Study Result

Sep 30, 2020

Slides

Good afternoon, and welcome to the Selecta Biosciences Phase 2 Compare Conference Call. At this time, all participants are in a listen only mode. Thank you, and good afternoon. During this call, we will discuss top line results from the Phase 2 COMPARE study of SEL-two twelve, a novel treatment for chronic refractory gout versus piglodacase. The press release reporting the results and the presentation that Carson and Peter will walk through are available in the Investors and Media section of our website, www.selectabio dot com. Joining me today are Carson Bruhn, our President and Chief Executive Officer and Doctor. Peter G. Traver, our Chief Medical Officer. During today's call, we will be making certain forward looking statements, including without limitation, statements about the potential safety, development, efficacy and regulatory and clinical products of our product candidates, including SEL-two twelve, future expectations, plans, partnerships and prospects. These statements are subject to various risks, including those related to the COVID-nineteen outbreak that are described in our filings made with the Securities and Exchange Commission, you're cautioned not to place undue reliance on these forward looking statements, which speak only as of today, September 30, 2020, and Celexa disclaims any obligation to update such statements even if management's views change. I would now like to turn the call over to Carsten Brunn, our President and CEO. Carsten? Thank you, Brad, and good afternoon. I appreciate you joining us today, and I'm very pleased to be sharing the top line results from the Phase 2 COMPARE study. As Brett mentioned, SEL-two twelve is a novel treatment for chronic refractory gout, which contains a proprietary pegylated uricase enzyme, pegatricase, combined with a selecta immune tolerance platform ImmTOR. Before we review the results, I want to remind everyone of the unmet medical need in chronic refractory gout. Approximately 160,000 patients in the United States suffer from chronic refractory gout, a painful and debilitating condition in which patients are not able to get their SUA levels below 6 milligrams per deciliter and therefore have several flares per year and can develop nodular masses of uric acid crystals known as TOFI. Elevate SUA levels have been associated with diseases of the heart, vascular system, metabolism, kidney and the joints. There's only one approved product on the marketplace in the U. S, KRYSTEXXA or padloducase, which is dosed every 2 weeks. There's a significant unmet medical need for more durable once monthly treatment for patients with this debilitating condition. The Phase 2 COMPARE trial is a head to head study of a once monthly dose of SEL-two twelve, which is a combination of ImmTOR and pegatricase compared to twice monthly doses of belodicase with a primary endpoint of the maintenance of serum uric acid or SUA levels of less than 6 milligrams per deciliter during months 36 combined. Evolikase is the only approved product for chronic refractory gout and is approved only in the U. S. Key secondary endpoints include the same measurements of SUA at months 36 individually and over reduction in SUA levels. The trial enrolled a total of 170 patients. Further, in June of this year, we entered into a strategic licensing agreement with Sobe for SEL-two twelve. Sobe will fund the Phase 3 clinical program and will have commercial rights in all markets outside of China. As detailed in the press release on September 23, the Phase 3 program titled DASOLVE, which will assess SEL-two twelve versus placebo, has randomized and dosed its first patient. We expect to report top line data from the DASOLVE program in the second half of twenty twenty two. We are thrilled to have Sobeys, our partner, and are excited to share the Phase 2 COMPARE data with you today. First, we're very pleased that we were able to actually successfully complete the study during the COVID-nineteen pandemic. We modified the statistical analysis plan and submitted the change to the FDA prior to the database log to account for increase in protocol deviations. Unfortunately, the SEL-two twelve arm was slightly more impacted by protocol deviations. While the COMPARE trial did not meet the primary endpoint of showing statistical superiority of SEL-two twelve to pegzodiazepine during months 3 and 6 combined, we're extremely encouraged that the data consistently shows stronger performance of SEL-two twelve versus spaglodacase across all endpoints and patient populations. SEL-two twelve showed a statistically significant higher response rate versus meloducase during month 3 and a numerically higher response rate during month 6 and during month 6, 3 and 6 combined. In the per protocol analysis, the primary endpoint was missed by 