Greetings. Welcome to the InstaLux Conference Call. At this time, all participants are in a listen only mode. A brief question and answer session will follow the formal presentation. Please note this conference is being recorded.
At this time, I will turn the conference over to Jordan Silerstein, Head of Corporate Strategy. You may now begin.
Good morning, everyone. On this call, Inclorx will make forward looking statements, which are statements regarding the company's intentions, beliefs, projections, outlook, analysis and current expectations concerning its business. For a discussion of risks and uncertainties that could cause actual results to differ from such forward looking statements, please refer to the factors described under the heading Risk Factors in Infarx's Annual Report on Form 20 F that was filed with the Securities and Exchange Commission. These statements speak only as of today, and we assume no obligation to update these forward looking statements, even if new information becomes available in the future, except as required by law. I'm going to turn the call over to Niels Wiedemann, CEO of Investor Relations.
Go ahead, Niels.
Thank you, Jordan, and thank you all for joining us on this call this morning. Myself and the rest of the Influx team greatly appreciate your patience as we have been working through all of the available data to better understand what happened in the SHINE trial in the 1st 16 weeks of this trial and how our next steps should look like. But before going over our findings and conclusions, I would like to explain what we have concretely done in the past 4 to 6 weeks. And our team, after receipt of the validated complete data set of these 1st 16 weeks of the SHINE trial, has started in-depth analysis our secondary and other endpoints. And we quickly became aware that our drug, especially in the high dose group, showed a reduction in the end count.
This was already suggested in the initial press release, but also in draining fistulas and that this was not adequately reflected in the high score. We also saw that the placebo group performed extraordinarily well on the high score in our trial. But when looking into further details, we also saw that it did on other endpoints. We therefore believe that it was important to first discuss our findings with leading medical experts in the field with key opinion leaders and professionals who understand the regulatory landscape, especially in the U. S, but also in Canada and Europe.
We wanted to get a better understanding on how these experts would judge our findings. In fact, I just returned this week from the U. S. Where our team concluded these personal discussions, and I would like to share with you some key learnings here that we made from these discussions. The high score shows a high variability and that it does not reflect certain benefits for patients well.
Another learning is that we could reconfirm that the reduction of draining fistulas and also especially of all inflammatory lesions, that means abscesses, inflammatory nodules and draining fistulas is very important for patients. And that's some of the experts we consulted favor using scores that reflect changes in all of these lesions. For example, the IHS-four score or just the crude count of these 3 called ANF count. The 3rd conclusion is that it's important that reductions of lesions should also correlate with patient reported outcome measures such as pain scores or DLQI, even though DLQI is seen by some experts as not necessarily being ideal for the disease, hedonitis supraactiv. With that said, I believe and our team believes that the information that we shared yesterday at market close to be very compelling.
And on today's call, I intend to walk through these findings in greater detail and share what comes next in our plan to further the development of IFRS 1 in HS. So I'd like to go over this data set and the press release we provided last night. And I would just like to briefly reflect on the trial. This was a randomized double blind placebo controlled study, multicenter study, which enrolled approximately 179 patients in 4 active dose groups and in one placebo arm at over 40 sites, including North America and Europe. And this makes it around 35 to 36 patients per dose group.
We recently had to report that we failed to achieve the primary endpoint. This was a dose dependent drug effect on the so called high score, hedonitis suppurativa clinical response score. So just to recall, this score to be responder, it's a binary score, and you have to have a 50% reduction or more of the total body count of abscesses and inflammatory nodules. And at the same time, you're only a responder if you don't increase the abscess count or the draining fistula count from baseline. So it's a binary score.
It does not reflect any reduction of draining fistulas, which may be meaningful in the context of this data set. As we reported, the placebo arm resulted in a very high placebo response rate of the high score of 47.2%. And when compared to earlier studies, the PIONEER 1 and 2 studies, which were the only large two studies reported on the high score, they read out a 26% 27.6 percent, both at week 12, and we are here looking at week 16. But nevertheless, this is a remarkable difference. So we learned from the trial that there was a very high variability in this high score and also very large fluctuation of the AN count.
The higher variability of the high score has not been reported before. So we're really practically the 1st company reporting on this. And it's a striking finding because it also means it's very difficult now for us to understand how you could adequately power trial when placebo can actually read out at almost 50%. Now, we first, of course, looked, do we have any clear differences from these earlier studies? So just to share again with you that the inclusion, exclusion criteria of the SHINE study were very identical to the PIONEER II study.
And it's therefore not very surprising that the baseline characteristics of the placebo group in the SHINE study were really comparable with those of the PANELA-two study. There was also a very good distribution over all groups in our study. So there was also not a missed distribution of the baseline characteristics. And I want to share with you just a few of them. So let's look at early stage 2 and 3.
So in the placebo group, we had 20 patients early stage 2 and 16 patients early stage 3, which is a decent distribution. And in the high dose group here, it was 18 patients early stage 2 and 18 patients early stage 3. So really just a 2 patient difference, but nicely distributed. And the same accounts for the other dosing groups, which in the interest of time, I'm not going to go into details. And then looking at the baseline access nodule count, in the placebo group, this was amine 12.4, very comparable to the results from the PIONEER study.
