Another FDA vs uniQure Episode

Ladies and gentlemen, welcome to the business brew. I'm your host Bill Brewster. Friend of the show Peter Mantis went to a hype conference, HIP, he wrote about what he saw. I like the article. I sent it to a friend. My friend was like, "That would be a good show. You should have him on." So I said, "Peter, would you come back on?" Peter said, "Yeah, I'll come back on." And I said, "That'd be sweet. Let's do it." So this episode is more of a discussion than anything. But we're going to go back to you and secure a little bit. We're going to talk more FDA. The heat is on for Mr. Marty McCarrie. I happen to think that's a good thing. I do also understand the arguments that science in the US needs to be more like science and more replicable. And there are standards that need to be improved upon. I am not one of these people that thinks the FDA has done nothing good. I am one of these people that thinks that just because science needs to be improved upon, certainly does not mean that we have to stand in the way of progress. That is somewhat unproven, especially for families that have no options. And it's been an interesting experience to learn about the forces at play. I encourage those that have minds that want to dig to dig deeper into Arnold Ventures, what their theory of the case is, who they fund, and how they may be tied to Marty McCarrie and Veney Prasad and the people in charge. I think it's interesting that you're starting to see them more mentioned mainstream media. But I will tell you that the general gist of one of their overarching sort of methodologies or ways that they view the world is, patients, you start with a baseline, what a life is worth. Let's call it $150,000. Then you quality adjust the life value. And if you have a rare disease like Huntington's, they would ratchet down your life value per year because you're sick. And then they start to say, "Okay, well, if you are saving people whose quality adjusted life values are lower, then you can only charge so much for drugs. And if you start to apply that to a small patient population and a lower drug price, you're basically saying to, you know, if you are also then requiring true randomized control trials, you're saying to people, you got to go through the whole rigorous process and you shouldn't be able to charge a whole lot at the end." Which seems to me like maybe that's more of a law thing and not an FDA thing, but anyway, I would just submit that if that is the policy that we're going to pursue as a nation, we should broaden out the application to many things. And I'm not sure that if we were to do that, our seniors would be very happy with the conclusions. Now, I suppose rich families might be okay because they can afford things, but I'm not sure that we want to have that kind of a society. I know I don't, but that is my own personal views and I encourage the listeners that get a sense of curiosity to do their own work and check it out because it's an interesting web to start pulling on. The episode is brought to you by Fiscal.ai, OG sponsor. They are your platform for all your data needs. They are my platform for my data needs. I'm Braden and I recorded, I refer you back to that. I got an email that said bang Fiscal.ai, 25% off sales starting this Thursday. They run two sales per year, ones on Black Friday and the other is around a big product launch. So in conjunction with this sale, they will be launching brokerage connections. This will allow anyone to easily connect their brokerage account directly to Fiscal.ai dashboards for real time portfolio updates and analytics. You can check it out and you can check it out by going to Fiscal.ai/brew. You can get my discount, you can get their discount. The promo is going to run from May 8th to May 14th, so make sure you hit that window to get your sale. It's going to run exactly one week. You get the 25% off by using my affiliate link, so use it. Fiscal.ai/brew. Those are the terms, this is the show. Hopefully it gets out before Marty McCary is fired because it's just not timely otherwise. Alright, enjoy it. Goodbye. Is it easier for my videos off from? I have it recording. I'm just going to end up doing audio anyway. It's best to do audio given that everyone's looking at your nostrils right now. Yeah, yeah, I'm at more like from a quality perspective. Oh, no, it doesn't matter. The fans of this program have come to accept not the highest quality. I joke. You know, in the beginning, it was pretty high quality. It's still as high quality. It's just now we'll see things done with AI. Sure. Sure. So basically, I'm an AI company. You are an AI company. And don't have a ton of revenue, which means this podcast should be worth like five to 10 billion. Yeah, easily. Yeah, right. Easily. I think so too. Sweet. Nice. Well, this is a good way to start it. If anyone wants to offer me half cash and half stock for that, feel free. We're killing the jokes. Bang, bang, bang. All right. So dude, I reached out to you after you wrote a piece like a week and a half ago. People that don't know Peter, he's been on the program twice. So go look at those episodes. But you did what in Baltimore with Unicure and the patients or the patient advocates. Yeah. So this conference was a hype HIP E conference. And it's very advocate and patient heavy. The just to set you the scene, you know, myself and a gonna colleague friend are the only investors in the room. All right. There's nobody there on it on any by side or cell side or this isn't JP Morgan health care conference. This is the audience are advocates and patients really. And it's kind of a chance for drug companies to present what's coming down to give them hope and to talk about the current political climate. How to reach out to your congressman from the advocates perspective. And to get just like a glimpse of like their hope, right. It was it's really. You know, for us, it was for me anyway, it was kind of sad that you're in this room and everybody's going to die. Like that's how you felt. And that's not uplifting. Yeah. And so the other thought that I had was, you know, you're in this room and you like how can anyone at the FDA or any regulatory body go to something like this and let patients suffer for something that has no standard of care. I like some of these people can take pills to, you know, relieve some symptoms. There's just nothing for these people. And it just, it's really kind of uncomfortable that thoughts where. And we're holding up therapies for people that have no hope that are going, that are going to die. And yeah, it was a little bit upsetting as well from that perspective. There was also a film crew there. They were documenting something. I don't know for what if it's on Netflix or something else. That was also there as well. So that's that's the last sort of like the stage, I would set for the. For the conference, very patient heavy. You know, there's other companies that have like, Teva was there, Roche and tech, you know, here obviously, no, artists. They're all there to present what's coming down the pipeline and, you know, potential therapies that that could help patients. So like Teva, for example, has a pill that kind of helps you not tremor as much. It's probably the best way I can describe it. Yeah, so it was just a way for patients to sort of see what's coming and give them a little bit of hope. So you said that a number of companies were at the conference. I mean, what was the general mood of the company is there? They were presenting in a fashion that tried to make it very accessible or hopeful to patients. This wasn't a presentation that you would see, like I said, a J.F.A. Morgan conference or a healthcare conference. It wasn't super scientific. It was really meant to break down the different therapies. It was there to be uplifting with stories. It was there to update them on their progress. It wasn't, it was very high level. Like it was really meant to break down, like, hope for these people. Yeah. But in the room, you have people, people that were in wheelchairs who like kidnought eat. Like they were imagining someone our age