FF94 C3 Glomerulopathy with Carla Nester

For me, it's handling patient expectation. If they know that they're entering a trial and there's gonna be an IFC now and a biopsy now, they enter the trial knowing that, and I think that that works fine. But I don't have a patient tell me, no, you can't have a biopsy. I do what I need to do to make them comfortable, make them safe, and tell them why this is important to me. And I think that managing those expectations goes a long way. - Carla, I can't get my patients to take a flu shot. I don't think it's a vehicle. (laughing) - The second biopsy. (laughing) (upbeat music) - Welcome to another episode of "Free Lee Tilt" the regularly irregular podcast where we summarize and discuss recent NFJC journal comments. NFJC was born on Twitter, raised by nephrologists, and fueled by the radical idea that journal often didn't do the conference room or even pants. What started as an experiment in post-obocation peer review is grown into online home, some raise visual abstracts, interactive chats, newsletters, and podcasts focused on the research and ideas of thriving and developing people. This podcast is for educational and entertainment purposes, only it is not an medical complex. If you have questions about your own health, this is very much not a place to find answers. If you're looking for a relic in journal club, the sky's as a podcast, welcome. You've found your people. This episode may include discussions of off-label and unapproved medications, considering this, your reminder to engage your clinical judgment in a healthy degree of skepticism. Hello, my name is Joel Poff, kidney boy on the socials. We got a full crew tonight, Sophie. - Hi everybody, I'm Sophia Ambruso. I have relocated, so I am no longer in Denver. I'm in Boise, Idaho with private practice, Idaho Neuphrology Associates, and happily here, seeing a lot more patients and doing a lot less administrative work, who comes up. - You're still working at the VA, don't you, right? - I am actually, and I just got my badge after working here for five months, coming from another VA. (laughing) - How many times did you have to go to get the cod? - Well, I just got at once, but I did go today to start clinic and I couldn't get into the computer. - Exactly, I could have thought. - The VA is consistent all around the country. - You're right, cosy. - Going strong. (laughing) - Natalie. - Hi, I'm Natalie Frieden. I'm the program director at Medical University of South Carolina. I am still in Charleston, and it is so hot that it is not possible to go outside these days. So you find me in air conditioned comfort with the Bayles. - Excellent, perfect, AC. - Hey everyone, I am AC. I am a fellow for 34 more days. - Woohoo! - Finally in a day. (laughing) - Current transplant, apology fellow of Mass General and MedPeds. Now board certified MedPeds Neurologist. - Me! - And I have no conflicts of interest tonight. - You have passed all three of those board tests. - All four of the board tests. - Medicine, pediatric, oh, Neuropeas, adult peeds. Oh, that's amazing. - Oh wow, amazing. - I was just saying you've been amassing lots of children and pets in the meantime though, right? - One child, but lots of pets, lots of two dogs, two dogs, yeah. And now I basically moved out to a farm, so we'll see maybe some chickens. - You're a farm now? - I basically moved out to a farm. - Cool. (laughing) - And on day 35, do you have a job? - I'm gonna take two weeks off. - And then you come back to Mass General. - I'm coming back to, I'm gonna be in Mass General, I'll bring him in Boston Children's. - Congratulations. - Awesome, congratulations. - And is that mostly a transplant job? - Yes, primarily. - And mostly kids or mostly adults or? - Mostly kids, but some of both. - Nice. - All done, I'll play it. - Excellent. - So, hey, I'm Swapnallinamut, I'm a nephrologist, I'm an adult nephrologist, only trained in adult nephrology in Ottawa, Canada. I'm a Swapnall on the socials. I don't have any conflicts, not only am I in not a G and export. I think C3G did not even exist when I went, did nephrology, so I'm going to be extremely ignorant and ask a lot of naive questions. - Good that you are ignorant 'cause we've got the world's expert. - We have a special guest, a carolanaster, Carla, introduce yourself. - Hi, I'm Carla Nester, I'm at the University of Iowa. I am a professor of internal medicine and pediatrics. And so, even this many years later, I'm still keeping all four of those boards up. But, so I actually, and what they call a complementologist, I do spend some time in the basic science lab, but lately, because of the clinical trials, I spend a lot more time that I ever wanted to in the clinical trial setting. And in fact, I think it's fair to say that we've tried almost every single complement inhibitor that has come out there for C3G. The only one we actually didn't run in the trial was an orsople map. And that's because we didn't believe that Electin Pathway was the correct direction. - A pinion. - Okay, excellent. So we have three med kids people on this podcast. Two of them have actually done the work and did pediatric nephrology. I did not. I took one look at that and was like, "No, turn around." (laughing) "I told you, where did you from medical school to like, "How, what's that story look like?" - Sure, so at medical school was at Penn State Hershey. And then because I was med-peeds and looking for a good med-peeds program, I actually ended up choosing University of North Carolina. So at Chapel Hill. And that was because it was a very well-integrated med-peeds program at the time that I was doing training. It just so happened that there really cool guys there were nephrologists. So that's how I ended up in nephrology. I didn't go there to be a nephrologist, but then also, incidentally, they were a well-renowned glomerular disease center at the time that I joined them. So that's how I ended up in nephrology and then as a glomerular disease physician and have practiced basically glomerular disease my entire life essentially. - But