Talphera, Inc. (TLPH) Earnings Call Transcript & Summary

Good afternoon, everyone, and welcome to the AcelRx Virtual KOL Event on Perioperative Use of DSUVIA. I would now like to turn the call over to Vince Angotti, CEO of AcelRx Pharmaceuticals.

Thank you, operator. And thanks to all of you for your attendance and interest in AcelRx today, and welcome to our KOL call with Dr. Tvetenstrand and Cassavaugh, who will be sharing their real-world experience and data on the perioperative use of DSUVIA and their perspective on this use. This very recent data has been extremely well-received at advisory boards and other institutions, and we thought it was important to share it with our investor audience as well. While most of you are aware of the DoD's history of interest in DSUVIA and its potential application in the ER setting, today's conference will provide insight into how it is considered by health care practitioners in the surgery setting. Today's content is strictly focused on the medical aspect of DSUVIA, and out of respect for our experts on the webcast today, we ask that you focus your questions on the medical and clinical facet and not on AcelRx' business or operation. [Operator Instructions] I would now like to turn the call over to our Founder and Chief Medical Officer, Dr. Pamela Palmer.

Thank you so much, Vince. And I would like to first introduce DSUVIA quickly. Many of you on the call probably already know about it. But we're very excited today to have 2 physicians who -- 2 clinicians who have used DSUVIA over the past year, 1.5 years, talk about their experience. But a little bit about the drug. So DSUVIA is a sublingual sufentanil tablet, otherwise known as SST 30-microgram dose, and it was approved in November 2018 with a broad indication. It's indicated for use in adults. We've not done our pediatric studies yet in a certified, medically supervised health care setting. Certified means REMS-certified by us. We have a risk evaluation mitigation strategy program, which is very straightforward. And it's just to make sure that the drug is only used in medically supervised settings and doesn't go home or use at home. And the indication, again, says such as hospitals, surgical centers and emergency departments. It's not limited to that. It's also approved for use in the battlefield and for management of acute pain severe enough to acquire an opioid analgesic. Certainly, we're not trying to grow the opioid market. If you need to use an opioid analgesic, we suggest that DSUVIA could be an optimal choice for you. It is a single dose, is a tiny blue tablet at the tip of a single-dose applicator. This applicator is placed by the nurse or health care professional under the patient's tongue. It is then ejected, and that small tiny tablet has a bioadhesive and dissolves within 5 minutes. It's very lipophilic. And it avoids first-pass metabolism through the transmucosal sublingual route. So basically, what that means is very rapid uptake into the blood and a very rapid blood-to-brain transition there. So as with all opioids, we do have a black box warning, and it talks about the REMS program, the fact that any opioid can cause life-threatening respiratory depression, addiction abuse and misuse. We are metabolized with the cytochrome P450 3A4 system, very similar to fentanyl. And so any drugs that affect that system could, in theory, affect the metabolism of sufentanil. And any concomitant use with CNS depressants and opioids, of course, you would want to lower your dose of those drugs. Our important safety information, DSUVIA is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting and with absence of resuscitative equipment. Of course, DSUVIA is always used in a monitored setting. And known or suspected gastrointestinal obstruction, including paralytic ileus, or a hypersensitivity to sufentanil. These other adverse events listed here are typical for opioids and is very standard opioid language. If you are interested in further important safety information, please see the prescribing information at www.dsuvia.com. Now a key advantage of DSUVIA, a key attribute of the drug, is its sublingual administration. So you see here, this is a slide showing 30 micrograms of IV sufentanil compared to 30 micrograms of sublingual sufentanil, which is in the gold. So the blue line there shows you exactly what happens when clinicians dose either IV sufentanil or other lipophilic opioids such as IV fentanyl. You have a very rapid high-peak plasma level, which then rapidly falls down to trough levels. And so, in fact, this can create, at the high-peak plasma level, significant side effects and then a rapid loss of analgesia as the levels start to plummet. And so, in fact, what the goal was, was delivering sufentanil sublingually was to decrease the peak plasma levels, which we did by 17-fold and just still to maintain a plasma level above the therapeutic concentration for 3 to 4 hours. So what you give up is onset of action. Instead of working in 1 to 2 minutes with an IV push, it takes 15 minutes. So what we see our clinicians doing is, in fact, dosing 15 minutes before a patient is going to need that analgesia. They are timing the pharmacokinetics to the pharmacodynamics. And it stays nicely above the plasma level that's required for analgesia for 3 to 4 hours, with, again, no tall dangerous peak plasma level that you would see with IV opioids. It's also a very high therapeutic index opioid, meaning the lethal dose divided by the effective dose is a very large ratio. It's a large window there. And so what we then see is, in fact, this study was run for the Department of Defense in emergency rooms, where they were looking at or asking us to look at the cognitive impairment possibly caused by DSUVIA. They were concerned because morphine and ketamine in the battlefield can cause cognitive impairment, which is, of course, very dangerous in that situation. And so they wanted to make sure that, that was not what was going to happen with sublingual sufentanil DSUVIA. So in these patients, the 75 patients, we, in fact, did a 6-item screener cognitive impairment assessment prior to dosing and 1 hour after dosing at the peak plasma levels of sufentanil. And what we, in fact, saw was that there was 0 change in the 6-item screener score for 85% of the patients. There was an improvement in the 6-item screener score by 1 or 2 points with 12% of the patients, and only 2 patients decreased their score by 1 point. If you're thinking about how did that break down with different ages, you can, in fact, see here that the advanced elderly have the best scores. They had perfect scores both before and after dosing. And anecdotally, this is what we've heard over and over again from folks who have used DSUVIA, especially with the elderly patients, maybe renal impairment, et cetera, they're seeing that there's this clearheaded lack of cognitive side effects, lack of semblance, lack of sedation on these patients, but effective pain management. And so again, we believe this is a combination of the blunted peak plasma level, combined with the high therapeutic index of sufentanil. So here today to talk about their experience administering and dosing and observing patients on DSUVIA is Dr. Christian Tvetenstrand, and following him will be Dr. Koth Cassavaugh. And they -- each of the speakers will introduce themselves when they come on. It is important that these studies were not supported or funded by AcelRx. The publications of the studies have been supported by AcelRx. And both Dr. Tvetenstrand and Dr. Cassavaugh today are being compensated for their time presenting today on this call. And I would like to say that we're excited that, recently, Dr. Tvetenstrand's paper we copublished with Dr. Michael Wolff, an anesthesiologist, was published in the Journal of Clinical Anesthesia and Pain Management. So without further ado, I would like to invite Dr. Christian Tvetenstrand to present data from his recently published article.

Thank you, Pam. Can you hear me well? Okay.

Yes. You are coming in clear.