And in the 1200 milligram high dose group IFX1, it was 11.6, so just slightly lower. Prior exposure to adalimumab in the placebo group, it was 6 patients only. And in the high dose group here, 1200 milligram IRFx1, it was 10 patients. So there were a little bit more patients in the high through more baseline characteristics, but overall speaking, we could not spot the problem in a misdistribution of the baseline characteristics. So then we looked further into this high placebo response and we did really numerous different analysis to understand whether there could be other factors involved.
So we looked at early stage true distribution, I mentioned that, but we also looked at various other subgroup and sensitivity analysis, for example, looking at patients with lower end counts, higher end counts, patients with no draining fistulab baseline and so on and so forth. And the conclusion of all these sensitivity analysis is that we could not spot a clear reason that could explain the high placebo response rate in the high score. Now when looking at other endpoints, I mentioned already that we have also a really good performance of the placebo group in other endpoints. So this brings us to the conclusion that in this trial, the placebo group overall performed extremely well. And as you can imagine, it's difficult if you have such a well performing placebo group to show significant differences in dosing groups.
Yet I want to show you today that we found in our eyes meaningful parameters and meaningful different efficacy analysis that showed a clear difference for the high dose group when compared to the placebo group. I'm not going today into too many speculations why we saw this high placebo group, but I just want to give at least 2 perspectives here. The one is that, of course, with 36 patients, just by chance and statistics, you may just have a case where you have a high placebo response rate because that's not too many patients that need to be responded on high score to make that happen, even though all the reports from earlier studies, even also the smaller studies showed a clearly lower response rate. Now another or other factors that we learned during our discussions with experts or discovered ourselves could be that this was a 4:one randomization. So patients were aware that they had in 4 or 5 cases a chance to get drug, active drug.
And then also, there were a lot of touch points. So every 2 weeks, patients were examined, were cleaned. So there was a lot of caretaking of the patients in the trial, which might affect the placebo response rate. And last but not least, also the fact this is an IV drug, which could affect placebo response rate because most of these patients have not been treated with IV drugs. Well, these are all speculative reasons.
And I want to leave it there for today. But of course, we have looked really as deep as we possibly could into this. And other than concluding that we do see a good placebo group here, we could not spot the problem in the trial setup or in the trial conduct. So let's look at the other efficacy signals. At the beginning, and I want to just reiterate here that at week 16, we saw quite a remarkable difference in the relative reduction in draining fistulas to baseline.
And you see you probably saw the figures and this is figure 1 of our press release. So placebo here had a relative change to baseline of in mean of about 18% versus the hydros group readout at 63.2% and very comparable the median here and both were statistically significant. I do realize this is well, even though beneficials were a secondary endpoint, this is, of course, a p value that is maybe not as meaningful because it wasn't the primary endpoint. But given the trial size, we thought we should look over the whole time course, and that's what we shared next that during the whole time course, there was at numerous time points, statistically significant differences. And clearly, these reductions of granifissla were a big separator between the well performing placebo group and the high dose group.
I want to also briefly mention here that this was a signal that we pretty much to a similar extent already saw in the first twelve patients that we examined in our Phase IIa study. These data are under revision for publication and unfortunately not yet published. But I think it's important that I share with you that this is confirmation of something that we've seen earlier. Now let me briefly go back to this AN count. I mentioned that already in the original press release that we had a signal on the end count, and we here look more deeply into the end count next.
So absence and nodules were clearly reduced in the high dose group and they were also reduced in the placebo group. But when you look at the median, the difference from day 1 and day 16, the pure difference in numbers from a median from baseline to week 16 is 8.5 versus 3.5 in the placebo group. So overall speaking, our drug did reduce the AN count quite well, and it reduced the draining fistula count even better. So when we first consulted medical experts on this and we had our first discussions during our one of our first meetings, an expert suggested that we should look at scores post hoc here, of course, that are considering all inflammatory lesions, because obviously our drug did reduce all inflammatory lesions, but it wasn't reflected in the higher score. So we were suggested to use the IHS-four score, which is a score that has been published and already partially been validated and was construed by an international consortium of leading experts in the heredinitis field.
And so we did this analysis and not too surprisingly, since our drug reduced all these lesions, we saw here quite a bit of a difference. We had a mean reduction of 51% versus 19.8% in placebo and a median reduction in the high dose group of 63.2 percent versus 35.2 percent in the placebo arm. So this was overall an encouraging signal because it meant that our drug clearly worked on these inflammatory lesions. And again, these p values you see in the press release are statistically significant, but they are post hoc and it's the 16 week time point. So also here, we did an analysis over the whole time course and we saw a very similar pattern, which we saw already for the draining fistulas.
And I also want to mention that when you look at the draining fistulas over time, similarly, we found the same thing in the IHS IV score that between week 10 week 14, we saw a temporary weakening of the signal. That doesn't mean that it was gone. There was still a clear difference to placebo group, but it was weakened. And we currently do not fully understand why this occurred. We have, of course, checked whether it's because of pharmacodynamic problems, so whether the C5a blockade was lost during that time or whether there was no more drug that or consumption of antibody, but we could confirm that this was not the reason for this temporary weakening.