and they're like shaking while they're bringing up a school. Like it's really bad. You also had some pre-synchomatic people. You had a couple people who were heads of an organ of an HD advocate subdivision or chapter that was like had HD, but this was pre-synchomatic. So it was. It was pretty eye opening. Like you had different stages of HD. You see from like people who are completely pre-synchomatic to people who are like full blown wheelchair. And there was one image crambling there with a baby. It was pretty, pretty like satan seated. It's generational. I would say it's generational. It was a pretty, pretty shock me. Do you think, I mean, this is kind of a silly question, but there's a difference between being a human and being some investor. But do you think that meeting the patients does that obscure objectivity at all to you? Or do you think that it benefits by sort of putting a real world like what's at stake type thing to the image? When we were there, we were like, the tone was, we felt kind of bad that we are there trying to analyze the landscape and ecosystem from a cap of our perspective, and investor perspective while these people are dying, but at the same time, if we're right, they're going to get their treatment. Yeah. And so, yeah, I think you need both to be honest, because the only way these things in advance with capital. From a bias perspective, I would say that it just opened your eyes in terms of these people will take any day. Like they will take any day. This has been something, and you could feel the anger as well, you could feel the frustration at the government. There's also just a level of confusion like why, why are we even having this conversation? It's not like there's a standard of care is not like this patient advocate group is not uninformed of the sides. Like they understand the different therapies and what is what is viable. So it's not like they're completely idiotic to it. So there's anger and confusion and like rage outside towards the situation and like also tired. It's higher of the Huntington's communities for let's say 30 years. It's that incredible roller coasters right you have a hopeful therapy that gets rug pulled because it doesn't work or you had money thrown at this space for 40 years trying to figure out a cure for it. And now you're at the finish line of something that is truly dizzy modifying. And the last institution or entity that they thought would rug pull them would it would be the government. So now there's like a different level of frustration or anger or you know exhaustion that they didn't think that have this battle on top of other battles event fast. That makes sense. Yeah, it does make sense. If to play devil's advocate here if you've got a community of people that are willing to take anything is is it possible that the doctors are looking for raise of hope. And I mean like for people that don't really know the unique your story you know I did a podcast and if you don't want to listen that whole thing it's sort of stitched together I think it can be summed up as the there are a group of three primary doctors that have 12 patients in a high dose cohort and it seems as though they're pretty universal in saying that they've never seen a cohort of 12 people do this well is that is that a fair assessment of what is coming out of that that high dose cohort and then the government is basically came back and said hey. You need a randomized control trial which also somehow they say is satisfied by just little nicks in the skull which seems pretty stupid to me but I mean is that that's pretty much where we are right. Yeah. So I mean is it possible that the doctors have motivated reasoning here like you like you know you've got a group of people that are looking for a solution are they seeing one where it doesn't exist or like where are we. I would say that what the tone of room was it was very it was it was there was like a level of frustration anger that I haven't seen before because the doctors weren't there to like sell anything it wasn't that kind of presentation it was more. They just couldn't believe what was going on and I mean I talked to guys and over artists table I talked to all the I'll talk to everybody and they were like what the heck is going on. The reason why there's the frustration is is too full the first is you have something that truly is does is modify like you back the back negative NFL readings you have the continued spread if you look at the grass of two years three years soon before year the spread keeps widening versus the control group they sort of the national history density score matched control group using external data. The political nature of what the government's asked them to do versus what other countries are willing to accept so like the UK examples willing except three year. The first rate of is not even the surgical piece of the trial of a proposed RCT as speed bump it's the the TFC 913 cohort so for those who don't understand the reason why it's problematic from an ethical perspective is there's that cohort is a group of people and a specific. The core range where if they leave that range due to time they can never get the drug again and so that's where a lot of the anger is so if you are right now in that TFC they call TFC total functional control cohort 913 if you're in that range and a neurosurgeon lies to you says you know what we're going to give you this therapy. The neurosurgeon knows that i'm going to give you placebo like air in your skull basically and you're walking them off the plank because once they're gone once they're past that court they don't qualify anymore for a 230. That's the issue that's unethical that's really frustrating to people is not only do we have something that you're forcing to delay. But that actually kind of works right and and data still being cumulative from the for your for your court but you're asking us to to walk off the cliff. And for the greater good for the very good yeah yeah that's that's hard that's where their anger comes from or the and I don't blame them like that's. That's obvious it's obvious why they shouldn't do this. But yeah that that's where a lot of their frustration is and like doctors. They don't that everybody in that room like I just straight up ask them like would you give your kids this drug right if your child had this sometimes if you try to qualify for this cohort. There's not even a hesitation they all said yes every hd advocate every everybody would say said yes not even an issue and these are people who are very careful because they they they're chill their child might have the gene but they're not symptomatic yet. Right so like they understand that I you know putting my childhood brain surgery for something that might I work on not symptomatic might be an issue but they all said yes like it was not even a like a question more that so for me. That's all from me. like that, the ZIO opening, just the drug, the drug, talk to any KOL, this thing works. And for what the FDA is absolutely to do is it lacks every bit. It's not only unethical, but it raises the credibility of the institution. Like, you don't have anybody who's serious about HD who is advising the FDA on this. Like, that's really what's called up. Because how can you actually advise them to delay this any further and provide them like on RCT when you know that cohort is going to talk. It's just insane to me. So yeah, I mean, I guess that what you tell yourself is that you need to show that something actually truly, I'm going to say this and then I don't believe it. But you need to prove how specifically it works in order to justify approving it. And if some people have to die along the way, it's kind of a numbers game, right? Isn't that? I mean, I think that's how you have to view the world. I mean, the auxiliary approval framework, mechanism, whatever it was started in 1992. Okay. I think it was under Bill Clinton for this very reason, which is if we are not sure that something truly works, but we're confident there's enough signal that it probably works, we will give you an auxiliary approval. Like I said before, an