PolyPid Ltd. (PYPD) Earnings Call Transcript & Summary

All right. Good morning, everyone. My name is Boobalan. I'm a Managing Director and Senior Biotech analyst at ROTH Capital Partners. I specialize in emerging companies in the SMid-cap space, particularly in the pharma and biotech sectors. So I'm delighted to welcome Dr. Steven Wexner to this KOL webinar. So before that, I just wanted to invite PolyPid team as well. Just as a disclosure, PolyPid is a $78 million market cap company. They have a product which is called D-PLEX100, which we'll discuss in detail today. And then just in case, I cover PolyPid and my recommendation is a buy rating. My 12 months price target is $9 per share. So why don't we start with introductions First, Dr. Wexner, maybe you can give us a high-level introduction. I think you can do better justice to yourself than me.

Sure, sure. So my name is Steve Wexner. I was at the Cleveland Clinic, Florida for 38 years as Chair of the Department of Colorectal Surgery and Director of the Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, past President of the American Society of Colorectal Surgeons, past President of the Society of American Gastrointestinal Endoscopic Surgeons, past Vice Chair of the Board of Regent for the American College of Surgeons and a variety of other things, Editor and Chief of Surgery, one of the most important surgical journals. As of November 1, I'm the Executive Director and System Chief at MedStar Health, Georgetown University Hospital, the 10 hospital system in the Maryland and D.C. area.

Great. Can you also tell us your core practice area and number of patients you treat every year, just to give some idea.

Well, typically, I would be doing about 250 or so major operations annually. That's considering that I'm gone about 1/3 or more of the year traveling, lecturing and teaching, but in the 2/3, I'm there, about 250 major cases, actively participating in research. My main areas of interest in clinical practice and in research are rectal cancer, ulcerative colitis, Crohn's disease. My practice is largely almost exclusively referral from out of state overseas. And a lot of those patients are for reoperative surgery because they've had other surgeries that haven't, shall we say, had the end result as initially desired. With those operations, I train surgeons from all over the world. I've trained probably a little more than 800 surgeons by now, about 200 from U.S. and about 600 from other countries.

Fantastic. And we also have PolyPid team on the call. So maybe, Dikla and Ori, can you please introduce yourselves?

Sure. So I'm Dikla, Dikla Czaczkes Akselbrad. I'm the company's CEO. I'm with the company now for 11 years in different C-level position, the last 4 as the CFO. Prior to joining PolyPid, I was the CFO of Compugen for many years which is an Israeli cancer immunotherapy company. Ori?

And I'm Ori Warshavsky, Chief Operating Officer. Just about 5 years with PolyPid. Before that, 10 years with Teva Pharmaceuticals. I'm mainly responsible for the U.S. activities for PolyPid, whether it's the commercial side, the investor side and some other activities as well.

All right. Great. Thanks, Dr. Wexner, and thanks, PolyPid for the introduction. So the way we are thinking about this particular event is this will be a fireside style question-and-answer. And obviously, if you have a question you can always submit it in the text box or you can send it to me by e-mail, which is [email protected]. So it's the first letter of my first name and my entire last name at ROTH.com. So all right. Now let's get into the fireside style webinar. So for the ease of clarity, we have segmented this discussion into 5 broad topics. So first, we wanted to spend some time set this ground for SSI. So people who are not familiar with the topic, they can understand or learn more about this. We'll essentially discuss the symptoms and potential risk factors. And secondly, we will dive deeper into how -- why SSIs are relevant for hospitals, in fact, even for physicians. I think this will be very important because we have an expert in this, and he is going to provide some high-level overview on this. And thirdly, we will dive deeper into D-PLEX100. This is PolyPid's agent that is designed for the treatment of surgical site infections. So we will spend a little bit time talking about the clinical data generated to date. And we'll also, of course, get some opinion from Dr. Wexner, what he thinks about the data and whether he would be inclined to prescribe these agents, assuming this gets approved. And fourth, we will speak to PolyPid management. They will guide us in terms of what are the expected next steps, including potential time lines for filing and approval. And finally, we will get some preliminary insights about PolyPid's commercialization plans, particularly in the U.S. and ex-U.S. setting. So again, if you like to submit your questions, you can submit to my e-mail or provide this in the chat box below. So let's start with topic 1, which is background on SSIs. So Dr. Wexner, can you maybe provide us a high-level overview of what is an SSI and what are some of the signs and symptoms that we are -- you are actually seeing when a patient has SSI? And what risk factors could make this more impactful?