So this is something we have not quite understood. When we discussed it with some experts, they mentioned that this is a so called waxing and weaning disease and that, of course, blocking CFS, they apparently reduces the inflammatory burden quite a bit, but it may not change the underlying cause, which is as of yet unknown. And it's currently believed that the inflammation starts at the follicles, at the hair follicles and the involved cells, the skin cells there and that this will usually go in circles. So similar to other diseases in the skin that have flares and vaccine and bleeding. So we are trying to understand this better in the future with research, but currently, we do not understand this phenomenon fully.
So we also looked at other signals. And I mentioned in the press release the HSPGA score, which is another way of looking whether patients that are scored severe or very severe shift into less severe cases. So the way that experts look at the score is they want to see patients shifting from the severe and very severe groups into less severe groups. And here we saw also a difference and a clear trend compared to placebo. We also saw again that the placebo group in and of itself performed really well.
But we saw a difference with the 1200 milligram group shifting to less severe patients and also seeing patients that were scored clear. And at week 16, this only occurred in patients that had received drug. So there were no clear patients in the placebo group. Of course, we looked at many other signals, not all of them are mentioned in the press release. We do see at week 16 a certain trend in the Sartorius score.
That means in mean and median, in the absolute change from baseline, but also in the relative change, the hydros group always performed better than the placebo group, even though this was not a statistic significant signal. We also looked at other findings. And one thing that I would like to mention was something that we learned from our KOLs should be important is the question of the correlation between a change, for example, in the IHS-four score or in the fistula count and the patient reported outcome. So we correlated the change of IHS-four with the DLQI and as well as with the pain scores and we saw a highly statistically significant correlation, the correlation was overall not a strong correlation as expected for patient reported outcome measures, but it was highly statistically significant correlation. The same was true for reduction of training fistulas when we correlated them with the DRQI and the pain scores.
And so this was encouraging because it meant from an expert perspective that the reduction of IHS IV and the reduction of draining fistulas itself should be medically meaningful. So with that, I'm coming to the end of the efficacy analysis for today, and I want to briefly talk about here the pharmacokinetic and pharmacodynamic analysis. So first of all, what we've seen is clearly we have a dose dependent suppression of C5a with the different IFX1 drug levels IFX-one doses chosen. And when we analyze this, clearly, the high dose group, the 1200 milligram group that was administered twice per sorry, once per 2 weeks offered the superior control over C5a levels. I also can share with you that the minimal and low dose group, this is 400 milligrams 4 weekly and 800 milligrams 4 weekly, did not result in a C5a control over time.
That means these doses were not efficient to fully block C5a over time. But the 800 milligram biweekly did show a decent suppression, but it was differentiated from the 1200. So we clearly spotted the 1200 milligram group as the best group when it comes to C5a control. Please keep in mind, when we talk about control of C5a, these are measures with ELISAs that always interfere with other antibodies, especially with antibodies that compete for the same target. And when we talk about CFA control, we talk about control in the human blood.
This means that there is still a question around how much tissue distribution do you get of your drug. And so even though you may see a rather full rather complete blockade of C5a in the human blood, you may still wonder, is this enough to reach high enough tissue distribution, especially in such a large skin area? So this is why we're currently running population PKPD analysis, which should be completed here soon. And we're also running statistical and, yeah, I would say, mathematical models that estimate the skin penetration. And this should further guide us on whether 1200 milligram biweekly is actually the right dose or whether there should be even an increase over this dose to achieve a maximum effect.
Now keep in mind, our Phase IIa trial was 800 milligram weekly. The saturation was the same, 3x800 milligram over 1 week. But then it was weekly continued at 800, and this is 1200 every 2 weeks. So there is a certain difference, but the trough levels were very comparable between these two groups. The control over CFFA was slightly better in the 800 milligram group, but only towards the end of the 12 weeks.
So overall speaking, there's a lot of effort going on to understand whether the 1200 milligram will be the ideal dosing for HS. It's also fair to mention that overall, we believe that there is a lot of complement consumption in this disease. As we've confirmed relatively high baseline levels of C5a in this disease, and we intend to share more of the data in the upcoming conferences that we're intending to present more data. So let me please, last but not least, come back to safety. We already reported that overall, there were no safety signals of concern in the trial, especially in the high dose group.
We can confirm that we have really no concern for this drug. We also looked at ADA levels, and we were very happy to see very low anti drug antibody levels. We included here in our statement less than 10% positive findings also pre dose because this is usually how it's specified because there are these are few cases only in this trial, but there are typically cases where people have cross reacting antibodies and that's very common. And we see just a couple of cases of that in the placebo group just as much as in the dosing groups. I also would like to share on today's call with you that the highest dose group, the 1200 milligram group, had the lowest anti drug antibody levels measured of all those groups.
But all taken together, it's less than 10% in the dosing arm. And I think this is a very good sign that this antibody, as far as we know today, and please keep in mind, these are all 16 weeks only reporting, so there will be more to come. But as of today, we see a very low immunogenicity of this drug. And that's why we believe this is a credible drug candidate to be taken forward. So with that being said, we have concluded from all of this that the company should continue working in HS with this drug.
