Study Result

Sep 10, 2021

Press Release

Welcome to the Bone Support Press Conference 2021. For the first part of this call, all participants will be in listen only mode And afterwards, there will be a question and answer session. Today, I am pleased to present CEO, Emil Bilbak CFO, Hakan Johansen and CMO, Michael Dusenbeck, please begin your meeting. Yes. Thank you very much, operator. This is Emil Bilbeck. I would like to welcome everyone to this information session Where the purpose is to quickly cover the FORTYFY study, the readout That we announced briefly last night and the path forward. And as the operator mentioned, I'm also joined here today by Doctor. Michel Dieffenbeck, who is our Chief Medical Officer and Executive Vice President and Haakon Johansen, our CFO. Yes, we can. So if you help me, operator, please can go to the next slide. So the FORTIFIED study was designed in 2015 2016. At that time, the only path to market For Saramen G, a bone graft substitute containing antibiotic would be a PMA route. And the study was hence constructed to show superiority of Ceram and G versus Purely standard of care. And the study design has been selected with that specific and only purpose. I'm not going to go through a lot of details on how the study was constructed because I think there's good information in the public domain on this. You have it also in the presentation in front of you. What I will mention though is that the primary endpoint was A composite efficacy score which weighs together 3 Independent effect parameters and arrive at a final number. Next slide, please. What I do want to spend a little bit of time is on just to describe the patient That has gone into this study. So what we mentioned in the sign is that this is Gustilo Anderson 2, 3a and 3b, and I can imagine that's a little bit cryptic. But basically what we're talking about here is trauma That have been exposed to subforce that the bone has penetrated the soft tissue and the skin. That's an open fracture. And the open fractures are the most difficult fractures and trauma events that can happen. And they're categorized on the So called Gustilo Anderson scale or categorization. The patients that were included in 45, 1 third of them was in category 2, 1 third in category 3A and 1 third in category 3B. These injuries are very severe and they also present a very high variability In bone healing infection, the infection can occur after the accident Or it can occur after a few months even with strong intervention. Mainly, the reasons for ending up in an open fracture as I said is traffic accident, but there are also Patients included from construction workers, for example, are ballistic injuries, people that have been Sure, simply or had a gun wound. There are also soldiers, for example, U. S. Army soldiers that have been included. 80% of the patients in Fortify are male And 20% are female. In the control group of the patients that received Therma G, the average Age was 38 years and the youngest patient was 17. We go to the next slide. This is not a real bone. This is a plastic bone. It just displays How the surgical technique was conducted with a metal rod or a metal nail That was forced down through the intramedullary canal to stabilize and immobilize the fracture. This is not a very common method used in Europe, but the standard of care in the study was defined based on What is used many times in the U. S. Circuit. Go to the next slide, please. So what are the circumstances specifically influencing 45? Well, I already spoke about the very high variability with trauma patients. That's why Studies made on trauma patients have to have big populations and they're usually very expensive studies and With certain difficulties to recruit, which we also have reported on in Fortify with delays that were announced at a quite early stage of the study. Also what you see normally with trauma studies is that patients It's not a chronic condition. It's something that happens. And once the patient has fully recovered, usually they walk away. They walk away from the situation, they walk away from health care and they walk away from studies that they might be part of. This is a common phenomenon. And unfortunately, the dropout rate in the FORTY-five study has been exceptionally high. In the end, only 143 patients qualified for the primary Composite endpoint. And the way that the study was constructed, even though patients were followed at certain time intervals, it's the 12 month Results, that matters. And you have to be part of the study for the whole way in with all the parameters included. If you We draw on one of the parameters, you are excluded regardless of how well you have performed on other parameters. So 143 study objects, if you compare the target studies, you could say, well, that's quite a high number actually. Well, no, it's not. If you have subjects with very high variability, you need a very large Patient population to be able to draw significance and make conclusions. And this is the problem we have seen with Fortify, But during the COVID pandemic, there has been an exceptionally high dropout And a dropout of the nature where patients have decided just not to show up at the hospital visit that they have been requested to come to. Next slide, please. So what has then come out in the results? Well, Unfortunately, the 4 to 5 results are inconclusive. This is very disappointing for, of course, The