PK profile in our development program. So what you're seeing here is the timeline, and we dosed on day seven in the morning. We know that payload release happens at approximately five to six hours. At eight hours, we delivered an oral laxative for bowel prep, and then at 18 hours, we also delivered an enema for bowel prep. So we did an extensive bowel prep in this healthy volunteer study, and then we did a biopsy approximately 24 hours later, so 22-26 hours later, following a full bowel prep, and really at the time of trough, so very low plasma levels during that time. The last plasma drug measurement was at 20 hours. We're really pleased that we saw evidence of drug delivery, even at this late time point, across all distal biopsy sites. At the splenic flexure, we saw it in 15 out of 18 biopsies, in the descending colon at 15 out of 18 biopsies, and in the sigmoid colon at 14 out of 18 biopsies. It's important to note that this is in the distal colon, where disease is most common. With proximal delivery, it was important for us to understand whether or not we would see distal delivery, and we did see distal delivery. Drug was measured in tissue across these distal colon sites following proximal payload delivery, and the results are consistent with pancolonic delivery. The colon tissue absorption was demonstrated despite a long dose to biopsy latency, a pre-procedural bowel prep with oral and rectal laxatives. And also, these are healthy participants, as opposed to patients with ulcerative colitis, who may have enhanced colonic absorption during active inflammatory disease, and we will have opportunities to study that in our next studies in UC patients. We're also pleased that we saw really, very strong correlations between tissue and plasma levels at the end of the dosing intervals. These are the plasma levels at 20 hours after the final dose, with the tissue biopsies done at about 24 hours. And what we saw were measured mean concentrations above the IC50 across all three biopsy sites at, you know, many half-lives post-dose. This strong correlation between the plasma and tissue levels enabled us to model tissue levels at earlier time points so that we could understand what we might see in UC patients in future studies. And so the reason why we care about this is because tofacitinib tissue concentrations have been shown to correlate with endoscopic response, with responders having a median tissue concentration above the estimated IC90, but really just overall higher than the non-responders. And you can see our tissue concentrations that were observed, and the mean levels were 338, 159, and 161 across all three biopsy sites. But that was at a very low plasma concentration, actually even lower than this, 'cause it was four hours later, towards the end of the concentration time curve, and the dosing interval. However, our modeling projected that at earlier time points, the colon tissue concentrations really should be much, much higher at a range of 3,000-10,000 nanograms per gram at approximately 16 hours. So, what this means is that the levels are expected to be above the IC90 during the dosing interval, and at levels at which we anticipate to see a better efficacy, potentially, at lower doses and safer doses than are seen currently with JAK inhibitors. Moving on to our safety data, BT-600 was well tolerated. Remember, this is the very first in-human study of the drug device combination, and all adverse events were mild and resolved, and they were consistent with those expected in a healthy population, things like headaches, sore throat, constipation. There was no evidence of device or drug colon toxicity. We did colon tissue histology on every study subject, and those were all within normal limits. There were also no notable changes or difference in safety laboratory parameters between groups, and we attribute this to low systemic concentration of drug. These are very important PD safety markers for patients who are treated with JAK inhibitors, in particular, LDL cholesterol and neutrophil counts showed over time here. In summary, we are quite pleased with our phase I trial results, and these results give us quite a lot of confidence to proceed to clinical trials in patients with ulcerative colitis, and support our clinical development plan. Our next step is to do a pharmacokinetic and safety study in patients with active ulcerative colitis. This will inform our future phase II dose selection as well as other aspects of future clinical trials. Following those data, we intend to move into robust efficacy studies in patients with UC, where we will be able to leverage these findings with the NaviCap platform and combination, as well as leverage all prior data from with XELJANZ. Thanks very much. I'll now turn it over to Dr. Brian Feagan. Well, thanks very much. It's really been a pleasure to be involved with this development program, because I think it offers something cutting edge and disruptive technology that we don't see often. So my role is to reinforce some of the principles that Bruce outlined, and really talk about the notion of regional drug delivery in the gut, and why it is such an attractive concept, but in practice, currently it falls short. So we've had a lot of experience with this concept, because it does make clinical sense, is to treat the area where the disease is, as opposed to systemically, and most prominently with 