Right. So I'm privileged to present our findings today. I'm the Director of Trauma Services and Chairman of the Department of Surgery here at United Health Services. And much like you in the audience, I went to a conference and saw all of Dr. Palmer's work with regards to the pharmacokinetics. And I said this is something really special, and this could really apply to our practice. I brought it back to our hospital, and of course, pharmacy had a lot of questions. So out of the questions and conferences that we had, we came up with a protocol. It's IRB-approved, and this is the result. And the study is titled, Reduced Opioid Use and Reduced Time in the PACU Following the Preoperative Administration of DSUVIA in an Ambulatory Surgery Setting. What we have is a very busy practice. I've been in business -- or a surgeon for over 30 years, do about 1,000 cases a year. So this seemed to fit my practice perfectly. And if I can have the next slide, please? So we designed the study to look at giving the DSUVIA 30 minutes before the surgery. It takes about 30 minutes to hit a therapeutic level. And noting that we don't get those peaks, we thought we might be able to reduce the amount of fentanyl that we give during the surgery. And in fact, this is what we saw. And in our study group, we gave the DSUVIA 30 minutes before. Our control group was -- went back in time 3 months, and we matched to demographics like BMI, length of surgery period. In both groups, more than 75% of the surgeries were abdominal in nature. Patients were considered eligible if they were undergoing abdominal surgery, defined as anticipated discharge on the same day. Of course, those patients that had complications or needed to be admitted were omitted from the study. Next slide. Next slide, please, of study design. In our control group, we had 80 patients, and we looked at their BMI, length of surgery and age. Typical opioid administration consisted of IV fentanyl boluses, additional intraoperative and postoperative opioids administered as needed. And in this group, we used IV Tylenol. In the DSUVIA group, 47 patients. We used the single dose 30 minutes typically before the induction of the anesthetic, and the dosing time averaged about 34 minutes. Additional intraoperative and postoperative opioids administered as needed, and as we went with the study, we dropped the use of IV Tylenol. Next slide. So these are our demographics. The control group, the average was about 52 in age; the DSUVIA group, 54. The mean BMI, 32 in both control and DSUVIA. The range for the BMI in the control group was anywhere from 16 to 60, and that pretty much matched the DSUVIA group, 15 to 61. The length of the surgery pretty well-matched as well, 40 minutes in the control group, 37.3 minutes in the DSUVIA group. Next slide. So what we saw in the pre and interoperative opioid use was reduced by nearly 50%. We could see that in the control group, those patients receiving IV intraoperative IV opioids was 97.5%. In the DSUVIA group, that dropped to 62%. But if you take a look at the MME, which is a way of converting DSUVIA in equivalence to morphine, we saw that in the control group, we were using the MME -- or 20 milligrams of morphine, while in the DSUVIA group, we were using almost 11 milligrams. So almost a 50% decrease in the amount of interoperative opioid. Next slide, please. So what happened postoperatively is very interesting as well. In the control group, almost 60% of our patients needed more opioids. In the DSUVIA group, only 10% of the patients, same types of surgeries matched for age, length and type, only 10% is needed. If we convert to the MME, 4.4 milligrams in the control group and a little less than 1 milligram in the DSUVIA group. Next slide, please. So if we add everything together in terms of interop and postop, we can see our control group got 24.6 milligrams of morphine equivalent. In our study group, that dropped significantly, and this is all statistically significant, of course, to 11.8 milligrams. Next slide, please. So what does this mean? What does this mean to our operations and our processes? So we look at the amount of time that our patient spent in a PACU, which is a pretty intensive place, one-on-one nursing for these patients that just had surgery, and it's a limited space in our -- most hospitals. So we see in our control group, our patients were typically spending 55 minutes. In our study group, this drops drastically to 36 minutes, quite a significant savings in time. Next slide. So we looked at some secondary end points as we went through this, and we found that in our control group, we were using pressors or agents to raise the blood pressure, particularly on induction. When you give fentanyl or a drug like that, you get a high peak. And a lot of times, on induction, the blood pressure will drop and the anesthesiologist is scrambling to give something like ephedrine, a pressor to reverse that drop. So we wanted to see how much ephedrine or pressors were used. And in our control group, almost 40% of the time, they were used; in the DSUVIA group, 19% of the time. And I might say that the amount used in the DSUVIA group was much less as far as dose. In the control group, we were giving almost 90%, unless contraindicated, IV Tylenol. And in the DSUVIA group, we said we stopped giving it, and we only used in 38% of the patients. Neither in the control or the DSUVIA group did we have to give a reversal agent like NARCAN or naloxone. Next slide. Now because of a lack of consistent adverse reporting events in the historical controls, we can't really make any comparisons. However, we can say, in the DSUVIA group, overall, it was very well-tolerated, and we saw no respiratory depression. What we did see too is we saw a lot less confusion. We saw people legging up a lot clearer and basically happier. Next slide. Now I would like to turn the call back to Dr. Palmer, who did a deeper dive on the study and broke down the costs of what we used in the control group versus the study group.

Thanks, Dr. Tvetenstrand. So when Dr. Tvetenstrand was presenting this data recently during an Advisory Board, we were asked the question, well, this is great data, but what does it mean from a cost standpoint? I mean anesthesiologists and surgeons usually aren't walking around with wholesale acquisition costs in their mind. So they asked us if we could possibly do a quick analysis of what sort of cost savings that he would see in his study. So we certainly know that DSUVIA is more expensive than a generic injectable opioid such IV fentanyl or IV morphine. But I think it's exciting that his study did show an overall reduced opioid exposure because, of course, we know that's advantageous from an opioid stewardship perspective. But we really do feel that this better patient care doesn't have to come at a higher price tag. So to compare apples-to-apples, we'll look at the wholesale acquisition cost for the different drugs used on both the control group and the DSUVIA group. So DSUVIA, the WAC cost is $58.31, but, of course, that cost is offset by decreased supplemental IV medications and of course, a decreased PACU time, which I'll quickly go through here. So again, we saved some morphine milligram equivalents interoperatively. As you saw, there was, overall, about 50% less IV fentanyl used interoperatively. But that doesn't save you much money. The whole goal is to decrease the opioid exposure, not necessarily to save the money because we know IV fentanyl is inexpensive. So we saved an additional cost of $2 of that extra IV fentanyl that the control group got interoperatively. In the postoperative setting, we saved an extra $1 on IV fentanyl. Again, IV fentanyl is inexpensive. So overall, $3 savings. But again, the key part here is less opioids, better opioid stewardship approach to the patient. Now what does start to get more expensive is some of your other drugs. So IV acetaminophen, for example, has a 52% less use in the DSUVIA group than the control group. And so, in general, what you see here is a cost savings of $24 averaged across the patients because it is $47 a dose. And what some folks don't realize is that although ephedrine and as Dr. Tvetenstrand mentioned, IV ephedrine is the drug that anesthesiologists grab when we've given our IV propofol and our IV fentanyl to induce general anesthesia and we watch their heart rate and blood pressure plummet. We grab the ephedrine to dose them because we want to make sure we get that back up again. Even though it's generic, it's $29 for single-use file as a wholesale acquisition cost. So if you look again at the savings of the use of ephedrine, not only is it better pain management for the patient from a hemodynamic standpoint, but you save an additional $6. So, so far, we saved $33 in additional supplemental medications that had to be given to the control group versus the DSUVIA group. But where the saving just really comes in is in the PACU time. So you saw here that the control group had an additional 18.6 minutes in the PACU. Now conservatively, that has been priced out in the literature at $7 a minute. So right there, you're saving $130 on average per patient with your savings through the PACU. Now if your PACU bed availability actually is limited in your institution or in your ambulatory surgery center, meaning if there's a bottleneck there and you start backing up into the operating room, you, in fact, start losing out on operating the indirect overhead revenues, which are priced out at $15 per minute. So if you look at that situation, each use of DSUVIA per patient is, in fact, saving you an additional $279. So added up all together, the cost savings observed was $163, if you don't have a backup into the operating room; minus the $58 wholesale acquisition cost for the DSUVIA, means you're still ahead per patient on average of $105. If in fact, you saved your operating room from becoming the bottleneck because of the PACU bed availability, you could, in fact, have a cost savings per patient on average of $384. So that's just some quick analysis that we ran to look specifically, and again, this is uniquely Dr. Tvetenstrand study. It's his study. It's the data he specifically collected at his particular institution. But I think as you'll see in the next study by Dr. Koth Cassavaugh, and again, I'll let him introduce himself, it's very similar data to what Dr. Tvetenstrand is seeing. And in fact, what's interesting about Dr. Cassavaugh's data is while Dr. Tvetenstrand's was general surgery, where all patients were treated by the exact same clinician, Dr. Tvetenstrand, so that was very consistent, what you'll see here with Cassavaugh's data is just across multiple specialties. And so -- in both inpatient and outpatient surgeries. So I think it's a very nice complementary subset of data. So Dr. Cassavaugh, the floor is yours.