1 patient. Additionally, SEL-two twelve showed statistically significant greater overall reduction in mean SUA levels versus COPIKLOVIKA's. Finally, in patients with TOFI, SEL-two twelve showed a substantially higher overall response rate and a statistically significant overall reduction in mean SUA levels for SEL-two twelve versus pegzilonicase, which we believe SEL-two twelve and belodicase were well tolerated. Now, I'll turn it over to Peter to walk you through the data in more detail. Peter? Thank you very much, Carsten. On Slide 3 of the deck that was distributed, I will discuss the design of the Phase 2 COMPARE trial. It was a Phase 2 non registration study that was conducted as a randomized open label trial in patients with chronic refractory gout with inadequate control of serum uric uric acid using conventional therapy. We as a company remain blinded to the primary endpoint of serum uric acid throughout the study. The U. S. Marketed intravenous uricase, peglotikase, was used at the recommended dose and interval of 8 milligrams every 2 weeks for 6 months for a total of 12 doses. This was compared to our investigative agent SEL-two twelve, a combination of a proprietary uricase, pegadriCase and ImmTOR, our novel nanoparticle drug for inducing immune tolerance to sequentially administered antigenic compounds such as non mammalian uricase enzymes. SEL-two twelve was administered intravenously once monthly for 6 months. The primary efficacy assessment in the trial was the comparison of the percentage of patients on SEL-two twelve versus piglodacase who achieved and maintained reduction of serum uric acid less than 6 milligrams per deciliter for at least 80% of the time during 3 months 6 months combined. The secondary endpoints included the same measurement in months 36 separately. Another important assessment of the relative potency and effectiveness of SEL 12 versus peglotikase is the absolute reduction of mean serum uric acid levels during the same treatment periods. In the following slides, I am pleased to report that all data are consistent with a stronger performance of SEL-two twelve versus peglodacase. As shown on Slide 4, 170 patients were randomized and dosed in the trial, with 83 patients assigned to SEL-two twelve and eighty 7 patients assigned to peglotidase. This represents the intention to treat or IPT dataset for analysis. In addition, we will report analysis using the per protocol dataset defined as patients who are administered any amount of study medication and having completed at least 65% of the study doses, unless they had early termination from the study after a study drug withdrawal due to meeting stopping rules or due to an adverse event or early termination due excluded from the per protocol set. Moving on to Slide 5, clinical trials conducted during the COVID-nineteen pandemic must take into consideration potential impact on study conduct and analysis as advised by the FDA in its June 2020 guidance. Only one patient in the trial, a piglodacase patient, had a confirmed case of COVID-nineteen, and this led to discontinuation. However, an increase in protocol deviations were noted due to disruptions in modified and submitted to the FDA prior to database lock in compliance with the FDA guidance. Modifications were focused on the potential impact of the COVID-nineteen pandemic on statistical analysis. We are pleased the COMPARE trial was completed during the COVID-nineteen pandemic. Trials conducted and completed during the pandemic may heighten the importance of the per protocol data set more than usual in analysis of the data. We still have work to do on the impact of COVID-nineteen after we receive the full data set. On Slide 6, I will provide some background on patient baseline characteristics and demographics. Randomized patients were on average 52 years of age, over 95% male, 77% white, and with a body mass index in the obese range. There were no there was no difference between the ITT and the per protocol groups. Importantly, approximately 41% of patients enrolled had clinically detectable TOFI or urate crystal deposits at baseline. Slide 7 shows the results on the primary endpoint measurement or the percent of patients who achieved and maintained reduction of serum uric acid for at least 80% of the time on study drug. The results showed that SEL-two twelve demonstrated statistical superiority during month 3 and numerical superiority during month 6 and during months 3 and 6 combined. The month 3 and 6 combined period was designated as the primary endpoint in the protocol and SAP. For month 3, the SEL-two twelve arm had 70% responders for both per protocol and ITT populations, while the pigload case arm had 54% 52% responders per protocol and ITT respectively. This difference was statistically significant in both protocol and ITT