5-ASA compounds over the past 30-40 years, and corticosteroids. There have been other attempts to use other drug classes, such as calcineurin inhibitors and some other agents, and these have been less successful. I think why there have been failures is that this is really a complex process. You have to get the drug into the GI tract, deliver sufficient concentrations to the tissue, and in the correct region that you're interested in treating. And finally, the drug has to get across the mucosa and into the tissue where it affects immune mechanisms. So this is probably a limitation of many of our treatments, that the doses needed to achieve sufficient colon tissue exposure are limited by toxicity, in some cases with systemic treatments, and that precise topical delivery could provide a solution to that problem. So let's talk about the current methodologies or technologies for facilitating colonic delivery. Well, you can just put unadulterated or unformulated drug in the rectum by enemas or suppositories. The problem with that is that patients with inflamed rectum do not tolerate substance in the rectum for very long, so ensuring adequate exposure is a problem with that method. It's also limited anatomically, in that with an enema, you can reach the splenic flexure, but you can't reach more proximal disease, which is important in many patients. And most patients obviously prefer an oral therapy rather than using enema or suppositories. So the existing solutions are mostly focused on oral therapies that use Eudragit, which is a pH-triggered mechanism, and/or bacterial release systems that rely on the microbiome to provide release of free drug. So these systems theoretically could provide a solution and do provide a solution, but they're subject to many confounders. And most importantly, the pH in the colon is highly variable, dependent upon inflammation. Inflamed tissue produces greater, well, more acid in the local site of the inflammation, and this can affect the release properties. Obviously, motility in the colon is highly variable among individuals, and things like the water content of the stool and the bacterial population can also affect release. So it's a complex system, and our existing methods are... Well, the clinical corollary of this is we often see capsules come out in patients with these formulations, indicating that there has not been appropriate release. So let's now look at the concept of ensuring that one gets efficacy by measuring tissue concentrations. This is the ultimate PK/PD relationship, if you're thinking about a therapy that's targeted regionally in the gut, is that you want to see adequate exposure in the tissue, throughout the colon, or if you're looking at targeting limited areas of the colon in that specific region. And ultimately, you also want to see the PD relationship, both clinically and with activation of the appropriate target. So surprisingly, given what I've just talked about, there's very sparse data regarding this question. Now, fortunately, with tofacitinib, we do have this study that was conducted with investigators in Leuven, and the sponsor facilitated the investigation. And it's looked at 30 patients with ulcerative colitis, just at the top panel there, and showed an association between higher concentrations of drug, tofacitinib, in the tissue, in responders than in non-responders. So, you know, at the most basic level, there is an association based on this study. Now, the question has been very hotly debated with monoclonal antibodies, is how important tissue concentration is. And here, the data are really, again, pretty sparse. But suffice it to say that probably the best study is the one shown in the middle set of figures, where, at the University of Miami, Maria Abreu measured REMICADE concentrations and TNF concentrations in tissue in patients with, ulcerative colitis, and this is 30 patients. If you look at the bar graphs, we see something pretty interesting, that in patients who had adequate, response, so a Mayo Clinic endoscopic subscale score of 0, so normalization of the mucosa, there was a relationship with tissue exposure. However, in inflamed tissue, patients with higher-grade Mayo scores, no such association could be demonstrated. That led to the hypothesis that perhaps the concentrations of TNF in the tissue actually interacted with drug and obscured any relationship between healing and the drug exposure in those patients. Interesting observation and needs to be confirmed, but probably one of the best studies about antibodies. Then, finally, on the bottom panel, we see a study that was done with adalimumab, looking at the association between tissue exposure in endoscopic responders. Here, we see a clear relationship with responders having higher drug exposure in the tissue. Moving along, this is probably the key figure of my presentation, and we've seen bits of this before, but it's a complex concept, and I'd like to walk you through it very carefully. So this is trying to get at the, relationship between serum exposure with tofacitinib and tissue concentrations. And, the company is very fortunate here in that tofacitinib was not selected by ac- by accident. It's a very active drug. It's highly effective, and it's effective at doses that are suboptimal. That because of concerns by regulatory agencies regarding toxicity, we were not allowed to explore doses of more than 10 milligrams