Thank you very much, Dr. Palmer. My name is Koth Cassavaugh. I am the Director of Pharmacy here at Auburn Community Hospital in Upstate New York. We're a 99-bed hospital. And a little backdrop into how we were looking at DSUVIA was -- it was during a time where Pfizer had recently bought out Hospira and it caused kind of a real shortage on PCA devices, working with PCA. And our bariatric surgeon, our primary bariatric surgeon, was looking for an alternative as we could not get these PCA devices for his bariatric surgeries. So we were looking for a product that would give us nice longer control of pain and still be highly effective as an opioid. So we found DSUVIA and worked with our Head of Anesthesiology and that primary bariatric surgeon to get it approved here at the institution. Our initial intentions were to use it primarily in bariatrics, but working with the Head of Anesthesiology, I said if you feel it fits in other cases, please let it expand. So as Dr. Palmer was kind of mentioning, we expanded pretty quickly as we'll get into it and show you in the data here. And we kept hearing all these positive reports coming from our Head of Anesthesia, our nursing people in the PACU, our folks going up on the floor, so as part of our annual certifications for our regulatory bodies' joint commission, we decided to do an MUE, which is medication use evaluation, to really see is DSUVIA giving us that -- the positive things that we felt or was it just people's feelings. So we collected all the data, and we'll move to the next slide here. And so our patient characteristics, as you can see, we had a number of 140 people that were unique and treated in the DSUVIA group. And we compared that up against our historical controls of 158 people. The nice thing was it was during the same exact time period with the same exact settings for ERAS protocols and everything as far as opioid stewardship. So we had all the same surgeons performing the same surgeries. We had the kind of typical adoption curve with our anesthesiologists because they were the primary people that were doing the dosing upfront. And we had early adopters as our Head of Anesthesiology was and then we had some late adopters. So we were able to compare 2 groups of surgeries with the different providers, different anesthesia providers, but same exact surgeries, same exact procedures and have a nice comparator group. So again, broke out very evenly, with female being 68% in our DSUVIA group and the control group at 70. The average age was about 50 for DSUVIA and 52 for our historical. And our weight was very evenly matched and as you can see is a little bit higher. And again, primarily, we were starting in the bariatric population, so that did have a number of a variety of things, so 93.3 versus 93.4 kilograms. So again, very evenly matched. Next slide, please. So as they started using it, and again, they felt that it was working really great, they expanded very quickly. So we have done a number of different procedures, including abdominal procedures, GI procedures, moved into ortho with hips, knees, shoulders. We did a lot of GYN procedures, GU procedures with lithotripsies, I mean, and a variety of different things. Our ENT folks have used it, and they have nice short procedures. And then we had a couple of spine cases in which we got to use it. And you can see, between our DSUVIA group and our historical control, it was very well-matched. We ended up with pretty much even percentages all the way across. But again, it was very interesting to see how quickly it expanded to the other subspecialties and other groups using it from our predominantly abdominal, where, again, the majority of those were bariatric patients. And interestingly enough, like I say, with the bariatric patients, they are a group that you worry a little bit more about sleep apnea and the effects of opioids on those people. And again, they did phenomenally there, and we'll show you the data on that. Next slide, please. So the vast majority of our patients in the DSUVIA group, 137 out of the 140, received the single dose of DSUVIA preoperatively, approximately 15 minutes prior to intubation or intraoperatively, 30 minutes prior to extubation for longer-duration surgeries. So we started to use the kinetics of the drugs following the curve that Dr. Palmer had showed you, where it takes about 15 minutes to take effect and then it will last for 3 to 4 hours, which is very consistent. So if it was a very short procedure, about an hour-long procedure or 1.5-hour procedure, our nursing staff would actually do the dosing of the DSUVIA 15 minutes prior to intubation and rolling into surgery. If it was a longer procedure, 2.5-hour, 3-hour procedure, we would wait until about 30 minutes prior to extubation. And then the anesthesiologist would be able to dose that rate in the operating room, and it's very simple with the device to be able to get in there even though the airway is protected to give them that nice sublingual dose very quickly, very easily and able to provide that pain control going out to our PACU. The 140 DSUVIA-treated patients received a total of 154 doses during the study period. So basically, 14 patients required a second dose of SST in the PACU. And these doses were included in the total morphine milligram equivalents that you'll get see here in the next couple of slides. Interestingly enough, we had kind of a learning curve as we first introduced it, and 9 of those 14 patients receiving the second dose were within the first 3 weeks of us learning how we wanted to use it. There were 3 patients who received a single dose of DSUVIA only in the PACU, so nothing preoperatively or interoperatively. And we kind of phased away from that fairly quickly. Next slide, please. So here is what we found in our data. We reduced the intraoperative use of IV opioids associated with the DSUVIA. So by dosing either upfront or during the procedure, we were actually able to reduce. And you can see in the overall here on the left-hand side of the screen, that we went from 15.7 morphine milligram equivalents down to 9.6 in our interop period, and you saw that across the board. And that was statistically significant, with a p-value of less than 0.001. Again, we saw this across the board. Abdominal, we had a nice drop of about 6 morphine milligram equivalents, from 17 down to 11.4; ortho, from 15 to 8.5; our GYN, 14.9 down to 7.9; GU, from 13.4 down to 8; and ENT, from 14 down to 8.8. Next slide, please. This was where we started to look at all the primary things. And this was how much we reduced those morphine milligram equivalents by using DSUVIA in that perioperative period. So overall, we had greater than a 50% drop in the morphine milligram equivalents. And again, that's something -- we didn't know Dr. Tvetenstrand was doing a very similar study down in his institution, and it was kind of amazing to see once we kind of compared results that we really ended up with very, very similar results. So again, we went from this nice 8.1, down to 3.6. So this fit very well into our opioid stewardship philosophy here at this institution, which isn't just to complete elimination of opioids, but instead rather to use the most appropriate agent in the best possible setting to maximize results. So we showed that by adding this DSUVIA upfront, we weren't just front-loading an opioid to save it on the background. We saw reductions in our interop and big reductions, like I say, greater than 50%, in our postop. And this, again, was across the board. Abdominal, as we've said, we had these patients in the PACU for quite some time and they were using, on average, 10.3 morphine milligram equivalents, and we cut that by more than half, down to 4.7, which helps expedite our patients out of the PACU. Ortho, we had greater than a 70% drop in our morphine milligram equivalents needed postoperatively. We went from 7.2, down to 2.2. And our orthopedic surgeons are just absolutely excited about that tremendously. GYN, 8.2 down to 3.9. Our GU group didn't use as much postoperatively in the beginning, 3.7, but did still see a nice drop, down to 2.9%. And ENT was about a 50% drop. So across the board, again, across all these subspecialties and multiple surgeons, we saw a nice average drop in our postop morphine milligram equivalents. Next slide, please. The reduction in PACU time, as Dr. Palmer had mentioned, is absolutely tremendous. And it is a very big cost savings for the institution. The more people we can get out of the PACU quicker, the better we can turn over those beds and perform more surgeries, which is beneficial for the institution. So overall, we saw about a 14-minute drop, when you took everybody into consideration, from 80 minutes down to 66. So again, that's pretty close to, like I say, basically, every core procedure has gained you an hour in the PACU, which is tremendous. We noticed in our abdominal patients, again, that they were using a very high amount of morphine milligram equivalent in the PACU, and they were in the PACU for quite some time. Their average time in the PACU was 92 minutes, over 1.5 hours. And we were able to drop that by well over 20 minutes, down to 69 minutes. So that was helping expedite our patients up to the floors and getting them up, getting them moving and getting them through the system quicker. Our ortho saw a nice drop, as you see, 73 down to 66; GYN, 75 down to 66; GU, 73 down to 60; and ENT had a slight bump-up, but they were fairly short at the start. And those are our Phase I PACU times. Next slide, please. So we did track our adverse events. So antiemetic use, we tracked how many people were using that. And albeit, all opioids do have an incidence of nausea and DSUVIA had some. We did see that DSUVIA was about 40% less than our historical group, and then we think that's part of that reduction in the opioid. So we had 10% of our patients, 14 patients used an antiemetic in the DSUVIA-treated group versus 16.5% of our patients in the historical control group. Naloxone, we didn't have any use in the DSUVIA group. And historically, we had 3 patients, so 2%, that ended up having to have a reversal agent due to decreased O2 stats. Another thing on the antiemetics, we did have 2 patients in the DSUVIA group who actually received multiple agents versus 6 patients in the historical group, so again, very similar data as far as that goes. So again, we felt and saw that these people were waking up better. As you see here, you'll hear that numerous people are talking about it. Dr. Tvetenstrand talked about it, and they're hearing it anecdotally across the nation. Our Head of Anesthesiology was being quoted as saying, this unlocked a third state for us. Before, people were either, well, pain controlled but had some degree of O2 saturation decreases. Or they weren't controlled, requiring more opioids. He said that this has now unlocked a third state for us, which the patients are awake, alert and comfortable. And they like to call them chatty, and all of our PACU nurses said this was great and all this other stuff. Again, the increased duration of action, that 3 hours of duration of pain, 3 to 4 hours of pain control, has also gotten us time to get our patients to the floor and buys the time for the nurse on the floor to be able to do an admission of plasma without having to immediately run for a pain control agent or another antiemetic. So we feel, again, this fits very well into our overall opioid stewardship program of using the most appropriate agent in the best possible setting to maximize our events. And from the data that we did internally, we are now opening up things and opening up use in our EDE, our oncology center, and looking for use on the floors. So it is expanding. And with that, I'll turn it back over to Dr. Palmer.

