maGreetings. Welcome to the InflaRx conference call. At this time, all participants are in a listen-only mode. A brief question- and- answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero from your telephone keypad. Please note this conference is being recorded. At this time, I'll turn the conference over to Jordan Silverstein, Head of Corporate Strategy. You may now begin.
Morning, everyone. On this call, InflaRx 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 InflaRx's annual report on Form 20-F that was filed with the Securities and Exchange Commission. These statements speak only as of today. 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 Riedemann, CEO of InflaRx. Go ahead, Niels.
Thank you, Jordan. Thank you all for joining us on this call this morning. Myself and the rest of the InflaRx 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 first 16 weeks of this trial and what our next steps should look like. Before going over our findings and conclusions, I would like to explain what we have concretely done in the past four to six weeks. Our team, after receipt of the validated complete data set of these first 16 weeks of the SHINE trial, has started in-depth analysis on our secondary and other endpoints. We quickly became aware that our drug, especially in the high-dose group, showed a reduction in the AN count. This was already suggested in the initial press release.
Also in draining fistulas, and that this was not adequately reflected in the HiSCR. We also saw that the placebo group performed extraordinarily well on the HiSCR in our trial. When looking into further details, we also saw that it did on other endpoints. We therefore believed 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 first one is there's an increasing awareness that the HiSCR 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 some of the experts we consulted favor using scores that reflect changes in all of these lesions, for example, the IHS4 score or just the crude count of these three called ANF count. The third 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 hidradenitis suppurativa.
With that said, I believe, and our team believes, that the information that we shared yesterday at market close to be very compelling. 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 IFX-1 in HS. 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, a multicenter study which enrolled approximately 179 patients in four active dose groups and in one placebo arm at over 40 sites, including North America and Europe. 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 HiSCR hidradenitis suppurativa clinical response score. Just to recall this score, to be a responder, the binary score, you have to have a 50% reduction or more of the total body count of abscesses and inflammatory nodules. At the same time, you're only a responder if you don't increase the abscess count or the draining fistula count from baseline. 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 HiSCR, 47.2%.
When compared to earlier studies, the PIONEER I and II studies, which were the only large two studies reported on the HiSCR, they read out at 26% and 27.6%, both at week 12, and we are here looking at week 16. Nevertheless, this is a remarkable difference. We learned from the trial that there was a very high variability in this HiSCR and also a very large fluctuation of the AN count. The high variability of the HiSCR has not been reported before, so we're really practically the first company reporting on this. It's a striking finding because it also means it's very difficult now for us to understand how you could adequately power a trial when placebo can actually read out at almost 50%. We first, of course, looked, do we have any clear differences from these earlier studies?
Just to share again with you that the inclusion/exclusion criteria of the SHINE study were very identical to the PIONEER II study. 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 PIONEER II study. There was also a very good distribution over all groups in our study, not a misdistribution of the baseline characteristics, and I want to share with you just a few of them. Let's look at early Stage II and III. In the placebo group, we had 20 patients early Stage II, and 16 patients early Stage III, which is a decent distribution. In the high-dose group here, it was 18 patients early Stage II and 18 patients early Stage III. Really just a two-patient difference, but nicely distributed.
The same accounts for the other dosing groups, which in the interest of time, I'm not going to go into details. Looking at the baseline abscess nodule count. In the placebo group, this was a mean 12.4, very comparable to the results from the PIONEER study. In the 1,200 mg high-dose group IFX-1, it was 11.6, just slightly lower. Prior exposure to adalimumab in the placebo group, it was six patients only. In the high-dose group here, 1,200 mg IFX-1, it was 10 patients. There were a little bit more patients in the high-dose group that had prior exposure to adalimumab. Okay. With those differences, I'm not going to go through more baseline characteristics, but overall speaking, we could not spot a problem in a misdistribution of the baseline characteristics.
We looked further into this high placebo response, and we did really numerous different analysis to understand whether there could be other factors involved. We looked at early Stage II distribution, I mentioned that, but we also looked at various other subgroup and sensitivity analysis. For example, looking at patients with lower AN counts, higher AN counts, patients with no draining fistula at baseline, and so on and so forth. 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 HiSCR. Now when looking at other endpoints, I mentioned already that we have also a really good performance of the placebo group in other endpoints. This brings us to the conclusion that in this trial, the placebo group overall performed extremely well.