management team, the Board of Directors, I can imagine the entire organization at Bond support and I can imagine also at Quite a few of the shareholders. We did expect based on study results we have seen from many other parts of the world with Other patients that this would come out in positive favor of CERMEND, but it didn't. The main reason for this is the very high dropout rate, which was 29%. FDA and well, the general community has a guideline that Below 5% dropout rate is a well controlled trial with a minimal bias. FDA has A limit at 15%. So FDA would not like a study with a higher dropout rate than 15% to Go into PMA application. There are some extreme cases where slightly higher numbers, even up to 20% has been accepted. But unfortunately, we are at 29%, which means that the entire study is labeled as inconclusive. None of the parameters can actually be used due to that fact. The composite endpoint is inconclusive and the secondary endpoints are inconclusive. The only solid readout is on the safety parameter For Cerumen G, that came out very well. The study was Intended to show superiority in efficacy and safety. The safety one was met, but it could not be shown that cement was better. I would like to emphasize one thing very strongly and that is this study Does not show that settlement G is equal to standard of care. That is not what the study is designed to do And no such conclusion can be read out of this. If that is what wanted to be tested, the study would have to be constructed in a different way with a completely different design. So I think that's important to keep in mind. The study could not show that 7 g It's better than PANDER OF CARE. But that's the only thing that could be read out at this point. In our press release from last night, we were prudent to show what the primary endpoint success was, both for the settlement and the control group, 64% with Ceramant and 66% with the control group. Of course, it would have been Nice to see Saramant have a few percentage points or quite a lot of percentage points higher than the standard of care. But this is actually Completely irrelevant given how the study was constructed. Only when these two Numbers are different enough to provide statistical significance. Does it really make any difference? The standard deviation with these patients enrolled Makes this number also inconclusive because it only takes a few patients In either direction to completely skew the results. And here we see now the difficulty and the challenge to make a study With few participants, few final objects completing the study and a very high variability in individual results. So next slide, please. And concluding up my presentation, What are the next steps? Of course, as I said, we're very disappointed to see this. We always knew that there's a risk of doing trauma studies and especially when you have a high dropout rate and come closer and closer to Where your statistical significance is impossible to show and then eventually pass that line. The Study results though from 425 does not at all influence the breakthrough device designation that has been given both in bone infections and in trauma. The results on Fortify does also not influence At all, the de novo application for CMG in the indication bone infection. We have a timeline For submitting additional data to FDA on bone infections, where In all de novo's, you have 3 major themes or 3 major categories. You have safety data that has to be in place. You need efficacy data and you need a control group. And with our submission on bone infections, it was the control group that needed to Strengthened, something that we have worked upon since March of this year and we're pleased to announce that we will meet the deadline as communicated back then. The team has worked hard and we have progressed. When it comes to the indication infection prevention, meaning using A bone graft substitute with antibiotic even though there's no sign of infection as you would have for trauma, for example. We will now Need to reconnect with FDA, take a look at the results and also discuss what potential pathways are there to The U. S. Market for Ceriman G for the indication trauma. We will be open minded And we will consider different options such as piggybacking potentially on a future approval on CRM and G For bone infections, will there be a separate de novo application for the indication trauma? We don't know. We cannot answer that question today. And we prefer to have a discussion with FDA and then give a clearer notice to the market instead of being speculative. We are, as I said, disappointed, But will not be done. We are determined to bring Ceram and G to the U. S. Market, And we will continue on that path forward and with that vision. So with this, I conclude my presentation And let's open up for questions that you can address either in verbal directly to me and the team here or in written, then we will also Bring them up. Thank you. The first question comes from the line of Eric Cassell from ABG Sundal Collier. Please go ahead. Your line is open. Hi, good morning everyone. So I have a couple of questions mostly on Clarification. And first off, can you give any more color on the individual component endpoints? Was there a statistically nonsignificant trend towards benefit in Cermangi? Sorry, I didn't hear the first part of the question. Was there a statistical significance on what? Statistically