FSHD Phase I/II clinical trial previews for Scholar Rock, Soufflé and Dyne.

[MUSIC] Hey, it's Peter here with my FSHD. All right, we're back with another episode at Longlast. I got to tell you, it's, you know, we get awfully busy in the lab, boy, our FSHD research testing. It's just going amazing. We have so many people requesting from around the world. We're setting up collaborations with hospitals and a number of countries actually. So many people need our testing. And we love to do it, but boy, it takes a lot of time. I think I spend all my most of my time doing saliva genomic DNA preps. Anyway, but you know, I heard from my friend Kate and my friend Samantha that they really appreciate the podcast and, you know, Wolf and Scott and a number of others have been posing some questions. You know, actually, I got a podcast coming up, we've already done the recording with the kids. They're actually our early onset of FSHD years. And they'll be editing that this weekend. We'll be getting that out, but it got me thinking, boy, there's a lot to cover. We got an awful lot to cover. And so, well, we'll give it a go. All right, reminding everybody, you know, why do we do this? Sometimes I kind of wonder because I take a lot of professional heat for doing it. And that's because one of the smartest men I know put it out there pretty clearly. Dr. Thomas Sol who deserves the title of doctor. When you want to help people, you tell them the truth. When you want to help yourself, you'll tell them what they want to hear. And boy, where'd you wisdom? You know, lately in the news, it's been pretty hard to find some scientists we can look up to. But I find I dug one up from about a hundred years ago. Marie Curie, brilliant Polish and Jewish scientist and the naturalized French citizen. They probably wouldn't take her in this day and age. But when a couple of Nobel prizes, she stated it very well. Now is the time to understand more so that we make fear less. And those were important words a hundred years ago, they're important words now. And then important words for FSHD because I know that when I give you a research test results to people and if it comes back consistent with FSHD because you know, we don't do a diagnosis in the US. Fear, right? That's probably a very common thing, right? Because fear of the unknown, what's going to happen to you? What's going to happen to your kids? What does the future look like? What does the therapeutic landscape look like? You know, everything. You know, suddenly it's just called into question. And so we're here to answer your questions, give you as much information as possible and let you know that yeah, it sucks to have FSHD, but you know what? There are a lot of things a lot worse, but you know, things are getting better too in the FSHD space. Not everything is breakthrough, not everything is going to work, but you know, there's a lot going on and some of it's going to work. And I'll let you know my opinions on the data and the actual data, which is the facts, which really shouldn't change. All right. So some of you may know that I am the Mick Hitchcock PhD in Dow Chair in Medical Biochemistry at the University of Nevada, Reno and in addition to being a wonderful philanthropist, you know, Mick actually is a scientist and he ran Gilead, which is a large pharmaceutical company for about 23 years, I believe, and they were a small company up to gosh, tens of thousands of employees developed Tammy flu, some of the hepatitis, some AIDS therapies, and some really done some amazing stuff. And he really is dedicating his life now to the next generation of scientists. And in this case, journalists. And so I pulled this article that came out in Nevada today, which I thought was really interesting, which is, you know, Mick is working, he started a program in the journalism school here at UNR to help journalists, you know, communicate science. But I think Mick's advice is actually for the scientists. All right. So here's actually a really great question. I saw it's just an interview by this young man and does want to kind of cover it. So do you have any advice for scientists or journalists on how to communicate science to the public while minimizing misinterpretation? Boy, is that a timely question? And Mick's response is the biggest thing is to get comfortable with uncertainty and to help your audience get comfortable with it, too, without letting it seem wishy-washy. Science is not black and white. Most things exist in shades of gray. And as you do more experiments, you refine your understanding and move down that spectrum. The temptation, especially under media and political pressure, is to present things as more definitive than they are, resist that. Also, don't just publish it in a journal where five people in the world can read it and understand it. This is good for scientists. The information needs to be translated into something to politician, a business person or a member of the public can act on. That's the extra piece that programs like this one are filling. Scientists get grants, they do the work, they publish in journals, but somebody has to take that information and make it usable for people who are actually making decisions. And here's a part that kind of, you know, I really appreciate. He says, "And to make it land, you need a hook." If it's dry and dense, people won't engage. Connect the science to something they already care about. Use nanodote, make it relevant. That doesn't mean dumbing it down. It means building a bridge. You know, I think there's biggest criticism I get from people is they want you guys to hate my stories. Do you hate my movie references? But, you know, I'm just actually trying to connect because I, you know, things pop into my head and how I think. I'm actually just showing you how I think. I'm actually not trying to be fun. I'm just this is literally what life is like around me. You can ask to talk your code, you can ask queries. I'm always like, "Oh, that's like the scene." And, you know, whatever. And I just pop and I try to share it with you a little bit about how my mind works and try to give scenes that you can relate to. And, you know, the scientists, I mean, actually, you know, we're just normal people like you going through life. And science, I don't know, it's just, I try to make it relatable. Of course, but you know what, for all the haters out there. Well, you can cram it with walnut, ugly. Well, that's one of my favorite quotes. All right. So, one of the things I wanted to do, and I got to tell you how late I am behind on all this, is I wanted to kind of go back to our previous podcast where we covered the big Epi CRISPR announcement where it appeared that they cured FSHD. They didn't say that. And no one actually said that. It was just very strongly implied. And broadcast widely. And that was interpreted. What kind of caught me was the way it was interpreted across social media by people out there, which is thank God. This is the treatment we've been waiting for. Can my kid get it? I mean, everybody, I mean, I understand, you know, companies put stuff out there and they put the best spin on it. But the interpretation from the desperate community. And I understand people are desperate for treatments and curing you, losing your muscle every day, time is muscle. Neil Cmarter is a hundred percent right. But it was just over the top. I couldn't believe what, you know, it's, and the reason I couldn't believe it, how over the top the reaction was, was because how pissed poor the data was. Okay. And, and the way it was presented, what was missing. You could say, well, the data they presented was fine. It was missing a lot of context. And so, you know, I put it out there that these two Facebook posts, one to one on the left from FSHD society, the one on the right from FSH Global. And I was critical of the foundations for saying, you're overblowing what they did. And boy, I got to tell you the first thing I heard from, as Emma Weatherly, the CEO of FSHD Global, he was like, Peter, I won't even try to do an Australian accent because it'd be insulting, but he's like, she's like, Peter, oh my god, she's like, I did it and she's kind of hurt, you know, but she also worried. And so, this is what makes Emma the best CEO in the business, hands down, bar none, the best. Okay. Because the last thing that Emma wants to do is mislead her community of FSHD patients in Australia, New Zealand, and quite honestly, a lot of other parts of the world as well. And she recognizes that she doesn't have a scientific training or background, but she's getting pretty good at the science. You know, she immerses herself in it, asks lots of questions, she engages scientists, and she wants to understand what she's putting out there. I really appreciate that because there have been some people around an organization that have been in the business longer that they don't. I mean, you know, everyone's got a different job, right? But Emma really wants to understand the science, makes great efforts, always asked me great questions. But in addition to that, Emma's a patient. And the concern is that actually that she's viewing stuff with like rose colored glasses and wants to basically be able to step back from being a patient where he's so bad, want to cure and so bad, want things to work, and make sure you give accurate and truthful information to your community. And Emma's selfish, she's like, you know, all we did is put, you know, this was the press release and we just put out the press release. Right here you go, here's the press release, bring it up. it was breaking news. It is a press