BID in ulcerative colitis. And that was despite the fact that in a dose-ranging study that included patients exposed to 50 milligrams PO BID for induction, that was the most effective dose. So we saw earlier, there's linearity between exposure, with dose and higher doses with tofacitinib, greater efficacy beyond the 10 milligram BID in tissue concentrations. And that's what this figure is showing. So it's showing the conventional XELJANZ dose of 10 milligrams BID, the highest dose in clinical practice. On the Y-axis, we see the tissue concentrations across the various plasma concentrations in this sample of 10 milligrams BID. You can see there's variability. Just to benchmark this, look at the X-axis of 10 micrograms BID, you see tissue concentrations of around 800, and then the linear association. So that's a very important observation, that there's a very tight linear association here with the benchmark drug, highly statistically significant and a very high R squared value. So that's important when we look at the data for NaviCap. So, two panels in the middle and on the far right, we see in the middle data regarding tissue concentrations versus serum concentrations for five and 10 milligram exposed patients. And on the far left, we see that, that's in the descending colon, so more proximally. And then finally, the most important, on the right-hand side, we see the rectal concentrations or, sorry, sigmoid colon, a more distal site. And, as Bruce identified earlier, if you don't control disease in the rectum, patients have tenesmus and urgency, and the drug will fail despite healing more proximally. So examining the two middle panels, we see that we can project from the data with lower exposures, both in serum and concentration and in tissue, than we would achieve with conventional formulation. So off the end of that curve, towards 10 milligrams, that we would ultimately get the exposures in tissue of north of 400... 4,000 nanograms per gram of tissue. And that's well in a, outside what we would see with the conventional agent. So this really offers up the possibility that with far less systemic exposure, as was shown earlier, that you would achieve higher tissue concentrations, and that efficacy will be driven by the tissue concentration. So this is really the potential of the drug. Not only for this drug, but for other drugs, that you're really getting drug to where it's needed at high concentrations and minimizing systemic exposure. So coming back to the basic principles of regional delivery, you have to have a drug that consistently achieves tissue concentrations, regardless of what site you're targeting in the GI tract. And that will be robust in overcoming all the potential confounders of differences in motility and pH, that can influence conventional preparations or formulations. And that's really what NaviCap does. It really precisely delivers a large amount of drug where it's exactly needed. So the precision release concept is really fundamental and, in distinction to other formulations, such as Eudragit or bacterial enzyme release formulations, that there really has not been an early release identified in the phase I trial. And then I spent a lot of time talking about the tissue exposure relationship and how that's fundamental, the PK/PD relationship, and operating on a different PK/PD relationship in the tissue than with a conventional oral formulation of XELJANZ. So I think that concludes my remarks, and happy to take questions later. So let me just do a quick summary here. As you heard, around two-thirds of UC patients are left with significant treatment gaps. Key issue is getting enough drug to the area of disease in the colon. People have tried several methods, you know, to try and reach the colon. These methods, often based on pH, enzyme, nanoparticle technology, others, quite variable and not consistent or reliable. NaviCap works extremely well, repeatedly, consistently delivering to the colon. You heard today that NaviCap tissue exposure is very encouraging, and we may be able to reach the threshold with a much lower systemic exposure. This is great because that might allow us to break this ceiling of 20%-30% response with other therapies, and we look forward to providing that benefit to patients. Our results from all our studies to date, certainly the ones discussed today, give us great confidence moving forward with BT-600. We're excited about the potential to use NaviCap to also deliver other molecules for UC and beyond. With that, I'll turn it back to Taryn. Great. Thank you, Adi. So at this time, we'll be conducting a question-and-answer session with our speakers. As a reminder to our audience, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. For our analysts that are joining us live, please use the raise hand function to indicate you have a question. Please hold for a brief moment. So our first question comes from Joe Pantginis at H.C. Wainwright. Please go ahead, Joe. Hi, everybody. Can you hear me? Yes, we can. Okay, great. Thank you. So look, very exciting data. Love the consistency of what you've been showing in the healthy volunteers. So you know, strictly from a you know, what you've presented standpoint, just curious, I mean, it was very few devices in the MAD portion of the study. Do you have any reasons or theories yet, data-wise, as to why the device did not detect colon entry, the very few that