So surgical site infection, which is SSI is a major cause of morbidity prolonged hospitalization, even in some cases, mortality. For what I do for colorectal surgeon, it's particularly high because of working on the bowel, although it can occur with any kind of surgery, including joint replacement surgery and lung surgery and the rest of it, but it's particularly notorious when we're working on the bowel because no matter what we do to try and cleanse the bowel prior to surgery with cathartic laxatives, with oral antibiotics, intravenous antibiotics, it's not -- nothing is infallible. So we end up with a surgical site infection despite our best efforts. Surgical site infection can cause anywhere from double to an order of magnitude, like 11-fold increase in mortality and is indeed life-threatening. Surgical site infection can be superficial as shown here, where it's a little redness of the incision or maybe there's a little fluid that's seeping out and -- of the incision, the incision opens a little bit. That can cause cosmetic disfiguration later with a wider, broader scar. It can prolong hospitalization, certainly increase cost because of the need to manage that wound. But when we start getting into the deep incision, the entire wound can open up and the strong connective tissue holding the abdomen closed can open up, which is, of course, a disaster or we get into even deeper infections within the pelvis or within the abdominal cavity, which starts to cost in the U.S. alone, something over $3 billion and increases hospital stay by estimates of up to around 10 days or so and increased cost of admission. It can double the cost of admission. So one of the major, major Achilles heels of what we do in abdominal surgery and colorectal surgery is surgical site infection, something that we absolutely want to avoid at all costs. And I don't just mean cost of dollar cost, but there's the morbidity. People lose time from work, people go home requiring antibiotics, maybe even intravenous antibiotics at home. That has its own set of complications. Time is lost from work. I'm not sure that's factored in these financial calculations of $3 billion to $10 billion. I think that's health care system cost that doesn't count disability to the patient. So it is a real, real major problem that we want to avoid. We take precautions, as I say, but there's no panacea, protecting the edges of the wound, all manner of things, irrigating. Until this trial came out, there really was nothing that was paradigm shifting that was moving the needle for us.

Great. Are there certain organs that are more prone to SSI risks or certain surgeries that are more prone to SSI risk versus others? Just curious. For instance, you talked about abdominal surgeries. Of course, there are some cardiac surgeries, there could be some gynecological and all that. So how does this SSI risk varies as you shift from one surgery to the other?

Well, again, I'm limited to colorectal surgery and is very high in colorectal surgery because it's what called clean contaminated surgery. By definition, it's contaminated. So if you had an operation like a joint replacement that is clean surgery, totally clean. There should be absolutely nothing to do with any bacteria. And in fact, if that happens, the patient loses the replace -- can lose the replaced joint. That's a much lower risk of infection. Gynecology is not quite the same magnitude of colorectal, but it's also concerning because generally, depending what they're doing if the gynecologists are working just on the ovaries, that's intra-abdominal, but if they're taking out the uterus, then they're dividing across the vagina, which also is latent with organisms that can cause problems. Then there's other abdominal surgery that's a bit cleaner, liver or gallbladder, but all of these operations lend themselves to the potential of infection. So colorectal is really at the top of the list, but that accounts for about 500,000 operations a year, give or take, in the U.S., worldwide, obviously much more. Within colorectal surgery, though, and the other operations, certain patients are at much higher risk, patients with diabetes, patients who've had radiation or recent chemotherapy, patients who are immunocompromised either by an underlying disease or because they're taking medicines to keep them immunocompromised to keep the disease from flaring like arthritis, for example. So there are many, many patients who are even higher risk than the baseline.

Okay. So because you mentioned about colorectal surgery, so maybe I'll restrict my next question, focusing only on colorectal surgery. Can you talk about what's the current standard of care for SSI prevention in colorectal surgery or colorectal setting? And if you can talk about what's the antibiotic you use and what kind of special precautions you take, if you can talk about all of that that would be great.

Yes. So it varies a little bit around the world, and it's kind of like a pendulum that keeps swinging. But where it seems to have settled at least in the U.S. is patients' bowels before surgery, the patient cleanses their bowels with cathartics like somebody would for colonoscopy. Adding to that our oral insoluble antibiotics that deliberately stay in the intestinal tract to try and neutralize the bacteria in the colon. On top of that, then there's intravenous antibiotics when the patient comes to the hospital, usually a single dose. And it's going to depend what's on formulary at the given hospital, but it's a broad spectrum antibiotic. One of the things I didn't mention in trying to prevent wound infection giving those antibiotics can cause an infection. They can cause antibiotic-induced diarrhea or clostridium difficile, which in and of itself is problematic. It's highly contagious and has a lot of morbidity. So giving the antibiotics to try to prevent infection can cause infection, ironically enough, at least the way they're typically given intravenously and orally. In addition, what we do to cleanse the bowel may have problems with the joint up healing, the anastomosis healing. And there's a lot of data on the microbiome now from a variety of laboratories around the world, showing that if you really do sterilize the colon, you're also killing the good bacteria, and that's problematic. So the solutions we have now are not ideal because you're just -- it's taking the shotgun at the fly, if you will, and you're giving all these antibiotics, which risks overly sterilizing the bowel, if you will, possibly having problems with the joint up healing, possibly causing antibiotic-induced diarrhea. We also, during surgery, are very meticulous the way we handle the bowel, and we use wound protectors so that we -- when things are removed or handled, there's no direct contact with the tissue of the patient between the fascia, the strength layer of the abdominal wall closure around the skin.