release. She said, "I think she was a little upset with me." She said, "I'm saying that they overbrew it." And it got me thinking, because what is the role of foundations? What is the role? You do want to take care of me. Honestly, I just greatly appreciate Emma's response, because she wants to make sure she's like, "If I'm doing something wrong, let me know." And actually, I wasn't actually thinking of her in particular. I was actually thinking of the FSHD Society, who was bragging about their partnership with Epi CRISPR. And I kind of global got lumped in with them. Because I think there are some concerns when foundations are partnering and invested in or co-hoots, so to speak, with companies. Where do you draw the line between being a patient advocate and being a company advocate? And that's why I was getting kind of concerned. But the honest to God, the truth is, they just put out here's the press release. And sure, pretty sure, people knew they were coming. And what does the press release say? It says, "Epi CRISPR reports first clinical evidence of increasingly muscle volume and patients with FSHD following treatment with Epi 321 increase muscle volume." Wow, FSHD is geared. Right? Well, what I was saying is, in my mind, it's important for whoever puts stuff out there. And this is foundations, but also the company, of course, they can't expect them to be completely honest. But even those of you that are forwarding this on, because basically these two little blurbs got forwarded by every foundation out there, and then forward and forward and shared and shared, and it's all over the place. And there was actually no context really put with this. In fact, there wasn't even really good context in the press release, but honestly, because the press release is basically an advertisement to get funding, because they were successful in doing it. So, what's wrong with this? Well, it's actually, everything they say is actually true. So, Jones, you're an idiot. Why are you complaining? Well, as Marie Curie says, that was the time to understand more. And as Dr. Sewell says, "If you want to help people, you tell them the truth." And when I say, "Tell the truth," that means the whole truth, nothing but the truth. Okay? So, what did we say? And Emma, you didn't do anything wrong, you are the best, and I apologize publicly for actually even applying that something, because I know it wasn't in my mind, and that's not what I was thinking. But you know what, we're straight and we're good. I'll tell you, if I do think you're doing something wrong, I'll tell you, we haven't crossed that bridge yet. I don't think we will. I hope we never do. All right, recap. And what did we say about the data? We did not say that the epicrisper trial was not working. We also didn't say it was working. Okay? In fact, they didn't say it was or was not working either. They were saying it's suggesting that it's working. Well, they put a pretty strong suggest on there. What did we say? We said that they did not show any direct data that their gene therapy is actually working. So, what do you mean? People had increased muscle mass. They got slightly, you know, better on some metric of a quantitative muscle metric. You know? Well, let's think about that for a second. The press release, well, the press release says following treatment with EPI 321. Was that the only thing they were given? No, it was not the only thing they were given. They were given a massive immunosuppression regime, right? In fact, you know, so, and if you are in the first group, you just got down, but the second group, which they didn't talk about, yeah, but they'll be talking about soon. You got triple immunosuppression regime. Was anybody in this trial not on the gene therapy? Was any placebo? The answer is no. There was no placebo, right? It was actually a hypothetical virtual placebo, which actually was not a placebo, right? So, how would you show that the therapy is working? Well, what's their mechanism of action? Well, they're using CRISPR inhibition, which we love. You know, that's why Curries is our CRISPR goddess. She invented CRISPR inhibition for FSHD, Stanley Chi, founder of EPI CRISPR. Actually, the concept of EPI CRISPR, he developed when he was a postdoc in Jennifer Dudinus lab. But, you know, we built off that work and brought it to FSHD in 2014. But what are they doing? They're fusing a DNA methyl transferase to the Cas9 protein and recruiting it to the FSHD locus. Hey, why would you do that? Well, we know if you're going back to our FSHD research test, the basis of that test, we don't measure the size of your DNA or your deletion like the traditional testing. We measure the activity state of the gene. In healthy or non-FSHD individuals, the FSHD region is transcriptionally and essentially silent, it's heavily methylated, it's heterochromatinized, and essentially it's it's off. There's one way to think of it. In FSHD1, basically, the signal to turn this region off is lost due to the deletion. In FSHD2, the off switch is broken, okay? In both cases, the region is no longer off. It has the potential to be on. You can think of it potentially to be active and it's un-methylated. So in healthy individuals, non-FSHD individuals methylated and off in FSHD un-methylated DNA, and it's conceptually on. So what does Epicurus we're doing? They are bringing a DNA methyl transferase there that is going to methylate the DNA, which is then going to lead to this DNA presumably to be turned off and back to a healthy state. That is their mechanism of action. This is different than my lab, which is a different act. We actually put just an off switch there. We don't try to methylate it because we don't believe the non-replicating cells can be methylated, and I've never seen evidence that non-replicating cells, which is the target tissue. The skeletal muscle that you know, giving you FSHD is not replicating. Okay. And so anyway, so what they did, they took biopsies before treatment. They took biopsies of three months and they're taken biopsies of 12 months. They had six months. They're doing MRI and some quantitative muscle measurements and some of you walk in and some stand up and go and some reachable work, whatever. They don't have much of things. So in order to understood DNA methylation data, you need genomic DNA from the muscle. That's the only place that this is going to be expressed. They have a muscle specific promoter that doesn't work so well on their preliminary data. They have a DNA methyl transferase assay. They have the biopsies. They have the DNA. And we know they have the DNA because they showed virus copy number, which can only be gotten from, only to be obtained. Sorry. If I'm muscle biopsy DNA. So they have everything in hand and they didn't show any DNA methylation data. Why not? If the data supports that this is working, wouldn't you show that? Hey, our therapy is working. See? You went from one methylated to now you're methylated back to a healthy state. Wouldn't I, I can't believe you wouldn't show that if you had. Well, maybe they just didn't have like three months to do it. It doesn't take that long, but maybe they're just holding it all waiting. Okay. So they didn't show any DNA methylation assay. So what, what does ducts for do? What's the second part? Now, we've done a bunch of clinical trials. We'll several clinical, a lot of pre-clinical data. And what do people do? They always show ducts for target gene expression. Why is that? Well, ducts for is a transcription factor that is normally off, right? It's expressed when you were four cells old. It drives a, the zygotic transcription. And, you know, the embryo starts becoming you. And then it gets turned off. And your muscle is driving that same program. This is only going to be driven in people with FSHD and not in people that do not have FSHD. And so, but now ducts for is really hard to assay. So as a transcription factor, it activates other genes. And these are genes that are not normally activated in muscle or not normally. Well, I mean, some of them are on a muscle anyway. They're on higher. But you can pick out a good set that very clearly gives you a fingerprint, so to speak, a genetic fingerprint of FSHD muscle. And look for these target genes, ducts for target genes. And say, are they expressed? Now again, you have to do this and skeletal muscle biopsies. Well, what do we know? We know that they have biopsies before treatment. They have biopsies at three months. Now they're doing it 12 months. So was the gene turned off? Because conceptually, you could not methylate the DNA, but still repress ducts for expression, and thus ducts for targeting expression, because DNA methyl transferases are transcriptional presses themselves. And I'm pretty sure they might have a transcription of press refuse to it. I'll look, come on, these days, I'm going to have to look that up. All right. So did they do that? Well, we know they have the biopsies, we know they have the RNA, and we know they have the ability to run the assays, because it's all in their preclinical data. And they didn't show that data. Yeah, maybe they're just holding all that weight, maybe I don't know, but they didn't show it. I actually don't know if they have the data or not. I don't know if they ran the experiments, and it didn't work. What I know is that there are two experiments that will tell me whether or not this is working. Significant increase in DNA methylation of the FSHD region in the biopsies, and that should happen easily by three months after treatment. That just tells you that the CRISPR is doing what it's supposed to do, but what you really need to see is is repression of ducts for target genes in the skeletal muscle biopsies. Now, what they showed is they showed a circulating biomarker. Now, the circulating biomarkers that are ducts for target genes are basically markers of muscle health. Okay? Yeah, they can be activated by ducts for, but they're released 'cause muscle is actually dying. That's what's happening, 'cause of the pathology. And if you get healthier muscle, you're gonna have lower levels. That doesn't necessarily mean that you've shut down ducts for. Okay, you still, at some point, need to make that connection. Avidity has made that connection and shown that. Okay? Full-crum never did. 