We're good to go? Okay, great. Thank you and thank you for joining us this afternoon at the Citizens Life Sciences Conference. Excited to be joined next by PolyPid, and joining us is CEO Dikla Czaczkes Akselbrad and Chief Operating Officer Ori Warshavsky. Thank you for being here with us this afternoon. Super exciting time for you guys, right? D-PLEX₁₀₀ NDA submission is right around the corner. You've talked about, you know, looking for an update on a commercial partnership soon as well, and a lot to talk about. Dikla, thank you for being here. Maybe I could just ask you to give a quick 30-second intro. Sure. Thank you for having us. As you said, we are at the midst of preparation of an NDA. Should be announcing an NDA submission any day now. That is on the basis of our lead program, the D-PLEX₁₀₀, which is designed based on our unique platform technology, the PLEX, to deliver 30 days of coverage of antibiotics in the surgical site arena. We just announced, well, just over six months ago, our top-line data, showing 60% reduction in surgical site infection in patient undergoing colorectal resection. Not just the level of effect, but also the statistical meaning of that, showing a P value that is lower than 0.005 in a 1,000 patient study, very robust data. After meeting the FDA this last December for a pre-NDA meeting, we're good to go and super excited to get to this next stage in the company's growth. Great. We'll obviously talk about the data as well, but maybe we'll start with the FDA meeting, the Mm-hmm pre-NDA meeting. It seemed very straightforward. You know, you came out right afterwards and said everything's on track. Just kind of hit for us what you were looking to get clarity on in that meeting and just where you think you have clear alignment with FDA now. Sure. First, I should say, you know, the product D-PLEX₁₀₀ has breakthrough therapy designation, so we are eligible for much more frequent communication with the FDA, and we took advantage of that. That is along the development time and period. We've asked question around CMC, around method, around our development report. Whatever we could clarified with the agency along the way, we tried to do that, to get ready and be prepared. That's one thing. The other thing, we met the FDA, or we had a pre-NDA communication with the FDA in early December. The thinking was, we want to make sure first that the FDA agree that the Phase three, the SHIELD I study, is sufficient for NDA approval, both in terms of efficacy and safety, that one Phase three plus the Phase two that we had is sufficient, and they were very clear that they are in agreement on that this is sufficient in terms of the data. We also wanted to align the timeline to make sure that we can submit the NDA on a rolling basis, and we can start and get an agreement on that. This was also achieved. In general, this was the spirit, to make sure that the FDA is aware of the data, aware of the process, in agreement on what we have. This was, as you said, it was very straightforward. The data is very straightforward, so it makes all the communication also pretty straightforward. Just walk us through the timelines. I know you, Mm-hmm You are about to initiate the rolling submission. Mm-hmm. Mm-hmm. When will that be completed, and then how do you think about, you know, review timelines, priority review? You've said you're gonna ask for- Yep You have the Breakthrough Therapy Designation that supports that. Right. Yeah Just. The plan is to submit the NDA any day now, before the end of the month. At that stage, we will be submitting the CMC modules as well as the preclinical module, with the clinical module to follow in less than two months after that. Yeah. We'll finalize the submission within a matter of few months from now. It's only two steps. Yeah more than that in the rolling, and then the FDA has 60 days for acceptance, and then based on the priority review, it's another six months of review. We're looking on a PDUFA date towards the end of the year, January timeframe. This is where we are. Okay, great. Let's talk about the data. I should just mention. Yeah In terms of timelines, that we're also planning to submit with the European authorities. Good point. a few months after we finalize the submission with the FDA. Has the interactions with European regulators been as clear as FDA? Yes. We are a little bit back. We still need to meet with them, but in general, yes. Okay. Yes. Great. The data, just walk us through Phase three trial design, you know, the endpoints and like you said, a very robust outcome from an efficacy perspective, really dramatic reduction in infections. The product is set to significantly improve the outcome of surgeries in the area of surgical site infection. What we are trying to do with our platform technology is really to change the way surgeons operate on patients, specifically in high-risk procedures, high-risk patients, where today they're kind of saying surgical site infection is the cost of doing business. Mm-hmm. We think this is unacceptable, and this is how we went out on this mission, where, after having some SSI data in the orthopedic area, in CABG surgery, we focused on the abdominal and specifically on colorectal resection. This was a deliberate thinking that colorectal resection is probably the highest elective surgery in terms