didn't? And does any data you have right now impact any of your upcoming studies or anything with regard to the device? So, thanks very much, Joe, for that question. We consider it to be really fantastic. Device function data, 100% in the SAD, 96% detected colon entry in the MAD, and, most importantly, no early releases. So, you know, we're quite pleased with this device function data, and, you know, and, we look forward to studying the same device in the next clinical trial. No, that's great to hear. Thanks. And I guess, look, I'll admit right now, my next question for Dr. Sands and Dr. Feagan, you know, are a bit forward-looking, but, you know, you've shown the nice correlations in the last slide, for example, very nice to see. I guess, this SAD/MAD data in healthy volunteers, how predictive do you believe they are in UC patients at this point? Obviously, you know, it's a bit of hand-waving, but you do show nice correlations. So first, a comment on the predictive nature, you know, for the phase Ib and beyond, and, you know, what would you consider, as of right now, a bogey to be, or a benchmark to be, of sort of response, response rates that you would like to see? Equivalence, better, you know, where would you view the bogeys as of today? Well, perhaps I could start, and Bruce can chime in. Well, as a general rule, with small molecules, you see greater exposure in inflamed tissue than with healed mucosa. And that, however, does vary from drug to drug, as you kind of alluded to, and so the devil's in the details, and the company needs to study patients with inflamed tissue, for sure. But I would bet, at this point, that you would see greater exposure in patients with inflamed tissue. And then the second component was really, well, what do you need for this to be a viable commercial product? At the lowest bar, you could say if you achieved efficacy that was similar, highly similar to XELJANZ 10 milligrams BID, and you did not see the calling card disturbances in lipids and CK liver enzymes, that would indicate that you're not seeing systemic PD effects that are concerning to the regulatory agencies, which is limited to drugs. However, I think, I hope the company does better than that, and we actually see efficacy comparable to the 15 milligram dose that was studied in phase II, because that really looked quite good. So if you could have that without the systemic toxicities, then that would be really a breakthrough. Sure. And maybe I can comment, too. I agree with what Brian said about the different pathways to success here. The only other thing that I'll add is, the reason that I think the healthy volunteers are going to translate well into what you see in diseased individuals is, the mode of delivery doesn't vary according to whether you're healthy or diseased, in that what is different in the diseased individual is there is increased motility, so things move through more quickly, and there is a difference in pH. This device is not sensitive to either of those things. It's going to deliver based on a different signal in exactly the right place, and therefore, I think there's a high likelihood that the results will be replicated in diseased individuals. No, I appreciate that. And I just have one more question, and I thank you for indulging me. So obviously, the broader question, which is, you know, not for today, is, you know, application for other drugs, but I want to take that question and use Dr. Sands' comment about, you know, the need and the future of combination therapy in UC patients. So, you know, your views, and maybe the company's views, of how the device might be used for combinations, you know, based on, you know, the drugs, each individual drug having its own individual PK/PD profiles. Yeah. I mean, it's safe to say that we're throwing things together because we have them. But the more kinds of things that we have, the better likelihood we have that we're going to have a safe and effective combination. But in all these combinations, it would be tremendously appealing to have at least one of them be topically active and colonically delivered. In fact, it would be preferable for both of them to be, because we think that's going to enhance safety, and we think it will enhance efficacy as well. It's hard for me to say which. You know, if you're asking me which drug should this be combined with, I can't really say. You know, we can guess that, for example, this might be combined even with an anti-TNF, which has its own safety issues, but maybe wouldn't be added to by something that's topically delivered in this way and has low systemic exposure. Or even better would be something very safe, like an anti-IL-23 and a JAK inhibitor would make some sense, although they're sort of somewhat overlapping in some sense, so not sure if they would be synergistic or not. But those are just some initial thoughts, and maybe Brian has more. Yeah. I guess I'd maybe take back it up a little bit and think about the big picture here. So for the next five years, all we're going to be thinking about is combination therapy.... And And a lot of the combination therapy is going to be systemically based. However, we know that payers are not particularly happy about parenteral administration of drugs, be it IV or subcutaneous. So the next phase will be oral drugs. We've already started down that road, and combinations of oral drugs. So this feeds into