'Cause it wasn't working. Okay, so that's the experiment you need to do. What did they do instead? They showed that there was an MRI that showed increased muscle mass, very small between like 0.7 and 1.3 pounds of lean muscle mass or something like that, and three people. Great. Can you put on muscle mass without shutting down ducts for? Absolutely. We know that. Get on the website. Our favorite Facebook group is FSHD supplements, nutrition, and peer support. And you'll just see all sorts of protocols, all sorts of people talking about how they put on muscle mass. I have friends all over the world that email me, telling me they're putting on muscle mass, their kids are getting strong. Now maybe it's a losing game eventually, but putting on a pound of muscle. My friend Michael told me to put on seven pounds with a routine, you know? Didn't shut down ducts for. Right? Nutrition, diet, exercise can do all of this. You say, well, do people didn't do any of that really? We know that that's not true. Okay? So maybe they put it on because ducts were shut down. But what's the other thing that actually increases muscle mass and makes you feel better? It makes you actually more active anti-inflammatories. FSHD could be characterized as an inflammatory myopathy. We know this tremendous inflammation in the muscles. Okay? Of FSHD patients. All right? We know that if you suppress that inflammation, really just about anybody that's got any sort of muscle pathology, you actually feel better. You know, Chris's dad is a medical doctor. He's a retired medical doctor. Now when we're telling him, he was telling him that, oh, you know what? This is what they saw. They said, you know, they gave people a strong regimen of bread and zone and they felt better. So, of course, they did. Yeah, always do. You feel better, you exercise more. You put on some, you know, you decrease some pathology. Again, you know, so how do you know it's not due to the immunosuppression regime? Well, we don't. Now, maybe it's not. But we don't know. So, but they have they addressed that. They said, well, we have this. We've done all these MRIs. It's Springbok, great company Springbok Analytics. Does amazing work with MRIs over time courses. You get to personalize MRI, full body MRI. They look at the fat content in you and they sort it all out. And they said, well, we can predict what you're going to look like in three months. And so they predicted what these people would look like if they weren't on at B321. But you know, suppression was not part of that prediction. So, the benefit that was reported, the movement, but everything could easily become this is just science. This isn't me being, I mean, I'm picking on them. So you do science. Control of do the proper control. You know, you just fail your bad exam. You know, seriously, you're not advancing in candidacy in the PhD program unless you're in R. All right, so now what are they going to do? So again, we didn't say it's not working. We just said they haven't shown that it is working. It's an easy account for that's a job of the scientists to ask questions unless you're listening to Tony Fauci which your job is to anybody that questions you non-scientific. Well, Fauci's an idiot. Anyway, so now what are they doing? Well, now they have a triple immunosuppression. Why would you do a triple immunosuppression? This is actually not part of the original protocol. But their primate studies, their non-human primate studies showed if they needed triple immunosuppression, meaning not just an anti-inflammatory, but you have to wipe out the B cells and the T cells. All right, these are the cellular response to not just the virus, but also the Cas9. They have to eliminate that or else they got clearance. This was actually what their primate data showed. In Dunction, Dwan, and standing scientists and Duchenne muscular dystrophy, showed this happens with Cas. We actually showed this happens with Cas9 CRISPR inhibition in the pig. That's the major problem, right? Is that Cas9 for expressing cells get eliminated by the immune system? Well, in CRISPR inhibition, if the cells that are expressing Cas9 are eliminated, that means the cells that are off are getting eliminated. If you're doing CRISPR editing, that means the cells that are fixed are getting eliminated. This is actually a huge problem in CRISPR field that everybody recognizes. So they're doing massive immunosuppression, which will give them a longer window where the opportunity to see what other kind of benefit again, while you're also wiping out the T cell and the B cell response to ducts four and the ducts four pathogenic program, right? In fact, it has been proposed by some of the smartest people I know that actually a therapeutic approach for FSHD would be literally exactly this, using retoxamode, which is okay, and serolimus, right? To wipe out your B and T cell response, and this can now, of course, the problem is you're gonna be immunosuppressed all this time, but maybe it wouldn't mind, it beats having FSHD. But this alone, without the gene therapy, would be a therapeutic approach. The science backs that up, okay? So this is what's coming, right? If it's coming, this is massive immunosuppression on this. And again, that's fine, if that's what you gotta do to keep this going, if that's how you gotta get your Cas9 expression cells going, at some point, you're gonna be off of it. But you gotta show us these first two things, you gotta show the DNA methylation data, and I guess you don't have to, you don't legally, you don't have to show anything, right? I mean, investors or suckers were learning, my God. I don't know who these guys get to advise them. I get these calls all the time. I get all these emails all the time. Hey, we have some investors that are interested in talking to somebody who's an expert on FSHD, would you, well, pay you whatever stuff, just talk to them for an hour, and I always turn it down, because you know what, they don't wanna hear what I have to say. I guarantee you, they're, they wanna hear everything as peaches and cream. All right, so we get back to this, 'cause you know, this is the breaking news. I honestly think we did it in a very fair, I don't think we're hard on, we just, this is, I treat this like I would treat a grad student presenting the data. I would say come back and show, you know, and if I was reviewing this as a paper, it would have been a rejection. I would have, if it was a grant, it would have been triaged, meaning, you know, because, you know, you're not showing us the data that tells us anything important. You're cherry picking the data, all right? And is it the job of the foundations or anybody out there in social media to say that? I don't know, you know, I wish they would, but I understand why they don't, but I guess that's why we exist, you know, and no one else has got the stones to do it. That's for sure, at least publicly. All right, so what happened? Well, they went ahead and got 90 million, so it worked, sucker for her every day. Anyway, I hope this worked. They got enough money for their phase three, but you know what's really cool? And I'm so happy about this. The world muscle society is coming up. That meeting is coming up in the beginning of October in Hiroshima, Japan. And we have it right here. It's in this article. The company will present additional phase one to clinical data, including six months results from six patients, which is the only show three already. So these are going to be some of its own safety findings, biomarker data, and measurements of muscle health. Well, safety, we know this is safe. We haven't argued that it's safe. In fact, that's one of the problems. The reason R8, so AV, R8, 74, which it involves a safe virus, it's really crappy virus, right? They're driving around with helmets on and a Pinto. I have no interest in winning the race, but they're going to be safe. And then it is safe, and every indication is it safe. Biomarker data, well, hopefully, that's DNA methylation data, and ducts for targeting expression data from biopsies. I suspect it might be a circulating biomarker, which again, if the immunosuppression regime is giving you healthier muscle, you have less muscle breakdown. The circulating biomarker is going to go down, and it doesn't matter that it's a ducts for target gene that's going down. Everything being released from creatine kinase is going to go down. Everything is going to go down because the muscles are healthier, okay? You know, just just by claiming it's a ducts for targeting, I don't care. Now, maybe I'm the only one who doesn't care. I've been told I'm plenty stupid by a number of smarter people in me. I told you I'm always the dumbest person in the room. But with this meeting, it is inconceivable to me that they won't show DNA methylation data and ducts for target gene expression data from the biopsies. Now, I understand they're not going to have a control for the immunosuppression, right? But you've got to show us some data and all showing the gene therapy is doing what's designed to do. I can't even, to me, it's just unconscionable to think that if it were me, you know, I couldn't give a seminar. Like, I mean, you know, I was at the American Society of gene and cell therapy, and we presented our negative pig data and showed the cast line, we have to redesign our cargo to make it less immunogenic, you know, because that's what the data says. We showed our negative, in fact, I just showed our negative data to a company yesterday. Yeah, yesterday, and they were amazed, and they were thrilled because that's always the concern. What are not, what are you showing us? It's what aren't you showing us, right? for those of you who are watching. who like the show, how I met your mother. Sorry, folks, I gotta put in some cultural reference, how I met your mother. Well, I think that's a hysterical show, despite some of the issues with it. There's a great episode called The Big Butt, okay? 