of surgical site infection prevalence. It's very intuitive. It's not just the risk of surgery. You're dealing with the guts, you're dealing with the colon. The risk is also from the inner, as opposed to every other surgical site infection, which is mainly in a sterile environment, and it's not what you could call contaminated, like in colorectal. Most of the patients that are undergoing colorectal resection are cancer patients. Mm-hmm. That's the primary reason to resect. Yeah part of the colon. We went out to do this study where the FDA, as part of this ongoing discussion, suggested that the primary endpoint will not just be reduction of surgical site infection, but we will also measure mortality and reoperation as treatment failure. As you can imagine, when the agency suggests something, you oblige with the suggestion. This is what we did. We focused on patients that are undergoing open colorectal resection, again, to have a robust surgical site infection intervention and process with those patients. This was the patient population. We had obviously blinded study, multicenter, 60 centers in the U.S., E.U., and to a much lesser degree in Israel. 1000 patient overall, where with the primary endpoint that was looking at 800 patient, we had 40% reduction in mortality, reoperation, and surgical site infection. Again, with a p-value that was lower than 0.005, to be more specific, it was 0.0013. It's a very robust data. Then we set up three key secondary endpoint that we met all three. The first one was obviously the SSI itself, the surgical site Yeah ... itself, which is what we have been set to prevent. Here we showed 60% reduction. We had another key secondary endpoint that was looking in addition to open colorectal also on around 200 patients that had to go through minimally invasive. Again, we were meeting the 40% at the primary. The third one, which is very interesting, was around when you give the surgeon another tool, a locally administered 30-day antibiotic coverage of the incision, the obvious thing that you would expect is to see a reduction in surgical site infection. That's obvious. It's another protection at the surgical site. When you come to think about it, you would ask me, "Okay, so you reduced by 60% the level of infection." When you compare infection to infection, are they the same? Are they more severe? Less severe? This was the third key secondary endpoint, which was measuring the scoring around the numerical scoring around the severity and the consequences of the infection. It's a score that is called an ASEPSIS score. Over 20 is considered severe infection, and it's measuring if the patient is being reoperated, if they get treated with IV antibiotic, if they have, if they are rehospitalized or any other measurement. We also saw here over 60% reduction in the level of patient that had over 20. when you come to think about it and when the product will be presented in the hospital to the surgeon, you're saying, "Here is a product that if applied, will reduce the level of infection by 60%." But you should also expect to see milder infection in the rest of the group, which is super, I think, exciting and interesting when you think about expanding behind it to other application. especially when you think about Mm-hmm You know, the patient being in the hospital and getting out of the hospital, not having to come back. Yeah. Yeah Yeah to the hospital. I mean, the risks there of reinfection alone are increased. So Right I think the point is that it should make very clear sense to hospital institutions that, you know, the product is a valuable product. Right. It's a benefit both from a patient leaving early. Right also from hospital managing capacity and cost related to that. Getting the patient out is very valuable. Yeah. I would also say that in many of these cases, those are cancer patient. Having an infection delays their oncology protocol. Right. It becomes life-threatening in many aspect. Yeah. Just from a FDA label perspective. Mm-hmm We've said, like, our base case assumption is that you get a label specific to colorectal patients. It's very likely there's an expedited path to where you can expand that label with not repeating a 1,000-patient study, for example. I think it's, we've also said that, you know, it's also likely that the product will be used more broadly. Surgeons aren't gonna look at this and say, "I should only think about this in CRC patients." Just maybe talk to us about the market and how you see the market and the opportunities to build the label, you know, further. Well, I'll let Ori elaborate about the market, but I think you're totally correct in the aspect of this is also our base assumption. The assumption is that initially we'll have a colorectal label, and then it will be fairly easily expanded to abdominal. Also from the aspect that it's very clear that abdominal is the worst case. Mm-hmm In terms of surgical site infection in the abdominal area. Abdominal from our perspective is just the beginning. There is an expansion from there to other surgery, whether I'll just give a sense whether you're talking about women that are undergoing breast mastectomy and reconstruction. In this area, you have between 20%-30% infection rate here in the U.S. If you're looking at patient with an LVAD, which is a growing- Mm-hmm Market, think about