All right. Great. So with that as a background, let's dive deeper into the impact of SSI on hospitals. So let's just imagine a situation where a patient walks in or gets admitted to the hospital for a colorectal surgery. He gets the surgery done, returns home only to find or he's experiencing SSI. And then he comes back to the hospital. So what are the steps he can take? And how does him coming back impact his own setting? Or how does it impact the hospitals and then we can take things from there.

Yes. So there's the financial impact, which you're showing here, so much so that the DRG may go up because of complications. The hospital is actually getting more money, but then they're being penalized for readmission. In addition, as an individual surgeon, you're having to explain to the patient why the patient has an infection, which is never a pleasant conversation, even though it's part of the informed consent prior to surgery. On top of that, you're having to present it at the morbidity and mortality conference. So you're having to explain again why the patient got this infection. And depending on the severity of the infection, you may be reoperating on the patient, which the hospital just loses all that money because it's an unanticipated reoperation. So there's a lot of downsides besides the financial CMS penalty, there's a lot of downsides emotionally, psychologically to the surgeon and the patient and physically to the patient.

Okay. So in the interest of time, what I wanted to do is I wanted to spend some time on the middle table that I highlighted, talking about HACRP penalties. So just to get to speed, so this was a retrospective study that was done that analyzed approximately 3,100 hospitals, which participated in the HACRP program. So HACRP stands for Hospital-Acquired Condition Reduction Program. So this analysis identified approximately 25% of hospitals that were included in the study, which is roughly 771, they were penalized by CMS. The finding that whatever the authors have found out, notably Florida and New York, for instance, they performed poorly, as you can see in the highlighted green box in overall rankings versus other states. And what is even more interesting, if you look at the table on the right side, some of the hospitals that have been known for their excellent service providing capabilities, including those that were chosen by U.S. News's best hospitals on this role, including Weill Cornell and then Stanford, they were also -- were under penalty. So this scenario, technically, it highlights the needs for U.S. hospitals to increase their service failing to do so, they will be in the bottom 25th percentile, and it will incur approximately, I think, 1% penalty. So with this as a background, I wanted to ask some follow-up questions. So how does SSI impact star rating for the hospitals? What are the implications of a lower rating? If you can maybe elaborate more on that, and then we can take things from there.

Yes. I'm not sure there's a lot more to elaborate beyond that other than we're all pulling in the same direction to limit surgical site infections, which in turn limits morbidity, mortality, readmission, financial penalties, reoperations for patients. And sometimes, quite honestly, permanent long-term adverse sequelae, that's something we've not discussed nor is that information captured in these dollar amounts. And what I mean specifically is if the patient gets a superficial and certainly a deep surgical site infection involving the fascia, the strong tissue that holds the belly closed at surgery or strong tissue that holds the belly closed without surgery, with fascia, that fascia can open up. And if that fascia opens up or even weakens, the patient ends up with an incisional hernia. And that now may cause problems in the hernia itself. The patient can get intestine, stuck in that hernia and up with an emergency surgery. Or more likely that's not going to happen, but the hernia grows and is unsightly and the patient ends up having to have the hernia fixed. So now there's another operation that's occurring outside of that immediate 30-day period, maybe outside of the first 12 months, that's additional morbidity potential complications from that surgery. Now maybe the patient has to have mesh implanted at a later date, plus the patients being exposed to the entire gamut of potential complications from a hernia operation. And that's all courtesy of that initial surgical site infection.

Great. And then maybe switching from hospitals to physicians, are surgeons personally impacted by or having -- or reporting high infection rates? How does it impacts the bonuses or ranking, thinking beyond the patient impact here.

Yes. I mean it's going to depend upon the health care system because some surgeons may be working fee-for-service, others may be full-time salaried, some in a hybrid position. But the common denominator is wherever you work, whoever is looking at the data is going to share with you your infection rates. And if your SSI rates are outliers, either good or bad. If it's really good, somebody is going to say, we want to share your best practice. If it's high, somebody is going to say, you need a best practice, what's going on here? So you're going to be called out for that in a negative way. How the metrics are measured by the various Newsweek and U.S. News & World Report and all the other Castle Connolly and all of these other reporting agencies, it changes all the time. So I'm not exactly sure where in their various algorithms, SSIs are captured. But I can tell you that they do play a role because it's your outcomes, right? It's part of your outcomes. And if the outcomes aren't as good, you're less likely to be cited in the top tier of providers.

Okay. So you mentioned that having an SSI is -- the conversation is not going to be pleasant between a physician and a doctor. In fact, there are some reports saying that patients have legal rights to sue hospitals if they have SSI. So with this as a backdrop, I wanted to ask this question, is every documented SSI qualifies a medical negligence?

I don't personally think so at all. I mean I'm not speaking on behalf of any society or institution, but I think that would be a pretty heavy hand to say that it's somehow malfeasance. It is a recognized problem and that's something that's part of the informed consent in the patient. But I don't believe by any stretch of the imagination, it's what you're potentially suggesting it could be. No, it's not at all. It's an unwanted problem, but it's not an unexpected problem.