sets. On a relative basis, SEL-two twelve showed a 30% to 37% greater percentage of responders than peglotikase. Analysis of treatment period 6 alone and treatment period 3 and plus 6 both showed similar results, with numerically greater, but not statistically significant difference in response rates. It should be noted that the per protocol population in both month 6 month 3+6 nearly reached statistical significance with p values equal to 0.053 and 0.0 56, respectively. These data show clear superiority of SEL-two twelve therapy over peglotikase in the 1st 3 months of therapy. A reduction in patient numbers over the course of the study may be one of the reasons why statistical significance is lost in month 6 despite maintaining numerical significance over PEGLOTA case. Moving to Slide 8, evaluation of mean serum uric acid levels during month peglotecase. The baseline serum uric acids were numerically, but not statistically, higher in the SEL-two twelve group than peglotichase. Despite somewhat higher SUA levels at baseline, SEL-two twelve treatment resulted in a 48% 40% greater reduction of serum uric acid than peglotecase in the per protocol and ITT sets, respectively. These results were statistically significant with P values of 0.00 3. These data suggest that once monthly dose of pigadricase, when administered with mTOR to induce immune tolerance is a more potent uricase than piglodacase for lowering serum uric acid in chronic refractory gout patients. Producing serum uric acid to low levels in a sustained fashion is a critical goal of gout therapy, particularly to aphasious gout, where the lower the level of serum uric acid, the more efficient is the dissolution of the uric acid crystals in TOFI. These impressive findings caused us to look at those patients with TOFI. You would now move to Slide 9. In the subset of patients with clinically evident TOFI at baseline, which was 41% of the entire population, There was a 19 percentage point and 16 percentage point greater response rate for SEL-two twelve versus piglodacase during months 36 combined in PP and ITT sets, respectively. This represents a large relative treatment difference of 49% statistical significance, the magnitude of the difference between therapies is greater than in the entire group of patients. Comparison of response rates for SEL-two twelve shows similar results for the entire population and the TOFI subset, with a response of 59% in the entire population and 58% in the TOFI population, considering only the per protocol set. In contrast, the response rates for paglodacase dropped from 46% in the entire population to 39% in the TOFI population, again, in the per protocol set. On Slide 10, we found a rather striking result when we looked at reduction of serum mean uric acid in patients with TOFI at baseline. SEL-two twelve demonstrated a statistically superior 60% overall reduction in mean SUA levels, even greater than the robust reduction in uric acid seen in the entire patient population. For the SEL-two twelve group, a mean baseline serum acid serum uric acid of 9 point 48 milligrams per deciliter would be reduced to 2.06 milligrams per deciliter, whereas peglotikase would reduce the mean from a baseline of 8.58 to 3.94, nearly a 2 milligram per deciliter difference between the two treatments. Because there is a significant inverse correlation between serum urate area under the curve and TOFUS resolution velocity, the greater potency of a single dose of SEL-two twelve per month versus 2 doses of piglodacase per month may be clinically relevant for treatment of tophaceous gout. On Slide 11, top line analysis of the safety database suggests that both therapies were generally well tolerated and there were no deaths during the study. There were no differences in serious treatment emergent adverse effects or TEAEs, treatment related serious TEAEs or infusion reactions between the two groups. A full analysis of safety signals, including gout flare incidents and severity, awaits evaluation of the full data set and will be reported along with full efficacy analysis at a future medical meeting. On Slide 12, just a reminder about the ongoing pivotal Phase 3 program for SEL-two twelve. The Phase 3 dissolve clinical program consists of 2 double blind placebo controlled trials of SEL-two twelve, in which SEL-two twelve will be evaluated at 2 doses of ImmTOR, 0.1 milligrams per kilogram and 0.15 milligrams per kilogram and one dose of pigadricase, 0.2 milligrams per kilogram in both studies. Each trial will aim to enroll 100 and 5 patients, 35 at each dose level and 35 on placebo. In DASOLVE-one, safety and efficacy will evaluated at 6 months and will have a 6 month extension. DASOLVE-two will address safety and efficacy at only the 6 month time point with no extension. The primary endpoint in both