another growing surgery patient that are undergoing abdominoplasty, large abdominoplasty surgeries. There's a lot of area where this could make a difference to patient. Ori, you want to- I would add that from a usage and from the doctor perspective, the trial was designed always to be in addition to standard of care. We're really not changing anything that the doctor does, but we add another layer of protection. Every surgeon, they're all aware of SSI. They all know their own SSI. From them, there's really no reason why not to put another layer of protection, both from the patient perspective, from their perspective, they're being scored on their infection rates, from the hospital's perspective. It's. You know, we haven't met a doctor that said, "No, that's not for me. Right. They can say, "I need to see the data." They can say, "I need to see the price." But from a user perspective, there's really no reason why not to use the product. Maybe to get to your question around the target market opportunity that we're looking at around 4.4 million abdominal surgery a year here in the U.S. Okay. When you think about to Ori's point, you know, a physician sees the data and says, you know, "There's no reason not to use this," but we know hospitals are still budget-minded. Have you started to segment the market by, you know, the higher risk patients and who might. Like, Like, you know, when institutions start to use this saying, "Hey, use this for- Yeah This subset," versus, "Hey, use it on everybody," is probably the best way to get traction early. Yeah. Yes. First, a surgeon knows when a patient comes in, as they walk through the door, they know this is gonna be a problem or not. Yeah. The risk factors are well-defined. The uncontrolled diabetes, hypertension, high BMI. There's a whole list. It's a known list of risk factors. Mm-hmm. We've done recently a market study with surgeons and pharmacy directors that sit on P&T committee. This is what they identifying as the target patient population, meaning likely the hospital will wanna see some sort of a pilot study to make sure that the product works. But we also heard from surgeons, "Once I see that it works, I'm probably gonna use it broadly." Not that we can promote that, but surgeons can do whatever they want. Again, another layer of protection. From the kind of hospital side, the academic centers are likely the major drivers there because they, you know, first they kind of train the upcoming class of surgeons on one hand. On the other hand, because everyone is measured and everyone is benchmarked to the other, there's sort of a, let's call it a cold war. You don't wanna stay behind that some other top institute adopted the next treatment or the best treatment, and I'm staying behind. This is gonna be the target. It's likely 1,700 academic institutes. That's kind of the target more or less. Can you talk a little bit more about the work you've been doing to get ready for launch? You said you've done market research data. What are you doing to, you know, educate the payer side of things or the hospital side, the formulary P&T committees? Mm-hmm What is the feedback you've heard? Yeah. We'll probably talk about later about the partnership and the launch, but a lot of these activities at the end of the day will be with a partner. In terms of what we're doing, market research is one, quite a lot on the conferences side, the publication side. We have a very strong relation with Surgical Infection Society, with kind of the past president, the current president, so a lot of these activities. We're starting now a big push around the pharmacoeconomics because again, it's kind of two levers of adoption. One is the clinical one, and the cost one is the other one. Educating and preparing the kind of the material to educate the pharmacy directors and finding those champions, the surgeon champions to bring new product into P&T is kinda on the docket now, stuff that we're doing now. another thing that is on the way in that regards is the NTAP. Mm-hmm. The product is eligible for the NTAP, so as part of the review process, at some point we will also be applying for the NTAP. Yeah. I think that could be a driver also for adoption. Yep. For sure. Partnership then. Can you just talk about what you're looking to get out of this? What are your, you know, your hard and fast rules and what, you know, what are you looking for in a partner? What are you looking to continue to contribute as the product moves into, you know, commercialization? obviously we can't share much of that, but what we are looking is for a partner that has a strong presence in the hospital and specifically in the surgery Mm-hmm suite. That could be part of the overall sale approach. The product, as we said, have a broad applicability, and potentially we're seeing it expanding the label more and more, so we need a partner that can really support this, that can really support having the product in the hands of the surgeon in many, many hospital. Wanna add something? Yeah. Sorry. I blacked out on my. Let me ask, how do you think about the U.S. versus ex-U.S. from? Uh- A partnership perspective as well? Um, let me just- Yep. You asked about what we will keep. Yep First we are the manufacturer. Yep. We are the manufacturer, so with any type of transaction, we will always remain because it