Diamyd Medical AB (publ) (DMYDB) Earnings Call Transcript

Welcome to this company presentation with Diamyd Medical. With me in the studio, I have the CEO himself, Ulf Hannelius.

Thank you.

And we have also gathered the entire crew in a team's call. It's been a lot of technical back and forth, but we have them all here. I'm going to start by giving you the word. And the next time you viewers see me, that's when we'll be back with the Q&A. So keep bombing the live chat with questions, and I'll give you the word.

Thank you, and welcome, everyone, to this webcast and especially a webcast about the Phase IIb top line results we released only a few days ago, which are very positive. And I'm -- today I'm very honored to be joined by some very distinguished presenters. So we have, first of all, Professor Johnny Ludvigsson, who is -- well, one of the top researchers in the world in type 1 diabetes. He's the coordinating investigator for DIAGNODE-2, and he's also the person who first time ever evaluated the possibility to actually inject an autoantigen directly into the lymph node, which we are doing here in DIAGNODE-2. So he will explain about the trial today and the results today. And then we will hand over to Mark Atkinson, who is a board member of Diamyd Medical, and he's also one of the worldwide known key opinion leader within the type-1 diabetes field. Very honored to have him here. He will explain about the more wider significance of the findings in this trial and what we are doing in Diamyd Medical. And finally, we have Professor Craig Beam, who is a very well-known biostatistician, especially within the type 1 diabetes field and clinical development, who's also here to really discuss about the findings we have and the data we have now in the company, which look very exciting. So I would like to welcome all our presenters today. And before I hand over to Professor Johnny Ludvigsson, I would like to, first, 3 takeaways from the top line results. So the DIAGNODE-2 top line results validate our previous findings from a predefined patient group that we found in a large-scale meta-analysis and that we now find in this prospective trial. So it was a predefined analysis we had in this trial. And there, we see that it's very clear, the diabetes vaccine Diamyd works in this predefined group. It does not work in the other group. And all our other data in the company point to exactly the same thing now. And this really highlights the importance of genetics when developing therapeutics for type-1 diabetes. And so we really take care of addressing this heterogeneity by selecting now the patients where we see that it really works. And lastly, this provides for us as a company, for the diabetes vaccine, a clear path forward now into Phase III with a precision medicine approach, which is, to my knowledge, the first approach of this kind, which is really in late-stage clinical development now in type 1 diabetes. So it looks very exciting. And without further ado, I would like to now hand over to Professor Johnny Ludvigsson, who's the coordinating investigator for DIAGNODE-2, and he will take you through the trial design and the results.