Okay. Nicely said. All right. We'll switch gears and talk about D-PLEX100. Maybe I can bring in PolyPid team for this discussion. So maybe Dikla or Ori, can you give us a high-level overview, the genesis of D-PLEX100, because you're -- essentially you're formulating a known drug, which is doxycycline with polymers and lipids. Obviously, doxycycline is known -- it's been in use for more than 50 years. So I'm pretty sure others might have thought about it and maybe they have failed to come up with a formulation similar to yours. So if you can talk about what attracted you about D-PLEX100 the most?

Well, so -- sorry...

Yes, go ahead please.

No, I thought it was for me. Sorry.

We'll come back to you in a minute. Take a minute.

So first, it was very interesting. I must admit, Dr. Wexner, you pointed out some things we, same as you in a way, breathe and -- breathe day and night the aspect of SSI and specifically abdominal SSI, but it was nice to hear your perspective. So thank you. PolyPid has invested over a decade developing our technology, our platform technology that allows for extended prolong coverage of the drug. And a couple of years ago, probably around 6, 7 years ago, we decided and understood that utilizing the platform into the area of surgical site infection could really make it different, could really bring innovation into area where there is none to very little innovation and not just bring innovation, but potentially bring something that could be transformational in terms of the level of infection that have been accepted for over a decade. And I agree with Dr. Wexner, and we heard that very often from surgeon that SSI is in a way the cost of doing business. It's not that you could -- whatever you'll do and even we -- although we are getting very close to that, no one will claim that they have 0 infection rate or that they can get infection level to 0 because the bacteria is out there. It's out there every day on a day-to-day basis. But what we are trying to do by covering, draining incision for 30 days, which is in most of the surgery, the way CDC defines surgical site infection. So CDC defines surgical site infection as infection that occurs within 30 days from the index surgery and covering the incision deep and superficial, including the fascia for 30 days could really make a difference. So time is of essence here. And the other aspect is the way we are presenting the drug to the site. The fact that it is at the open or where the bacteria could go in from the outer to the inner, although with colorectal, we are also bearing the risk from the inner to the higher, this is why we see a much higher infection rate than in other surgeries, allows us to enhance the antibiotics to create local minimal inhibitory concentration that probably cannot be achieved without very significant side effect in a systemic manner.

Dr. Wexner, do you have any thoughts on that? What attracted you the most about D-PLEX100?

Yes. So I had the privilege of chairing the Data Safety Monitoring Board. I was not an investigator, but I was immediately attracted to the concept of eliminating -- potentially eliminating some of the other types of prep that are used. And in fact, the majority of cases, cases were not done in the U.S. and the majority of cases were not done with the triple preparation as we did -- as we do in the U.S. with oral cathartics, oral antibiotics, intravenous antibiotics, which is great news because maybe we're overkilling. And maybe instead of trying to do things in all different directions, we just focus on the incision itself with this long-acting potential, and we can get rid of some of the potential adverse sequelae of oral antibiotics, of intravenous antibiotics. I mean even bowel prep itself, giving patients cathartics can cause significant dehydration, it can cause kidney dysfunction, acute kidney injury. We'd like to avoid those things, obviously. And this is a totally novel way to deliver, as was mentioned earlier, an agent that's been around for a very, very long time that we wouldn't typically pick. This wouldn't be a drug we would use for much of anything. But now suddenly, it has a role. So I was very intrigued by this as being something really in my entire career that's new for SSI prevention. This is truly new. This is a paradigm shift for us. It represents a different direction. And that's what attracted me to it. Also, when I heard the size of the study, that was also very attractive because sometimes people have underpowered studies, and I'm not interested in participating in underpowered studies because they're not going to tell much. But this is a very, very robustly powered study. And I thought that was a second very appealing factor to me. If I'm going to get involved in research, I want it to be meaningful research.

Fantastic. All right. So let's dive deeper into the D-PLEX100 clinical program. Maybe, Dikla, you can just give us a high-level overview. What are some of the goals you have set prior to launching this program? And obviously, you have done Phase I, Phase II and you have done multiple Phase III studies, and it worked for the third time. I think SHIELD II was very -- the lessons you have learned from the past that you kind of like implemented in SHIELD II that led you to success? And then we can talk more about endpoints in a bit.

Sure. So maybe just as an overview, the SHIELD II and all of our abdominal studies were designed to show reduction of infection within 30 days from the surgery. We also follow the patient for additional 30 days for safety, so overall 60 days. Obviously, all the study were prospective, multinational, randomized, controlled double-arm and blinded studies. With the Phase III studies based on the feedback from the FDA, from the agency, we also added to the primary endpoint measuring mortality rates, as well as reoperation, which is a common problem, specifically in colorectal resection. And this was our primary. SHIELD II was focusing on open colorectal resection, large incision, although in addition to the 800 patients that were the intention to treat population, we also added about 200 patients that had laparoscopy procedure in -- specifically in colorectal resection, those are having still a relatively large incision of 7 centimeters for the portion of the resected colon. So still high risk of infection even in a laparoscopy procedure.