non significant Trend towards benefit with Cermangi, basically the point estimate, was it significantly better with Cermangi than the control group? So when you look at the detailed results and looking at age groups, Looking at different Gustl Anderson categorization and dividing it down for some other analysis we have done, You can see clear trends in different directions. The unfortunate part with this Once you go down in the subgroup and you already from the top down have too few patients, you end up in Speculations because there's not statistical significance. And we have our policy. I think this is very well supported in the dialogue with FDA that we don't give data that we cannot prove and validate. So I prefer not to talk about some of the trends that we have seen in the material as that could create false impressions. Okay. Understandable. But given the anticipated dropout rate was 15% to 20% in this study, Which would have yielded somewhere between 116 and 170 patients. Then 143 is not that far off, I mean, 17 patients. So I mean, the increase in sample variance should not weigh on the significance a lot here, In my view, but could you perhaps clarify this a bit? And if it was a close call on any of the secondary parameters? That was a close call on some of the secondary parameters. And What made us anyhow come to this conclusion is that with a dropout rate of 29%, The FDA would, with very strong certainty, conclude the study as inconclusive. The Primary endpoint as defined back in 2007 together with FDA is a composite, Which, of course, can have one of the parameters that makes up the composite be in strong favor of either the treatment or the control group. But it could then be derailed by other parameters of the composite endpoint. That is a big risk you take when you construct a study with composite endpoints. Okay. I understand. And then what magnitude of benefit on the secondary component endpoints On the infections and reoperation, respectively, what's the study powered to detect? We have to look that up, and I'm not sure we released the data as the agreement with FDA was that it was the primary end That should be successful. And that's how the study was defined. There are some of the secondary endpoints that are closer to statistical significance. And where I probably disagree a little bit with you is that Even though 143 looks to be a decent number, there is a very high variability With those patients that are included. So the standard deviation is borderline extreme. There is also this component of who are the people that drop out. And unfortunately, this becomes a bit speculative because once the person drops out, they are excluded, of course, from the Final primary endpoints, but there's a big difference here between CerroMD G that has an 18% loss to follow-up And the control group of 9% loss to follow-up. And loss to follow-up is, of course, where the patient Besides, I'm not going to go to the hospital, if it's fear of COVID or if it's because the patient has healed or other reasons. We can only speculate on that because when we cannot reach the patient anymore, we cannot ask them for why they have made such a Difficult decision. So unfortunately, when you have this dropout rate, there becomes a lot of uncertainties. And We don't share more data because we're used to say this can lead to speculations rather than clarity. Okay. Thank you, Emil. Just the last one for me. I mean, the U. S. Case doesn't seem to be over. I mean, the optimal way forward is obviously de novo For trauma and infection. But how likely do you think it is that you have to collect any additional data for this to come through? Do you think you can use the EU data for this de novo application? And if you have to collect more data, how much Casper, do you expect that would result in? I think those are very good questions, Erik, of course. And I think those are questions that we should jointly try to answer over time. I mean, I can clearly tell that you're thinking you're in the right direction. The Norway is definitely the pathway which You would find retrospectively now is more suitable for a combination device like this. But it wasn't available, as I said, when this study was constructed. So I think What we want to do now is, of course, to get together with FDA first and make sure that we have a shared view on what the next steps could be. And then I'll promise we will be very clear in communicating to the market how we see that going forward. We should bear in mind though that the burden of data, if it's clinical data, retrospective data, data mining It's significantly less with the de novo than it is with the PMA. So we're talking about different dimensions of cost, Of course. But I would like to come back to that once I can give statements which we can stand behind fully. Okay. Thank you very much, Emil. I'll jump back in. Thank you, Harry. Thank you. The next question comes from the line of Stian Vesterweig from Analyst Guidance. Please go ahead. Your line is open. Yes. Good morning. Yes, trying to straighten out the patient numbers. 