the concept of the device. And finally, probably beyond that, beyond just combinations of oral drugs, it's going to be the whole concept of targeting the mucosal compartment as opposed to systemically. You can imagine very sophisticated approaches that may take into account, and here I think the company should speak out about what they see in the crystal ball for development of the technology, about different drugs and ability to different drugs in different places. You can imagine a drug that you want to optimize small bowel absorption, and for a component of the product, and then still have colonic delivery. There's really a very large number of possibilities here, but I think that is the way to think about it is that short-term combination is here right now. Oral drugs are coming, and then oral combinations and targeted delivery in the gut are going to be, it's fairly predictable. Thank you very much for the comments. Thanks for the questions, Joe. So our next question comes from Xinwei An at Canaccord. Please go ahead, Xinwei. Thank you, and congrats again on the successful data in the trial. So my first question is about the phase Ib trial that you have already planned. I maybe you could share a little bit more with us about the trial design, such as if you plan to assess additional doses as compared to this current scMET study. Because I believe you mentioned earlier in this presentation that the UC patients' colon tissue absorption of the drug is expected or maybe will be higher than healthy volunteers. And of course, please correct me if I'm wrong on this. Yeah. Thanks very much, Xinwei. So yeah, we are planning a phase IB study focused on pharmacokinetics and focused on the doses that were administered in the phase I healthy volunteer study. However, we're doing additional analysis and modeling and considering whether, you know, other doses in the 1B study might be appropriate. Okay, thank you. I have a second question that's regarding the device success rate that you have reported from the MET portion. 96 is very high. I totally agree with that. But just to be thorough on all potential possibilities, do you believe there is a chance for delayed delivery, which will maybe will cause accumulation of multiple doses of the drug in the colon tissue or a missing dose of the drug? And if so, if there's such possibility, do you have a sort of a designed assessment to test for it or to mitigate the risks? Thank you. Yeah, thanks. Thanks very much, Xinwei. So the question about delayed delivery is really quite important, and actually, the device has been designed to avoid that. So we will not have, you know, many multiple doses delivering at the same time in the same patient, because the battery shuts down in time to avoid that. So we have that safety principle in place for the NaviCap platform device. Okay, thank you. Thank you. Thanks for the question, Xinwei. So our next question comes from John Vandermosten at Zacks. Please go ahead, John. John, you may be on mute. So while John gets his audio fixed, I'll now turn it over to Charles Padala at LifeSci Advisors to read the remainder of the questions from the webcast. All right. Thank you, Taryn. First question is for Dr. Feagan. Are there any other viable colonic delivery technologies available? Yes. Well, there are a number of injection- type of devices, and we're seeing some preliminary data from those type approaches. I really like the AMT approach, which was with the colonic cholera toxin co-transporter. However, that was paired with IL-10, which ultimately proved to be a mistake, I think. That I think that technology is still very interesting, yeah. But other than that, there's not a lot of data in the clinic with regard to some of the more advanced approaches. Okay. Thank you, Doctor. Next question is, I think, just a general. Are tissue levels observed at 24 hours what you expected? So thanks very much for asking that, Charles. So, the tissue, we're quite pleased with those tissue levels. When we designed the study, we actually didn't know what kind of tissue levels we would see 24 hours post-dose, because we were just understanding the PK of the NaviCap combination device. So while we're quite pleased that we were able to see colonic tissue absorption at 24 hours, that we didn't see any evidence of accumulation, that we saw very low troughs in this study, and we think that that bodes well for, you know, future studies of efficacy and safety. Okay. Thank you, Dr. Kelman. I think this question is also for you. Did the levels in the tissue indicate no drug accumulation after repeated dosing? Yeah, we didn't see any evidence of drug accumulation with repeated dosing. I think we have a question from John Vandermosten. I think he had audio issues. Let's see. Of the patients that do not take tofa due to either poor efficacy, due to not enough delivery, or side effects, how much of this group will benefit from NaviCap delivery? Yeah. Now, thanks very much for asking that. We intend to enroll, potentially, patients like that in future studies. And we'll have a better sense with time. But, it is a potential option for patients who have, you know, are either new to treatment and have moderate to severe disease, or who have failed previous treatments. So that's yet to be seen, and that could only be tested in a much larger clinical trials in the future. Yeah, I'd just add, too, that I