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, I just want to give at least two 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 responder on the HiSCR to make that happen, even though all the reports from earlier studies, even also the smaller studies, showed a really low response rate.
Other factors that we learned during our discussions with experts or discovered ourselves could be that this was a 4:1 randomization, so patients were aware that they had in four out of five cases a chance to get active drug. There were a lot of touch points, so every two weeks, patients were examined, were cleaned. There was a lot of caretaking of the patients in the trial, which might affect the placebo response rate. The fact that this is an IV drug, which could affect our placebo response rate because most of these patients have not been treated with IV drugs. These are all speculative reasons, and I want to leave it there for today.
Of course, we have looked really as deep as we possibly could into this other than concluding that we do see a good placebo group here, we could not spot a problem in the trial setup or in the trial conduct. Let's look at the other efficacy signals. Draining fistula I mentioned at the beginning. I want to just reiterate here that at week 16 we saw quite a remarkable difference in the relative reduction in draining fistula to baseline. You probably saw the figures, and this is figure one of our press release. Placebo here had a relative change to baseline of a mean of about 18% versus the high-dose group read out at 63.2%, and very comparable the median here, and both were statistically significant.
I do realize even though draining fistulas were a secondary endpoint, this is, of course, a P value that is maybe not as meaningful because it wasn't the primary endpoint. 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. Clearly these reductions of draining fistula 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 12 patients that we examined in our phase II-A study. These data are under revision for publication and unfortunately not yet published.
I think it's important that I share with you that this is confirmation of something that we've seen earlier. 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 AN count. We here looked more deeply into the AN count next. Abscess and nodules were clearly reduced in the high-dose group, and they were also reduced in the placebo group. When you look at the median, the difference from day one 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. Overall speaking, our drug did reduce the AN count quite well, and it reduced the draining fistula count even better.
When we first consulted medical experts on this, we had our first discussions during 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. Obviously our drug did reduce all inflammatory lesions, but it wasn't reflected in the high score. We were suggested to use the IHS4 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 hidradenitis field. 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% versus 35.2% in the placebo arm.
This was overall an encouraging signal because it meant that our drug clearly worked on these inflammatory lesions. 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. Also here we did an analysis over the whole time course, we saw a very similar pattern which we saw already for the draining fistulas. I also want to mention that when you look at the draining fistulas over time, similarly, we found the same thing in the IHS4 score that between week 10 and 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 pharmacokinetic, pharmacodynamic problems, so whether the C5a blockade was lost during that time or whether there was no more drug or consumption of antibody. We could confirm that this was not the reason for this temporary weakening. 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 waning disease, that, of course, blocking C5a apparently reduces the inflammatory burden quite a bit. It may not change the underlying course, which is as of yet unknown. It's currently believed that the inflammation starts at the follicles, at the hair follicles, and the involved cells, at the skin cells there, that this will usually go in circles, so similar to other diseases in the skin that have flares and waxing and waning.
We are trying to understand this better in the future with research, currently, we do not understand this phenomenon fully. We also looked at other signals, I mentioned in the press release the HS-PGA score, which is another way of looking where the patients that are scored severe or very severe shift into less severe cases. 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. 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.
We saw a difference with the 1,200 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. 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 high-dose group always performed better than the placebo group, even though this was not a statistically 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 a correlation between a change, for example, in the IHS4 score or in the fistula count, and the patient-reported outcomes. We correlated the change of IHS4 with the DLQI and as well as with the pain scores, and we saw a highly statistically significant correlation. The correlation was overall not as strong correlation as expected for patient-reported outcome measures, but it was a highly statistically significant correlation. The same was true for reduction of draining fistulas when we correlated them with the DLQI and the pain scores.