'Cause everybody's got a butt. Everything is fantastic, but she's perfect and butt. What's my butt? You know, and the butt is not a physical component, it's the, you know, no one, everyone tells you (laughs) no one wants to tell you what's wrong. That's the thing, that's wrong. We could tell a part of this with the Oh Honey episode. This is Oh Honey, which is how I feel I should say to this, these investors, right? That's what I want to say to these investors. I'm gonna say Oh Honey, pat him on the head. I know you meant well. All right, so what's The Big Butt? Well, let's hope that we're gonna find The Big Butt as they won't show us that their drug therapy actually works. Everything looks good, but, there we go. But, you know what, we're gonna find out soon. 'Cause I can't believe they're gonna stand up there and tell you it's working, not give us this data. And I hope, I hope that, I mean, honestly, I mean, again, we haven't said it's not working. We have said they haven't showed it's working. I would love it if they stand up and they show while we're getting, we went from, you know, 15% methylation to the locus, to 40% methylation of the locus, that would actually be what you need to see, to go from an onto an off. And that would be fantastic. See the ducts for jittargetine expressions, crash down to near zero? That would be spectacular. Wouldn't that be great? Then you can say, okay, all right. And you're getting increase in muscle mass and you're getting better functional data. It all makes sense. Everything's working, release the doves. That's fantastic. I hope that's the case. And then they can go on to the phase three, you know? I honestly hope that's the case. I'm looking forward to the data. Rest assured we'll cover it. All right, but you know what? Anyway, it's a one thing to keep in mind. I love this picture of Amber. It's fantastic picture. - Sharon, just remember, it's not a lie if you believe it. (audience laughing) - All right, there were some other news out there though. You know, there were some Evidity Novartist news in myatonic dystrophy and a number of people have contacted me about this because of the concern. Because Evidity, of course, has an FSHD trial that's in phase three. The myatonic dystrophy, DM1, that's myatonic dystrophy. There's DM1 and DM2, just different mechanisms of disease. Their phase three trial basically failed, okay? Now, why do we care? Well, because Evidity is a platform company, right? They're delivery, they're chemistry, their whole approach is the same across the board. They're just using different sequences to target different genes for knockdown, right? Honestly though, you know what, I'm not going to knock Novartist for this. Because you know what, the Evidity data for myatonic look great, is this a concern? Yeah, yes and no. Because I got to tell you, the myatonic dystrophy preclinical data from Evidity looked fantastic. The phase one, two data looked pretty good, but what's going on? Well, this is the same platform for delivery and knockdown as with FSHD. But there are key differences, right? The mechanism of disease and myatonic dystrophy is very different. Now, these are both SIRNAs that are trying to knockdown an mRNA or eliminate an mRNA. And FSHD are trying to eliminate the ducts four on RNA. And myatonic dystrophy is the DMPK mRNA, but it's not just a normal mRNA. The DMPK gene and FSHD in myatonic has gone through this expansion of a tri-nucleotide repeat. And this expansion, it's a CUG expansion, leads to binding of splicing factors, OK? And it becomes these insoluble kind of foci in the nucleus. So that's OK. So that's what's going on, the disease mechanism there. It's not making a pathogenic gene product like ducts four. It's actually removing what the cell needs in order to function normally. So what's the deal with splicing? Well, remember it goes DNA to RNA to protein in general. And the DNA has coding sequence that becomes the protein, that's the exons. And then between them, there's introns, which are regulatory sequence, and they can be spliced out. And you have splicing factors, OK? You need to be able to put the exons together. And if you can't put the exons together, the problem is the intron sequence, if those aren't properly spliced out, lead to incorrectly translated proteins. And often non-functional proteins, and often protein that are just degraded and thrown out by the garbage system of your cell, the ubiquitous system, OK? So what's going on in myotonic dystrophy is the SIRNA needs to get into the nucleus, because that's where these are, and actually function in these foci to bust up these foci and release the splicing factors so that they can function in an even normal gene expression in the muscle cells, right? So it's just a different target. It's a different beast, right? It's a different mechanism. It's harder to knock it down. Now they've shown this works. These SIRNAs do work, but it's a little bit different, right? Now, how is it targeted? Well, they're using a monoclonal antibody to the transfer and receptor, and that's the same thing they're using in an FSHD. And we've gone over a little bit of that targeting. Why we like arrowheads approach better than evidities approach? They use the targeting a different receptor. But this is what's going on. So is it a concern? A little bit. It could be a concern that they didn't meet their end point, because one of the things we've learned from this trial is that they be increasing doses doesn't make things better. They seem to have a dose limiting, an upper dose limit. And one of the reasons is this transfer and receptor turns over very slowly. And there appeared to be some toxic issues. So we will see what's going on with FSHs concerned. Just have it in the radar. But hopefully the FSHD phase three trial continues to work. But you know what? Actually, there's a lot of other knock down approaches coming, right? We know that souffle is coming to trial. Are we talking about them? In fact, that's our next slide, right? souffle therapeutics is announced their trial. Dine therapeutics is announced their trial. Both souffle and dine are SIR and ACE targeting ducts four. And they're a little bit different than evidity. Scala rock is also in trial. Now that's got nothing to do with ducts four. That's myostatin inhibition. We'll cover that, too, and others. But there's more stuff coming. So we hope that if he works, I like a validity. I see my preclinical data looks good. Their phase one, two looks good. It could be better, maybe a mistake. And we've said that from the beginning. The validity, in the best case scenario, for what I've seen with the validity, I believe that others can do better. But now we got, you know, dine is a platform company just like a validity. And they have myotonic data. They have Duchenne data. So we know that there's the dosing in the tox with that. Slightly different targeting. And then two Flays coming out of left field. We don't know a whole lot about them, except for their presented preclinical data, which we may cover one of these days. And then there's others coming. So there's a lot in the pipeline, okay? So, you know, let's keep our fingers crossed for everybody. In the meantime, we're going to take a break, and then we're going to come back, and we're going to talk specifically about these trials. And what's going on? And try to address some of the questions that have come off. But I got to go with one of my-- I was trying to decide the song. But I'm going to go with one of my favorite actresses, Anna Kendrick. [MUSIC PLAYING] I've got my ticket for the long way round. Two by the whiskey for the way. And I sure would like some sweet company. And I'm leaving tomorrow, what do you say? What I'm going to do? You're going to miss me when I'm gone. You're going to miss me by my hair. You're going to miss me when you wear all. Well, I'm gone. I'm gone. You're going to miss me by my jaw. Oh, you're going to miss me when I'm gone. The one with the prettiest of you. It's got mountains, it's got rivers, it's got sites. You should have, but it sure would be pretty good with you. When I'm gone, when I'm gone. (upbeat music) ♪ When I'm gone, when I'm gone ♪ ♪ You're gonna miss me when I'm gone ♪ ♪ You're gonna miss me by my feet ♪ ♪ You're gonna miss me everywhere ♪ ♪ You're sure you're gonna miss me when I'm gone ♪ ♪ When I'm gone ♪ ♪ When I'm gone ♪ ♪ You're gonna miss me when I'm gone ♪ ♪ You're gonna miss me by my walk ♪ ♪ You're gonna miss me by my talk ♪ ♪ You're gonna miss me when I'm gone ♪ (cow mooing) - All right, I always like that. It was a good job and pitch purview, honestly. I