Thank you very much, Ulf. I'm really happy to participate in this presentation. It's a great day today. Actually, you saw that I have been working with type 1 diabetes in children and adolescents for 50 years clinically. And 40 years ago, we found a molecule in the blood of children in Linkping in Sweden, which showed to be [indiscernible]. And then we worked with this for many, many years. And today, I think we have come to a point where we really can show that now we have come to something which will work and which seems to be helpful. Here, you see the title of DIAGNODE-2. It's a complicated title, but it's a randomized double-blind, placebo-controlled, multicenter study. And we have, as Ulf said, in this study injected GAD into lymph nodes. The idea was we have earlier done that in -- subcutaneously, but we thought -- a few years ago, I got the idea that why not try to pass that step and go directly into lymph nodes to see if we can get better efficacy and actually, we did. So next slide shows the objectives and the clinical efficacy end points. The primary objective here is to see whether this treatment compared to placebo, of course, is better in preserving endogenous insulin secretion or, I would say, beta cell function because we don't know whether C-peptide AUC is also important. And therefore, we have also taken, as you see on the right side of the slide, the primary end point is changed in C-peptide, area under the curve, from baseline to 15 months. And the primary end point, when we started in trial, that was for the whole group, that we have then also, in the meantime, prespecified certain interesting subgroups. The secondary objective is, of course, although I will say something about that later, C-peptide and residual beta cell function is very important. It is clinically very important that we will also, of course, see whether we find effects on the treatment like diabetes status, insulin requirement, metabolic control. And we will also study, and we do study, the effects on the immune system and also the quality of life. And you see on the secondary end points then change in insulin dose, hemoglobin A1c and the combination with these. And you see also, of course, safety as this is very important. When we talk about children and adolescents, where we have, we have to say, a reasonably good treatment with the traditional insulin treatment with pumps sensors and so on, it has to be safe treatment. This is a safe treatment. It is a simple and safe treatment. And I want to underline also, you see here predefined HLA analysis. We have, from the beginning, defined that there is a special group with HLA-DR3-DQ2, where we have seen before that these are the ones who tend to respond to this type of treatment, and therefore, we are especially interested in them. And it's not a small group. It's almost about half of all patients, which I think is a large and very important group. Next slide. Here, you can see the main criteria. We haven't treated younger than 12 years of age. The treatment is safe. I can imagine that in the future we will go down in ages. But so far, it's from 12 years up to less than 25 years. We have said they should have some fasting C-peptide and reach 0.12, which, in our experience, long experience, is saying that they usually come up to 0.20 when you stimulate. And that is what we have seen from other trials. It's important to prevent complications -- late complications. So it's a reasonable beta cell function when they start. And they should have GAD auto-antibodies so we know that they see this entity and then they react against it. But we did not want to have extremely high concentrations because we have it done before at those very, very high concentration. Maybe in something else. And then there are some exclusion criteria, as you understand. They shouldn't be on other immunosuppression. They shouldn't have any heavy anti-inflammatory drug. And they shouldn't, of course, be on any other type of treatment for diabetes. And regarding vitamin D, we have used that to support the system. It hasn't any big impact on the beta cell function [ plus C ] and the natural course. But we know that it may have some positive effects on the immune system, so therefore, we added that. And they should, of course, not continue with that. And then we have an experience from previous studies that it's not -- we don't think it's good if they take another vaccination at the same time so we had that in the exclusion criteria. So next slide, where you can see Europe is not -- the death rate of COVID-19. It is actually rather the 4 countries participating in this trial. In Sweden, we have 6 [indiscernible]; in Spain, 8; in Czech Republic, 2; and then 1 in Netherlands. One can say that about 1/3 of the patients are from Sweden, about 1/3 are from Spain, about 1/3 are from Czech Republic and then just rather late, Netherlands came into the study and have not so many. So altogether, 109 patients randomized into 2 groups. And these patients, as you can see, they completed the trial, which is a good sign because that shows very well that this is a tolerable treatment. It's no problem. It's not like I have participated myself in a number of different immune interventions since the end of the '70s, and some of them are rather heavy. Some of them are rather heavy both for the patient and for the health care system, but not this. This is an easy treatment, and they have participated. And now we will add a follow-up after 24 months, but that was decided a bit later so only about half of the patients can do that. That will be also interesting. Next slide, you see the design, the clinical trial design and procedures. And there you see that we need only 4 microgram, a very, very small amount of this antigen, and then we have placebo in the other group. And we start with vitamin D, 2,000 units per day. And then after a month, we give one injection in the lymph node. A month later, another injection. Another month later, a third injection. That's all. That's all. Very, very easy type of treatment. And we have then looked upon after 6 months and 15 months, and we will also then follow some of them up to 2 years, as you see. So this is the trial design. And the next slide shows what does it mean actually in practice. They come to the -- to our hospital. Usually, we have seen them. We have talked to them. We see that they feel well and everything is okay. And then they go to the ultrasound unit. It may fool somebody and look -- they may think, oh, this is very difficult. But I understand it is not difficult for the people who work with this ultrasound needle guide. They see very clearly the needle go under the skin and prick the lymph node a centimeter below under the skin. It's very easy. It seems to be very easy. And for the patients, they have usually told us it didn't mean anything. It's actually often less problem than an ordinary venipuncture. So a venous sample may be worse than taking this injection. It seems to be a very safe procedure. And the end points then, as I said, we look at C-peptide, we look at hemoglobin A1c, insulin dose and the combination and safety, of course. We have again, of course, looked at the whole group and the prespecified HLA group. And the result is, in my mind, very impressive, and I am just happy at this time. And I feel safe now for future trials because we didn't see effect in the full trial population because those who respond are the ones for the HLA-DR3-DQ2, and that is about half of the population. But there, we see more than 50% greater preservation, highly significant of residual beta cell function, of endogenous insulin secretion, which is just great. And we see then, of course, in this very small group of individuals, it's difficult to see so much else, but we see clear trends in change of hemoglobin A1c, insulin dose and the insulin-adjusted hemoglobin A1c in relation to the C-peptide. We don't see any effect in the others. Those with the wrong HLA type, they may probably need another autoantigen or something else. But here, we have the effect in our large half of the patient group with correct HLA type. This is beautiful. And here, you can see top line results on the next slide, where you see that overall, there are no differences, more than -- a very slight tendency, as you see. But if you look upon HLA type DR3-DQ2, yes, visit 6 months. There, you see already for those 29, that they are almost significantly different from the placebo group. And it's favorable already in the 6 month. And what is then more important is that 15 months, you see a very clear difference and highly significant. And this indicates that the slopes are different. The slopes are different. It may even be so, which I can hope, but we don't know that yet, that the difference becomes even greater the longer the time goes. So it may be so after 30 months, there is an even greater difference. So why say residual insulin secretion in my last slide? Is that so important? Yes, it is very important. If you have good enough insulin secretion, you do not have diabetes, right? That's it. If you have some residual insulin secretion, it's much easier. It's easier to get blood glucose stable. It's much easier to treat. You don't necessarily need to be so extremely active, and you do not get severe hypoglycemia. It's shown in other studies that you avoid unconsciousness because of severe hypoglycemia, and you don't get ketoacidosis, which is dangerous, very dangerous. You get a much better quality of life. And then in the long run, of course, you also get less vascular complications like that we've shown from the old DCCT trial in the U.S. and other trials. And of course, perhaps some patients gradually improve. When we now have the first step to do this treatment, we can improve it. I'm rather sure we can improve it in the future, and then we get perhaps remission. And if somebody comes up on the surface and produce enough insulin, then he is cured, obviously. And of course, prevent type 1 diabetes. So safe residual insulin secretion is very important, and we are -- I'm very happy with these results. And with this, I would like to hand over to Professor Mark Atkinson, who is from the University of Florida. And as Ulf already said, he is a member of the Board. But I don't know him as a member of the Board. I know him as a very good and very active and very competent scientist in the field.