This was encouraging because it meant from an expert perspective that the reduction of IHS4 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. First of all, what we've seen is clearly we have a dose-dependent suppression of C5a, with the different IFX-1 drug levels, IFX-1 doses chosen. When we analyzed this, clearly the high-dose group, the 1,200 milligram group that was administered once per two 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, four-weekly, and 800 milligrams four-weekly, did not result in a C5a control over time. That means these doses were not efficient to fully block C5a over time.
The 800 milligram bi-weekly did show a decent suppression, but it was differentiated from the 1,200. We clearly spotted the 1,200 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. When we talk about C5a 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. Even though you may see a 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.
This is why we're currently running population PK/PD analysis, which should be completed here soon. We're also running statistical and I would say mathematical models that estimate the skin penetration. This should further guide us on whether 1,200 milligram bi-weekly is actually the right dose or whether there should be even an increase over this dose to achieve a maximum effect. Keep in mind, our phase II-H trial was 800 mg weekly. The saturation was the same, 3x 800 mg over one week, but then it was weekly continued at 800, and this is 1,200 every two weeks. There is a certain difference, but the trough levels were very comparable between these two groups. The control over C5a was slightly better in the 800-milligram group, but only towards the end of the 12 weeks.
Overall speaking, there's a lot of effort going on to understand whether the 1,200 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. We intend to share more of the data in the upcoming conferences that we are intending to present more data. 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 these are few cases only in this trial, but they are typically cases where people have cross-reacting antibodies, and that's very common, and we see just a couple 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 1,200 milligram group, had the lowest anti-drug antibody levels measured of all dose groups, but all taken together, it's less than 10% in the dosing arm.
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, there will be more to come, but as of today, we see a very low immunogenicity of this drug. That's why we believe this is a credible drug candidate to be taken forward. 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. 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. Therefore, we are, of course, have a high interest of concluding all the results. Then the next steps will be post phase II discussions with the regulatory authorities. Of course, this will be very important for us to understand the potential pathway for future further development. With that, I would love to hand over to Q&A session. I thank you very much for listening in today. Now I'm happy to take questions from the audience, and I will revert back to Jordan.
Thank you. At this time, we'll be conducting a question- and- answer session. If you'd like to ask a question today, please press star one from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to hook up your handset before pressing the star keys. One moment, please, while we poll for questions. Thank you. The first question today comes from the line of Anupam Rama with JP Morgan. Please proceed with your question.
Hey, guys. Thanks for all the additional analyses here on the SHINE study. Your comments certainly suggest that there's an openness from physicians on outside measures of clinical efficacy beyond HiSCR. In your discussions with regulators in the past, any color on how regulators view endpoints outside of HiSCR as potentially registrational endpoints? Thanks so much.
Yeah, thanks very much, Anupam, for this question. We have not completely discussed in the past regulatory endpoints that could lead to an approval outside the HiSCR. Please keep in mind, with the published data so far, the HiSCR looked very well handleable inasmuch as the placebo groups performed very tight around 26% and 27.6%. With a strong signal from the phase II-A, we knew that we could probably reduce draining fistulas and that would not be reflected in the HiSCR. As you can imagine, discussing with the regulatory bodies to change the primary endpoint requires additional efforts and maybe more time and analysis. We believe that we could also use the HiSCR.
We haven't concretely asked the questions, we know from the document that led to the approval of adalimumab that there were initial discussions from AbbVie around just looking at the AN count by itself. The AN count itself was not seen, apparently, to reflect enough the patient benefits. There is a hint already in these discussions that the regulatory bodies, the FDA, suggested or basically wanted to have the draining fistulas also somewhat reflected, which is probably how the HiSCR was constructed. 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.
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 800 milligrams four weekly, which may lead to less of a response rate, and we will see. 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 and what we've seen in the phase II-A, 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 calm down the overall skin inflammation. 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, draining fistula change and also IHS4 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 our questions.
Absolutely. Thanks for calling in.
The next question is from the line of Joseph Schwartz with SVB Leerink. Please proceed with your questions.