Great. Well, operator, I think we're now ready to enter into the Q&A portion of this call.

[Operator Instructions] Our first audio question comes from the line of Brandon Folkes with Cantor Fitzgerald.

And congratulations on the data. Maybe just on the controlled group for both the doctors. Can you just elaborate how the control group regimen compares to real-world practice? We've seen some data or some companies coming out and starting to talk about adding OTC oral generic analgesics creeping in, whether it be preoperatively or postoperatively. So I guess, maybe just any commentary in terms of how the control group reflects your current practice today and how you treat patients prior to DSUVIA would be fantastic. And then maybe just following on -- I'll just ask both my questions now. As you get more experience with DSUVIA, are you looking to stratify towards certain patients? You talked about the advanced elderly and the renally impaired. Or is this something you may look to use broadly?

Great. Well, so with that 2-part question, I think maybe I'll start off with Dr. Cassavaugh. Your control group, what were they typically getting for -- were you using multimodal sort of ERAS approaches for those patients?

Yes. As I kind of quickly mentioned, that was the nice thing with our study. We were in the same exact time period. So we were using ERAS protocols where you are getting either IV or oral acetaminophen, sometimes gabapentin and some [ kontoralax ]. So we were using multimodal anesthesia -- or analgesia, sorry, to treat our patients, which is very common in most institutions. This was a different product that we brought in and like I said, tried to see where we would make that fit. And again, that was the nice thing that we found was that we weren't front-loading with opioids to save on the back end. We used an opioid and saved all the way through the procedure. So it has now become our standard. And even our late adopter anesthesiologists are now all fully on board once we showed them the data. So every one of them is using it as part of our ERAS at this time to get people through and move them along.

Great. And for your second question, Brandon, there are certain types of patients. Dr. Tvetenstrand, I'll go to you for that question. I mean how do you think about DSUVIA? And is it for all patients, certain type of patients? What are you sort of seeing in your institution?

Well, as we gain more experience with the drug and use it in some of our frailer patients, and I think you spoke to the clearances of the drug and the fact that there's no active metabolites, it struck, as an -- being Director of Trauma here, that this might be a good drug to use in the elderly population. We have a tidal wave of geriatric patients that are hitting our emergency departments, and our prototypical patient is an old grandma that's fallen down and broken her hip. And heretofore, these patients were being treated with anything, with drugs like morphine, Dilaudid. And we were actually taking functional people and actually turning them into patients that had to go to skilled nursing facilities afterwards. We basically put a stop to that, and we're using preferentially DSUVIA. And as you can remember from Dr. Palmer's slide about the cognitive impairment not being there with DSUVIA, we see the same thing with the elderly. So we're picking up a lot of benefits here. We're not turning them into nursing home patients. We're getting them back home. They're participating with physical therapy sooner. So our length of stays in the hospital is dropping as well. So there's cost savings all around. If you can prevent a patient from going to a nursing home, that's huge in terms of insurance costs. If you knock a couple of days off from the hospital, that's huge as well. But it's just the right thing to do for these patients that are so frail. And the fact that it clears so easily, that even if the patient has renal insufficiency, which we have seen in a number of the elderly patients and there's no active metabolites, we're not getting dose-stacking, which we see with drugs like morphine and Dilaudid, that the metabolites themselves, which they have to be renally cleared, are building up and these patients can actually suffer respiratory depression and even arrest in some cases. So we've taken that out of the equation. So we couldn't be more thrilled in our institution to have implemented this for our geriatric patients.