Thank you, Johnny. And again, I want to just introduce myself by reemphasizing something. I think there's a few people in the world that could have pulled off this trial like Johnny, and he's done an amazing job in that. And he -- congratulations for these fantastic results, and kudos to you. So if the slide is up on the screen, which says when will type 1 diabetes be cured, this might seem like a big paradigm shift in terms of what you've just heard with trial results. I don't have the honor of saying, like Johnny, that I'm a half-centenarian, meaning 50-years in type 1 diabetes, but I have been around for 37 years in the disease. And a big part of my activities has been with patients as well as their family members. And one of the most -- the reason I put this title on here is that one of the most oft asked questions is, when we're going to have to be cured? And part of this has to do with there is so -- and again, all throughout my whole career -- and I'm sure for those on the call who follow diabetes, in the old days, I'm old enough to know what a newspaper is. And when I'd open up the newspaper, I'd say, "Oh, the cure is here or though the cure is at." Now today, you pick this up in social media and Internet. And we've just heard about so many cures for type 1 diabetes being out there or ways to prevent the disease. And it's been frustrating because these are usually put out with -- all within 3 to 5 years. Because the challenge is a lot of these have been based on, what I would say, poor evidence. But it's not a novel phenomenon in that if you click the next -- hit, old -- actually, when we're about -- hopefully, you get the next one. The back -- we're about the 100th anniversary of insulin discovery or in terms of pharmaceutical, the centennial will be held next year, people claim that we've had a cure for type 1 diabetes for essentially 100 years. But what happened was is with the late 1930s, early 1940s, we found out that insulin actually was not a cure and that we need to do something better. So if we go to the next slide that has the type 1 NOD mice. Now one of the main reasons that there has been, and the reason on this call I want to emphasize this is, again, almost monthly, you'll hear about another cure of type 1, another cure of type 1, another cure. But most of these have been, and almost all of them, have been using this animal model for type 1 diabetes. And animal models are great. We've learned a lot from animal models. In fact, part of the GAD story came from animal models. I'm not disparaging all animal models for disease. But I can say that across the board, not just in type 1 diabetes but in many fields, there's a growing consensus that sometimes, from cancer to allergies to whatever, that animal models may not reflect with the best of intentions what you see in humans. And so one of the things that we've been doing in -- here at the University of Florida is monitoring ways to prevent or cure diabetes in mice. And as of March of last year, if you can click the insert, there are about 714 ways that can prevent or reverse type 1 diabetes in NOD mice. So working on diabetes in mice, you can cure a lot, leads to a lot of headlines. But what is important, and if we can go to the next slide, is that this has also led to a leaning out of therapies that actually can be important. And this -- if you're seeing the slide called immune modulating nonantigen-specific trials. This is an article published in Lancet about a year ago, where, unfortunately, our field has taken a lot of these therapies that worked in the mouse models and said, "well, let's take these. They worked there, and we'll try it in humans." There have been dozens and dozens of trials attempted in humans to try and do what Johnny just mentioned, preserve C-peptide, reduce insulin dose, have an influence on hypoglycemic events, et cetera. The challenge is that almost every one of these trials did not achieve the accomplishments that Johnny just spoke of. There's multiple reasons for that, I believe, and this is an opinion. Number one is a lot of these trials, they just essentially took the data from the NOD mouse and said, "Wow, this worked in NODs. Let's try it in humans," and it didn't translate. And then the second reason is that many of these agents that were in here, it's that they may have been people would do trials because they worked in other disorders of autoimmune nature, and they thought, "Well, let's just try it in type 1 diabetes," and it didn't work. So the reality is just that -- and the reason I put this, and I only have one more slide to go. The Diamyd trials are rare air, if -- and I know that's a slang term in terms of actually seeing efficacy in a human population. If we can go to my last slide on advantages of Diamyd, and then I'll turn it over to Ulf. But again, what's the -- what are the major advantages of Diamyd that I see right now, again, having been in the field almost 4 decades? Number one is safety. And so I head the COVID research efforts in the state of Florida for NIH and [ IAD ]. And it's just because I'm so involved in immunology -- and I'm also a member of different platforms of doing type 1 diabetes trials in humans. And I can tell you with assurance, there's concern over some of the leading agents that are being proposed to treat type 1 diabetes both in the new onset cases and prevention because of their ability to -- that they may not be safe. And with approaching 1,000 people with type 1 -- Diamyd being in nearly 1,000 people and not having severe SAEs, that is a really good thing. And I'll get back onto another issue of safety in a second. Another thing is that there's been reproducibility across labs. One of the major factors that have limited science in this area is that one team will find one aspect, another -- a different outcome and it becomes conflicting. I think the research on Diamyd has been good. Johnny mentioned, and Ulf did, about where we're moving toward designer medicine as a society and the ability to use genetics to predict who might be a responder and more importantly, who might be a nonresponder is good. Meaning this is a prototype that we want to treat the right person with the right drug at the right time in the right dose and not waste resources or -- and so I think this is a good thing. One of the nice things that I get is the ability to act across ages and then not only for type 1 diabetes, but we have this other disorder [indiscernible], which we'll maybe come across later. And again, as I opened in -- my notion about safety. The other comparator drugs in terms of intervention in type 1 diabetes might have some challenges move forward because of their modulation of immunity in that do you want to be giving drugs that cause immune suppression in the era of COVID-19? It's just a topic. Nothing has -- or other emerging viruses. It's just something there. Ease of delivery. Every -- from MMR and all the childhood vaccines, people are very familiar with the notion of vaccines. So I think it's in a pragmatic form. It is likely to be accepted by practitioners, both in the public realm as well as in academic centers. And the final thing is that in terms of prevention trials and moving forward, we really need to think of not just family members of people with type 1, but in the general population. So for all these reasons, like Johnny said, this -- and Monday, when we first saw the results, I kept saying this is a good day. This is a really good day. And so with this, I'm going to turn it over to Ulf, who will close it out. So thank you for listening.