Hi. Good morning. Thanks for taking our questions and all the other color. My name is Dae Gon diving in for Joe. Just a couple of questions on my end. Niels, if we look at the draining fistula data in the figures that you provided, just wondering if you could provide a little more color behind the variability. Waxing and waning, 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? Second question is, just looking at data set 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 thought plans regarding the studies of higher doses, given that 1,200 seems to be sort of the highest efficacious dose so far? Thoughts there would be helpful. Lastly, if we can think about going forward, you're obviously going to complete this open label extension and discuss what potential plans thereafter of another set of studies. 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. First question here is really more insight on this week 10 to 14. There will always be certain outliers when looking at things that fluctuate a lot. What we have seen is that draining fistulas don't show the same extent of fluctuation that the AN count shows, interestingly. While I wouldn't exclude that there are some outliers driving a certain part of it, I would definitely believe that the overall, call it a 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. Remind me of your second question again. The second question was-
On higher dose-
The third one was-
Given
Oh, yes. Of course, I mentioned we're running right now population PK/PD analysis and also estimates for tissue distribution. 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 mg weekly we chose in the phase II-A is slightly higher. This is something we're looking into. 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 in other diseases. The reason for me saying that is because, first 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 his or her chronic status, the overall C5a measurement at baseline are comparatively very high. 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. Now people already quadruple the dose to see an even better effect. 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. For us to conclude from this that we could only use 1,200 mg biweekly or more in other trials, that's really definitely too early.
I also mentioned that the 800 mg 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. It's a little too early for us to make any conclusions as to how we dose in other trials. Just to reiterate, in HS, we really want to conclude these population PK/PD analysis and tissue estimates to get the best possible feel for maybe the ideal dose moving forward. Your third question was concerning the runway and the financial situation. Of course, you see that the company was hit by a pretty steep stock drop. Then, of course, we understand that we have to be extremely cash cautious right now.
The first thing we did is, after we had discussed the signals, is understanding whether or not we would be able to run an additional trial in HS. Of course, obviously, this very much depends on the size of such a trial and the extent. While this decision has not yet been made, we have a decent runway. 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, Pauci-immune Granulomatosis, which is also including the planned and put together oncology trials. 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 three years or 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 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. There's a lot of questions relating to the outcome of the discussions with the regulatory bodies. I hope I could give you a comprehensive overview of where we can get with our current cash runway.
Niels, just as a clarification, when can we expect that population PK/PD data set readout?
That should be concluded within the next few weeks. Again, we're also running these estimates with mathematical specialists in medical science that oftentimes they do this for oncology studies to estimate tissue distribution. I expect this to be done in the few weeks. Again, the dosing for HS is an important question, 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?
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 patients? 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 dose versus, let's say, the second-highest dose? Did these responses in fistula correlate with the degree of knockdown?
Yeah. 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. These were baseline C5a levels in median, I believe. They were clearly elevated across all dose groups. There was not any dose group that had normal C5a levels in average or in median. The other question is whether we could directly correlate the knockdown of C5a with draining fistula. We have not really fully done this analysis to conclude this. I think the overall conclusion was that the 1,200 milligram biweekly led to a tighter control.
Also in the 800 milligram, we saw a decent control inasmuch as we saw levels over the whole time period, in median, in the normal range. Again, the key question is not so much what you see in the blood, but what happens in tissue. What I can confirm with you is 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. 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. Clearly, there was a difference to the 1,200 group.
We currently really believe that there is a threshold that you need to get a full effect, that you ought to penetrate the tissue. Oftentimes, over the thumb rules that I learned from oncology, 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. That's why we're running these additional estimates to get a better hands-on and a better feeling for what could happen in tissue.
All right. That's helpful. Just maybe a few more questions. Did you also look at the IV antibiotic or oral antibiotic used, and if that could have hampered how the placebo guys responded?
Yes. There was a very low rate in IV antibiotic use for flare-up or what other people called rescue therapy before an HS, and that was equally distributed over the groups, just upfront. Also the overall use of antibiotics was equally distributed. The analysis, whether or not antibiotics at baseline, that means those two 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. The rate is not very high, it's just a few patients. 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. This is still running.
I expect to get this by someone by next week. I ask 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. I can already share with you that there's no misdistribution when it comes to antibiotic use between the groups, which is at least already part of the answer, we will see when we get the whole picture.