tried to underscore that the current dosing of 10 milligrams BID or 10 total with tofa is probably underexposed. And if you accept the notion that tissue compartment PK is the important driver of efficacy, then the drug has potential in patients who have failed conventional dosing. All right. Thank you. We have an additional question from Zacks. One item listed in the label for tofa is GI perforation. Is that a concern with greater GI delivery of tofa, and will the FDA bring this up? Yeah. Now, thanks very much for asking that. So, we are doing a colon tissue histology in these studies, and we also have looked at very high levels of tofa in colon tissue in our preclinical studies that led up to our phase I. And we haven't seen this as an event. We also haven't seen any histology abnormalities, and so we actually don't... We're aware of this in the label, but we haven't seen it as an issue, and we don't predict that it will be a problem with colonic delivery of tofacitinib. And I would also ask Dr. Feagan or Dr. Sands to comment as well. Yeah. I think the issue where we really see that as a problem with is with specific monoclonals to anti-TNF or to IL-6. IL-6. One would think that, based on the notion that where systemic exposure is less, and that probably is a substantial contributor to the actual issue, would be complete ablation of IL-6 would be the ultimate. But monoclonal antibodies don't do that. But certainly, they're more potent at interfering with IL-6 than the JAKs are. So I, I think there's probably a safety window there that's adequate, I guess. Right. So it's really an extrapolation of safety. The safety of anti-IL-6 antibodies, to the, you know, tofacitinib, which is said to be a pan-JAK inhibitor, does inhibit to some degree, IL-6. So it ends up being sort of a hypothetical risk, even though it is in the label. Another question here from Zacks. This is for the group. What are thoughts on other oral options for delivery of tofa, if there are any out there that you've seen? I have not seen others using tofa. Brian already mentioned others that are really earlier in development. Thank you. And I think, I think Joe from H.C. Wainwright has another question. Go ahead, Joe. Okay, thank you. Thank you very much for taking the follow-up. So I think maybe for Adi, you know, we're, we're talking about very large markets here, so I would be remiss if I didn't ask about your thoughts about business development. Obviously, you know, based on prior comments, the BioJet program is your lead BD efforts, and I guess based on the data you've now presented in the clinic for NaviCap, how do you think this is currently impacting your BD thoughts around this? Yeah. Clearly, as you mentioned, we've been focused on doing BD for BioJet, which is going extremely well, the BD conversations. What we haven't talked about is we have had some inbound interest, even for NaviCap, and certainly, we expect with the data that we have now, that that could expand, and we expect to explore that. As you heard from Dr. Feagan, Dr. Sands, that, you know, other molecules might also benefit. And, you know, we've done some work with adalimumab. As you know, we have some of that. There are other molecules, and there are several people still trying to get in the market to try and help. You know, we've talked about this 30-ish% ceiling of response in this space, so it's a pretty active space. You know, even recently, there was another $3 billion acquisition of a phase II asset, so a lot going on. We have seen some inbound interest. We could expand interest. We're pretty excited with the data. We're gonna continue pushing forward a little bit with our clinical, but BD is certainly expanding, and we're open to that discussion. Great. Thanks for the follow-up. So, Taryn, are we, are we taking more questions? Are we at the end of the time? Charles, any more questions from your end? Yes, we'll do our best to answer them offline. I think we're out of time for now. Okay. Well, I wanted to thank everybody for joining us. I want to thank Dr. Sands, Dr. Feagan. We appreciate your input and thoughts. You know, and I couldn't help. I heard a lot of the questions when people started asking about what about that 3% or 4% that didn't make it in terms of devices? And when we say that 96%, it doesn't mean the other 4% didn't work at all. In some cases, you couldn't retrieve it and test it, so we couldn't report on it. And in some cases, I think you heard Dr. Feagan talk about how some pills go in and come out the way they went in. There are several other oral technologies, some of them even have on their label that, you know, 60% or 70% of the time it actually works, the rest of it doesn't. So, we wanted to stay safe, a 95% confidence interval is often used in many different conversations. We think this device is performing extremely well. We have multiple trials to prove that, so it's a very consistent way to deliver things. We're really excited that we got tissue data after 24 hours, five half-lives, colon prep, healthy volunteers who probably have less absorption than patients. Despite all of that, we have actual data that shows pretty good colon tissue drug concentration. So we think we're in a great place to take something forward that could really benefit the UC community. We appreciate everybody's time. We look forward to talking more about this in the future. Thank you so much.