Well, thank you, Johnny, and thank you, Mark. It's difficult to follow up based on those presentations, but I'll do my best. And what I'll do is that I'll try to wrap up the story by, again, emphasizing the results we have and the results we have since before as well in the company. And this was really major milestones we had. It was a publication only around a month ago in Diabetologia, which is a high-impact journal focused on diabetes. And this publication is based on a large-scale meta-analysis we did in the company together with both Craig Beam and Johnny Ludvigsson, where based on data and here from 3 previous clinical, placebo-controlled clinical trials, one in Sweden, one in the U.S. and a Phase III in Europe in several different countries, we combined all of those data, we analyzed it, but with a specific hypothesis that we believe that the HLA genotype of the patient may influence the effect of the vaccine. And the results do show quite clearly that that's the case. So if we look at those results first here in the 3 plots, again, just to explain, if you're on the right side of the dotted line, that favors the effect of the Diamyd vaccine. If you're on the left side, it favors placebo. And here, first, on the top side to -- it's the individuals who are negative for the specific HLA haplotype. So if they were given a low dose, which means 2 injections underneath the skin, they don't get -- they seem to get a slightly positive effect, but it's not significant. But when you increase the number of injections, 3 or 4, you see that it starts actually trending towards the negative side. Still not significantly different from no effect at all, but you see a trend here. If you then jump to the individuals, the other half of the patients who are actually positive for this haplotype, you see that with a low dose, you get a significant effect of the vaccines. You can see that if you look at -- the confidence intervals are actually not overlapping with one here. Most interestingly, when you add 3 or 4 injections, you see that the effect is improved. So you seem to get -- even if it's not statistically significant, the actual dose response, you see a clear trend that you seem to get a better and better effect if you increase the dose and actually, a trend in the opposite direction if you are not positive for this HLA genotype. If we then plot the results from DIAGNODE-2 on top of this, you see here in the individuals who don't have the HLA genotype, you see again that this negative trend seems to continue, which, first of all, emphasizes that it seems that this intralymphatic seems to emphasize the effect of GAD. In this case, if there seems to be a potential negative effect, it seems to enhance that one. But if you look then in these patients who are positive for the HLA genotype, you see, again, the trend going even -- you see an even better effect of the intralymphatic administration. So it very clearly shows that we have the effect in the individuals who are positive for HLA-DR3-DQ2, and we clearly don't have an effect in the individuals who don't have this haplotype. And we see also this kind of a dose response trend coming here, which is very interesting as well, and this makes perfect biological sense to me. But in this place, as a nonstatistician, but with a huge interest in statistics, I would still like for Craig Beam, who is the expert in the room, or at least in -- virtually in the room, to comment on these results and the data we have in the company now.