auxiliary approval is not a gift on a company. It is a burden. It's going to get a very strict label. Yeah, I'll give you an AA, but you're going to do this. You're going to give this job to max or 1000 people and those are 1000 people. You're going to follow them for two to three, four years extra. And on top of that, you're going to still do a trial, right? But this trial is not going to be placebo based. It's going to be you dose another 25 people and you follow them and you update the N-Roll HD data. That's what an AA looks like. It's not an unfettered, hey guys, we're now in the market in the United States, we do this 20,000 people. That's not what are oddly enough, the current FDA is idiotic to not understand that when you force someone to do phase three, that's what happens. You get an unfettered approval, right? When you force a company to go to phase three, they can control the marketing, they control the sales, they control the label, they control everything. They've met the endpoint, there's no reason to control it. But the AA is meant for this kind of purpose where you have two back to back at FL readings, which is an indisputable biological biomarker for a neurodegeneration. The more that number gets negative or the consistently negative, your cells are dying less. You continue to spread versus a natural history cohort. You are getting better and theoretically should be getting better for many, many years after that. So in AA, I said, like I said before, there's enough evidence here for an exhilarated approval because it probably is beneficial to patients, probably. And you track them and you say you could only do 2,000 people. That's called a restricted label AA. They could have done that. They didn't. So the pushback is if the FDA were to allow that to happen, it might back insurance companies into a position where they have to pay a bunch for treatment that may or may not work. I mean, is this the pushback? I don't know what the pushback is, but insurance is already willing to cover it. Centine already said they'd cover it. Centines notorious for like not covering anybody. Because anyone could have a break into the ROI, Huntington's disease is a 25-year death sentence. It is a slow bleed. You get it at 30, you die at 55. Okay, your what you pay is an insurance company, probably upwards of $7 and $9 million per patient. And you have a one-time gene therapy for three that will extend their life. And like, you know, theoretically that person can go back to work in some ways and become part of the tax base and start paying insurance again. You're beyond the quality assessment. But anytime a drug gets covered by insurance, they do a QALY assessment. Right. What is the met benefit versus where the currently is? What I'm suggesting or what cure can do is something beyond that. Not only is there a cost benefit from current treatment, those people go back to work and sign up to united health health insurance again because they're now working. Right. So there's an ROI to insurance companies and ROI to the population. There's an ROI to the healthcare system. Right. If you have 10,000 people who no longer need 24/7 nursing care, a hospital bed in their house, physical therapists, you know, pills they got to take every day to measure motor control, a wheelchair, a wheelchair ramp in their house because they can't walk. Like I said, this isn't like you die only a year. This is 20 years of, you get it 30. Imagine this. Imagine a Nike executive. He's 30 years old. He's making 300K a year plus stock out his providing family. He gets to 30 by 40. He's out of work. Now his wife has to get out of work to take care of him. By 45, he needs not only his wife, he needs like full care and nurse, maybe physical therapist, maybe, you know, a hospital bed in the house. Right. Like it is a generational disease that leads to poverty. And that's one thing that I would say that people understand is people who get this start off, you know, you can see them upper middle class. And then by the end of it, they become lower middle class because it takes away your family from. And the time you're earning years, right? And your face. Yeah. Oh, yeah. We finished. We finished. So, you know, the insurance is not an issue here. It's more defensible to pay that kind of money for someone who's high performing and go back to work and someone who's 85 might have Parkinson's who's going to live for another five years. Yeah. So that is a different like an art situation. Yeah. So the QALY is quality adjusted life year, right? The interest is if you're at 30 and you, like one way to look at it is these people have a devastating disease and you ratchet down the value of their life in some sort of actuarial decision, right? The other way that you could potentially look at it is you are improving the quality adjusted life years from your, I don't know, what 40 to 80 in a way that should be additive to the value of their life, right? I mean, I just, I don't understand how the focus, I mean, look, if you wanted to be, should it be a million a half, should it be three million, what, like the price of the drug, like that's, that seems to me to be a fine debate for the insurance companies to have. What I don't understand is the FDA saying there's no evidence that this thing works at all, especially, I think, I think it's more precise maybe to say like we don't know the exact mechanism with which this acts and therefore it's impossible to prove scientifically. But to just say like there's no evidence that it works, I mean, to your point, you said almost everyone in the room said that their kid, they'd give it to their kid. I mean, what's their view, obviously, on whether or not it works? Is it just like crazy speculation, or is there some reasonable basis to think that I just have not had a single qualified professional nose HD. I say, walk me through why and how a back-to-back negative NFL reading does not work. Like tell me how you can rebuttal that and you can go on the two layers fear and people who can talk about the efficacy of any drug, but at the end of the day, when you have back-to-back negative NFL readings, that is the purest sign of neurodegeneration. Your cells are not dying. So is that reasonably providing some kind of meaningful benefits of people? Yeah, if your cells are not dying as quickly, it's probably a good thing. And that's the standard of AA. It's not meant, it doesn't need a clinical endpoint. Which did? The merits of the drug have already been met. It already met and surpassed this clinical endpoint. The 75% reduction in disease symptoms. On top of an NFL biomarker that's negative. So you have a spread between someone in a natural history cohort of 40% 50% versus someone who's taken the drug ever three years. So it met the clinical and the NFL reading, which is a biomarker, like an indubatable undisputed biomarker has already been met. So I'm not met anyone who sophisticated in HD, walk me through how this drug doesn't work. Right? I don't think the FDA is talking to anybody. And HD, I don't think they're talking about song, I don't think they're talking about this. To breezy, I don't think they're talking about wild, I don't think they're talking anybody. Right? So I don't think the understand what HD is quite frankly. Go ask them, do you know what Huntington's is? Do you understand the DNA mechanism? Do you understand what it does? Do you know what this drug does? I don't think they can give you a straight phase answer to that question. Now that being said, I feel like they I feel like they would like sort of not tongue in cheek, but I think they'd say they would respond by saying, do you know what this drug does and how it acts? I really think that would be the response. Yeah, we can talk about that. Right? Right. Yeah. I mean, that would be it, right? They'd say so. How do you know? Well, because you've been NFL biomarker, that's negative back to back. Right. For those who don't understand, Huntington's disease is your DNA has four letters. Three of them, repeat, C-A-G. And if you have over 40 of that repeat, you have Huntington's. The more you have, if