studies is serum uric acid control at 6 months. Secondary endpoints include tender and swollen joint counts, TOFUS burden, patient reported outcomes of activity limitation and quality of life and gout flare incidents. The DASOLVE program has dosed its 1st patient and select ENSOVI expect to report top line data in the second half of 2022. I will now turn the call back to Carsten. Thank you, Peter. To reiterate, we're very pleased that we were able to successfully complete the COMPARE trial during the COVID-nineteen pandemic. As outlined, we modified the statistical analysis plan and submitted the changes to the FDA prior to Databizlog to account for an increase in protocol deviations. As mentioned, the SAL-two twelve arm was slightly more impacted by protocol deviations. We'll further analyze this imbalance once the full data set is available. But overall, we're extremely encouraged that the data consistently shows stronger performance of SEL-two twelve versus peglodacase across all endpoints and patient populations. SEL-two twelve showed a statistically significant higher response rate versus peglodikase during month 3 and a numerically higher response rate during month 6 and during month 3 and 6 combined. In the protocol analysis, the primary endpoint was missed by one patient. Additionally, SEL-two twelve showed statistically significant greater overall reduction in mean SUA levels versus pegloty case. Finally, in patients with TOFI, SEL-two twelve showed a substantially higher overall response rate versus spaglodikase and a statistically significant overall reduction in mean SGA levels for SEL-two twelve, which we believe is very important finding to actually demonstrate the efficacy of SEL-two twelve. In addition, the COMPARE study demonstrate that both SEL-two twelve and flodicase were well tolerated. The clinical evidence on SEL-two twelve to date clearly demonstrates the promise of our ImmTOR platform to selectively mitigate unwanted immune responses and allow sustained therapeutic activity when combined with a highly immunogenic enzyme. We're confident that SEL-two twelve has the potential to improve the lives of patients with chronic refractory count. We look forward to evaluating SEL-two twelve in partnership with Sobeys in 2 double blinded placebo controlled Phase 3 trials and continuing to assess our ImmTORP platform to amplify the efficacy of biologic therapies, including the dosing of life saving gene therapies. I also want to reiterate our gratitude to the many people who have been integral in moving SEL-two twelve forward to clinical development, including our patients and their families, our investigators who spearheaded the COMPARE trial, our participating trial sites and our development partner Sobeys. Lastly, I'd like to thank the selected team who have worked tirelessly to bring SEL-two twelve to where it is today. We plan to share further updates about the broad potential of the ImmTOR platform throughout the year. On this remark, I'm closing the presentation and will open the call up for questions. Operator? Thank you. We will now begin the question and answer And our first question will come from Elena Mearle with Cantor Fitzgerald. Please go ahead. Hey, guys. Thanks for taking the question. Just on the protocol deviations, could you give us a little bit more color on, I guess, maybe what the most common protocol deviations were by arm? And I guess how these were treated statistically in the per protocol analysis? And then secondly, just in terms of the number of maybe missed visits or missed doses, is there any more color that you can give just in terms of the number of patients that did not receive did not miss any doses or did not miss any visits? And maybe what the data would have looked like for that group? And then I have a follow-up question. Thanks. Yes. Thanks, Sal. That's a great question. So I'll let Pierre share some of the details in a second. But obviously, it was a broad range of deviations. It was missed blood draws. It was delayed blood infusions. It was in some cases, there was a death in the family actually. So patients didn't feel comfortable actually to come in to a site. But I think what's important is if you look at the overall numbers actually Ali, I mean, so we had a total of 83 patients for SEL-two twelve and a total of 87 in the ITT population. And on the pegzone case arm, about 17 patients were lost in the protocol analysis, about 20%. And for 2012, it was about 29%. So there's an imbalance of 7 patients that we're looking at. But you can also see that actually that imbalance actually drives the efficacy outcome, right? If you look at the overall number of patients lost until time 0.3 is actually very consistent across all groups. And if you look at our per protocol, the loss between treatment period 3 and