143 of 201 patients were evaluated, meaning that 58 patients were not Evaluated. This number, 58 patients, is not corresponding to the lost or follow-up, which I calculate to be some 27 patients. Am I getting the numbers right, Erinn? If that is so, what is making up the difference between 58% and 27%? Yes. Thank you, Stan. So the dropout the total number of dropout patients is 58. And that means the dropout is defined as people or sorry, patients that have been enrolled and included. That Then doesn't fulfill the follow ups and the parameters that are required for the 12 months. Loss to follow-up is one of the reasons for dropout. So you're correct on your numbers. And you can say that in addition to loss of follow-up, there are other reasons. There are people that have patients that have died during this period. There are also patients that Have had potential comorbidities that have made them excluded from the study or other things that have happen in their life that they haven't continued. Why we decided to publish Not how many people that have died because we found that to be irrelevant, but how many that are lost to follow-up is patients That have seemingly gone through successfully the parameters tracked in the study, But for no reason that we have been able to determine decided to walk away. And that measure stood out. There's a lot of different reasons for dropout, but that one stood out in this study With a very high number for the CerroMed group and also quite a high number for the Control group. So the Lost to follow-up is a subcategory under the total dropout. Okay. Second question, if I may. The historical infection rates Where we've sometimes, I think we've heard numbers like 50%, at least in the Group 3, Gustila Anderson. They cannot really have been the case in this study. I mean, it's enough To fail on one of the components in the composite endpoint in order to Not reached endpoint, I guess. So infection rates appears to have been pretty low In this study, is there any reason to speculate in not very reflective Ostad did not reflect the general infection rate in U. S. Centers? I think that's absolutely a valid question. What we have seen in Gustil Andersen Category 3 is infection rates up to 52%, but it ranges basically From 30% to 52%. And then with lower categories, of course, The infection rate drops even further. But you are correct. Every clinical study is a microcosmos With certain procedures and processes that have to be followed. And If you walk into a hospital and you sit down as an observer and you look at how patients are being treated with trauma, You will come out with a certain infection rate as an observational study. If you have an Intervention and you say this is how you need to treat the patients and we will be standing here monitoring every step, many times There is a slightly better outcome. Infection rates decrease because there's more meticulous protocols to be followed. We have seen in this study slightly lower infection rates in the control group Then have been in other reference studies. And that could have influenced also. But again, it could be Speculative to make statements on that as the difference between the groups were inconclusive. Okay. Finally, one last question. I mean, we are experiencing extraordinary times in health care, and You've not really picked up the COVID item in your study. In what way could The pandemic have provoked the loss to follow-up. It's difficult for me to see why there would be a Difference between the group and what would you care to expand a little bit on how COVID could have influenced the study? Yes. It's absolutely undeniable that COVID has influenced the study and The follow-up and especially the loss to follow-up. We Given also that you see that loss to follow-up is significantly higher with the treatment group, somehow, I mean, we know from other studies that When patients recover, they are less likely to be compliant. And if you have an environmental factor with Concerns about infection, fear about the COVID pandemic. I think it's fair to say that it has a Contributed effect on people unfortunately decided to self isolate and not Continue the study that otherwise was the aim for following them up with this injury. We followed over time both the recruitment of the study As well as the follow-up, not all data has been disclosed to us. So the very high dropout rate was also a big surprise for us When we open the envelopes yesterday, and we can see that both follow-up and Recruitment rate in the study in general was strongly influenced by COVID. And I think also if you look at the announcements that are being made around the world for medtech, biotech and pharma companies, We are not alone with this observation if judging how many clinical studies that are being posed or postponed Or modified during these very special times. Okay. Thank you. I'll get back in line. Thank you. We have no further questions, so I will pass back to the speakers. Yes. So thank you, everyone, for joining this call. Hopefully, we have been able to provide a bit more clarity and detail On the FORTIFY study, that came out inconclusive. And again, what that means is that the study cannot be used for the purpose it was intended And no conclusions in either direction can then be given. We thank you for your participation. And we also encourage Those of you that would like to learn more about the company to contact us directly. And we will try to be as open and frank as we can also about our way forward. Once we have had further discussions with FDA and we have a clear direction, we will make sure we communicate it in a transparent way as we always do. Thank you very much. Thank you for attending. You may now disconnect your line.