you have 500 K-A-G repeats, you're going to get Huntington's at like 30 years old. Okay. And what that does, I'm going to bring it out very simply for people, is that it creates a mutant gene because you have a mutant effectively mRNA, that's creating a mutant gene that creates mutant fragments. And that fragments and mutant proteins create misfolds and cause incredible amount of distressing toxicity to your body, to your brain. Right? So when you have a negative NFL breeding, that means the toxicity is not impacting the cells and the striatum, which is where the source of this problem is. Okay. And so what Unicure's drug does is it sends in an AAV-5 virus with some instructions to silence the mRNA causing the toxic gene. Right. So think about this way. Imagine you have a factory floor and you have a pipe and that pipe is leaking a ton of water. Right. When you're 30 years old and you got a leaky pipe, cool. That's fine. All you gotta do is seal the pipe. And Unicure, that's what it does. It seals the pipe. Right. Something like a varnish, which is a pill, doesn't seal the pump. It puts barriers on the factory floor. So it slows down the flow of water. So if you're 20, if you're 40, you're 45, 50 years old with HD, and you've got 22 decades of water flowing in your factory floor, yeah, your floor is still really wet, even if you sealed off the pipe, even if you have barriers, you might need something else to soak up the floor. But if you're 30 and your floor is not really that wet, one time A and T1 30, yeah, you probably have a lifelong treatment that you're doing and doing anything else again. So this is why I think the ecosystem becomes sort of like HIV. You have an anchor therapy and then you have a bunch of other things to solve other problems as people have accumulated across their life. Right. And I've given a very high level overview of how the mechanism works, what the the biomarker reading is, what the total functional score has been across your NICURI's results. And you cannot credibly tell me that this therapy is our thing. You can't. And I would go step further, which is there has been rumors to breeze these presentation of proteostatic repair, which if that's the case, then you have something completely game changing. Okay. And that might come out in the four year date. And for those who don't know what that is, what that is is if I'm sealed, if I've sealed the pipe early enough, does that give a chance for my brain cells to repair itself? And if it repairs myself, that's how you see someone get out of a wheelchair and walk yet. That's how you see someone picking up a fork without shaking. That's how you see someone being able to like, you know, go back to work. Right. If that it truly happens and you have something that's beyond the clinical benefit, that's like, well, we count. And that's where the FDA runs a risk, by the way, because if it is truly proteostatic, or there's even a hint of it being proteostatic, okay. Then the FDA looks like an organization, which does not know what HD does, does not know HD at all and has not listened to any care wells. And if you're not doing that for HD, how can we trust you that you know what you're talking about for cancer, for Alzheimer's, for ALS, for Parkinson's? Like the credibility of the institution is now very severely damaged. The scientific and academic reputation of the heads of those organizations are finished. I don't care if you got a PhD from UCSF. You refuse to learn op HD and you refuse to learn the mechanism of how this drug is truly a category differentiator in this in this ecosystem. Your academic education done. You're not an inquisitive, curious mind who talks about gold standard randomized control trials. You're someone who has something else like over you that is influencing your scientific curiosity. You know what really pissed me off about the the RCT, the randomized control trial comment is if you really want the gold standard of randomized control trials, you can't just do it with a few nicks. Right, right? Like it doesn't make any sense what they're saying. And to the extent that there is some repair in the brain, I mean if there's even rumors of that, it's a little bit frustrating to hear somebody say there's no evidence that it works and then to have, you know, McCary just like blindly defended. Well, I know you're in danger zone. You're an institutional danger zone. Right? Like your institutional danger zone right now, you have three years of data with back to back in the fellow readings that are negative and clinical benefit of 75% back to back. Well, they're going to say they're digging up. He does all cherry picked, right? I mean, that's what they're going to say. And then they're going to point to the fact that there wasn't a big differential on the one year placebo group, which by the way, the FDA told the company it could stop monitoring the placebo group and offer them the chance to get in the trial. So it's kind of it's kind of frustrating as a citizen. And, you know, yeah, I was long and M long or whatever, but it's frustrating to see an FDA that gives guidance and then subsequently says, by the way, we know we told you to stop following this group or to let them get out of the placebo. Now that you've done it, we're going to tell you that you know, not doing it was the problem. And you got to restart, even if you have three to four years of data against a robust control set. Yeah. Well, you know, the the mechanism of the therapy is very hard to track after one year because you're effectively putting in an MRI, a factory, more head. And it is a bit of ramp up time. And so the data is going to get better as time goes on. And so you say, well, how much time is enough time? That's really the question, right? Three years back to back NFL reading that are negative. It's probably enough time. Now we want to if we want to talk about, how does a placebo last for a year? That's kind of shocking to me. You couldn't do it for a year. You have to do for like five years. No, I'm saying because to breezy has said the placebo effect wears off after a year. It's surprising to me that a full year like the placebo effect can last that long. Oh, yeah, for sure, because the issue is surprising me in a negative way towards the treatment. I was like, it feels long. The thing is, but the treatment is like, you're taking getting brain surgery in your head. Okay. Like minimally minimal brain surgery. But like when you're when your brain gets open up, there's a bunch of hormones and stressors that happen to the brain. Like it knows it's exposed. Okay. So your NFL reading spikes a day, the hormones go crazy. And once you're sealed back up and you go do a TFC, you do a functional scoring test, you actually feel a little better in the beginning. Like you're doing the clinical endpoint of this is like, can you walk? Can you like go do banking? Again, you do a bunch of like mental to to tests. You do a multiple choice test. Like it's a bunch of stuff, right? So your brain tricks itself a little bit. I think clinical endpoint can be messy because you don't really know if this person's actually benefiting from the fact that he just had open brain surgery or a therapy. Yeah. Right. Yeah. You feel a bit better. Sure. And your brain's going crazy because you literally had some nicks in the head. And you feel like you might be able to answer these. Well, you maybe do well because your brain got a tricks itself. So that's the other issue with the placebo effect back to one year, which is you just got stitches in your head. Yeah, you probably do feel a little bit better. The therapy hasn't started working. The only thing that can that truly shows whether it's working in my opinion is the end of all reading. Like if you want true unbiased data is does the narrow fill that white chain FL is that a reasonable marker for someone being clinically beneficial is it clinically beneficial? Is there a meaningful way that that provides a clinical benefit to people? I think the answer is yes. Does anybody who lies in native reading is functioning? doing better on those scores. Less than a