We believe that we have not only seen meaningful changes in comparison to this well performing placebo group, but we've also vetted them with medical experts. And we feel encouraged by reports we hear and we see and we look forward to sharing with you more of the RUNNING trial. Obviously, the trial will be concluded soon. We expect that the last patient will be dosed end of August of this year. And therefore, we, of course, have a high interest of concluding all the results.
And then the next steps will be post Phase II discussions with the regulatory authorities. And of course, this will be very important for us to understand the potential pathway for future further development. So with that, I would love to hand over to Q and A session. I thank you very much for listening in today. And now I'm happy to take questions from the audience and I revert back to Jordan.
Thank you. At this time, we'll be conducting a question and answer session. Thank you. The first question today comes from the line of Anupam Rama with JPMorgan. Please proceed with your question.
Hey, guys. Thanks for all the additional analysis here in the SHINE study. Your comments certainly suggest that there's an openness from physicians on outside measures of clinical efficacy beyond high score. But in your discussions with regulators in the past, any color on how regulators view endpoints outside of HiSCOR score as potentially registrational endpoints? Thanks so much.
Yes. Thanks very much, Anupam, for this question. So we have not completely discussed in the past regulatory endpoints that could lead to an approval outside the high score. Please keep in mind, with the published data so far, the high score looked very well handable in as much as the placebo groups performed very tight around 26% 27.6%. And so with a strong signal from the Phase IIa, we believe that we knew that we could probably reduce straining fistulas and that would not be reflected in the high score.
But as you can imagine, discussing with the regulatory bodies to change the primary endpoint requires additional efforts and maybe more time and analysis. So we believe that we could also use the high score. So we haven't concretely asked the questions. But we know from the documents that led to the approval of adalimumab that there were initial discussions from AbbVie around just looking at the end count by itself. But the end count itself was not seen apparently to reflect enough the patient benefits.
So there is a hint already in this discussion that the regulatory bodies, the FDA, suggested or basically wanted to have the draining fistulas also somewhat reflected, which is probably how the high score was constructed. So other than this evidence in the past, we have not led these discussions and we really need to start these discussions on the basis of the entire data set.
And just to confirm, we're going to
be waiting for the full 28 week OLE data before regulatory discussions?
Yes. We feel it's important to get as much information on the drug as we can. Now we do realize and it's also public that we are putting the responders now in a dose group that is only 8 100 milligrams 4 weekly, which may lead to less of a response rate, and we will see. And we also put the non responders, regardless which reason they are non responders for, into a group that goes 800 milligram biweekly. However, what we learned from our discussions that and what we've seen in the Phase IIa that maybe some patients still have a benefit in the long term, even though maybe your dosing may not fully block C5a anymore, but it may still down the overall skin inflammation.
So this is something we would like to look into. Of course, we want to understand the full set for the ADA analysis, for safety analysis, and we want to have as much arguments at hand before we approach the regulatory bodies. Please keep in mind to discuss other endpoints, you also need to do a lot of validation work. Some of that I shared today with the correlation work, which is very positive for us that these endpoints during fistula change and also IHS-four change really correlates with these patient reported outcomes because it is our understanding that this is something that regulators definitely want to see.
Great. Thanks so much for taking my questions.
Absolutely. Thanks for calling in.
The next question is from the line of Joseph Schwartz with SVB Leerink. Please proceed with your question.
Hi, good morning. Thanks for taking our questions and all the other color. My name is Dae Gon Daeun in for Joe. So just a couple of questions on my end. Neil, if we look at the draining fistula data in the figures that you provided, just wondering if you can provide a little more color behind the variability.
So, width and waining you mentioned in your prepared remarks in the weeks 10 to 14, is this due to several outliers or is this a general trend that you see across all 35 to 36 patients across both, I guess, placebo and all the other dose groups? And then second question is, just looking at dataset overall that you provided in the press release, it looks favorable and also buoyed by safety profile like you mentioned in your prepared remarks. Wondering what are your current dose so far. So thoughts there will be helpful. And then lastly, if we can think about going forward, you're obviously going to complete this open label extension and discuss with potential plans thereafter of another set of studies.
So any additional insights on cash balance and runway guidance as to what we can expect within the milestone achievements? Thanks.
Sure. Okay. Let's start with the first question. Thanks for these questions, by the way. So first question here is really more insight on this week to 10% to 14%.
So there will always be certain outliers when looking at things that fluctuate a lot. What we have seen is that draining fishlets don't show the same extent of fluctuation that the AM count shows interestingly. And so while I wouldn't hump or weakening of the overall system during that time point is really based on numerous patients showing that. It's not just driven by a couple outliers. So remind me of your second question again.
The second question
was On higher The third one was
So, of course, I mentioned we're running right now population PKPDMS and also estimates for tissue distribution. And should these analysis reveal that we could expect an even better effect in HS with a higher dose, we would definitely look at this because I mentioned that the 800 milligrams weekly we chose in the Phase IIa is slightly higher. And this is something we're looking into. Now I would not conclude from this that because we saw this in HS that this means we need to now dose differently in all trials and other diseases.