Well, that -- and that's great, and you did emphasize the lack of active metabolites, which I didn't even really mention earlier on with my brief introduction, so I'm glad you brought that up, Dr. Tvetenstrand, and I think that as more and more data comes out on the problems with morphine and hydromorphone in renaly-impaired patients, I think that's definitely advantage and even beyond the elderly, how do you feel about it with your larger BMI patients, for example, the way Dr. Cassavaugh is releasing an advantage in use institution. Have you seen that in yours as well?

Yes. It's very interesting. If I may answer, with our larger patients in Binghamton, we tend to have a larger BMI here. And so we're dealing with patients routinely with BMIs in 50 to 60. And you're just putting this tiny little tablet under their tongue, it dissolves into the lipid tissues under their tongue. So there's no distribution to the massive weights that some of these people have. It's very clean. So the dose that you give to someone with a BMI of 18, which is a skinny person to someone that's tremendously overweight, it's the same, and the effect is the same. So we don't have to sit there and calculate and give -- well, anyway, 400 pounds, we have to give so much more drug. You just give them 1 pill and you get the same effect. And it's almost too good to be true.

But it is true. And both -- and that's what I think is so interesting is that both of you all, completely unbeknownst to each other, were running medical -- medication use evaluation studies at your own institutions in your attempt to look very thoughtfully whether to adopt DSUVIA or not and you're striking the similar data across, as you mentioned, different BMIs and different age groups and in fact, even across different types of surgeries. So that really, I think, is quite remarkable. So we'll -- is there another question we can move onto?

Our next audio question comes from the line of Michael Higgins with Ladenburg Thalmann.

We're looking at the papers and what you've been talking about on quarterly calls, but great to hear their feedback. And one of the questions I was hoping to talk about is how this is comparing versus oliceridine. When oliceridine was being developed, it was considered to be higher effectiveness same adverse event profile or maybe lower adverse events profile by comparable efficacy. And it just really didn't turn out that way. It's gotten approved. I'm wondering if you have any use and experience with it and how do the experience compares to DSUVIA?

Well, oliceridine is not -- it's not approved yet for -- or it's approved but not commercially available yet. But I will let either physician answer if they worked with it or aware of it.

I've read about it and had the -- and I'm with Dr. T on that. We have not had the opportunity to fully evaluate that and look at that.

Okay. Fair enough. Dr. Cassavaugh, you mentioned in your comments that you find the -- if you were dosing DSUVIA intraoperatively while the patients were being -- were intubated. Walk us through how that's working? I assume that there -- that you're dosing at the same and -- but I guess if you could just kind of walk us through how that's working. I don't know if they're -- if it's still below the tongue, which would make sense. And do you keep the tongue down and how that's working?

So yes. The anesthesiologists will administer it during the procedure due to the design of the device and how it was handled. And again, I know that was worked a lot with the military. It is very easy for them to handle. They can position it under the tongue, as Dr. Palmer had mentioned, as a bio adhesive. So once they click it out of that device, it adheres right to the sublingual buccal space, and it dissolves very quickly, as she said, in under 5 minutes, and they start getting maximal effects in about 15 minutes. So again, based on our timing and the kinetics of the drugs, that's where we recommend if it's going to be a very long procedure, about 2.5 hours, 2-plus hours, that they wait until about 30 minutes before closure to maximize giving good pain control throughout the PACU period, as we obviously are doing some pain control within the intraoperative period. So again, the anesthesiologist being right there at the head can administer that dose. We store right in our Omnicell machines right there for them to pull and administer. Does that answer your question?

Yes, that's very helpful. That was exactly what we're looking for.

And I'll just jump in, Michael, sorry. We do have sites who are, in fact, seeing so much of a cost savings with DSUVIA that typical with their longer cases, as Dr. Cassavaugh was saying, they're actually dosing DSUVIA pre-op and dosing it then 30 minutes before extubation. So they're actually just using DSUVIA for their case, both pre and intra for their longer cases.

Right. Another question, if I could. I was a bit surprised to see that the pharmacodynamics impacted the analgesic agonist used without surprise to the doctors.

So Dr. Tvetenstrand, since that was your result, why do you think DSUVIA is causing less ephedrine use?

Well, right. When I first went to the conference, and I saw the slide and went over to the science about the pharmacokinetics, it struck me that we could actually get our patients induced without using a fentanyl, which gives you a very high peak. And this oftentimes associated with hypotension. And it was actually the question that I wanted to answer with the drug, and that's how I built the study around that question. And what we did is we gave DSUVIA 30 minutes beforehand to make sure that we had a therapeutic threshold of at least 24 picograms. So then when the patient got intubated, they were intubated without the traditional fentanyl, which can lead to hypotension, where we like to say hemodynamic instability on induction. And my -- I actually posited that, that probably will lead to less use of the ephedrine. It's very disturbing as a surgeon, you're working way down below, then all of a sudden your anesthesiologist's scrambling around for medication. And that's what really piqued my interest. I wanted to smooth out the induction process and we actually were able to do that with the proper use of the DSUVIA. Some of my colleagues are using it in different ways, and some of the orthopedics will dose it just toward the end of the case. And they're getting their patients out of the PACU just as quickly. But yes, actually anticipated that. Didn't expect it, but it actually turned out. So it was a real great surprise for us.

Well, and I think we all -- I mean, sufentanil was invented by Paul Jansen back in Belgium in the 1970s to make a more cardiac stable opioid. Historically, morphine, I mean no one uses morphine intraoperatively on induction because it really plummets blood pressure, releases histamines and mast cells. And so that's why everyone has moved towards fentanyl. But sufentanil, in fact, was developed to be even more cardiac stable. When you combine that attribute of the product with a slower sublingual gradual uptake, absolutely like Dr. Tvetenstrand was saying, you're not seeing that pharmacodynamic instability on induction. And in fact, it's been shown -- and the Cleveland Clinic published a couple of years ago that if the mean arterial pressure drops below 65 intraoperatively, there's actually downstream morbidity and mortality consequences of that. And so I really -- that's why we're -- as anesthesiologists, we're running around trying to give a bedroom to get that back up again, but not having to do that, not risking that hemodynamic stability on induction. And in fact, having that smoother hemodynamic effect, I really feel is an advantage that we weren't even thinking of. I have to be honest, at AcelRx, the Dr. Tvetenstrand data really highlighted that, that is just another key advantage of DSUVIA.

That's really interesting. Thank you, especially for that last comment, Pam, I hadn't considered that impact. If I may, there's a comment on respiratory depression. Just trying to get a sense, we saw 3% or so in the slide, but what are you accustomed to in these same patients? What rate of respiratory depression are both of you expecting? But did you see necessarily DSUVIA?

Right. And I'll clarify that 3% was the control group in Dr. Cassavaugh's study. Just, but -- so I'll let maybe Dr. Cassavaugh, you can talk as a Director of Pharmacy. You probably have a good idea of overall what sort of respiratory depression rates you're seeing with the typical -- from IV opioid perioperative use?

Yes. I mean, it's something, again, we track consistently. It's one of the things that we have to maintain for our regulatory bodies, is to track how many reversal agents are given. We do have the fairly tight set of parameters. So if the O2 SATS drop below 94% and 95%, then they do want to use the reversal agent just to keep ourselves from getting into any problems in that. And that's pretty close to historical data for us, that I think we're typically historically a little bit lower, about 2%, 2.5% overall. But it's again, something we don't want to have happen. So again, the lower the percentage, the better. So -- but it is something that does exist. And with tight controls on it, you do tend see it used from time to time.