thousand years. Two and three years. But after the first, when you do the first test, when you do your first clinical test, your NFL might not be going down, but you still feel a bit better. Because you just got all the brains, your homeones are going crazy. There's a bit of a trick that happens. But it's odd that that lasts for a year. I mean, that's a long time for it to last. Especially with a sham surgery. I mean, I think that is one of the data points that doesn't, you know, I mean, obviously it's what the FDA is hanging their entire hat on. I don't think it's as big of a deal. It's changing so as DNA. You're going into their DNA and changing the epial. Like it takes a while. And for that to then start producing, again, like to seal off that pipe and then analogy, I have completely to then see that benefit. Yeah, it should probably be a minute to be here at least. Like that's just the science behind it. Right. And that's why you've seen the two of them in a three year. So robust because it's like the factory, the pipe that you feel is now really working. Like you can feel it. You see it. It's like if you take, if you take your ACL. Seriously, you know, you can be out for six months. Seven months before you can even try. So you get back and play football. Before you can even get to physio. In some cases, right? Let alone something that you've had for 30 years. A genetic issue that is deep in your striat, striatum and people don't understand too. The striatum is deep in your brain. It's like a meat cartilage. Like it's a, it's a, it's a thing in the middle of your head. And for that thing to have the source of narrow degeneration for Huntington, like that's where Huntington resides. Right. It's going to take some time before you have that therapeutic benefit. And they admit that they give you the reason why after one year. You only, you don't see tremendous benefit. And by the way, you start seeing a little bit of it in the high dose. But it does take some time. So theoretically, here's two, three, four, five, six. We'll be pretty sure that we'll see some pretty strong data. Yeah. I, you know, it's funny. I've spent a lot of time on this. But hearing you say that in this way has got me thinking that it's part of the issue is that to your point, like it's almost as if you get some sort of injection right after you tear your ACL. And after two weeks, they look at you versus somebody who tore it without the injection. They're like, well, there's not really a big difference. But it's because there hasn't been a sufficient amount of time for the injection to actually take hold. Yeah. That's right. And that injection is like, you know, you're changing, you're changing MRNA instruction. Some sort of code injection issue. Yeah, because this part of the brain is not tied to blood vessels. It's not tied to cerebral spinal fluid. So, you know, you're, you're ACL or your MCL. I mean, I guess they're not tied to blood vessels too, but anything close to blood vessels will feel faster. I think tie to that. Those parts of your body will feel faster because blood flowing is regenerated. But this part of the brain is away from that. That's why things that go to the spine. Like there's, there's, there's HD drugs that are injected through your spine. When they go through your spine, they can't hit your straya. All it does is it creates a shower into your brain. It goes on the outside. Right. And so this right and it's kind of removed completely from the rest of your body to a degree. And so it takes a really long time. Something that goes through your spine has to be constantly redoast. Like often every month, every two months, every three months. Unicres is a one time injection. Take one injection for the rest of your life. Because you are changing instruction. You're changing the mRNA. Versus other therapies are going to be constantly. And those things can't hit the straya. So you're never going to have the X-on-1 fragments suppressed in the way that you will. But you're gonna cure this drug. And that's why they call it dual suppression. It's the only dual suppression drug. So when you have hunting tends, you have this mutant protein. And then you have this like X-on-1, a free radical. Okay. It's the only drug that suppresses both because you're going right to the straya. When you take a pill or when you take a, like a spinal injection, maybe just suppresses this. But this is still going around your head. Yeah. Right. And so. For those who don't we can't see this. I have two fifths of an I'm showing two different things. Anyway, that's why it's mechanistically and categorically a different therapy versus anything else. And that's why I think it'll be an anchor therapy, meaning you take it. If you're 50 let's say, and you might have to take a large pill at the same time. And something else as well. But if you're 30, you might have to take it. And then that's it. If you're precondomatic. You might not need to take it, but you might take something else. And then eventually, and you want 30. So it's just it becomes a ecosystem. Yeah. Well, interestingly, I mean, the, the, uh, unicure earnings call was today. And I think that they hinted or explicitly said that they were. They were applying in the UK, but they also mentioned the Gulf States. It'll be interesting to see whether or not people, I mean, obviously it's going to cost a lot. But whether or not people try to fly over there at a young age to, uh, to actually get it. But to your point, I don't know how many people are going to be able to afford it because. That's a lot of money out of pocket for a family that has historically had a problem. Worming enough to generate a lot of wealth. The UK endorsed the drug the Wednesday after they got drug pulled. Yeah. And they reached out on the official UK government website. Right. And they reached out to you to cure. They didn't need it for your data. They don't obviously don't need a right and left control trial. They know that this works. And remember, the UK is the University College London. It's like the headquarters of Huntington Z's research. Like that it wants you to discover the gene of night three. They're the ones who are heavy into understanding what HD does. So for them to say, yeah, I feel like this is game changing. But to be able to say that, and these are experts and wasn't good for them to say that in their experts. It really brings up the credibility issue of the FDA. Like you have not spoken to anyone with HD. What's especially concerning when the FDA is saying, you know, we still want to lead in. Drug development. And you know, China overtook us and phase one trials under the Biden administration. It's like I get that we're in an environment where we love to throw the previous administration under the bus. But there should be some ownership for the cost that we're currently putting on the US. It's not great if we lose that. I think that's what we're doing. I think we're going to have to be able to do that. We're going to have to be able to do that. and the accelerator approvals in the past, makes no sense why they haven't been able to justify. I think they have the tools to justify an accelerator approval here, which is very simple. You're gonna serve 2,000 patients, you're gonna follow those patients, you're gonna take all the real world evidence you can from this 2,000 patients, you're gonna update all the databases. And if it doesn't work, we're gonna pull it. Very simple. I don't understand why that's not the reason for that. I just scientifically, I don't understand, given the policy framework that they had. Well, the answer is because you pray to the altar of, I guess a group of people that thinks that you have to have perfect science before common sense can rule. And who happened to think that driving down drug costs rare diseases is one of the big problems. Which I don't fully understand. But that's an insurance question and they're fine with it. So I don't understand, like thousands of people will be going back to work. That is a net benefit to your society. And you're saving the system money through this drug. It's a one time $3 million