remember I could go put pitch perfect on the TV and like, first off, I thought it was a baseball movie. (laughing) Whatever. I want to act that turned out, I really like it. Pretty good. And she's one of my favorites. I gotta tell you, I'm an accountant. Well, I've got to see a movie. I give you some cultural stuff. Up in the air is actually a great anachendic movie, George Clooney. Anyway, check out up in the air. Actually, I always think we know if I have to write a really good letter of recommendation for somebody, really top letter, I think about on the very end of that movie with George Clooney and the letter that he writes for Anachendic's character. And I think that's, well, I'm not telling you as a boss. That's kind of the letter I want to get from somebody. (laughing) And that's kind of the letter you want to get. It's really good. It's fun movie. Check it out. Up in the air. All right, so let's talk about Scala Rock. It's a phase two study evaluating a pita-gromob for the treatment of FSHD. Now, when you can see these names, you wonder when they come from. Anytime you see MAB at the end of a name, that's going to be monoclonal antibody. Okay, there's a reason this name this way, because MAB is short for monoclonal antibody. And this is going to be talking about Maya Staten inhibition. We saw that Roch recently killed there. Maya Staten inhibition trial. Acceleron had a trial. It got back when I was in Boston, man. We're talking like 2013, 2014. They may have been the first therapeutic put into our FlexFSHD like mice come to think of it. God, that was before we even had anybody know we had them, 'cause we were in the area and we got in touch. You know, we were giving our mice out to companies long before we publish 'em, 'cause we wanted to move the field forward. And, but you know, every Maya Staten inhibition approach in FSHD has failed. What essentially tends to happen is you get larger muscles that are not stronger or more functional. But you do increase muscle mass and muscle fiber size. You get what we call hypertropic muscle fibers, okay? But they don't necessarily work better. So why are they doing it? Why are you beating the dead horse? It's just, well, Scalar Alpha has a slight, I know it doubles in the details, and there are different approaches. I get, you know, I gotta tell you. There are natural mutations in the Maya Staten pathway. You see these cows that are just ginormous and things. And so, you know, it just feels like, you know, there's got to just, you just gotta be able to do it right, right? So Scalar Rock has come in, and this is a randomized phase two study to a value of, remember, phase two, it's gonna be FSHD patients, and it's efficacy and safety, really. And this is a monotherapy. Now, where I've been excited about Scalar Rock has been as a combo therapy. Combined this with a Vittadeek. Combined this with Suflay, if that were to work. Combined it with something that Nax Sound Ducks for. This is not gonna have any effect whatsoever on Ducks for, sink in and you're bailing it out faster, okay? But they're doing it right. Unlike Epichrist, not again, Epichrist was safety, but they're doing it right. Randomized, double blind, placebo controlled. Now, it does say multi-center 52-week study. So that's, there's only one center currently recruiting. This was September 2nd that I pulled this off clinical trial by Chuck today, this is September 17th, and I checked it out and they have not updated it. Austin, Texas is the only one recruiting, but there will be more. They're gonna try to get 60 people enrolled. And unfortunately, it's only 18 to 60 years. They're gonna say, well, so our kids are upset. Gotta tell the kids are pissed. Gonna hear about them in our next podcast. Our early onset FSHDers, unhappy about it. And rightfully so, because I can understand why some companies are gonna not go with under 18, if their technology has never been in kids. Scholarok is in SMA, right? They actually combine to the SMA therapeutic. So I would think that they should be able to be in kids. So what's going on? Well, how is there approach different? Why are they even doing it? Well, in general, the way it kind of works is cells express these growth factors that are latent form, so they're not active, okay? And then the latent factor gets processed into a mature growth factor. It separates from a pro domain and it becomes an active molecule. So myostatin starts out as latent myostatin and it then becomes activated and most approaches are targeting active growth factors, active components of the myostatin pathway. What does myostatin do? It puts on a brakes on muscle growth. And so the idea is to get rid of myostatin then you take off the brakes and so now the muscle is gonna try to continue to grow. So you're gonna be building muscle while it's going away because you don't have a ducts worth therapy. And so you're battling the boat out faster than in sinking, that's the idea. Now, how is Scholarok different? Scholarok is different because they are going to target the latent growth factor, which most of the companies do not target, okay? So that also means that they can be much more selective. Okay, only targeting a particular part of this pathway. And you can see this is directly from Scholarok's website. Our antibodies target the latent form of growth factors and prevent release of the mature growth factor. Given the chemical and structural differences of the pro domain, our approach allows us to generate antibodies with extraordinary selectivity. This enables Scholarok to potentially treat diseases with high unmet need while limiting unintended side effects. So that's one of the things with myostatin pathway as multiple components. You can often it's been very hard to block only one part of the pathway and so you get some side effects, right? So in addition to getting larger less functional muscles, you have side effects to deal with. And so they are saying that they have kind of gotten around that which is fantastic, right? So what's the other thing that makes this actually particularly interesting? It is actually FDA approved. All right, it is FDA approved for SMA when combined with an SMN gene therapy or anti-sense, okay? So essentially an SMA, the SMN gene, right? You're not making functional protein. They're able to replace it with SMA gene therapy or skip it with oligos and make it functional enough protein or activate in some ways. I don't know if that's approved at activating the other form, but you're able to get some benefit and they saw benefit in these SMA patients. And so the idea is now we actually have a myostatin inhibition approach that is showing benefit in a neuromuscular disease, give it a try for FSHD, why not? And when people are asking me, can what I'm telling people is I've been telling people, again, I gotta be careful. So this is just between us. If you're getting rejected from these other trials because you're too strong, you're too functional, this might be a good trial to go in because the trials that are targeting ducks for are looking for people that are kind of on this measurable decline. They don't want you on the plateau. They want you going downhill, not all the way at the bottom though, right? If you're too weak, they can't measure if you're getting better, but if you're too strong, they can't measure if you stay in the same getting worse. Right? And so if you're being turned down, it's a year-long trial, it might not be a bad choice to give this a try because if this is going to work in my scientific opinion, I think it's gonna work better on people who are less affected, okay? Because people that are really affected, one thing we know about myostatin, the levels are really low already in people that are really affected with FSHD. The mRNA levels are almost non-existent. The protein levels are very low, but so there's very little target for this if you're really, because your muscles are regenerating like crazy already. Right? But if you're pretty healthy, but you know, you still feel in some decline, but if you're generally pretty healthy, you probably have a decent amount of myostatin in your healthy muscles might be a good approach. I would actually, you know, I guess what I would say is if I was affected with FSHD, and again, I hate to put myself in your shoes because I'm not in your shoes, but I'm gonna do it anyway and go against my own advice. And so I think this would be worth taking a look at. I would say that if I'm being rejected from trials that are targeting ducks for. Fundamentally, I wanna be in a trial that's targeting ducks for expression or shutting down ducks for one way or another. That's my first choice. And there's any number of approaches goes in, but if I can't get into those, you know why I'm sitting around waiting. I'd also be exercising, I'd be eating well, and I'd be doing everything well that my friend tomorrow I suggest, okay? But you know what? None of this is a medical advice because we don't do that. All right, so what's going on with Colorado Rock? Well, like we said, they have spinal muscular atrophy greater than two years old, commercialization. Now wait a minute. We just saw that they only let people that are 18 and up into this trial. There are people who look at this. Well, I mean to run under two years. That's who's, we get spinal muscular atrophy. That's who gets it, right? This is for kids. You know what's safe in kids? How can you not buy wine? Come on, guys, why are you not letting our early onset FSH theaters get some of, especially the ones, you know, not, you guys say, well, some of them are really affected. And