why aren't you an Anca specialist? How do you do that? - No. - Jump the compliment. That's the wrong, that's the wrong glomerular disease for that. - Yeah, well, I was trained as an Anca specialist and of course worked in the lab doing that. But you know, my senior year, a Charles Jeanette was one of my mentors. And one of his research texts knocked out factor B as in boy in their Anca mouse model. All of a sudden the mouse model didn't get Anca. So now all of a sudden we're calling this Posse immune disease. Maybe it is compliment related or compliment mediated. And so Charles looked at me and said, "Carla, you're the senior fellow. "I was the fourth year fellow." And he said, "Okay, it's your job to figure out "what the heck is compliment doing in our disease." Quote, unquote. So I spent my fourth year of fellowship studying compliment. - In this Anca mouse model? - Well, in general, what is it doing? Yes, but yes, in that model. So residency in fellowship at Chapel Hill and then came straight here to Iowa. And I came here to Iowa because I wanted to get back to the Midwest. So it turns out that this center is about five hours north of where I wanted to be. But turns out they were doing a lot of basic science in the compliment field. And so I just spent a year studying compliment so it made sense to come here plus as a med-peats person. They were willing to let me build a Glamariler disease clinic. And that was one of my, you know, check boxes as I was deciding what I wanted to do. So it all actually fell into place, right? Right at the right time. - Outstanding. So we're gonna be talking about the valiant trial. And this is for C3 Glamarialopathy. - Immune complex. - Immune complex, Glamarialopathy. You know, this is kind of the, I don't wanna say it's the end of the chain, but there's, this has been a disease that we have tortured with different compliment inhibitors. We've tried to go at it with aculismab didn't do much. We tried a vacapan, didn't do much. We tried dynacapan, which is a factor D inhibitor, which I had not heard of until I was kind of reading about that. That didn't do much. There's another study that was published very close to this one looking at a vacapan. - That has some biological activity. - No, clearly. - It's out of cap. Peg set to coplan. - Exaticoplan? Would it swap you at a different way? I'll say how do you pronounce it? - I said pexetaclopan. - Headsetacloplan. - But Dr. Nestor, maybe the right person. Yeah, yeah, Carl, what do you got? - I've called it very many different things. And often it's just Peg, Peg seticoplan. I think is what I'm choosing right now. - Yeah, Peg, Peg. Yeah, Peg is good. Just like we, you know, - Peg is good. - Yeah, Peg is good. - Peg for the cool kids. - Peg is a bad, right? Yeah, Peg gets. This one seems to have worked. And it's interesting is you've kind of looked at these different couple of minipers. As you've got to go up the ladder and you get more and more proximate, you get more, it's more and more effectiveness. It's almost as if you want to stop the lead, turn off the faucet. That may be the best way. - Can I ask a question before we go into the therapeutic? Like when I went to, again, I'm not trying to date myself, but it was just MPGN. Right, we had type 1, MPGN, and type 2, and type 3, C3 didn't exist. Like we had to understand, and the terminology has changed. So what can you, again, all the new, you know, the freshly trained people know all this, but can you tell us something about that journey as well? Because I think that was essential for us to understand what could work, you know? Like Joli's talking about these new drugs. I remember, you know, steroids, cyclophosphamide, antiplate, it's all kind of weird stuff being thrown at MPGN, none of which work. - Yeah, so the simplest answer is is that PGN2, so became dense deposit disease. And the reason it became dense deposit disease is it turned out that probably only about a quarter, maybe a third of those patients actually had MPGN. So it was really inappropriate to call it MPGN2 at that point. And so it gained its new name, and then you were probably aware of, I think the publication in 2007 from the French group that said, "Oh, wait a minute, there's this other thing that is C3 predominant or even C3 isolated." but it's not dense deposit. So they call it GC3P. It subsequently got the name C3GN later, but it turns out they're not all MPGN. In fact, that's one of my soapboxes. We need to change all of our algorithms that start with MPGN. We need to say proliferative glomerulin nephritis and then work down and decide whether it's MPGN or not, because especially in children, many of them are misangil proliferative in the beginning. They're not split basement membranes yet. - Interesting. - Was there a patient that you had that got you interested in this particular flavor? - Yeah, my first month on service. - Has a mental state. - No, as a new staff member, I had just biopsy to patient. And my pathologist called me. I started my new staff job in July and I was on service in August. My pathologist called me on a patient, I had just biopsy to and he said, "I don't know what this is." There's like all kinds of C3 deposited on here. There's nothing else there, but it's not dense deposit disease. I don't know what you want to do with this. So I had to figure that out. - You had a patient with C3DM before it was a disease, a well-known disease entity. - Well, they published it in May. Luckily for me, I saw my first one in August. So I had their report to go back to my pathologist that maybe it's this. - Oh, that's pretty cool. You need to know I'm at the collar disease. It needs to take that over now. (laughing) - That's actually what the C stands for, right? (laughing) That's what we're being taught now. (laughing) - No, to be fair, to be fair, the French group did publish it. I believe it was in May because I was able to refer to their publication to sort of help me figure this out. - And then how did this journey with these therapeutics that Joel mentioned? How did that happen? Like