treatment period 3 and 6, we lost about 6 patients or 14%, whereas we lost 24% in the per protocol and that's largely driven through protocol deviations. So as I said, we've got to look at this a little more closely. But I think what is interesting is that there's an overall trend is actually very consistent. One of the findings that we were actually very positively surprised, we described significant, is the overall impact of or efficacy of SL-two twelve in patients with TOFI. And there you actually don't see a large difference between the ITT and per protocol population. There we lost about 15% of patients between treatment period 33+6, so very consistent. So it's really in the ITT subgroup is kind of the outlier with an additional 8 patients we've lost, which we're looking at into more details. And with that maybe Peter, you can share a bit more details around the actual protocol deviations. Yes. Thanks, Carson. That was a very good explanation, and I won't duplicate what you said. But I'll just point out, Ellie, that all clinical trials have a large number of protocol deviations and a smaller number of those are major protocol deviations. And then an even smaller portion of them are major protocol deviations that affect the efficacy signal. And so we are in the process of analyzing all of those. We did have a number of COVID-nineteen related protocol deviations as a small proportion of those deviations. And we're looking at those to see whether they disproportionately affected one arm versus the other. But the way we define the protocol deviations, it was and I'll give you an example here in a moment. If it was a major protocol deviation that caused the change in the efficacy assessment that led to removal from the per protocol group. So for example, if somebody missed their day 21 uric acid blood draw by 10 days versus the operating window that we had of 3 days. That was a major protocol deviation and that would lead to a change in the efficacy endpoint because that's a critical measure on the SEL-two twelve arm. So what we did not find was that they were all in one category or another, and we have not done the full analysis to try to understand how COVID might have impacted the rates, although we do see a general balance in COVID related protocol deviations between SEL-two twelve and peglota case. So I don't know if that additional detail will help, but I'll turn it back to Carsten. Thanks, Peter. Ellie, you had a follow-up question? Yes. That was helpful. I appreciate the color. Just on the safety, I'm curious, it seems like you saw a pretty balanced safety versus the KRYSTEXXA arm. Curious sort of what you think drove that and any points of differentiation that you did see emerge on the safety, outside of, of course, the effects on Tofia, although that's maybe perhaps more efficacy. But just how you think that the safety profile of cell-two twelve would then compare to say KRYSTEXXA plus methotrexate from a safety perspective and any key potential advantages or differences emerging from this data set? Yes. So obviously, I don't want to speculate on a trial that is still ongoing with mesotrexate. I think what we can look at and obviously I'll hand it to Peter for some more color on the safety data. But I think one good point to look at is actually discontinuations through the adverse events and that's number we do have. And we lost a total of 10 patients to adverse events and KRYSTEXXA lost about 13. So it's obviously a very small numerical difference, but there is a small difference. And obviously, if you add another immune suppressant to a regimen, you obviously do have additional side effects. And I don't want to belabor methotrexate, I think it's well known some of the side effects obviously has a black box warning around a number of end organ toxicities. There's limitation around alcohol use, which we believe obviously is quite important in this patient population. On methotrexate, you can have more than 3 drinks. And I think the other limitation that is really probably the most relevant actually is that you have to exclude patients with chronic kidney disease and that's a fairly large population in chronic factory gout. In fact, in the KRYSTEXXA Phase 3 study was 49% of all patients. We believe from an epi perspective, it's probably about 30% of patients that you have to exclude. So but as I said, we haven't seen any control data on the combination. But we definitely believe that adding an additional immunosuppressant will change the overall safety profile. Yes. And Ali, related to specific adverse events and so forth, we don't the full data set will have patient level specificity around AEs. That we didn't see any difference. But the mild to moderate AEs and those of special interest to the both drugs will be sorting out once we get the full data set