dose versus $7 million. How is that not saving money? I don't understand that piece, the economic piece. So then it goes back to, well, it goes back to because you don't understand HD. That's truly, truly, there is some kind of philosophy that is blind-siding if there wants to understand this disease. Yeah, well, I mean, I think that people that are listening to this still may want to go into your favorite search engine and look a little bit into Arnold Ventures ICER and whether or not there's any ties to the people at the current FDA. And then do some research into what the governing philosophy of some of those bodies are. I do find it interesting that an ICER, pretty sure some insurance heavyweights sit on the board of that or at least contribute consistently. So it's kind of odd to me that we are in a regulatory regime that is calling the Huntington's Disease Community Advocates the Swamp, meanwhile, a major influencing body seems to be somewhat captured by insurance execs. But we're not asking why we want to keep these drugs off the market. Funny. Yeah, just some threads to pull on. I'm sure it's all a coincidence. Sure. It couldn't possibly be connected. I don't know, man, it's crazy, especially with all the waste in the system to target this, right? And like to to to be against curing sickle cell because you're worried about cost, like I just don't understand where that mentality comes from. I don't understand. They're just not doing an analysis. Like sickle cell, you're the hospital 220 days a year. Does it cost money to be in the hospital bed for 200 days a year? I get that that's crazy. Does it cost money to have a nurse by your side all the time for years? Does it cost money to go through fertility treatments because when you have sickle cell, like screws out your work or drug system, does it cost money to have a professional therapist, physical therapist, handle your body because you can't move. Like what the current standards are expensive. It's not like there's any price cows and they're already very expensive. So I don't understand the economic rationale. They're just not doing the math or not doing the calculation. Centin is already accepted, aimed to 130. Centin is notorious for not covering drugs. They will do everything to not cover drugs. And they've already accepted it. Yeah, it was like graph guidance, right? Drops guidance, right? Right. So I'm going to go depend on Arnold Ventures, a former end run natural gas trader to go and say, hey, you know what, this shouldn't, you shouldn't cover this. This is too expensive for the system. It's like you don't know HD or you have some other philosophy that I'm not aware of, like you get it. So where you don't want these people to survive. I don't know what it is. I'm not going to hear it assume, but it's not about price and it's not about cause and it's not about the system. Yeah. I think there's something else that I'm just not aware of. I mean, the dude is obviously a competent natural gas trader. I don't know why that means that he should be able to have the FDA captive at the moment. Other than, you know, we just live in a world where billionaires are able to influence everything they want to touch. Yeah, I think that it's, you know, this organization, the institution is historically been democratic, democratic. The other ones who funded Hillary Clinton against Marne Schreley. And I think what happened was, if you want my theory, is the Maham movement went a bit too far and he saw an opening, which kind of aligned with his own philosophy. Cause wherever you go, you all bit too far right. You eventually kind of comfortable circle. And similar if you go too far left, you may find yourself dancing with the far right. Right. Just think of it. Why wasn't he present under the Peter Marx FDA, which was Bible democratic? Peter Marx FDA was very pro industry, very approaching therapy, very much solutions oriented like, Hey, we don't know much about this disease. We don't know much about the brain. You know, we're going to trust you when you're K.O. Wells and your researcher. Like that's the Peter Marx approach. Let us figure out a way to get this through because we don't know much about it. And maybe there's a benefit. And if you can prove to us that there's a clinical and like a surrogate benefit, yeah, we'll get you over the line to worry about it. But here I think you had this Maham movement led by RFK who put quite frankly to these lackeys that were from Arnold ventures who have the resume that looked like scientific, goes to Adam, it really are just clouds. And he saw a moment where he can infiltrate fairly quickly. And next thing you know, you have the fewest amount of biology, drugs, approved since 2018. Right. Instead of you're approving peptides and psychedelics. So I think there's something going on that I'm that, you know, I'm not pretty to, but I think that's how I, how I see which to be probably I don't think you and I would sit here and advocate that judging the efficiency or or I efficacy for lack of a better term of the FDA is dependent upon the raw number of biologics approved. However, when that is, when that is the case at the same time as AI is theoretically like fully putting gas on the fire of what is capable and of being figured out. And there's real world evidence that that drugs actually are working, but they're just getting pulled because of trial design. That seems to be like the people that are like hyper dogmatic about being a federalist or loving religion or whatever. It just seems to me that they're, they are so tied to some sort of theoretical textbook way to analyze the world that they're incapable of actually making. Like like actual real world risk risk reward decisions. Yeah. And you can argue that they're not your big scientific, not you can dogmatic scientifically like and they're just being just being stupid. Yeah. Cause like true scientific rigor. Also admits that you don't know what you don't know. Right. And if you're a cardiologist or actually or a similar to an oncologist, you don't know any people but HD. So maybe she'll talk to me who spent their debt payments of life studying this thing, finding out the gene that causes it, finding out all the issues around it. Like where it, what is the source of all this? Like learn up on this or go talk to the experts, but they're not doing that. They just remain dogmatic for maybe it's ego-tistical reasons. Narcissistic reasons are called nerd rage reasons. Maybe it's some other reasons to run trials that they deem fit regardless of the disease, regardless of the other factors. And by the way, I'm not against phase three trials. Like, you know, um, a unit here has a team 260. 60 right? Yeah. That's going to be a complete knowledge. It's got to be phase three. They're like, yeah, it's easy to do that. There should be phase three because level one seizures or severe seizures like that. They don't, they're not life threatening in the way HD is. There's already standard of care that can control a lot of the symptoms. Right. They're not completely stabilizing to someone's life. They can be, but they're not usually thought you feed so mechanisms quick too. Right. Did you have a seizure? Did you not? Is you not? Right. You figured out really quick. Do not, you're not being like shown off the plank or off the cliff to die. Right. Especially when it's up there. treatments around that can help. So it should be phase three. Parkins and Steven too, you can argue, can go to phase three. Why is that? Is it's a big enough population? Big enough population. You're just looking at specific motor symptoms, which is like, that's good enough. Like you're trying to figure out very simply. You can make an argument that it shouldn't go to phase three, but you can also make an argument that's going to phase three. Huntington's, it's just because you have this specific cohort. You have this very specific cohort that you are in leading them to die. And if you're in, forget even a patient signing up. If you're a neurosurgeon, how do you participate in that placebo? I couldn't. Right, I'm going to lie to a patient and