And just if I could jump in on that. I mean, I think people have asked why is our adverse event profile so low? I mean, if you looked at the front page of our package insert, our adverse events, there's only 5 listed that are greater than 2%, and none of them are respiratory in nature. And that's very different than other opioids, including recently approved ones. So what people did -- why is it? Is it the molecule? Is it the route of administration? And I think this slide sort of nicely summarizes sort of why I was interested in this drug and this route of administration to begin with. And sufentanil is very fat loving, very lipophilic, inherently with the molecule. It also inherently has a very high therapeutic index. And I mentioned this at the beginning of the conversation. But that's a lethal dose divided by a factor of -- so think of that as sort of a therapeutic window, the larger the window, sort of the less chance you're going to get to that lethal problem if you're effective at much, much lower concentrations. Those inherent molecules, combined then with the sublingual administration resulting in dramatically lower peak plasma concentrations. I showed you the pharmacokinetics of IV versus sublingual for the 30 micrograms sufentanil, 17-fold lower. So I mean, if you asked why are we seeing sort of this less respiratory depression, I have to believe it is a therapeutic index combined with that blunted peak plasma level that is really allowing, not only this nice AE profile that we have in our label, but that lack of cognitive impairment that we saw in our emergency room study. And it's really, I think, as Dr. Cassavaugh showed, also why there was no naloxone use when he usually runs made 2% to 3% there. As a reminder, we had absolutely known naloxone requirement for any DSUVIA patients in any of our clinical studies for approval. So we really feel like it's the molecule attributes and the route of administration that's combining together for this enhanced recovery of the patient and the reduced patient discharge time, which both studies sign. And I didn't even have -- we don't even have on this slide, the lack of active metabolites. So thank you, Dr. Tvetenstrand for bringing that up. That's also critically important. But I will still -- are there any other questions on the line?

Our last audio question comes from the line of Ed Arce H.C. Wainwright.

This is Thomas Yip, asking a couple of questions for Ed. My first question for Dr. Tvetenstrand, we have seen a number of advantages of DSUVIA for patients and from a cost standpoint as well. From a clinician, such as yourself, what are some advantages by DSUVIA over IP opioids?

Well, let me just the ambulatory surgery patients that we do that I would present it. And what we don't see in the tables and the data is the quality of what the patient's experience is. It's much smoother, they're waking up as Dr. Cassavaugh said, chatty. It's almost as if some of the patients relate that they're waking up out of a dream, and they're a little ticked off that we woke them up. But they're totally with it. They're not nauseous. They can participate in their recovery. They're getting out of the hospital a lot quicker. And our acceptance scores go up. So they like us better. So that's one big thing that struck me that doesn't come with the data.

I see. I see. So it sounds like you're fairly convinced by DSUVIA. But what about among your peers at Rosen Medical who are still using IV opioids? Where are some pushbacks from them?

Well, it's new. Anything new is going to have a knee-jerk reaction to it. But as they've seen my results, they want to participate and have the same results. And in fact, our orthopedic surgeon that does about 20 total joints a week has started using it, uses it on 95% of his patients. 5% that he doesn't use it on is because they can fill the paperwork out right. He absolutely loves it. You see the -- a real change. He started using it about 3 weeks ago. We're collecting his data, and we'll have maybe another presentation for you with regards to that, but he is just over the moon with it and his patients are doing very well. So slow adopters. We all have -- our newer surgeons are going to start using it in the upcoming weeks for spine cases. They're just waiting. We like to do everything through an IRB. So we're waiting for an IRB approval, so that the results that, I guess, can be publishable. So he does about 10 fusions a week. So he can't wait to get this into his practice as well. As far as our trauma team, all the trauma surgeons, they were slow to adopt. But now the team is excited about what I've been seeing with the geriatric patients, and they're starting to dose as well. So it's an experiential thing. It's -- as they have a saying in medicine, you don't want to be the first to use something, but you definitely don't want to be the last.

I love that saying.

I should say, if I could add to that, from our perspective, we had a lot of the physicians really jump on board, but also nursing has very -- has grasped us very, very well. They save a lot of time from a lot of the duplicate documentation that's required for waste and all that stuff that is required according to laws. So they don't have any of that stuff because it's 1 dose, 1 dose fits all. There's no waste. There's no partial dosing. Which is what you get into with a lot of the IV stuff, it saves me a lot of aspect of time because I don't have to chase around diversion, concerns as much. And then, like I said, it buys time going to the floor. And as Dr. Tvetenstrand said, our patients are much happier. They're feeling a lot better, and they can be cognizant with you. As we said before, we've got them in because we are looking to replace the PCA, which is a big heavy box that goes on a pole that they have to walk around with when they're upstairs. And now with this noninvasive mechanism of delivery, we don't have them attached to a line that's attached to an IV line, and they can get up and get moving quicker as well as not having that cognitive decline. So it's been well received by everyone throughout our whole role.

If I might add to that, we have got a fair amount of adoption by plastic surgeons. And I think, as you all mentioned, when it comes to elective surgery, these patients have a choice of where to go. And so when they're seeing that 1 clinician is using the newest, latest opioid and it's a patient-friendly opioid, sublingual, et cetera. And they're experiencing, as you all mentioned, this wide awake and alert after surgery, they don't have the typical opioid side effects they may have used to having with earlier surgeries. It really does speak to that patient satisfaction and their confidence in their physician and wanting to refer them and our people to those. So from a plastic surgery standpoint, it's so much about patient satisfaction. And in fact, what we've heard anecdotally is that they do a lot of call up the night up. You're calling up and making sure the patient's okay, how are you doing with your Vicodin and Percocet at home. And we have heard, in fact, they're so comfortable upon leaving that they've noticed that there's this sort of delayed use of those outpatient opioids they're so typically using that evening. Sometimes they're not even taking them 'til the next day. So I think it's exciting to hear both, whether it's inpatient surgery, outpatient surgery, even procedural type -- in the clinic procedures that this sort of patient satisfaction is important in all those aspects as well as nurse and physician satisfaction.

Okay. Perhaps one last question and it's for Dr. Cassavaugh. You mentioned that about 14 out of 104 patients received a second DSUVIA dose in a PACU. Can you tell us what are some criteria for a patient to receive a second dose versus just 1 single dose?

So according to the indication there for moderate to severe pain. So if they continued to have moderate to severe pain in the PACU, so greater than 4 or 5, as a level when they report it off the scales, they would have that option to repeat a dose. And again, in the beginning, we had it a little more open. The physician was looking to a repeat dose much quicker. So they were trying it, and that's where we said that we had 9 of those 14. We're kind of in our first 3 weeks of the folks getting it, they recognize that, that was unnecessary, that people were doing very well on a single dose. So that's why we tightened it up and made it to where they could use it as long as they had a moderate to severe pain level still in the PACU. And again, we were not seeing that. We only had 5 doses in the 1-year period after that first set of 3 weeks.