And the
reason for me saying that is because, 1st of all, HS seems to have a very large complement consumption overall. We always saw very high C5a levels compared to other diseases. When you think of this as a chronic disease where you don't put patients in a life threatening acute inflammatory status, but in its chronic in his or her chronic status, the overall C5a measurement at baseline are comparatively very high. And also what we've learned and what you can learn from other drugs when you look at adalimumab or currently other drugs that are being studied, adalimumab was approved at the double dose compared to its dosing in all other indications. And now people already quadruple the dose to see an even better effect.
So from our discussions and our learning in HS, this seems to be an area where all the substances tested should go to really high doses to achieve an effect. So for us to conclude from this that we could only use 1200 milligram biweekly or more in other trials, it's that's really definitely too early because I also mentioned that the 800 milligram biweekly treatment group also resulted in a decent control that when you just look at blood levels, you would probably say that that's good enough for other diseases when you just want to control C5a in the blood. So it's a little too early for us to make any conclusions as to how we dose in other trials. But just to reiterate, in HS, we really want to conclude these population PKPD analysis and tissue estimates to get the best possible feel for maybe the ideal dose moving forward. And your third question was concerning the runway and the financial situation.
Of course, this is you see that the company was hit by a pretty steep stock drop. And then of course, we understand that we have to be extremely cash cautious right now. And so the first thing we did is after we had discussed these signals is understanding whether or not we would be able to run an additional trial in HS. And of course, obviously, this very much depends on the size and of such a trial and the extent. And while this decision has not yet been made, we have a decent runway.
So we have a several year runway in front of us and that includes running all the studies that are currently running, which is the ANCA vasculitis trials, the STARTED PG trial, palDermagangrenosum, and which is also including the planned and put together oncology trials. So even with another HS trial of similar or a little bit larger size than we just conducted, we could have a runway of several years, several meaning maybe around 3 years or so. So we're not in an immediate crunch of financing the company. However, should the discussions with the regulatory bodies be very positive? And should there be should we get a reflection of what we hear in the expert community that there is a real readiness to include other parameters and to change to other endpoints for approval, should that be reflected?
Of course, we then need to understand what would be the risk appetite based on our current data and what would be the potential to move this maybe faster to approval than just doing another exploratory study. So there's a lot of questions relating to the outcome of the discussions with the regulatory bodies. But I hope I could give you a comprehensive overview of where we can get with our current cash runway.
So Niels, just as a clarification, when can we expect that population PKPD data set readout?
Yeah, that should be concluded within the next few weeks. But again, we're also running these estimates with these are mathematical specialists in medical science that oftentimes they do this for oncology studies to estimate tissue distribution. So I expect this to be done in the next few weeks. And again, the dosing for HS is an important question. But the most important one for us is concluding the trial, concluding the entire data and compiling them and then really going to the regulatory bodies to say this is what we have, this is what we want to achieve, do you agree that this is the right path?
Okay, great. Thanks for taking our questions.
Absolutely.
The next question is from the line of Yatin Suneja with Guggenheim Partners. Please proceed with your question.
Good morning, everyone. Thanks for taking my questions and appreciate all the color. I do have a couple of questions. Did you look at the baseline C5a level? Can you tell us how high they were relative to normal patient?
And then the second part of that C5a puzzle is that could you maybe quantify the robustness of the knockdown or the control that you saw at the highest stores versus, let's say, the 2nd highest dose? And did these responses in fistula correlate with the degree of knockdown?
Yes. So to your first question, I can confirm that we had clearly elevated C5a levels at baseline. I don't have the concrete levels in front of me for all the different groups, but they were clearly in the range of around 50 nanogram per ml. So I mean, this were baseline C5a levels in median, I believe. And so they were clearly elevated across all those groups.
So there was not any dose group that had normal C5a levels in average or median. The other question is whether we could directly correlate the knockdown of C5a with Drainie Fischler. So we have not really fully done this analysis to conclude this. I think the overall conclusion was that the 1200 milligram biweekly led to a tighter control. However, also in the 800 milligram, we saw a decent control in as much as we saw levels over the whole time period in median in the normal range.
Now again, the key question is not so much what you see in the blood, but what happens in tissue. And what I can confirm with you that we do not have the same extent of draining fistula reduction at all in the second highest dose groups. We see trends, but we don't see the same extent. So yes, we do believe that you need to dose higher in order to get enough tissue distribution and enough effect, not only in the blood, but also in the tissue. When just looking in the blood, the 800 milligram biweekly did not perform bad.
It performed decently well. But clearly, there was a difference to the 1200 group. So we currently really believe that there is a threshold that you need to get a full effect that you also penetrate the tissue. I mean, oftentimes, over the thumb rules that I learned from oncology that oftentimes antibodies are expected to have around 10% of their concentration you see in the blood should be present in the tissue. Obviously, this depends very much on the subtype of antibody and so on and so forth.
But that's why we're running these additional
helpful. Then just maybe a few more questions. So did you also look at the IV antibiotic or oral antibiotic use and if that could have hampered how the placebo guys responded?