say, you know, you should participate in this trial. I know you're going to die. You'll never be able to get this drug because you're in part of the placebo group. But I'm telling you that you're not part of the placebo group. This is part of why I think if you want to do an RCT, you really have to do an RCT, it's got to be proper, right? It's got to be double blind. No one can know what's going on. You can't, like you can't just be in surgery for three hours when other people are in surgery for 14. You got to really do it if you're going to do it. I think the reason the FDA didn't say you have to do that is because if you say that out loud, you're a fucking schmuck. Like no one in the world actually thinks that's a good idea. Right. So, yeah, I mean, I personally think if they, I always, let me just wait, forget the surgery needs. I think it's unethical to do a phase three. If someone came across, if someone came up with a pill that is dual suppression, which won't happen, but let's say someone did, let's say a company did in 30 years. Okay, and you had the same TFC 913 cohort issue. It's unethical to do a phase three trouble a pill. Because of bad luck here, you're leading them to die. And they'll never qualify again for that drug. How can you sit there and push someone to death? Yeah. I would say just circling back to your Parkinson's example. I would say it would make sense to me logically, if you said that there's a drug that can reduce the movements of associated Parkinson's, that could be phase three. But if you truly had something that could stop the progression, I'm not sure that I would, I mean, logically, it seems like that should not be phase three either. Unless it was somehow like really quick feedback. I don't know. I would agree with you, but I'm more, I would say, more simple, like open to it. I'm more open to it. I'm less open to HD because, once those toxic cells become truly toxic and are all over your brain after that certain core, like there's no going back, man, like you're dead. These are going back from Parkinson's though. Nobody's come back from Parkinson's, right? I remind you. No. It's not like you're building toxicity in your brain though. It's a different kind of, again, it's very motor based. The thing with HD is you build up this toxicity and you first go your executive functions, next go your motor and then like next thing you know, you're self-actualization leaves, like you kill yourself. Best route. So you know, you eventually all your organs die, except for HD or, yeah, there's no going back. Like once you're outside of that core, like your finish man. And if you don't get that treatment, that's what's really sad about the whole situation. If you don't get the treatment in the right time, you're done. Like it impacts your entire family, whole family. So it's a little bit of a different situation in Parkinson's. Parkinson's is motor, it's control, uses similar tests that HODEC does from a quality of life perspective. But you're like 80 years old, you're 75 years old. Like you're not in your working prime supporting a family, okay? And they, you're not going out killing yourself. Like you're not creating, there's no toxic fragments floating in your head that is causing you to die. So it's a little bit of different situation. But yeah, I think there's a case where that shouldn't be face to be either. And NFL progression is actually, I mean, that's, that's like a measure in Parkinson's, right? Yeah. And A L I and I believe all zombies. It's almost all neurodegenerative diseases, right? And except NFL as the biomarker. Yeah. That's right. Why couldn't they accept that for a certain? Yeah. I have not had anyone tell me why. Why is that not enough for an accelerated approval? Is it because it wasn't pre-specified? That's on the clinical. Okay. So tell me why an NFL reading was not a reasonable biomarker reasonable keyword, it's reasonable. Data point of that it probably provides a clinical benefit to you. Right. If I tell you that as an example, your blood pressure is lower. Low blood pressure, lower blood pressure is a reasonable estimate of whether they're going to have a heart attack. Okay. And there's a drug that reads that lowers your blood pressure. Should it be approved under AA? Not, yes. The example is not perfect because the cardiovascular drugs are as many things around. I'm just giving you an example of something where that is a reasonable signal towards the health of a particular organ that provides some kind of benefit to you. Okay. Should that be approved? Probably. And you should approve it. And if you really want to be careful, you give it to the most sensitive people who are going to die anyway, 1,000, 2,000 people, you submit real world evidence from those people, you update all the databases, you follow them every month, and mentor check ins. And heck, even do a face three trial on top of that. But you do it in a way where everyone gets to dose and you follow them. Yeah. Why watching? Yeah. Well, that's the issue, right? It's not, I don't think anybody is arguing that this needs to be, that AMT 130 should be fully approved and not, I mean, like not monitored or anything like that. I think people are just saying for those of us that want it and for those of you that politically believe in the right to try, can't we try and can't you follow us? And if we don't progress, when everything else in the world would show that we should be progressing in this disease, isn't that sufficient to keep going? Yeah. That's the bar. That's all we're asking. Yeah. But that's what the patients and advocates are asking, right? Yeah. But that's why AA was invented. That's the whole reason for it. If you're not going to, if you're not going to use AA for this, what are you going to use it for? Yeah. And then what does that say about the funding of research in America? Like what are the knock on effects from this? Pretty significant. If it doesn't get the AA or saying if it, like what are the knock on effects from what's going on? No, I'm just saying. I mean, to somebody that's listening to this and thinking about like, you know, what did I'm just saying? Like, there are knock on effects of this. There's a reason the Wall Street Journal is going after Marty McCarry, like crazy right now. And it's not necessarily because the industry has co-opted him or the Wall Street Journal rather. I'll be very honest with you. You have the humanity changing gene therapy here. This is the surrepte from us who are just your feet. This is one of the five big neurological horsemen that changes the basic humanity. If the only disease in humans that mice and mice don't have, okay, we have to give it to mice to test it. There is an absolutely devastating, terrible death sentence. Top three worst diseases in the history of humanity. Saying it right now from what I've seen. Okay. If you don't give something that has the only dual suppression mechanism that truly works, that actually provides clinical benefit, the unicure should have been approved under AA for clinical benefit, let alone circuit. Now you have back to back negative, functional scores against the national history core, against the most devastating disease in the world in my opinion, other than maybe 20 years ago pancreatic cancer. The knockout effects are very big. Biotech farm funding ecosystem, the venture capital ecosystem, rare disease ecosystem, a logical funding ecosystem, all get pushed. back because you don't have a winner. You don't have something that biologically should be approved on the merits, getting to market. And I'm telling you right now, when I spoke to people at that conference who are at your companies, they're nervous. You're like, what the hell is going on? If you're not approving, you need care. We're toast. We're toast because they're not here to compete with you in care. They're not here to say that that their pill is going to go to the striatum and suppress the exonal and fragment and seal up the quote unquote proverbial pipe and stop the brain from leaking toxicity. They're not saying that. They're saying we have a complementary solution that we