is the know-how of platform is for D-PLEX, but it's from beyond that. That's one, and the second piece I think how to build the future expansion is something that we'll likely keep some of the medical pieces, stuff that kind of go across territories that's not just focused on U.S., but an activity that impacts U.S. but also can downstream impact other markets will remain with us. Regarding other geographies, so our first priority is the U.S. Of course, yeah. That's our first, and we're very, very focused on that, both in terms of the approval process as well as partnership. We do see a similar approach in other geography in the sense that we'll also partner around that. Could be with different partners, could be with the partners that we already discussed and have a good presence in this area. Okay. Great. I wanted to flip over to the platform again. Can you maybe just give us a very brief overview of the platform? Then I think more importantly, or as importantly, what are you gonna do with it next, right? There's a lot of opportunities. Yeah that you can think about that are applicable. You've got to prioritize obviously on the investment. Just yeah. Yes, I think probably that's the hardest job, focusing everyone when you have such a broad platform. Every day there is a great idea but in order to create value, you really need to focus. If I need to very simplistically describe the platform, you should think about a matrix of thousands of alternate layers, a book or an onion that is built from a combination of very solid platform that has been able to introduce drug along the years, and those are polymer and lipids. Think about it as a matrix that is built from thousands of alternate layers where the polymer is the backbone of this matrix, and in between you have the drug surrounded by lipids. This condensed infrastructure first prevent from water and enzyme to go into the inner layer. Once the drug is administered at the incision site, at the tumor site, as a depot, which we'll discuss in a second, body fluids create what we call surface degradation. The outer polymer layer is disintegrated, and the drug is released, and again and again and again, thousands of times. D-PLEX₁₀₀, as an example, our late-stage asset, has 10,000 layers that are supporting 30 days of exposure. This is really the uniqueness of the platform because what we are actually doing is creating a high local concentration of the antibiotic with no systemic exposure or with no clinically meaningful systemic exposure. Think about it, everyone in this room, when we are taking an antibiotic at some point, we're always told to also take something to protect our microbiome because we are bombarding or poisoning the whole body in order to treat an infection at a specific area, as opposed to our approach, which is having a much more targeted exposure. That's the platform. What is nice about this platform that it's now been validated in more than 2,200 patients that have been enrolled in different clinical studies. We've built our own manufacturing facility, as Ori mentioned, so we are also in control of the manufacturing, which wasn't a trivial thing in those kind of unique approaches. Our next in line is our program in the metabolic health. What we are bringing here in this fairly crowded area I think is very unique in the sense that our GLP-1, which is the first drug that we are pursuing, but not the only one, is a long-acting, or I would even say an ultra-long acting GLP-1, 50, 60 days, that is again without this fluctuation that you find in today's medication. Another attribute of the platform is that we can control the release, and we're looking at a release profile that is zero-order kinetics. There is no spike, and everyone is aware of current medication that is really suffering from this spike at the beginning of the week and then much less drug is in the bloodstream. And there is a lot of notion that many of the side effects are attributed to this. The side effect point is obvious one, but there maybe this isn't the direct example, but there are gonna be examples where having that consistent release profile helps from an efficacy perspective as well. Yeah. Right? Yeah. If you're hitting a receptor more consistently without peaks and troughs. Yeah that could translate to efficacy benefits. If you could be more precise. Yeah with the amount of drug, maybe you have less Mm-hmm body lean mass reduction, but much more control around the fat reduction versus the lean body mass. And, and- You don't want. What are the next steps with that program? This program is at preclinical stages. We are now building a robust preclinical package around that, both in terms of efficacy, we wanna show PK studies that shows that GLP-1 is in the bloodstream for a long period. The thinking is that this program will also be partnered at some point, once we have this robust preclinical package, both in terms of efficacy and some safety data. I think that a lot of players out there are looking to grow, and there is an advantage in this area for partnering with large pharma that can pursue this product all the way to the market. Fantastic. Great. Well, Dikla, Ori, thank you for being here. Yeah. Like I said, you know, a lot happening very soon, so we will be paying close attention. Thank you very much. Thank you. Thanks for having us.