and don't have much more to report on that at this point. Thanks, Peter. Thanks. And our next question will come from John Newman with Canaccord. Please go ahead. Hey, guys. Thanks for taking the question. First question I have is just curious if you can give us any color on anything that you saw with regard to gout flares in terms of the difference between the 212 arm and the KRYSTEXXA arm? And then the other question I had was just a follow-up. Can you give us a sense as to whether the difference between the 212 arm and the KRYSTEXXA arm in terms of the primary endpoint, whether that difference widened as patients as a higher percentage of patients in a group that you looked at completed most of the visits. I'm just curious if as the number of completed visits goes up as a percentage, does the difference tend to also increase between the two arms? Thanks. Yes. Great questions, John, as always. So around the Gausslayers, that's part of the data set we'll get with the full data set, which we have not received yet. So as Peter mentioned, we'll report on that once we have the data in hand. Around the difference on the primary endpoint, so we at this point only have really top line data and we haven't really had a chance to dig too deep in terms of differentiation. But I think one of the things obviously that is very profound is that there is statistical significance at month 3. And then you still have a healthy numerical difference actually if you look at the per protocol, and I mentioned during the presentation, there was actually one patient's difference. So it's a p value of 0.056 or even tighter for the 6 months endpoints 0.05 3. I think the other piece, which I think is very important in terms of efficacy action, and I mentioned this briefly, and that's really, I think, a very relevant finding is the patient with TOFI showed really a profound difference. So you're looking at obviously, it's a smaller data set, so the study wasn't powered for it, but showed a difference of 19 percentage points in the per protocol arm and 16 in the IGT arm. So there's no real difference between the 2. And what's interesting as well is that we had about 41% of patients with TOFI. If you look at the KRYSTEXXA Phase 3 study, it was a higher number, actually 72%, 73%. And probably also if you look at patients presenting and the most severe patients actually, it's probably a higher number, right? So we're probably a little bit on the lower end. And the learning here is really that we show consistent efficacy in patients TOFI and no TOFI with SEL-two twelve versus we see a lower response rate in patients with on KRYSTEXXA with TOFI. The other findings I think is interesting in terms of just differentiation on the endpoint is the overall reduction in mean serum uric acid levels. So if you stay with the patients with TOFI, there's a pretty small number of patients, but we actually demonstrated significant significance here. It's actually quite profound 60% difference. But also for the primary endpoint for the ITT population, you're still looking at a reduction of 40% versus, pedlodacase with quite a significant P value of 0.003. So I think there's a couple of nuggets that we still have to mine, John, but overall, we're quite impressed by the overall reduction and all the numerical trends we see. And obviously, we have to look at what happened kind of between 2 and period 3 and the 3 plus 6 where we lost an additional couple of patients on protocol deviations. Okay, great. Thank you very much. Our next question will come from Raju Prasad with William Blair. Please go ahead. Thanks for taking the questions. Tarsten maybe or Peter, can you just kind of talk me through a little bit on your thoughts on why the change in responder rate declined so much from 3 months to 6 months in the Cell-two twelve arm versus the KRYSTEXXA arm? I mean, it's like 10% to 11%, or is 8% or 10% in the Scl-two N2 arm. Is there a mechanistic rationale for why that occurred? And then I have a follow-up. Yes. No, I mean, we obviously don't believe there is a mechanistic. I mentioned earlier, we see actually very consistent response. It's really in the ITT population where we lose an additional 8 patients. Out of those 8, actually 5 are protocol deviations and that we have to look at. And maybe it's I mean, we looked at some of those, actually some are just sheer bad luck. I mean, 3 took a drug that was contraindicated during the course of therapy. And but yes, we definitely don't think there's anything mechanistic because the data actually is very consistent. And actually the data set with the patients with TOFI is kind of a good control where we see actually very consistent numbers, right? I mean, we kind of we see in the patients with TOFI, obviously, a smaller population, but about a 15% drop between treatment