that is true, and it might not work in some of them that are really affected, but they're not getting any other trials, so they're getting worse, so maybe it would work. But a lot of them are actually affected. They're almost like the wheelhouse of where you want to be. There's an awful lot of, you know, 12 to 18 year old kids out there that are affected enough that are getting tested for FSHD, but they're just going to be sitting around losing muscle for the next, you know, six years. You know, this might be the best group for you to find out if you're a thing or if you're treating my works, okay? Come on, man, let's open that thing up. Yeah, kill him. All right, souffle. All right, now I've talked about souffle. We, you know, they kind of came out of stealth, came out of nowhere, shocked everybody, suddenly, here we are, you know, and they now are all gone really fast, and they're actually announced a clinical trial in Australia and New Zealand. At least those are the sites they've announced so far. It is called a trial to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of SFL 0821 and adulterative FSHD, goddamn, sorry, it's, it's adulterative FSH. Now, now I, I, I'll cut to play some slack here, though, although I'm kind of annoyed, but I won't cut on some slack. This is their first molecule of this type in clinic. They can legitimately say, let's figure it out if it's safe. This is safety phase one, too. Of course, the guy with a bunch of primate dead, I'm sure. But let's figure out if this is safe in 18 to, well, they got 18 to 60 year olds, something like that. I'm 65, and if it's safe there, then we'll talk to think about the kids. I hope that's what they're thinking. And I can kind of cut on some slack for that. The scholar rock, that's been in all sorts of kids, right? And quite honestly, the technology for the other anti-senses have been in enough things that they should be in our early onset as well. But that'll be the next podcast. You'll hear the kids that, and rightfully so. So what's going on here? The purpose of this study is to evaluate the safety tolerability and preliminary efficacy of SFL 0821 and adult patients with FSHD. That's just literally their title. It is a randomized double-blind placebo-controlled single and multiple ascending dose trial to assess the safety tolerability, well, again, what they're doing. So they're going to have multiple doses, increasing doses, placebo-controlled double-blind. They're doing everything on remember in the Epicrisper trial. It's not blind. Everybody's on the drug, and everybody knows they're on the drug. I mean, tell you a big thing to know that you're on a drug in a trial, OK? That's one of the reasons we have placebo. So scholar rocks who flay, you're doing placebo-controlled, fantastic. All right, they're going to be in one, two, three, four, five sites in Australia and one site in New Zealand. They're going to try to find-- I think they're going to try to find 60 people for this trial. And so see how it goes. Now this, what's going on, what is suflay? Suflay is an SIRNA that is linked to a ligand that is going to deliver this to skeletal muscle. Yeah, that sounds like a validity. Sounds like dine. Sounds like myrokyl. Well, so what's special about suflay? How is suflable good thing? There's a quite-- there's actually an article. How is suflays? SIRNA approach different. This is-- I don't know if this is called page5.org, but this was an article by Sebastian Genseoir in October. So it's been a while. But when they first came out of stealth, the question was, why are you guys so cool? And so I thought this was a pretty good article. So I'm just going to go directly from it because I was at said, well, I could say this myself. But you know, see about us here, does a good job. Suflay's core focus is on solving the delivery problem that has vexed the field of gene therapy and RNA therapeutics. Ensuring medicines reach specific cells and tissues beyond the usual targets, like the liver. Now remember, let me just stop quoting for a second. So the transfer and receptor that's being targeted by a bit of the endine, that's an end others. That's not muscle-specific. That helps get the SIRNA into muscle compared with, say, non-targeted, no, non-linked. But it's not muscle-specific. It gets into all sorts of tissues. It just helps it also get into muscle. So that means part of the dose, and a good part of the dose, is going to other tissues where it's not needed. And this could affect levels, toxicity levels, and off-targeted things that are bad. And so even if you go to the alpha, what is the alpha, 5 beta, 7 omega, that the arrowhead is using, that's a little bit better, right? But again, we need to get a muscle-scullet on muscle-specific, right? That's really what they're going for. Now, the other difference with Suflay-- again, I have no-- I am not actually-- I'm not employed by Suflay. So I'm just, you know, I just like this approach. Is that these other companies are platform companies. They're married to their delivery technology. I'm going to read what's going forward now, because it doesn't sound like that's the case for Suflay. And it's hard. Suflay is developing a platform for cell-specific drug delivery. The approach involves attaching SIR and molecules, which can silence disease causing genes, to target emolities, such as antibodies or small nanobodies, that bind uniquely to receptors on particular cell types, OK? So it sounds like they're going to say, we have this SIRNA for this gene that's going to affect this disease that needs to go to this tissue. And they're going to design the whole system to be specific, customizable for that situation. So an FSHD would be skeletal muscle, and in another disease, it could be neurons, or it could be the heart, it could be kidney, or it could be lung. They're going to design the approach. And so now, on one hand, that's a lot of extra science. But on the other hand, it's actually the way we run our lab. That's actually kind of caught me about these guys. Is it think about we've always run our research lab? As think about what's the best way to answer the question. Find an important point. What's the best-- now, what do we have on hand? What is easy? What can I order from a company? But what's the best way to answer the question? And then develop the tools or the technology to do it? That's how we-- that's what we've been following with our CRISPR inhibition. That's why when the whole field of FSHD went for CRISPR editing. When CRISPR drivers came out in 2012, 2013, these are that horrible approach for FSHD. And the foundation of funding, grant after grant, they're following over themselves to fund grants on CRISPR and then they find out in CRISPR cutting. Don't worry. We went for CRISPR inhibition because, right away, because we're the only ones that did it. And we're the first people to do CRISPR because it was the best approach. We had to develop the technology, again. That's why she's the CRISPR goddess, right? What do you need to prove that it works? We needed a large animal model. We developed the pig, developed the mouse, talking to develop the mouse and the pig. Are you developed the tools? Companies don't necessarily do that. They develop platform technology, develop IP, intellectual property on the technology. And then they've been married to it. Now, you gotta use that for everything, right? Well, let's see if ladies not doing that. They're actually saying their technology is their approach. Let's get the best targeting molecule to pair it up with the best knockdown. Or do you think I'm very, yeah, I'm very, I like their approach because I can relate to it. It's actually, I love it. So once then C-Bass goes on to say, once bound, the conjugate is ferried inside the target cell, delivering the therapeutic SIR and into the cytoplasm where it can do its work. In essence, the therapy catches the free ride and shuddles in. Thanks. By engineering cell-specific ligands that enable active cellular uptake of RNA, the company aims to precisely hit disease-driving cells while sparing others. A notable departure from traditional systemic gene therapies. Yes, that is true. They go on to say soufflé's most critical asset is its cell-specific delivery platform, right? It's still a platform company, but the platform is to the right delivery for the right disease for the right cells. The company is developed a suite of proprietary technologies to identify unique cells surfaced receptors and craft ligands, antibodies, nanobodies or other target molecules that bind these receptors. By optimizing these ligands and conjugating them to potentus RNA payloads, who flake-created therapies that actively internalize into target cells, crossing the cell membrane, and release their genetic cargo precisely where needed. The company engineer has cell-specific ligands that shuttle genetic medicine across the cell membrane to their target. Okay, so I just like, now, do I know that it's going to work? You know, they've presented some preclinical data at MDA, and I believe they're at the FHD meeting. They've gone to clinic pretty fast, and, you know, I'm just very optimistic about this, okay? Because it's a different approach, devil's in the details. Different targeting. I'm not a fan of the transfer and receptor that's why I like to arrowhead, they're moving to it. I'm now, what can go wrong? Well, there could be an immune response against this, right? There could be a dose limiting toxicity, right? There's all sorts of things that could potentially go, now, of course, they've, you know, done mouse data. We've seen the data