Can you talk about the endpoints of this study? And what would make the study successful at that point when you launched the program?

So this is a very interesting question because we were obviously looking to show a substantial reduction of infection. We wanted to show -- we said we are giving the surgeon another tool to their toolkit, what we believe is a very powerful tool. We would expect to see fewer infection. But the other thing that we were set to show is that when you evaluate infection versus infection, yes, in the D-PLEX treated arm, there are much less infection versus the standard of care, but we also thought that we should see milder infection. So we were looking for a dual effect in a way to see fewer infection in the treated arm, but also milder. And I think we -- I'm very pleased to say, and we are all very pleased to say that we've been showing that in this Phase III in the most robust way possible.

Okay. Great. And then Dr. Wexner, here's -- I'm showing you the demographics and surgery characteristics. These are from SHIELD II data. So I wonder, obviously, there's a D-PLEX arm, the standard of care arm. Is there anything that is striking out from this slide? Or do you feel the population or the patients that were enrolled in SHIELD II, they're reflective of real-world population. Can you provide some broader thoughts on that?

Firstly, yes, it's everyday practice for most surgeons around the world in terms of distribution of cases. But secondly, very importantly, the groups are well balanced. And again, that has to do with the statistical design of the study. So the stratification was appropriate. We don't end up with morbidly obese patients in one group and aesthetic patients in the other group or one group very heavily weighted towards inflammatory bowel disease where they'd be immunosuppressed. There's small percentages in both groups. So I think it's well -- it's well designed. It's well balanced, and it is representative of standard practice.

All right. Great. So I'm showing you here the primary efficacy endpoint. So Dikla, when you launched this program, what was your expected SSI rate for the placebo or the standard of care, sorry? And what is that you wanted to show in the treatment arm? And how does the results satisfy your expectations?

So we were thinking about a 10% infection rate in the standard of care arm. And we were hoping to show more than 40% reduction in surgical site infection. What we see here is the primary endpoint, which is combined with mortality and reoperation. So you see that the standard of care arm have 18% of the 3 together. So patient can have a surgical site infection and they can end up having a reoperation to try to treat the surgical site infection, and they can even die at the end of that process. So we have more than one risk factor or major risk factor that is attributed to surgical site infection among other things, and those were the numbers in the standard of care versus 40% reduction with the D-PLEX arm. If you move on to the next slide on the key secondary endpoint, I think that is really looking just on surgical site infection, where we believe D-PLEX have a major role in reducing the numbers, and we've seen that all along the way. And you can see here, 60% reduction from almost 10% infection rate to less than 4% infection rate with a p-value that is lower than 0.005, so very robust. I must say, and I'm curious to hear Dr. Wexner's opinion on that, from the time that we had this Phase III data, we shared this with [indiscernible] with surgeon. And we were getting 2 observations, which we all found interesting. The first one, most of them, if not all of them said that the 9.5 is lower than what they see in practice in their clinic for patients with open large incision. And to that, our response was that it makes perfect sense. This is a clinical study. We cannot enroll patients that undergo emergency surgery. It's very hard to have them sign a consent or patients that are very unstable. So it makes perfect sense that this is a bit lower than the 11%, 12% they expect in this patient. And the other observation was that with D-PLEX in large open colorectal resection, we have less than 4%, 3.9%, which is usually lower than what surgeons see in laparoscopy procedure. So that was something that we've heard quite frequently, and we found quite interesting.

Okay. Can you also talk a little bit about incision length greater than 7 centimeter, because I think this will potentially help you to broaden the label opportunity. So if you can provide some thoughts on that.

Yes. And this was the purpose of having this almost 200 patients, 177 patients to have a broader patient population. This patient population gets the study to close to 1,000. It is over the intention-to-treat population. And you can see that we maintained the same overall level of efficacy close to 40% in the primary endpoint and very robust, again, p-value, which is lower than 0.005.

Okay. Can you also talk about the safety profile of D-PLEX100 from SHIELD II data?

Sure. So -- and maybe Dr. Wexner would want to add to that. From the perspective of the study ongoing, we found the data, first of all, very robust. We have now overall more than 1,000 patients that have been treated with D-PLEX in different studies. We haven't seen anything that could suggest that there are adverse event at a higher rate in the D-PLEX arm, if at all, lower. So we found that the study is very appealing in terms of the safety aspect.

Okay. Maybe I'll turn to Dr. Wexner. Dr. Wexner, what are your thoughts on SHIELD II data? If you can specifically talk about the primary endpoint and the secondary endpoints, including the ASEPSIS score that is shown on this slide, a little bit on safety, that would be helpful.