think can provide meaningful benefit to patients that can help them in their lives. And I'm saying to you that if you don't approve unicure, it's a problem. It's a problem for the United States. It's a problem for the funding ecosystem. It's a problem for everything. This is going to be the biggest thing therapy in the world. You cannot be serious about gene therapy and not prohibit cure. Ask yourself this other question. How does a microcraft company on this size? Because such a ruckus with the FDA because it's serious. You understand that these patient advocates got 51,000 signatures out of nothing. But I was at this conference. They never seen this kind of support from people that no one gave a shit about unimmunities before this. But all of a sudden you have a drug that works and people care. So there's a reason for that because it's like the most real disease modifying drug that we have ever seen in humanity. We are the most right now in 2026. We are the most advanced we've ever been in solving honeydgens. Which is insane. It's truly insane. And so the knock on effects for this are pretty big. My opinion. Pretty significant. Well, hopefully hopefully that the FDA gets a little bit of I wouldn't say religion because I would argue they're praying to the wrong religion right now. But since common sense. I also don't understand the political upside. Right? Like, you know, companies like Unicure, they have a lot of leverage here. So I don't understand why Marie MacCory wants to go through this hell storm. I'm not even sure Trump's being told the truth. He doesn't know anything about HG. I'm sure if he found out about this, he'd be like, yeah, prove it. It's obvious. This is obvious. Why are you wasting time? Right? I don't know what the political upside is. I don't understand what the reputation of upside is. Right? Like if you're a sod or MacCory and you're getting money from our adventures, it's like you just ruin your reputation scientifically. I don't care that you want to jump off into UCSF. Like, you think you're getting a job after this at any large biotech company to navigate the FDA? Well, it's the swamp, right? But I don't. Yeah. Right. Well, you go. I point. Like, that's what happens with these guys. The FDA, they go get nice cushy jobs and biotech has funds or biotech companies to navigate the compliance process or to give them some insight, etc, etc. or they go back to academia or they go back to whatever it is. But you're going to be noticed the guy who put up loopholes or not loopholes rather, barriers for one of the biggest drugs in the history of mankind and literally called like Huntington's clinical trial mix in the skull. That's what's going to be lasting from this. You're that guy. And so from someone who who is proud of where they came from, their heritage and their ego and their knowledge and their education and their rigor, right? And their CV. That's the last thing that's going to happen that you're going to see. You're the guy who cannot decipher between regentex bio and unicure. Reppel Newn and Capricore. You're the guy who doesn't understand gene therapy. You're the guy who doesn't understand HD. You're the guy who had your lover boy gone air and stay nixed in the head. That's your reputation. That's your lasting reputation. You can see whatever you want about plausible mechanism. Bloomberg and Wall Street Journal articles are there for life. The internet is free and it's there. Right? But what is the upside? I don't know. So either it's a massively big political this calculation. Maybe it's a total. I don't know what the political upside is for something that works biological. I mean, the only argument that I can think of is the FDA has led too many drugs go through that don't show any efficacy. So we are going to put our flag in the grant as sand or whatever and your trial design better be perfect in order to get anything through. But. Was you putting your pretty good pad on it? It's like the dollars. You don't think the psychedelics trial design or Joe Rogan's whatever that cocktail that he wants to be. I think the deluxe are helpful for a very useful population. But in terms of the scientific biological differentiator to AMT 130, what that does for Arnington is not even on the same leak. That's the thing. The thing is that the people that need this drug need it. Yeah. Yeah. Yeah. Yeah. So to the extent that you're worried about safety risk, this is the exact group that when you have a drug that is promising and they sign off and say, we are willing to take the risk. This is the exact group that I would want as a citizen to be able to take the risk. Yeah. That's right. That's what that's built for. Yeah. Like the whole right to try stuff is for these people. Yeah. Yeah. Well, I think that's a decent place to end this one. Hey, well, the political pressure is going to be pretty powerful. You're going to get a UK approval before the US. You're going to get a Gulf State approval before the US. So you're going to get could patch the care program to cross the world before the US. You're probably going to get the EU before the US. Okay. And the political pressure that's going to happen to explain why are these foreign jurisdictions who are English speaking ish and have semi-American values, right? Why are they approving a drug that doesn't need the for your data and we do and the for your data is going to come out and it's probably going to be okay. What are you going to do then? The institutional political damage you have to have right now is bad. When that comes out, it's going to be devastating. Because then you no longer about sides. Yeah. Good. Oh, yeah. And then you have like Howard Johnson on your ass and Oshin's Lash on your ass and like congressional investigations up the ass. Like, you want to talk about winning the war against China and biotech? Are you like you're a joke? It's a total joke. Well, if you wanted to undermine the FDA, this would be one way to do it. Sure. Yeah. Yeah. That was like your big Macchi-Vellian plan. Yeah. And maybe there is something I hate. I don't know. Like, maybe somebody's playing 3D chess on a bioweiro. No, I don't know that that's 3D chess. The idea of running it all down is not exactly 3D. I think it's pretty 2D to be honest. It's checkers when you should be playing chess is what it is. Yeah. I think you're right. Yeah. Yeah. Dressed up as intelligent. Oh, well. Here's to hope in that some common sense in smarts enters the room sooner than later. Hey, I'm trying to write some blogs that are about biotech and I try to spread the word on cure. You know, I've done a lot of work on this and I'm trying to break down as simply as I can, which sometimes it's a very complicated disease. Very, very complicated. And I'm trying to break it down as much as I can. But I would not be this passionate about something if I didn't think it. It's real. And it works. I've seen a lot in biotech and I've seen companies try to go after greenfield opportunities that don't have standard care that meet the clinical endpoint. But like, you could kind of question whether or not this thing works. This thing is crazy. It is going to be very interesting when the four year data comes out. And it's going to be very interesting when we hear what patients will have to say in Q3 about what this drug is all about. And I think you've seen that preview with Tabrizi talking about certain patients. She's pretty much done like working on symptomatic patients and she wants to work on pre symptomatic or it might making that up. I think she might have said that, but she did also provide an inclination, but there might be some proteostatic repair that might not be outlier. Yeah. It's okay. I'd be very interesting when we find out more patients like that. Well, there's no evidence at all that this works. So there's that. Don't forget no evidence. Make sure you say that in front of Timbery'sine wild and Victor's song. Just make sure you say that. Yeah, that's right. Well, we'll see till you return. Thank you again. Yeah, it's hot. All right, man. I'm gonna hold you to that. Okay, of course. All right. >> Yeah. >> Yeah.