Got it. No, I've got it. Just a question on your understanding of this disease. Are there certain elements of this disease that are maybe more driven by neutrophils, hence you might see a C5a working, let's say, a fistula and maybe AN count as more driven by, let's say, monocytes or lymphocytes where a TNF would work? Just help us understand how much more understanding you have about this disease now that you have a lot of these data.
Yeah, that's a very good question, Yatin. Thanks for asking that. I think one thing we clearly need to say, the relative change in draining fistulas has been already seen in the phase II-A. This is confirmed, but also an AN count reduction in general is confirmed. For us, it is difficult to say whether we will work more on the fistulization, on the pus drainage, than on the other aspects of the disease. But the fact that the drug seems to work strongly, at least in the high dose, on the pus drainage seems to be rather unique. That's also something that we heard early on in the Greek community when we had these 12 patients treated. The data we have right now confirmed this.
Certainly, I would add to our understanding that the draining fistula seem to be very much, or the other way around, C5a seems to be very much involved in draining fistula and in pus generation. 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 would stop neutrophil overactivation. I would not conclude from 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's some evidence when you look at the draining fistula reductions that there were some suggestions in the PIONEER studies.
I do believe that there's a difference from what we see here. While my conclusion would not be that this is 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. If you take one and one 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, that's something that also experts said to us because, they also don't know which part plays a role.
Looking at skin pictures, looking at the overall inflammation, 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? Did they drop over time, and then did patient response mimic to C5a depletion or other inflammatory cytokine depletion?
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. These are completed soon and then as we learn more from this, we will put it out. 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. We haven't looked at this yet, and this is 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 Luchini with BMO Capital Markets. Please proceed with your question.
Hi. Thanks for taking the questions. Good morning. A couple from me.
Good morning, Matt.
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? Would the company really prefer to try to jump right into phase III with these new endpoints if accepted? If that is the preferred outcome, how would we be able to get comfortable, given that this is based on a post-hoc analysis? Of course, all of this assumes that additional dose ranging work isn't needed. I have a couple of follow-ups as well, please.
Sure. Thanks Matt for these questions. 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 agrees with an endpoint we suggest as an approvable endpoint. Can we get that achieved with the first meeting on the 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 HiSCR. We have even a more pronounced AN count reduction. Still, it's not reflected in the HiSCR.
Obviously, the HiSCR does not reflect the mode of action of our drug, and it is known that the HiSCR does not give you credit for any reduction of draining fistulas. Our drug has shown this now basically the second time in a larger control 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 draining fistulas. We need to discuss with the FDA that there should be an outcome measure which reflects this. I think we have a good argument in hand. The second question is now, would the FDA just be willing and say we need more data around this and this?
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 approvable outcome," we have to go back and ask ourselves the questions, how can we possibly jump directly to a phase III program, which obviously carries a higher risk and obviously requires a different setup financially. With the current finances, I can confirm we could not run a phase III program, meaning two independent large trials and gear up for commercial. That is very clear. That's why I try to separate these two questions.
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 two 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. 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.
Please, at this point in time, it's too early to say one way or the other, but at least I can 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. A clarifying question on figure one 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 one draining fistula at baseline. Are each of these groups, were there patients that didn't have at least one 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. They were pretty well distributed over the groups. We're still speaking about groups of around 24 patients or so. 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 at baseline.
Okay.
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 zero draining fistula 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, 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. Then last question from me. Are you able to provide any more visibility on timing of when the phase II-A data will be published?
Well, I can share with you that we're now in the third revision with questions like we would like the figure of X a little bit more tuned like this. 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 two days ago, and we were asked for another couple of weeks of patience. That's where we are. That's publishing results. It's a very good journal, and we don't know what they will conclude, but we have submitted this approximately half a year ago. We would hope that we have satisfied all the revision wishes of the reviewers now. Apparently, we need a few more weeks until we have knowledge whether it 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 questions.
Good morning. Thank you. Could you just clarify the reason for not testing the 800 milligram once-weekly phase II-A dose from phase II-B, given it sounds like ultimately you might be considering going back to that dose or a higher dose, going forward.