Well, in terms of safety, I can tell you, again, having the privilege of chairing the Data Safety Monitoring Board is safe. Safety was not a consideration. We had multiple opportunities to stop the trial if there are any concerns, and there were none. And at the end of the day, there are none. So I think it is very safe. And I think even just logically, intuitively, delivering antibiotics directly to the tissue rather than through the mouth or through the vein is going to be a safer way to do it. I mean, without having any PhD in microbiology, anything like that, it just seems a better mousetrap. Secondly, in terms of the efficacy, so safety is fine, efficacy, I think that I've only participated maybe one -- firstly, just to preface, I have over 1,200 peer-reviewed publications, okay? So I'm an active researcher. I would say once a decade, I participate in a study as an investigator or the study author, in this case, the DSMB, where there's more than a 50% improvement over the control group. Very often, it's as was hoped. You get a marginal improvement and then you're trying to justify, is it worth it. This is great. I mean this is, again, a rare finding that you have more than a 50% improvement in efficacy. So I think surgeons are going to be very pleased and non-surgeons, too. I mean, probably the infectious disease doctors are going to say, why are you giving all these other antibiotics by mouth and by vein when you can just use something that you put in a surgery in the wound and it's good for 30 days, and we know that it works and it's safe. So I'm impressed. It's rare to see this degree of efficacy in a trial.

Okay. Can you also talk about potential applicability to other surgeries, let's say, gynecology or urology and other surgeries based on the data you've seen in the colorectal surgery setting? I know you are a colorectal surgeon, so you're limited in terms of what you can say.

Well, in terms of what I do, but in terms of what I've supervised in my years, 12 years as Chief of Staff, and I've served as Chief of Surgery and other things. So -- and being, again, editor in chief of one of the major surgical journals, I am familiar with other fields. I just don't perform surgery in them. It has applicability anywhere an incision is made. I mean there's probably -- I don't know, there may be applicability in oral surgery for dentists, maybe veterinarians. I really don't know, but one would guess that anywhere an incision is made, there is the potential for a market to try to decrease SSIs because they are problematic in every type of surgery. The mouth is another area just off the top of my head. So I see this going in a couple of directions. I see it broadening. And again, surgeons are just always try and improve outcomes for patients. So something comes out and the label says something and somebody says, well, I'm going to do an investigation and see if I can push the limits and do this in some other areas. So it says 7 centimeters, but I'm going to do a study and look at some other number. So people are going to start doing creative things is my guess because that's human nature. Secondly, I think there's the entire arena that's not yet explored of laparoscopic and robotic surgery. So you mentioned urology and prostates, that's robotic. Port sites get infected, too. Extraction sites get infected. So I believe that there is going to be an expansion of utilization as people also try to prevent port site infections and infections of these little specimen extraction sites. So that's not anything official because it's not labeled. I'm just telling you what I think.

Okay. This is a highly upbeat view. That's good. All right. So we'll move on to topic 4, which is D-PLEX100 next steps. Obviously, we want PolyPid management to answer some questions. So Dikla, so you had your sort of pre-NDA meeting discussion, but not necessarily an in-person meeting, which is actually a good news. So can you walk us through like what happened from the time you released SHIELD II data until now? And then what are your next steps? What can we expect to see from PolyPid?

Yes. Thank you. So we were very pleased to report a week ago on the outcome of the pre-NDA process. We reached out and we were preparing a pre-NDA package to get to an agreement with the FDA on the NDA, and we are very happy with collaborative and the answer that we got from the preliminary meeting correspondence, which got us to the understanding that we have an agreement with the agency on the NDA submission and that maybe the most important thing is that they found that the SHIELD II data is sufficient for an NDA submission and initiating review. We plan to submit the NDA early 2026. Everyone in the company is very focused on that. We are preparing for that for a couple of months now, if not more than a couple of months. And the plan is to submit the NDA early next year. The product has breakthrough therapy designation, so -- and 3Q IDPs and Fast Track designation. So we are eligible for the priority review, which is 6 months plus 2 for acceptance. So we expect that towards the end of 2026, early 2027, we should have a PDUFA date. Along this time, we also expect the FDA to come and do a pre-approval inspection in our manufacturing facility. This is also part of our planning and preparation these days. And in parallel, we are going also to submit with the European authorities with a short gap from the FDA, probably something around a quarter post finalizing the submission to the FDA.

Okay. Great. So there are a lot of questions I wanted to ask, you already answered in advance, so which makes my job a little bit easier. But let's dive into the most important one, potential for advisory committee meeting. Obviously, this is a technology that is -- I don't know whether -- I wouldn't call it necessarily new, but there were some polymer-based or lipid-based products that are approved by the FDA. So what are the chances of having an advisory committee meeting for D-PLEX100? I also wanted to get some thoughts from Dr. Wexner for the same question. So maybe you can go, Dikla first and then we'll have...