Yes. So there was a very low rate in IV antibiotic use for flare up or what other people called rescue therapy before in HS and that was equally distributed over the groups just up front and also the overall use of antibiotics was equally distributed. What the analysis whether or not antibiotics at baseline, that means those 2 groups of antibiotics that were allowed for stable treatment have an effect or not. This analysis has just started yesterday because after consulting with another KOL, we thought we should look at this again. However, the rate is not very high.
So it's just a few patients. So I don't expect that we learn too much from it. But we're going to run this analysis and we're also going to run another analysis where we're looking at everyone who has gotten any type of antibiotics versus the rest. So this is still running. So I expect this to get this by the someone by next week.
So I asked a little bit more patience. Again, we have tried to turn around practically every stone. And I appreciate this question. It's an important question because it was also suggested by medical experts that there can be a temporary benefit. However, I can already share with you that there's no
And then just a question on your understanding of this disease. I mean, are there certain elements of this disease that are maybe more driven by neutrophils? Hence, you might see a C5A working, let's say, fistula and maybe AN counts as more driven by, let's say, monocytes or lymphocyte where a TNF would work. Just help us understand like how much more understanding are you have about this disease now that you have a lot of these data?
Yes. That's a very good question, Jatin. Thanks for asking this. I think one thing we clearly need to say, the relative change in draining fistulas has been already seen in the Phase IIa. So this is confirmed.
But also an end count reduction in general is confirmed. So for us, it is difficult to say whether we will work more on the end of fistulization on the puff drainage than on the other aspects of the disease. But the fact that we work so that the drug seems to work strongly in at least in the high dose on the pus drainage seems to be rather unique. And that's also something that we heard early on in the Greek community when we had these 12 patients treated. So the data we have right now confirmed this.
So certainly, I would add to our understanding that the draining fistula seem to be very much, I would say, or the other way around, CVA seems to be very much involved in draining fistula and in pus generation. So this is certainly something that completely goes in line with the mode of action of our drug. This is something we would expect when you will stop neutrophil over activation. I would not conclude from that, that we wouldn't work on the other parts of it. But you're right, there is a T cell side of the story because clearly adalimumab works and others may do too.
But I don't think that the T cell part is as strong as the neutrophil part, especially on the draining fistula count. There is some evidence when you look at the draining fistula reductions that there were some suggestions or something that we could just say, oh, our drug only works on fistulas, it's still going to stay intriguing, which part of this disease is more T cell driven and which part is more neutrophil driven. But if you take 1 and 1 together, if both are true, were to be true that there's a neutrophil driven part and a certain T cell part, then we should also think about combining certain therapeutic approaches in the future or at least testing it. And that's something that also experts said to us because they also don't know which part plays a role. But looking at skin pictures, looking at the overall inflammation, we have our team has a strong conviction that this drug shows at the right dose a very strong anti inflammatory effect in this disease.
And that is not necessarily reflected by the high score. That's something we clearly learned.
Got it. Last question, I promise. Did you also look at other cytokine level in these patients, like did they drop over time? And then like any or did patient response mimic to C5P depletion or other inflammatory cytokine depletion?
No, I have not looked at the cytokines yet. These are all part of secondary analysis. We are running right now an interesting other analysis where we're looking at a neutrophil activation marker, a certain protein. And these are completed soon. And then as we learn more from this, we will put it out.
But we have not looked at cytokines. But as you may recall, this disease doesn't have a clearly established biomarker. So it's very difficult to say these are the cytokines I follow. Keep in mind, cytokines have a huge variability per patient. When you look at certain interleukins, you see very large variability.
And looking at 36 patients, it's difficult to see much, but we haven't looked at this yet and this something that's still on our agenda.
Great. Thank you so much for taking all the questions.
Absolutely. Thank you, Yatin, for your questions. Appreciate it.
The next question is from the line of Matthew Ascini with BMO Capital Markets. Please proceed with your question.
Hi. Thanks for taking the questions. Good morning. So a couple for me. First, kind of big picture.
Wanted to come back to the path forward and try to understand a little bit more specifically what from your perspective the ideal outcome would be from the interactions with FDA? Is it preferable to run another study and validate some of these initial observations in a proper trial? Or would the company really prefer to try to jump right into Phase 3 with these new endpoints if accepted? And if that is the preferred outcome, how would we be able to get comfortable given that this is based on a post talk analysis? And of course, all of this assumes that additional dose ranging work isn't done, isn't needed?
And then I have
a couple of follow ups as well, please.
Sure. Thanks, Matt, for these questions. So I would like to separate these two questions because the first question would be what is the ideal outcome? The ideal outcome for us is that the agency the ideal outcome? The ideal outcome for us is that the agency agrees with an endpoint we suggest as an approvable endpoint.
Can we get that achieved with the 1st meeting on basis of this data is the big question. I think we have a very good line of argument in our hands, and I want to lay that out again. We can prove here that we have numerous efficacy signals, which are not reflected by the high score. We have even a more pronounced hand count reduction. Still, it's not reflected in the high score.