period 33+6, we see a 14% drop with all patients ITT for all patients on the per protocol for 212 and it's the 24%. So it's the additional 8 patients really that drive it. But we don't think this is anything mechanistic. Okay. And then on the changes to the SAP that were submitted, can you just give me a little more color on what was it just the per protocol analysis that was changed or were there other changes that were made to the SAP? Yes. So I'll let Peter give more detail. But one of the key change definitely was the per protocol set. And then we gave a bit more flexibility around dosing visits to allow obviously for people change schedules and we had a couple of sites closed down to COVID, so patients have had to be redirected to other sites. But Peter, maybe you can provide a bit more detail. Yes. Sure. Thank you. Of course, in a clinical trial, there are many, many things that operationally need to be specified in terms of measurements and so forth. And so really the SAP was focused on allowing the per protocol set to take to absorb the potential for disruptions to operations from COVID-nineteen. Of course, the intention to treat SET is set. You can't do anything to change the intention to treat, but the per protocol is what we looked at. So for instance, the per protocol set takes into account the period of time of treatment. So how many treatments does one need to have to be considered part of the PIRR protocol? Is it enough? And all studies kind of look at that. A lot of them a lot of studies have 80% versus less. So we decided that you had to have at least 65% of the treatment in order to be in per protocol. The other and that was a change from before. The other areas were more related to measurement of things. So you also define windows, like I mentioned earlier windows around, say, day 21 blood draw or the day 28 blood draw. And while the windows might have been we tried to make the windows a little bit larger in order to account for when sites might be closed for due to COVID and so forth or we needed to send home health care people to draw blood, etcetera, but not too large that they would affect the efficacy endpoint. So those were the kind of things that we defined and proposed to the FDA, and we got a reasonable felt that everything was reasonable and what we had recommended. I don't know if that helps a little bit. It does. Thank you. Our next Look, I think strongly trending data against your primary competition with half the doses and trending on efficacy. This is not a bad profile for 212. I'm not concerned there at all. But I don't think that's your most important long term value creator. I think you'd agree with me. So I kind of like to drill into this similar safety profile as much as we can. I appreciate that the data set is still being analyzed. So maybe just to start, do you think the PEGLOTA case arm on efficacy and tolerability performed in line with expectations? Yes. So I would definitely say, I mean, look at what the job is of the Urokase. The job is to reduce serum uric acid levels, right? And there we have a profound impact, statistically significant actually across all the endpoints, right? I mean, we're reducing 40% versus the lowercase. So absolutely, yes, I think it does the job exceptionally well with giving it once a month only versus twice a month, right? So I think that's a fundamental difference as well. I think what's important to consider as well, Chad, obviously, the Pegora case is given alone at the moment, whereas the pediatricase is given with ImmTOR. And if you give the pediatricase alone, which we've seen in our Phase 1 study, we have I think those 5 or 6 patients with pegatricase alone. And out of the 6, only one patient actually made it 2 month 1, whereas now you're able to redose 6 times and get a response rate between 50% 60% depending which data set you're looking at or even potentially higher for the patients with TOFI. So I think there's a profound number 1, the GAPID case is a very effective enzyme, but it's also a highly immunogenic enzyme. And I think ImmTOR does an outstanding job actually inducing tolerance. So actually, patients are able to tolerate, if you compare it versus spighettosibilone. Obviously, the price of the game here is to be differentiated. And we as you right said, we feel we actually have very strong data. Of course, and you said, right, you said there's a lot of value in the platform. And I think we definitely feel very strongly that we set a pretty high bar for IMTORE with the PEGATIVE case and I'm extremely pleased actually with the data and the efficacy we see with the combination and the impact that Intor has on that. Yes. I would just add that emphasis to that. I think it's a remarkable thing that ImmTOR did here, which is take a drug that you could get less than 20% people