Hello. Thanks, Ulf, very much for the intro. And I want to say that I'm very pleased to be able to be here today to discuss these results because this is a study that worked prospectively at the possibility of a precision medicine approach to type 1 diabetes, which, as I understand, is something entirely novel in this field. And so I feel that it's important that we underscore the fact that the design upfront was with these subgroups in mind to begin with. So these are not spurious findings. Another thing that underscores the strength of the findings of this possible dose response relationships, there's a biological plausibility that supports this data. And so I think overall, if you take all of the evidence together that's been accumulated by the Diamyd studies, everything is pointing in the direction of an effective and safe treatment for type 1 diabetes in a particular subgroup, i.e., precision medicine approach to type 1 diabetes, which is avant-garde and it's cutting edge. And I hope that research will continue on to the Phase III phase. Thank you.

Thank you, Craig. And well, the answer is we will definitely continue into Phase III. I don't think it's -- the case is so clear here. And I think I can end with the same 3 points that I started with to really -- again, what does this mean for us? And what does it mean potentially for the field? But again, these -- the top line results from DIAGNODE-2, they do validate what we knew before based on the large-scale analysis at the GAD vaccine. It works in the predefined group of patients who have this certain HLA genotype. It doesn't work in the other group. It's very clear. And it highlights, again, you need to address genetics when you develop therapies for type 1 diabetes. Type 1 diabetes is a heterogeneous disease. It's a complex disease, and we now have a way -- a very pragmatic way how to take care of that heterogeneity. And this provides a very clear path forward now into Phase III. We do know -- we will address this group of patients in the Phase III program that we have already been designing for a long time now, and now we can really focus on this patient group. And it's -- like Craig was also highlighting, and I think Johnny and Mark as well, it's the first true precision medicine effort in type 1 diabetes. So it looks very promising, and it's -- I'm very excited, but I would like to move into questions and answers here because I'm sure there are a lot of questions out there. And so thank you for this, and let's go to questions.

Yes, let's do that. There's been a lot of questions, for sure. The live chat is running so quick that I can't really catch up. But I've been -- I managed to type down a few of them and have also gotten a few from e-mails earlier today. So I'm going to start with that. A question that -- okay. So we've established that success was not found in the primary goals, but in a subgroup, about 40% of newly diagnosed DT1 patients. Can you explain how this study differed from the first study back in 2011?