So obviously, the high score does not reflect the mode of action of our drug, and it is known that the high score does not give you credit for any reduction of draining fistulas. Our drug has shown this now basically the 2nd time in a larger controlled study that we are reducing draining fistulas. There's a strong relative reduction to baseline. And we believe this is meaningful for the patient. There's in our view very little doubt because this is a big burden, the pus drainage when patients have drainage fistulas.
And so we need to discuss with the FDA that there should be an outcome measure which reflects this. So I think we have a good argument in hand.
Just be willing and say we need more
data around this and this? Just be willing and say we need more data around this and this, then the outcome would likely be that we have to do another Phase II study. Of course, you may or may not use this later on for approval, but that would be the outcome of it. If the FDA follows what we believe here is a good line of argument completely and says, yes, this is an approval outcome, then we have to go back and ask ourselves the questions, how can we possibly jump to directly to a Phase III program, which obviously carries a higher risk, and obviously requires a different setup financially. So with the current finances, I can confirm we could not run a Phase III program, meaning 2 independent large trials and gear up for commercial.
That is very clear. So that's why it's right to separate these two questions. If the FDA follows our argument to say, yes, we believe what you're suggesting here can be an approvable outcome, then we are going back and ask ourselves the questions, can we go into a Phase III or should we do one more trial to confirm it and then make that one of an approvable of 2 approvable trials? That means losing time and maybe value, even though we believe the mode of action of this drug is still pretty unique. It's not a cytokine blocker.
But the other way around would also mean that we take a much higher risk. And how are we going to take this if we're going to be able to get it financed through the market or if we need to find a partner to do that with us? Those are all questions that will come up if we are looking at this option. But please, at this point in time, it's too early to say one way or the other. But at least I can ask you the first part answer the first part of your question well.
Our ideal outcome is that the FDA agrees that there should be a different outcome measure and that it should be approval based on the data we bring to them. That's our ideal outcome.
Okay. Thank you for that. And then a clarifying question on figure 1 from your press release as it relates to draining fistula. Can you just tell us the size of each of these groups? The description says at least 1 draining fistula at baseline.
So are each of these groups were there patients that didn't have at least 1 fistula in each of these groups? Yes.
I can share that with you. We had overall in the trial a total of, I believe, 47 patients that had no draining fistulas at baseline. And they were pretty well distributed over the group. So we're still speaking about groups of around 24 patients or so. Please don't I don't have the exact number for each group in front of me, but we're still talking about 24 or so patients per group when you exclude patients that have no draining fistula baseline.
We found this number, 47, relatively high. We cannot compare it to the HUMIRA trials because when you look at the median and the minimum, you also see that they have clearly patients with 0 draining fistulas at baseline, but they didn't disclose how many patients in total had no draining or how many percent of patients had total no draining fistulas at baseline.
Okay. So we should think of it as 47 basically evenly distributed across the groups?
Is that
Relatively evenly distributed across the groups, exactly.
Okay. Fine. Great. Thank you. And then last question for me.
Are you able to provide any more visibility on timing of when the Phase IIa data will be
published? Well, we are now running I can share with you that we are now in the 3rd revision with questions like we would like to take our X a little bit more tuned like this. And it's a process of over half a year now that we have submitted the first one. And we have just made an inquiry at the journal 2 days ago, and we were asked for another couple of weeks of patients. So that's where we are.
That's publishing results. So it's a very good journal and we don't know what they will conclude, but we have submitted this over half approximately half a year ago. And we would hope that we have satisfied all the revision wishes of the reviewers now. But apparently, we need a few more weeks until we have them have knowledge whether that gets published or we have to resubmit it in a new journal.
Okay. Thank you for taking all the questions.
Sure. Absolutely. Thanks for your interest and your questions, Matt.
Your next question comes from the line of Steven Seedhouse with Raymond James. Please proceed with your question.
Good morning. Thank you. Could you just clarify the reason Could you just clarify the reason for not testing the 800 milligram once weekly Phase 2a dose and Phase 2b given it sounds like ultimately you might be considering going back to that dose or a higher dose going forward?
Yes. So we looked at thanks Steve for the question. We looked at the total dose administered and we felt like the most important part is that we get control over CVA at an early time point. And when you look at the 1200 milligram biweekly, keep in mind we had a saturation basically of 3 doses, 800 milligram in the 1st week in the original trial and in the SHINE trial. And when you look at the trough levels, because we didn't do a full PK PD analysis back then in the Phase IIa, but when you look at the trough levels and certain peak levels that we have, you can see that the level of control is very similar.
So it's not that we were completely off. It's practically at a time point 8 weeks or so, it's practically identical in the 2 groups. So it's not that we were off with our estimations. And of course, one month thinking was convenient, but also the other knowledge that we are the belief that we dosed really high with 800 milligram weekly. However, the one difference could be and that's a difference that we need to take in consideration now is whether even though you see a similar control of CVA levels in blood, whether that is still reflective of what you see in the tissue.