Okay. And just as a reminder. No, sorry, Just as a reminder of our dosing. According to our label, we can be dosed hourly, if needed, that we've actually shown the safety of that. Up to 12 doses in a day, which is great because no one's using us that way. As you see, it's sort of 1 to 2 doses here and there, sometimes 3 or 4 if the patient is being used -- it kept overnight up on the floor at -- some hospitals are using it that way. But certainly, people aren't dosing out for maximum, but it's still nice to know from a safety standpoint, that, that was deemed a safe way to dose DSUVIA based on our clinical trials.

Right. So what I was asking kind of eats into your comments as well. DSUVIA has been in good amount of experience so far based on the feedback that you received from clinicians. Approximately what percentage of patients typically receive more than 1 DSUVIA dose?

I will just tell you, overall, we've got about 90% of patients receiving just a single dose. So maybe 10% are receiving more than that.

Okay. That's -- yes. So more or less along the line with the study that we saw today.

We got a lot of questions. We've got a lot of questions coming in from analysts and investors on the webcast. So I'll read some of these out and you can direct these through either of the doctors. First one here, how significant a factor is the lack of cognitive inhibition with DSUVIA use on its uptake in the ASC setting?

I mean, wonderful. I will start that out with Dr. Tvetenstrand then.

It's absolutely critical that -- to more timely discharge from the PACU, to have a patient that is awake and alert on arrival and not suffering some overdose from a Dilaudid. And oftentimes, they used to give a dose of Dilaudid on the way recovery room. You see, if you go back to the pharmacokinetic curve, we give -- it lasts for about 3, 4 hours. My surgeries are about 40 minutes. So we give it 30 minutes beforehand. I got 3 hours. So I get them through that PACU very fast, and they go home quickly. And they're very pleased and pleasant. And as Dr. Cassavaugh said, they're chatty. It's a very positive experience and our scores are probably going to reflect that in terms of whether the patients like us or not. So it is just good medicine. It's just, we're not giving too much. It's not too little. It's just the right amount.

Great. And Dr. Cassavaugh, what are your feelings?

Yes. I would completely agree with Dr. Tvetenstrand. As we said, we see these people chatty, as he says, it's not too little, it's not too much. We kind of joke around and call it the Goldilocks effects. It's just right, gives them that long coverage. And from our data and discussion with our anesthesiologists, that's what's helped open the door for our ED. They're very excited to have a noninvasive method of pain control, that's not going to, as we like to say, gork somebody or knock them out. That nice blunted peak without that cognitive decline, is showing that we're going to get really good pain control without the patient having to sit here for an additional 2, 3 hours to wear off that cognitive decline and that gorked feeling. So completely agree.

Well, and I think also as an anesthesiologist, we know that patients are awake, alert, chatty and breathing at a rate of 2, right? I mean respiratory depression comes after you have sedation somnolence, cognitive impairment, you're starting to go down that CNS depression state, and then you start slipping into decreased oxygen saturation, respiratory depression, respiratory rate goes down. And then you're dealing with your naloxone or God forbid, sort of a code blue situation. So the one thing I love about it is I always consider that cognitive impairment as an early sign of possible negative downstream effects such as respiratory depression. So when we're not even seeing cognitive impairment, it makes me as an anesthesiologist feel very comfortable about the drug from a respiratory standpoint.

Okay. Another question here. When you mentioned this drug to clinicians in other unaffiliated facilities, what is the general response?

So I will take that maybe to Dr. Cassavaugh. Would you want to respond to that?

Yes. I've talked about it in a couple of different things with our GPO group, I belonged to their clinical pharmacy practice council. So we've brought it up, and people are interested. It's one of those ones. Again, it's following the typical adoption curves. There are the early adopters, such as myself and Dr. T. But other people are hearing it and starting to see the data, and I think that's where you're really going to see some more bank for the buck as more publications come out and you're starting to see some bigger centers really getting involved in studies as well. People are interested in hearing -- they're hearing these anecdotal reports and starting to see data. So the initial fear that was initially out there with the FDA, the words Sufentanil has kind of really subsided and people are now hearing how positive the results are and wanting to see that and wanting to learn more.

And I will say, yes, I mean, it's -- when you say that, I mean, the headlines when we were first approved, sufentanil is 1000x more potent than morphine. And we're -- of course, it is. I mean, that's why we use a 1000-fold less drug. I think people really do get in the medical world that potency is just something you simply dose adjust for. So morphine's dosed in milligrams in sufentanil's dose in micrograms, right? That's 1000-fold less. So it's -- but they are used to, again, sufentanil in the IV form of delivery. So I think when people see the data, especially the data coming out at Dr. Tvetenstrand's and soon to be published from Dr. Koth Cassavaugh here, that it really is having them realize sublingual is fundamentally different than IV and really reminding them of that high therapeutic index of -- that's inherent to the molecule, really has them rethinking whether IV is the right way to even deliver an opioid when you have a sublingual route that is available.

Okay. Pam, I think, you've touched on this question, but maybe a bit differently. But here's a question. How can an opioid be opioid sparing? And what do you think the reasons for this are?

Well, I'll just jump in. I mean, you'll see it in the slide we've got here, at the bottom of the slide, the attributes, as shown by both of the studies that we've just talked about today, this lower MME. And so, right, how can DSUVIA, which is equivalent to 5 morphine milligram equivalents, how can that reduce overall the amount of opioid that you're getting in. The way I look at it is we typically use IV fentanyl in the operating room. And especially in the PACU, we're also using mainly IV fentanyl as well in a lot of settings. And what happens when you bolus an IV dose is that you have a rapid tall, what I call, vertical area into the curve. So this rapid high peak plasma level that goes well beyond any therapeutic level you need for that drug. And then it comes crashing back down to maybe a level that keeps pain management going for about 20, 30 minutes, that's 25 to 50 micrograms, and you have to redose by every 20, 30 minutes. So in essence, in my mind, if you were looking at, you're wasting sort of that morphine milligram equivalents in that tall vertical manner. Whereas the sublingual sufentanil is taking the drug and giving you a horizontal or flattened area into the curve, such that it's peaking right above the level you need, and it's sitting right above the level you need for 3 to 4 hours. So that tall dangerous high area into the curve where all those MEs are really excessive and being wasted, you're not doing that with DSUVIA. So you actually -- when you add them all up, as both of these clinicians have done, you see an overall reduction because you avoided all that wasted tall vertical area of the curve with those MMEs. I mean that's just sort of my simplistic way of explaining it.

Okay. For either of the doctors, you can direct this. Has DSUVIA been approved for the emergency department? And if so, is there a reticence on behalf of the emergency doctor -- emergency room doctors to use it?

So Dr. Cassavaugh, I'll move to you on that one?

Yes. Yes, once we came up with our data from our MEV, we did present it to our ED physician who in the beginning was a little against the thought of sufentanil in the ED. And from seeing that and then again, discussions with our Head of Anesthesiology and the physicians involved, they were saying without that cognitive decline and the efficacy that they're seeing from it, they were very excited to be able to add it to their group. They're getting them all trained and getting them all up and running, getting it stocked up there. So that way, they can have a noninvasive way to treat some of these painful procedures that might come in, whether you're doing a reduction or some stitches or some other painful procedure that they won't need to be in the ED for a terribly long time, again, you can do effective pain control in that, knock them out, and again, in the elderly population, as Dr. Tvetenstrand had mentioned, that's where we have more risk of making them less able and having to possibly admit them and now we're looking to be able to just discharge those people home. They're thinking that will help improve their throughput and now they're excited about it. And the other thing that we say from our experience is because that blunted Cmax, we kind of took away the worry a little bit from the ED physicians of drug diversion because people who are diverting or looking for -- drug-seeking aren't looking for their next pain control, which this drug gets, they're looking for their next high, and you're not getting that with that blunted Cmax. So we help that from that perspective to eliminate the worry of people coming in to do drug seeking, and they were very excited about it, and we're excited to get it going and start tracking our data with that.