So first of all, it's important to know -- state again that the -- it's not a subgroup per se. It's a predefined group that we had already predefined in the statistical analysis report. We had defined it in the clinical report, and we did this immediately when we found in December last year based on a large-scale analysis. Here, we have a subgroup where it seems to work, and then we made sure that all of this is specified in the protocols before we get the results, and it's part of the top line, the most important analysis done in DIAGNODE-2. The biggest difference in this specific trial was especially the administration mode. Previous trials have been underneath the skin, subcutaneous. And this was intralymphatic, which is a very novel method of administrating, which Johnny first tested in the pilot trial, which showed very promising results. And this was then a continuation on that one. And even more importantly, this is the first trial where we have prospectively defined that subgroup to really -- not do it in an exploratory manner. We really defined it upfront, and this is a subgroup we didn't really need to address. And it turns out to be very clear. It's -- that's where it works. It doesn't work in the other patients.

You sound very confident, and that brings me to my next question. You earlier voiced the intent to apply for early market approval after the study was finished. Is that still the plan? And what's the time line?

Well, it's something we will definitely evaluate. Again, given these very positive results, it's definitely something we have to evaluate. Anyway, we can go as fast to market. But again, go in the right way to market as well because it's very important that we don't rush things unnecessarily. The most important thing is that we can come out with a safe and effective treatment that can reach as many patients as possible. We will do a Phase III study. That's clear. It will -- plan is that it will be in Europe and in the U.S. Now we know we'll focus on this population of patients. And obviously, we will then also see what is the best way of getting this to the market.

The best way -- so when you say the best way or the right way, does that mean that the market can expect to have an announcement about a partnership before we get the market application? I'm thinking that maybe you need to discuss with a partner before you choose the route.

Well, we will never obviously sit and wait until we are quite clear in moving forward into Phase III and how we will do that one. But -- and we've been very public about we are in discussions with potential partners, and there is an interest both in type 1, and it's increasing in type 1, especially because of the relatively recent successes we have shown and others have shown. And obviously, with this data, we have a very strong data package. But for us, it's important that we partners, especially to cover a global need. We, at least today, don't have that kind of organization that can cover the whole globe. So it's -- a very pragmatic way of moving forward is to have a partner at some point.

What kind of partner is that then? Is that the Johnson & Johnson size?

I won't mention any names, but there are obvious names out there. And obviously, for us, it's important to have someone who is knowledge -- who knows the area, is interesting and like burns for the same question to really get this out and long term, be able to cure. And thirdly, almost obviously, the financial details need to be in place for 2 -- for both parties to make a deal there, but yes.

It sounds like a process as well to find someone suitable to partner up with. If it came to push, do you have the money to finance a Phase III study by yourself? And I'm thinking about the money that you recently received from the Companion sale. Is it enough?

No. To cover the whole Phase III plus all the other operations going on, it wouldn't be -- to go all the way, no. What it gives us, the proceeds we had, and now what we got very recently is that we can definitely accelerate all of the ongoing activities in the company, including planning the Phase III to make sure that it's in place to launch also the manufacturing facility in Umeå. So we are taking control of the active component in the vaccine and establishing our own manufacturing. And then also, we obviously have another drug in clinical trials that we are in. So -- but what it means is that with this data and what the -- all the positive attention we are getting and what we said, we are publicly looking both for partnerships and also these larger, long-term investors. But it's -- again, it's important for us to all the time be able to move forward. And now we have also the cash at hand to really move forward now and accelerate so...

So there's been a lot of questions about the Phase III study, of course. Can you spill as many beans as you can about how it's going to be structured?

Well, we will obviously come out with details later on. But now we know, very importantly, which patients to address. So that's very important. I think the most important thing, we've reduced so much of the potential variation in a Phase III trial now that we can very clearly select the patient population. And like I said, it's -- the plan is to have it in Europe and the U.S. Size, they are usually quite similar sizes when it comes to Phase III trials. So no big surprises there. But again, we will come out with more details as we go, but it's been under planning already for a longer time.

Now this is a bit more forward-looking, this question. We talked about market approval. We talked about the Phase III study, a bit about finances and partnerships. When do you think the first patient can receive your treatment and use it? What time line are we talking about?