Yes. So I think that we -- and this is, again, part of the benefit of having the breakthrough therapy designation, we and our team have been in contact with the FDA along the years, meaning many of the aspects of CMC, of preclinical, whatever we could get to an agreement with the agency prior to the process, this has been already done. I don't know to tell you specifically about an advisory committee at this stage. I think that there is a process that is in place. We are very confident with our filing and with our NDA and hopeful that this will be something that will go smoothly. In terms of the platform itself, -- at this stage, the way we're looking at it, I mean, we are a 505(b)(2). So the drug is a known drug. And the platform is unique, but in a way that we are using known excipients. So it's hard to say at this stage.

Okay. Dr. Wexner, same question, thoughts on AdCom.

Yes. I think it is paradigm shifting. It is truly innovative revolution. And I personally hope it's going to be fast tracked and I should think it would be. Again, in my almost 40 years of doing this, most of the applications are for something incremental. It's something a little bit slightly different flavor of ice cream or something, but it's not a new substance. This is a totally new delivery method. And I think the FDA -- remember, the FDA, CMS, these are all government agencies, which have the same view. They want to improve outcomes. They want to decrease the cost of health care. They want to give access to patients for the best possible tools and therapies. And I personally believe this is in that book of definitions. So I'm optimistic and on a personal level, hopeful because I'd like to be using it in my patients.

Okay. So Dikla, let's go back to the filing process again. So you're planning to do it on a rolling basis, and there's 5 modules. And you said the earliest module might go out in the -- the first module might go out in the first quarter '26. So when do you expect to sort of wrap up the filing process? I mean, what's your assumed completion date? Do you think end of '26 is -- I mean, you can still get approval by end of next year? Is it still a chance?

So as I said before, we are targeting early 2026 for submission. We do not expect more than a 2 months gap between the first model and the last one. This is something that we've already discussed with the FDA as part of the pre-NDA process.

Okay. Right. So meaning assuming you get everything done by first quarter of next year, there's still a chance that you could get the approval by fourth quarter of next year?

Yes. So this is why I said that we think that the PDUFA, the approval, we should look at end of 2026, early 2027. I want to be more realistic and...

Are there anything special steps you have to take to make sure you pass the FDA on-site inspection, if you can talk a little bit on your manufacturing capabilities, especially there is this domestic push towards producing everything in the U.S. So if you can talk about some of the challenges because you're based in Israel, any potential challenges, that will be helpful.

Well, I think that the fact that we built our own manufacturing facility 6, 7 years ago to make sure that we have the capability to manufacture these large clinical studies as well as later on for commercial stage gave us the opportunity to build a lot of experience around the manufacture to establish very robust CMC processes. We are as part of the European regulation and the Israeli regulation are regularly audited and reviewed for GMP. So this will not be the first time that we are audited. Having our own manufacturing facility that is dedicated for D-PLEX, the facility does not manufacture anything else. It's not a CMO that has several clients is also in our benefit. So all of that makes this facility very, very focused on D-PLEX, very focused on the GMP processes for D-PLEX. But that said, we don't take this inspection lightly. We are engaging a lot of -- we have a very detailed plan, including several mock inspection to be prepared for the inspection.

Okay. And then maybe Dr. Wexner, I have a question to ask. Assuming D-PLEX100 gets approved, can you maybe talk about any challenges for hospitals or physicians to adopt this product? I mean, do you see the surgeon making the decision? Or do you see any infectious disease specialists in the hospital in this decision-making process, whether or not to adopt D-PLEX100?

I think health care situation and certainly in the U.S., and I believe around the world has changed. It used to be that a surgeon wanted something and said, I want this and it would appear. That's no longer the case. Everything has to go through a formulary committee. Everything is going to be subject to analysis. Is it -- if it's a substitution for something, it's easier than if it's a new product. Having said that, if it's a product that's going to save money, that's certainly favored. And this one would because it may save readmissions, which are penalized. It will save time in hospital, which is a financial loss to the institution and all the other things we discussed earlier. So it will have to go through that process of a formulary committee, which is often chaired by someone in infectious disease, not always, but it has a variety of people on it. It may have surgeons of different disciplines. It may have internist. It will have administrative people and a decision will be made. And the case has to be made both to the surgeons and to the administration that it's a cost-effective, efficacious, safe product. But I believe that all of those data exists, and I think it's going to be fairly compelling. In terms of the surgeon then using it, I think once it's in the hospital then it's going to be very easy for people to say. And I think surgeons are going to resoundingly say, yes, I'd like to reduce SSIs in my patients. And since it's on the shelf, I want to use it.

Okay. So do you also see surgeons sort of expanding the label, meaning like even though the first indication would be colorectal surgery or abdominal surgery greater than 20 centimeter, do you see surgeons like using this product for other surgeries where SSI could be a risk because the drug is already on formulary, assuming that?

I mentioned that earlier. I think surgeons are always looking for best outcomes for patients. And if you look at things like aspirin is not labeled per se to reduce myocardial infarctions or to prevent blood clots when you're flying on planes and people use it. And people use all manner of different drugs, vitamin C to try and prevent colon polyps. There's lots of things floating around out there. So the answer is yes. In my opinion, people will try to offer the benefit in a variety of scenarios.