Thanks, Steven, for the question. We looked at the total dose administered, we felt like the most important part is that we get control over C5a at an early time point. When you look at the 1,200 milligram biweekly, keep in mind we had a saturation basically of three doses, 800 milligram in the first week in the Original trial and in the SHINE trial. When you look at the trough levels, because we didn't do a full PK/PD analysis back then in the phase II-A, 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. It's not that we were completely off. At the time point, eight weeks or so, it's practically identical in the two groups.
It's not that we were off with our estimations, of course one thinking was convenient, but also the other knowledge that we believe 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 C5a levels in blood, whether that is still reflective of what you see in the tissue. Obviously looking back, you can say, "Why don't you take 800 milligrams weekly?" Well, at least our PK/PD analysis and our knowledge around PK/PD parameters in the blood confirmed that we were not wrong on what we see in the blood.
However, seeing now that the 1,200 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, Steven.
Okay, thanks. What are the doses being tested in the ankylosing spondylitis and PG trials?
We haven't disclosed these doses yet, 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. I think you need to look indication by indication to understand your ideal dosing. Again, the evidence for that is that other drugs in this disease are dose double. Adalimumab is approved at the double dose. Cosentyx is currently tested at the double dose. Others are tested at higher doses. 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.
Okay, thank you. Can you just clarify, going back to the ADA rates, in each treatment group, can you quantify what was the post-dosing ADA rate in all of the groups, including the high dose group?
No, I don't have these numbers in front of me, that's why I made the statement during my intro here that there were just a couple of patients that showed pre-dose. 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. It's still an important measure. This number is very low, but here and there you find a patient. I did confirm that the 1,200 milligram dosing group had the lowest ADA level. Overall speaking, which is quite normal, oftentimes you see it at lower dosings better. That's often seen for antibodies. Overall, it was also in the treated groups, in each treated group, clearly below 10%.
That I can confirm, the final numbers we will put out when we have the final report because they're now considered two confirmatory assays. What I have shared with you is the data less than 10% really includes all that have shown one confirmation in the first confirmatory assay. The final report will also respect not only the 16 weeks, but also look at all the weeks. 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. Last question from me. You're suggesting, not only that you reduce fistulas, but also AN counts, so abscesses and inflammatory nodules in the high-dose group. HiSCR is basically dependent on those three parameters, either improving to a certain threshold or not worsening. I'm just trying to understand why you think HiSCR is not the adequate scale to assess your drug if you're in fact having an impact on all three of those comprising parameters. Is it just a threshold issue that you're just not potent enough to hit the HiSCR threshold?
Yeah, that's a very good question. Thanks, Steven, for asking that. I think the HiSCR in and of itself, that took me also a little while to really fully understand why we don't see the AN 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, we had more reduction in certain dosing groups than in placebo, but it didn't show in the high-dose group. The reason for that is two things. It's the threshold, 50%, which you have to hit in each patient. Then also these two 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, this explains a certain fluctuation already. The pure inter-rater variability seems to be higher than we thought. By chance, when you look at 36 patients, a few patients can really make it happen that you have a higher placebo response rate. 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%, so it's adequately reflecting the HiSCR, which is what AbbVie has shown in their trials. The real reason is the HiSCR doesn't give you any credit for draining fistula reduction.
Since our drug apparently reduces all of them, 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 HiSCR may not adequately reflect what our drug can do. The last thing I want to mention here is just think of the pure fact that you can have, with 36 patients, a placebo response rate in the score of close to 50%, in this case, 47.2%. 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?
There is, through this binary nature, this large fluctuation in the HiSCR, there is a question for us how useful it is, especially for our drug. Since the fistulas are not there, we believe our mode of action is not adequately reflected in this HiSCR.
Thanks for taking the questions and thanks for doing the call.
Absolutely. Thank you.
Thank you. At this time, we've reached the end of our question- and- answer session. 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. Really understand to the best we can whether this drug has a path forward. Our conclusion is, yes, it does have a path forward. I just want to reiterate, there is a dependency on what the outcome may look like with the regulatory authorities. 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.
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.