So obviously, looking back, you can say, why don't you take 800 800 milligrams weekly? Well, at least our PKPD analysis and our knowledge around PKPD parameters in the blood 1200 milligram worked and the other doses didn't show this efficacy, you may wonder whether you're better off going even higher. And that's why we are running the additional analysis, Steve.
Okay. Thanks. And what are the doses being tested in the ANCA vasculitis and in PT trials?
Yes. We haven't disclosed these doses yet. And as I mentioned earlier, what you see necessarily in HS doesn't necessarily mean that you have to believe that this is all applicable to other indications. So I think you need to look indication by indication to understand your ideal dosing. And again, the evidence for that is that other drugs in this disease are dosed double.
Adalimumab is approved at the double dose. Cosentyx is currently tested at the double dose. Others are tested at higher doses. So there seems to be something about HS and the large amount of inflamed areas in the skin that make this more challenging to control from an anti inflammatory perspective.
And can you just clarify what the going back to the ADA rates in each treatment group, can you quantify what was the post dosing EDA rate in all of the groups, including the high dose group?
No, we don't. I don't have those numbers in front of me, but that's why I made the statement during my intro year that there were just a couple of patients that showed pre dose. And normally, when you report ADA to authorities, you include those because there may be patients that have been treated with other antibodies that may cross react. So it's still an important measure. This number is very low.
But here and there, you find a patient. But I did confirm that the 1200 milligram dosing group has the lowest ADA level. So and overall speaking, which is quite normal, oftentimes you see it at lower dosing is better. That's often seen for antibodies. But overall, it was also in the treated groups, in each treated group below 10 clearly below 10%.
So that I can confirm. And the final numbers, we will put out when we have the final report because they're now considered 2 confirmatory assays. And what I have shared with you is the data less than 10% really includes all that have shown a one confirmation in the first confirmatory assay. So and the final report will also respect then not only the 16 weeks, but then also look at all the weeks. But at least for the snapshot we have, we have a very low ADA rate, especially in the high dose group.
That is what I can confirm.
Okay. Thank you. And last question for me. So you're suggesting, not only that you reduce fistulas, but also, end count, so abscesses and inflammatory nodules in the high dose group and high score is basically dependent on those three parameters, either improving to a certain threshold or not worsening. So I'm just trying to understand why you think high score is not the adequate scale to assess your drug if you're in fact having on all three of those comprising parameters?
And is it just a threshold issue that you're just not potent enough hit the high score threshold?
Yes, that's a very good question. Thanks, Steve, for asking that. So I think the high score in and of itself, that took me also a little while to really fully understand why we don't see the end count reduction. Because even if you look at the relative changes, some of them we published in the first press release, there was clearly a trend. And we had more reduction in certain dosing groups than in placebo, but it didn't show in the high dose group.
And the reason for that is 2 things. It's the threshold, 50%, which you have to hit in each patient. And then also these 2 other endpoints, these 2 other important little things that are oftentimes overlooked that you may not exceed abscess count from baseline or draining fistula count from baseline. Now what we learned that oftentimes when you are doing the examine that larger nodules are sometimes confused with abscesses. And so this explains a certain fluctuation already.
So the pure inter rater variability seems to be higher than we thought. And so by chance, when you look at 36 patients, if few patients can really make it happen that you have a higher placebo response rate. And the other thing is that I mentioned in the call, it's very clearly the reason why we don't believe it's adequately reflecting. I mean, you could say, look, our drug also performed around 50 percent, so it's adequately reflecting the high score, which is what Epi has shown in his trials and their trials. But the real reason is the high score doesn't give you any credit for draining fistula reduction.
And since our drug apparently reduces all of them and since the experts we have consulted, especially in the U. S, really believe that it's important to look at the inflammatory lesions and not just at some of them, we believe that there is a credible path forward and that high score may not adequately reflect what our drug can do. And the last thing I want to mention here is just think of the pure fact that you can have with 36 patients, a evo response rate in the score of close to 50%, in this case, 47.2%. Just this pure fact alone, which was completely unknown to us, this pure fact alone says, to me, we should question whether that is a good endpoint, because how do you power the next trial with 27% or 50%. So there is through this binary nature and this large fluctuation in the high score, there is a question for us how useful it is, especially for our drug.
And since the fistulas are not there, we believe our drug is not adequately our mode of action is not adequately reflected in this high score.
Great. Thanks for taking the questions and thanks for joining the call.
Absolutely. Thank you.
Thank you. At this time, we've reached the end of our question and answer session. Now I'll turn the floor back to management for closing remarks.
Okay. Well, thank you so much for calling in. I appreciate again your patience. This has taken some time. But again, we try to make any effort not just to put some statistically significant signals out there, but really vet them with experts globally and especially in the U.
S. And really understand the best we can whether this drug has a path forward. And our conclusion is, yes, it does have a path forward. And I just want to reiterate, there is a dependency on what the outcome may look like with the regulatory authorities. But when looking at our drug, I just want to convey the conviction that this is a viable drug candidate in our eyes and that we see signals that are worth pursuing in HS clearly.
Thank you very much for tuning in. And with that, I'd like to end the call and thank you all. Thank you. Bye bye.
Today's conference has concluded. Thank you for your participation. You may now disconnect your lines at this time.