Okay. Maybe in the last 5 minutes or so, I wanted to spend a little bit on commercialization strategy. So Dikla or Ori, maybe you guys can take the question. So obviously, 4.5 million abdominal surgeries in the U.S., roughly 600,000 cases belong to colorectal surgeries. So you -- I mean your partnership discussions are happening. What is that you're looking for in a potential U.S. partner, assuming the drug gets approved on time, how are you planning to expand on the D-PLEX use?

Yes. Maybe I can take that. So the product, because it is a hospital product and because as we just heard, there's specific knowledge that is needed to get the product on the P&T committee, we are looking for partners, and we are advancing our discussions with potential partners for the commercialization of D-PLEX. The partner needs to be a partner that knows the hospital, kind of knows its way through how to get product on P&T committee, how to talk to infectious disease specialists, how to talk to surgeons. So it's a very specific type of partner. We already have a partner in Europe for the product, Advance Pharma, which is responsible for all the commercial activities in Europe. And we are looking to do the same both in the U.S. and in other major markets as well.

I just got a question from audience. It says, does Dr. Wexner anticipate colorectal surgeons would readily replace current triple therapy ABX Prep with D-PLEX? Or is it more likely to be treated as an [indiscernible] intervention?

No. Well, it's a prophylaxis, it's not a treatment. So it's not a rescue agent. It's prophylactic. So I think that it's going to be a mix. I think some people are going to say like belt and braces, I'm going to do everything I'm doing plus add this. But for those people, and there are many of them who think, well, I don't really need the mechanical bowel prep or I don't need the oral antibiotics. I think it will be a substitute instead. So I think it's going to be a mix. I can't guess the percentages, but it's going to be a mix. For some people, it's going to be another add-on, but others are going to substitute. And I think what's going to happen over time is it's going to become a replacement therapy for the others. I think people are going to realize you really don't need all of these systemic agents because you've got something that works locally. There'll be exceptions. But I think in many cases, it's going to be a replacement therapy.

Okay. And Ori, maybe you can tell us a little bit about the market research study that you have done recently and maybe highlight a couple of high-level takeaways.

Yes. Yes. So this market research is really trying to independent in a way, validate what we just heard from Dr. Wexner. We asked surgeons. We showed them the data on a blinded basis and asked them first, and this is what you see on the left side here is kind of to help us understand what are the patient population that are -- that fit for this product. And they highlighted the risk factors, just as Dr. Wexner mentioned, the obese, the uncontrolled diabetes, the transplant patients, colorectal, of course, because that's where the study is. And also large open incision, incisions greater than 10 centimeters is almost, by definition, is a risk factor for -- or increases the risk for infection. So that's what was highlighted. And then what you see on the right here, we asked -- if you can just switch back for just 1 second. What you see on the right here is we asked about the willingness to use the product. And we ask if the product -- the yellow boxes, if the product is on formulary and is talked, the surgeons say that -- 80% of them said that they were extremely likely to use the product. The next slide talks about similar questions, but from the pharmacy director perspective, those who chair and lead the formulary review process. We ask them first, and this is on the left here, what is the -- how the review and acceptance process will happen in the hospital. And as they mentioned, a multidisciplinary team, surgeons, IDs, finance, all looking at the different benefits of -- and risks of D-PLEX. They would likely ask for a pilot study to really make sure that the product works as we claim it is, and then there will be a formulary decision as well. I will say that once -- it is a long process, but once the product is on formulary, it's a very sticky product. And just like Dr. Wexner said, people will start using it, word to mouth goes around the hospital, so we can see quite a broad use of it. On the right here, and this is very critical, we ask the pharmacy directors, how likely are you to put this product on formulary. And you can see the 90% here. So 90% of the people asked said they are extremely likely to put it on formulary. And then we added if you get this additional reimbursement from the NTAP program, this number, this 90% actually go as high as 100%, we'll put it because the financial benefits here with the clinical benefits are almost a no-brainer for coverage.

What is the sample size for your market research study?

Yes. So this was a qualitative research. There were 10 surgeons from different disciplines and 10 pharmacy directors. And really, the idea was to get a sense of where the hospitals are.

Okay. We also have a question from audience. I think this is probably the final question. What is the expected pricing for D-PLEX100? Is this something you can talk about?

So we...

Sorry, go ahead.

The pricing. So we -- in the past, we spoke about around $600 per vial. Without going specifically into the details, we tested -- the numbers that you see here, we tested a higher number than $600 per vial. And still, you see the numbers for -- both for usage and for having a formulary is high as you see.

I would just add that the feedback was even higher once the product has NTAP.

All right. So we are running out of time. I think this is a great discussion and Dikla and Ori and Dr. Wexner, great talking to you. Thanks, everybody, for dialing in. Hopefully, we can talk again in some other appropriate time. Bye-bye. Thank you.

Thank you.

Thank you. Thank you very much. Thank you.

Thank you for having us.