Well, and I will add that we're really excited about a unique patient population that's very difficult-to-treat from a pain management standpoint in the emergency room, and that's sickle cell disease. It's been shown that tying to first analgesic is critical to get on top of a sickle cell crisis, and they're often very difficult IV access patients. So we're, in fact, really getting some interest nationally on DSUVIA's use in sickle cell and the ED as well. And Dr. Tvetenstrand, if you've got any thoughts about the emergency room use of DSUVIA?

We've been using it. Mainly, the trauma surgeons used it, but now the ED physicians are starting to get a little jealous. So I see that it'll be more widely adopted. But yes, will they use it right when they come in? Absolutely. So -- and the nurses love it. They know which patient's gotten DSUVIA and which one has gotten fentanyl without checking the chart.

Well -- and also, we published 1,000 patient publication in 2018 in the top journal anesthesiology of my specialty. And in that paper, we looked at organ impairment, whether it was renal or hepatic impairment on the clearance of DSUVIA and neither all the way from mild, moderate to severe showed any change in clearance for either severe renal or severe hepatic. Of course, our label warrants to make sure you monitor those patients carefully, but we actually did not see any difference in clearance. And I think that's important because the emergency room nurses have to take care of that pain before they get the labs back they don't necessarily know who is walking through the door, what their organ status is. So as opposed to giving any drug with an active tablet, I think it's really exciting that they're able to give this without starting an IV quickly under the tongue, shorter time to administration of analgesic, don't have to again worry so much about the organ impairment. So Raffi, are there additional questions?

Sorry, I was on mute. Yes, there are a lot of questions here. For -- this was for Dr. T, but I think this could go to Dr. Tvetenstrand or to Dr. Cassavaugh. What was the initial reaction of the P&T committee to your request for formulary approval of DSUVIA? And how has that changed since?

That's a fabulous question. Because I came back from a conference. I did all my reading on it. And the initial reaction was rejection, and then after much discussions, and we came up with an MUE, and it was just limited to myself. And as it went on and my results were being leaked out to a pharmacy department, they sort of apologized to me. So we're all friends now. And we actually developed a way of approaching questions and so they dismissed that at hand, in indeed reactive fashion because like it was said earlier, who needs another opioid? They have an opioid crisis. They're going to solve an opioid crisis with another opioid? It is a little counterintuitive. But no, you're -- the problem isn't so much the opioid where you have to address the pain and you have to have the right opioid is the key. And that's why this is counterintuitive, and I would say a little disruptive to the normal paradigm in which we, as clinicians, take care of patients that have pain, whether they are orthopedic, surgical induced or trauma, you got -- you have a drug here that really doesn't create any of the ill effects that we associate with opioids: Cognitive dysfunction, respiratory depression. And it has a very good therapeutic index, and it lasts 3 to 4 hours, what's not to love? And they're coming around to it. But again, it's human nature. Who needs another opioid?

Okay. And our institution was a little bit different. Obviously, I was the one, kind of brought it to our Head of Anesthesia and to our primary bariatric surgeons. They were my champions when we presented at the P&T. But again, there was so many positive things, as Dr. Tvetenstrand just said, looking at that onset, looking at the duration, non-invasive, we were very excited about not having those respiratory effects. It's, again, why we were looking in our bariatric population, it kind of the niche that wasn't out there before where you have a rapid-acting drug that's noninvasive and lasts for a long time. It's -- that's not a typical thing you can find in the opioid field, there's some fentanyl lollipops, but that's not your best option in most institutions. So this really put this unmet niche for us, and we thought of it doing that. Again, being the pharmacy director and being in charge of diversion and a lot of other things like the packaging and the barcoding, set us up very well for being able to track everything and handle everything very cleanly and clearly 1 dose fits all. There was a lot of things from our P&T side that we liked from a pharmacy perspective. So it went through P&T very easily. And now we're gaining more at the back end where other physicians hearing about it, seeing it and seeing -- asking that they can be involved and have it in their areas. So we're a little opposite of Dr. T. But again, clearly similar path overall.

Great. We'll squeeze the last one in here, because we're running short on time. Why is there -- and you may have touched on this already. Why is there less ephedrine used with DSUVIA patients?

Yes, I think we covered that earlier, but Dr. Tvetenstrand, you can certainly jump in on that.

Well, simply put, giving the DSUVIA before injection, which is oftentimes associated with hemodynamic instability takes that instability away. If you take that instability away, you don't need to give the rescue pressor ephedrine or federal ephedrine, neosynephrine. You don't need to give it or you give much less or even just a partial dose. And as Dr. Palmer alluded to, if you have a patient that -- they're scrambling because the pressure is down to 60 in systolic, she's quite correct. These patients are going to have more problems downstream because you've dressed that patient out at that point in time. So there's consequences to doing that. So the pharmacokinetic cardial curve answers the question. If you look at that, you'll see that they've got the right amount, but not too much. They get induced without hypotension and then they have a smooth journey through the anesthetic and they wake up totally alert.

And I think that it really does speak to the IV bolus administration of an opioid is just not a physiological way that the body wants to see a drug. It causes high amounts of side effects. It causes hemodynamic instability, it causes [indiscernible] And it's just -- we've got the frame shift people away. Because again, as anesthesiologists, such as myself, that is what we were trying to do. That's all we know is to give IV bolus administration. Sometimes we run infusions, but usually in an ambulatory surgery center, it's a hassle to set up a pump and infusion, anything else. So we tend to use the boluses. And it just is really not physiologically correct. So I think by giving them an option, which is just a simple under the tongue sesame seed, that they're able to avoid the adverse events, the short duration of action, the hemodynamic instability of your typical IV fentanyl intraoperative opioid.

Okay. I think we're running out of time, cannot get to all these questions, but I'll hand this back over to Vince.

Great. [indiscernible] me off mute. And I'd just like to thank Dr. Tvetenstrand and Cassavaugh for sharing their experience today. It was interesting to us that 2 separate institutions with different health care providers and systems, both evaluated DSUVIA in the perioperative setting, and they both ended very similar finding. As we've mentioned previously, there are several other institutions conducting their own studies on DSUVIA, including among others, 2 investigator-initiated trials that we are supporting, 1 from Brigham and Women's hospital, evaluating the use of DSUVIA for patients undergoing spine surgery, and another from the Cleveland Clinic, assessing the effects of DSUVIA post-operative recovery from orthopedic surgery. So we're excited to see those results. And hope it will have the same consistency and positive effects on patient, on care move forward. So again, thanks to all of you for attending this call. We look forward to providing additional updates in the future. Please take care and be safe for you and your family amongst this pandemic -- seems to continue. Thanks again for your interest in AcelRx, and have a great day.