to respond to with only one therapy, 1 month of therapy and then turn it into one that you can give 6 months and have the kind of results that we have. And I think it bodes very well for the platform of ImmTOR being able to induce immune tolerance, not just to agadvocase, but to other antigens that were in our pipeline. Yes. That's very helpful. Obviously, what I'm kind of focused on and concerned with as well. You had some interesting flare data in your earlier studies. Is that something you have now or anything you can comment on? Yes. So you guys know the asset well. So John asked the same question. We don't have the GauCeare data yet. That comes to the full data set and we'll report on that. And obviously, we're also curious to see that data as well, but we haven't received this. It wasn't part of the top line readout. All right. Okay. Well, great. Thanks. I appreciate the additional color and we'll be following this with interests. Thank you, Chad. Our next question will come from Derek Archila with Stifel. Please go ahead. Hi, Bill on for Derek. Thanks for taking our question. Can you just briefly talk about we've talked a bit about your goals with about how you're thinking about the Phase 3 program now? You've got the additional dose in there and sort of what you would want to see and expect to see in that program to sort of confirm the differentiation that you've been talking about? Yes, that's a great question. So obviously, as you've seen, we already started the Phase 3 study. What's important is that the COMPARE trial, as Peter mentioned, is not a pivotal study, not a regulatory study. So they're independent. We don't see any really major changes for the Phase 3 protocol based on this data, to be honest. I think in terms of differentiation, obviously, it is a luxury to have direct head to head data already in a Phase II. I think it's quite unusual. And I think as Chad pointed out, there's very strong data here to mine. And because I mean ultimately what you're trying to do in chronic refractory gout is to reduce serum uric acid levels as fast and as low as possible. I mean, that's obviously the endpoint below 6 is on the time is a rectory endpoint. What is relevant clinically, and that's actually why our PI, Rob Keane is extremely excited is the statistically significant reduction in overall SUA levels you see. I think that's really a key driver around differentiation. The other differentiation is obviously the convenience with the once monthly in a patient population that we know is not very compliant to begin with. So we obviously think that's very important as well. And just as a reminder, the Phase III is a placebo controlled study, so there's no active arm. Thanks for taking my questions. Just a couple, if I may. Can you shed additional light on the specific nature of the protocol deviations seen so far and what measures you might need to take in order to prevent these from being apparent in the DASOLVE trial? And then secondly, I wanted to know whether you can comment on, logistically speaking, whether the DASOLVE studies are likely to proceed directly, concurrent with one another or if you expect them to be somewhat staggered in nature and therefore have differential in terms of the timing of the readout of the top line results? Thank you. Yes. Thanks, Wim. I'm not sure we can provide a lot more color on the protocol deviations, but maybe, Peter, you can summarize one more time for Ram. Yes. Ron, those are very good questions. And as you know, the moving parts in a clinical trial as complex as the one we just completed with COMPARE are great in terms of the operational issues. So we learned a tremendous amount from the compare trial that will be applicable to the operations of the Phase 3 trial. And it comes down to a whole variety of operational things in terms of ensuring that patients get the right tests at the right time and how they're screened and how they're and so forth. So I would say that much of what we learned in the COMPARE trial will be implemented in the DASOLVE trials and it should make for a more effective operation. So because we know the things that cause deviations and we can prevent them. And there are quite a list of those, but I think safe to say that there's a lot of learning. The second question you asked is that the DASOLVE-one and DASOLVE-two trials will be running concurrently. So we will be enrolling the 1st patient in DASOLVE-two in by the end of this year. This concludes the question and answer portion of the call. I will now turn the call back over to Selecta's CEO, Carsten Brunn, for any closing remarks. Carsten? Yes. Thank you, operator, and thank you again for joining us, and this concludes today's call. Thank you very much. Thank you again for joining us. This concludes today's call. Please have a great day.