that's been presented at MDA, which seems to be fine. Certainly, they've done some primate safety data, but, you know, this truly is a phase one, two. The first time this technology is in, it's going to be enough for safety patients. I'll give them a short-term pass on 18 to 65, but once you guys see it safe, I want to see this in 14 and up, maybe 12 and up, okay, 14 and up. 16 and up. I mean, come on, guys. You got to work with us, man. Kill 'em, eh? All right. Third one we're going to talk about is DINE. DINE announces US FDA clearance of IND application for DINE 302 and FSHD. We've been hearing about DINE forever, but you know what? They're more interested in DMD in my atonic dystrophy. FSHD has always been the third wheel here, and they've, but they're finally getting around to it. I've seen the technology for ages. Oh, boy, God. Things forgot. I thought they forgot about it. But, you know, they're going, I haven't, they don't have anything posted on ClinicalTrial.gov, but this is what they say. Here's their trial and their press release. It's going to be a phase one trial detail. I'm not sure why it's not a phase one, too, because they're going to be using FSHD patients, but they've DINE clients who evaluate DINE 302 and a phase one randomized placebo-controlled, double-blind, multiple ascending dose, ClinicalTrial, and ambulatory adult individuals, FSHD. There it is. Again, ambulatory adult individuals are early onset and non-ambulatory gang is pretty upset again, and they have a little more right to be upset here, because this technology has been in, not this specific anti-sense, but this technology has been in plenty of kids in the DMD trials, and we know that the part that's going to cause any safety or tox concerns is not the sequence. It's going to be likely not the sequence. And you're going to say, "Oh, you just said likely." That's why we don't want to do it in kids, fine, but you better be getting into the under-18 pretty soon. Okay, so what are they going to look at? Well, first off, placebo-controlled. There you go. Sounds good. Double-blind. Not everybody's going to know they're on the drug. All right. Different doses. That's good, too. So the endpoint will be safety and tolerability, of course it will be, but they're also going to look at other things, right? Going to look at, "Hey, the Dux4 transcriptome." Okay. In muscle, and they're going to look at the plasma KHDC1L levels. Okay. This is the circulating biomark of the dividities using so that they can hopefully avoid doing biopsies. I get it. But they're still going to make the connection. They're going to show that their anti-sense is going to -- their SIRNA is going to knock down the Dux4 transcriptome. The Dux4 target genes are going to go down in muscle biopsies. See, people are going to be giving muscle biopsies. And at the same time that the KHDC1L levels track with that. So they've got to show that the mode of action is actually functional, right? And the first cohort is going to be nine participants, three intravenous doses every four weeks. And randomized two to one. So that means six people will be on it, and three people will be on placebo. They're going to start with 1.5-megapig. And then after this, if everything goes well, they're going to go higher. And then they're going to go higher, right? And then, hey, here you go. Open label long-term extension. If you're in this trial, you get it for an additional 96 weeks. OK, that's pretty good. OK, so you get to stand on the therapeutic as long as it's safe. And it looks like it's working. OK, so what's going on? So here's actually their profile. Here's a bunch of data that they presented. I think a lot of people are familiar with it, but briefly to go through it, right? They have their platform, right? They have the force platform. The idea is you have an antibody and a linker and then the SIRNA. But what they're going to do is they're going to actually use only part of an antibody. Avidity uses an entire antibody, a monoclonal antibody. These guys are using a fragment called an FAB fragment. That is only one arm of the antibody. If you know what an antibody structure looks like, it looks like a Y. And the binding that's specific for the target that's very specific and tells it where to go is like in the arms of the Y, right? If you do the YMCA thing, right? The constant region is your body and the arms going out. They're just using the arms. So this means it's much smaller, OK? And so maybe that means they can use higher doses, right? Govels in the details. It's a little bit different, right? So avidity del Brax, OK? They're using a targeting monoclonal antibody, OK? Again, this is against the transfer and receptor, right? It's a del Brax. It's a proprietary monoclonal antibody that binds the transfer and receptor conjugated over their S-I-R-N-A, right? In force, but form, it is also targeting the transfer and receptor. So that's a similarity. But it is an FAB fragment. It's not the whole antibody. Whole antibody is 150 kilo-daltons in protein mass. An FAB fragment is much smaller. Molecule, is this going to be beneficial? We'll find out. OK, what do we got? Fab, right? You know, they're going to ask that question. Is it beneficial? And hence delivery of payloads, you know, it's much smaller. So lower risk of effector cell activation, lower risk of complementation activation, OK? And large scale manufacturing. So they're saying it's easier to manufacture. And now complement activation, this means this will get dose limiting toxicity, right? This is your immune system is recognizing this massive amount of antibody on the constant domain, the Fc domain, OK? The Fc domain, let's go back to our antibody picture. The Fc domain is down here. It's the gray part down here. This is your body trunk, if you're doing the YMCA dance, you know? And so this is what triggers often an immune response, whereas that's not going to be actually present in dynes molecule. So it could actually be safer in allowing you to then go to higher dose, higher dose means more SIRNA, or SIRNA could mean more ducts for knockdown and more efficacy and maybe even longer lasting. Remember, this is going to target the ducts for mRNA. We already know about that, right? And how are they going to test it? Well, they tested it in, well, what do you know, the flux ducts for mouse, very specialized ducts for mouse. This is the mouse, the Tocca Come, they came out of our lab, the I inducible flux ducts for it. But they did something very clever. And actually really cool. It had, they actually, the mouse has, of course, a transfer and receptor. Now the trick is, if you're using an antibody against a protein, well, mouse and human often very similar, but monoclonal antibody, these things have specific enough that sometimes, if it interacts with human, it won't interact with mouse or if it interacts with mouse protein, it will not interact with the human protein. And so what do companies do? Well, most companies, what they do is they say, well, we have a mouse version and a human version. And they do all their preclinical work with the mouse version in mice. But then they have to switch to the one that binds the primate version for the primate tux and for the things, but there's always this disconnect. Doesn't matter. I don't know. But what Dine did is they took our mouse model and they introduced the human transfer and gene into the mouse genome in place of presumably in place of the mouse transfer and gene. So now they can actually use their real therapeutic molecule with the human FAB fragment and put it into the mice, just like in the human trial, they don't have to have two different molecules. And they did the uninduced, which is our slowly progressing myopathy model. This is the one my lab uses most of all to show that you, because this is most like FSHD, this chronic sporadic ducts for activation, but you can also really push the system. If you're using an SIRNA and use the inducible, remember, this is tomoxifen inducible mouse model and they able to hit it with tomoxifen actually make a huge amount of ducts for a lot of cells that will be expressing ducts for when you do this and they can test that knock down. So they did both models. I love it. I love actually everything that they did with this. I love the fact that they made that they actually, instead of saying what tools avail our tools, you know, tools good enough for us. We made it for us. I love that they modified it with the human transfer and receptor and made a better tool specific for their program. Maybe I should cut them some slack and take them so long because they were doing something. I love it. It's good. I like to see when companies show their own vested. You know, of course this is going to be all around better in my opinion. So what do they do? They're looking at dosing. They do a dose of their therapeutic. They're dying 302. They do one make per cake, two make per cake, and six makes per cake. Okay. So they're able to put in a really heavy dose. They look at ducts for a target gene versus vehicle. They almost completely eliminate ducts for a target gene expression. Right? It comes way down here. Right? This is vehicle 100%. It comes all the way down below 20%. Even 12 weeks later. Right? Yeah, their trials, they're going to say they're going to do the dosing. I think every four weeks. But they're showing the great activity 12 weeks out in the quads, the gastroc and the TA. Okay. Looking at down here. And they are still getting dose dependent. Remember, Avidity topped out at their dose. Right? They basically four make per cake. Didn't it wasn't any better than two make per cake? Well, that was a clinical data. This is mouse data. The six make per cake looks pretty good. Okay. Now they're going to basically they can go on to treadmill. Right? And they're going to treat before, you know, this is the chronic model. And they're going to treat early. And they're going to see what happens and run the treadmill. So can they prevent the mice from getting pathology? If they pre-load the mice with their dine 302, is it can they do it? Can they prevent you from getting worse? Right? Essentially. And they load these guys up and they hit them with some tamoxifen here. This induces ducts four here at day zero. And you can see the vehicle right online. This is exactly the data that we see. Then by 14 days, the mice have totally crashed in their distance running. The one make per cake. Yeah, it rescues it a little bit. But now the two and the six actually rescue it pretty good. You're not getting a whole lot of a dose response here. Two and six, you kind of topping out right here. But that's okay. You're basically right there with normal control. Okay. So they will it prevent you. They look at transcriptome. All you need to know if you're looking online. The normal transcriptome and the flex ducts four transcriptome is very different because ducts four is a transcription factor. When you add dine 306, it goes back to normal. Right? Normal is green. Vehicle. These are all the changes in the gene expression due to ducts four transcription factor activity. Inflammation gene and flammination response, muscle damage genes are activated. And then the dine 302 brings it back to a healthy state. That's great. What about now if you actually look at an interventional treatment? Previously, they looked at a preventative treatment. Now it's interventional. They're kind of basically induced the pathology in these mice first and say what happens? They induce the pathology. The tomoxifen. Now they're going to come back and they're going to do the IV dose after the mice are already declining. And what do they find? They find, you know, the mice are doing okay. They had a lot of tomoxifen. The mice all decline. Right? They all have forced treadmill running. And then the ones that are on the dine 306, six-meg per gig recover. Well, the other ones don't. So interventional. So I like it. There's a great way to do the experiment. This is how I would design it. If I were doing it, then they went and they looked on IL-6 suppression. What is IL-6? That's interleukin-6. It's an inflammatory cytokine. Our lab showed at the same time with Sabrina Tsukone's lab in the east. We collaborated and published that interleukin-6 levels are elevated in people with FSHD. And it's actually a circulating biomarker for FSHD because FSHD is inflammatory. Remember, now if you're an anti-inflammatories, well, you might actually get better. Right? Which is why you need to control, if you're on anti-inflammatory. In fact, Sabrina Tsukone and Nese has a clinical trial. I'm blocking IL-6 inflammatory signaling as a therapeutic for FSHD. Inflammation is a big deal. I'm sorry, I'll go back to our first thing. What do they show? Dine 302. They shut down the inflammation because the ducts war is going down. Gamma interference suppression also, okay? So conclusions for target gene knockdown and chronic mouse model. Normalize the inflammatory and muscle damage transcriptome FSHD mouse model. These are functional improvement in an FSHD mouse model with preexisting and severe disease and supports going forward. This is great preclinical data. I love it. Great job, Dine. I got to tell you, though, I was surprised when I found my name here. So I got into full disclosure. They acknowledged me. First off, if you can acknowledge anyone from our lab, we should acknowledge Takiko. She is the brains behind the mouse model. She created the mouse model. She raised the mouse model. I just got funding for the mouse model. That's what I do, okay? So Takiko Jones should be here at University of Adirino. But honestly, all we did was give him the mice. Maybe we maybe gave him some advice back in like 2014 or something like that. God, it was before we came to Reno in '17. It really was like 10 years ago. We gave him some advice. I appreciate you still remember us. But you know what? I actually didn't have any say in how they were doing this. And I actually don't feel any conflict of interest telling you, I think it's fantastic work. So what's the lever? All right. They're not recruiting yet. It's not up there. They're going to start with 1.5 make per kick over every four weeks. With preclinical data suggests they'll be able to go higher and less frequently. But you know, they're going to be moving. And get us some under 18 into this trial, folks. I know it's safety, okay? But we also want to know that it's safe in kids. It's important to know that it's safe. We got to do safety in kids as well, right? You're going to say, well, we don't want to do it in kids so we know it's safe. But you're still going to have to say, yeah, let's get some on there. Let's get them. They're losing muscle. They're losing muscle faster than anybody. All right. So what do we know about dying though? Dying, like I said, they are a platform company. They do have a myatonic data out there and they're achieved trial, right? And you can look at their data. And what you can actually see is that they do have some safety. They did it all the way up to six make per kick and dosing it eight weeks, right? It's actually pretty safe, okay? Even at six makes per kick. That's really what this is telling you, right? What, how did they see how it worked? Again, this isn't people. Myatonic dystrophy in people. And as I showed you before for the Novartis data, they did myatonic data. This is to me a harder bar to reach than in FSHD. FSHD, you're not going to the ducts for mRNA that is cytoplasmic, some of it's nuclear, but it's available. It is not in these foci. It's just more like traditional SI RNA work and what did they find? They found that it actually works pretty well. Okay, DMPK mean change from baseline. They're able to knock down the mRNA of splicing correction. Now, remember the DMPK mRNA in these foci takes splicing factors and removes. So the other transcription of other genes is faulty because the splicing is screwed up because the factors that regulate move, you know, gluing the exons together aren't present because they've been squalched out of there. And so splicing improves. So splicing actually improves. And so what they actually see also, these myotonia is kind of like where your hands kind of lock up. And the functional improvement in the people summary is that, you know, favorable safety of the TAs are not related to the drug. So it's very safe. And they're actually able to do 6.8 make per gig every eight weeks as the registration dose for this. Okay, now this is again, some older data. I just need to follow up on this. This is the harmonia trial. So what about FSHD? Okay, they're doing it right. placebo controlled, double blind, ascending dose, change from baseline and muscle ducts for transcriptome. They are going to take some biopsies. All right. There you go. Packed a lot in. Actually, you know what's popping into my head? Concern for our early onset and non-ambulatory FSHDers. That's what's actually popping into my head. inconceivable. All right, Princess Bride. It is inconceivable that these kids are still unable to get into trials. I know, I know a validity opened. There's up to 16. And I've heard that arrowhead is also open. There's up to 16. But I have also heard that nobody's been registered for these trials yet. Please correct me if I'm wrong. But the idea being that people still there's read some logistical reasons. I'm on the company side that haven't been able to enroll kids. So if you can open up the trial of 16 and under or 16 and over, you got to put some of them to the front of the line. Okay. But anyway, that's what's going into my head. We just had three trials announced and not one of these three trials has taken any of our early onset or non-ambulatory FSHDers. We got to work on that. I understand there's some reasons and logistics behind it. But you know what? I'm only going to give you a pass for so long. All right, everybody. Well, my next podcast coming up is going to be with our early set non-ambulatory group of kids and young adults. And they're going to talk straight to you, talk straight to the companies and make their case and why they need to be included in all of this. They want to do their part. We want to get them. They're losing their muscle and and faster than anybody. There's still a lot of work to be done. It's very exciting that we have these clinical trials going on. But you know what? There's a lot of people out there with the disease. And so far, you know, let's see if anything. Hey, and don't and we got, you know, World Muscle Society, Epic CRISPR is going to be sharing their most recent data. My prediction is it's going to be a blockbuster of benefit on MMI. R.I. functionality and muscle mass. I really hope they show DNA methylation and ducts for target gene data from the biopsies. And I hope it's good. I do really do. I really wish them the best and hope they do. Hey, but we'll see. I'm not in charge. Peace out. Thank you for listening to the My FSHD podcast where we share with you the latest news and information on FSHD as we strive for a cure. You have a question for Peter. He'd love to hear from you can reach him at [email protected]. Thank you for listening and join us again next time for more news and information.