how long and anything you can share from your participation in those trials? - Well, we were one of the first groups that started using Ecculizabeth back in 2010, 2011, when it first became publicly available, if you will. But we knew because of the animal models that C-3-glomeral opathy, it is a disease upstream. It's not a terminal complement pathway disease. So it didn't work, or it half worked. But I will say that the director of my lab, I'm the associate director. So he's the director of the lab that I work in, has been working in this area for a long time. And they know by in vitro studies that there needed to be an upstream approach, if you will. So blocking where the convertases work. And then I'll refer to the UK group because they created, I believe, two mouse models. One was a factor H knockout, which is the mouse model we all use in the lab to study because it has C-3-gN. Then they also knockout factor B is in boy. And they discovered that that C-3-gN mouse model no longer had the same C-3-gN. It would seem to be ameliorated, if you will. So, and then there have been C-3 knockout rats and end-and-and. So-- But early on, you had a good idea. This is a target. This is what if we could stop this. Yes. This is going to take care of it. Oh, that's interesting. Can we briefly-- because I feel like when we're really comparing the two C-3-gN interventions, it's mainly the pegsetico plan in the Ibtapecan. And I know that Ibtapecan is acting sort of on the C-3 convertase, correct? But the pegsetico plan is more targeting both the classical pathway and the alternative pathway. It's a good question. But the convertases are made of C-3 and factor B. So the convertases would in theory be a target for both drugs. But you bring up the point that if-- since C-3 is a substrate for the classical pathway, if you're also blocking C-3, it's blocking the convertases, yes. But you may have an effect on the classical pathway. And if you speak to the sponsor-- again, I'm not saying this because I know internal information-- but apparently, they designed the drug to have partial effect on the classical pathway. And I don't-- you know, profess to know what that really is or what degree, if you will. But it does appear to have some effect on the classical pathway. I'm going to assume there are a lot of listeners who haven't thought about the classical of the lectin pathway, the alternative pathway for a long time. So I'm just laughing right now, thankfully. So we're on the same page. Can you give us a very brief description, 20,000 foot view? How would you explain to us six-year-old the differences between them? Yeah, so it's hard to do in a very short. But let's just say classical is triggered by immune complexes. Lectin pathway is triggered by moieties-- you know, pamps and damps, if you will. The alternative pathway is on all the time. But importantly, the alternative pathway is the amplification loop for all three. So that's what makes the alternative pathway an attractive target period, because if you can block it, you potentially could block all three pathways. But it's the alternative pathway that is the center of a disease such as C3G, for instance, or ICMPGN in many of those patients. And again, that's why it would be a target in that setting. I know that was super short. It's the ADHD of all the pathways, just always constantly running around. Constantly running. That's why the regulators are so very important. And that's why some of the genetic abnormalities that again, is into trouble are genetic abnormalities in the regulators. And then if you were to look at those two particular medications, is there anything about one or the other that's going to be potentially more effective? I mean, I was looking at an abstract that was published a while back, or I guess, at ASN Kidney Week. And it was-- they were trying to use all these fun comparisons that swap knows a lot about to compare the two trials. And it looked like they thought that pegs at a cochleon might actually be better than Eptapacan. What in the design of its mechanism of action would contribute to that? Yeah, I honestly don't know for sure, but you're right. Just taking at face value the end points that were offered in both of those trials, it does appear that pegs at a cochleon could be the stronger slash more efficacious drug, if you will. I don't know if that's because it-- one's a small molecule, one is not. Does have that extra feature of being potentially affecting C3, which may have more of a global response, et cetera? I don't actually know for sure why, for me, on a very simplistic level, they both block the convertases. So that feels like the right thing to do. And thanks, Nat, for asking the question that all of us had. But using the readers as an excuse. But the alternate-- it's a misnomer, right? The alternate is maybe-- is the most important. It's not really an alternate pathway. It is like the baseline pathway, or the always on pathway, or something. It's part of your innate immunity. It's the one that kicks in before you've been immunized, before you've been exposed. It's your first line defense, whereas the classical pathway depends on an antibody having been made, and an immune complex, et cetera, et cetera. So it's a very basic part of your innate immune system. The classical pathway plays a role in innate immunity, too. I don't mean that. But it's a very basic part of your immune system. What if you're a parent and you're constantly exposed to the kid's cuties the entire time, which one is more active? Any opinions for our scientists? I'll turn you into a package. Kids are just the constipation of exposure. I mean, right. Swapples can start running. We are not going to miss Nyan with you, then, Nat. She's just-- [LAUGHTER] So methods. So this was a phase-- we are discussing the valiant trial of pexetaclopans. So this was a phase three double bind randomized placebo-controlled trial. It was conducted in 122 centers in 19 countries. And when you'll see the number of patients who were recruited, you will see that the number of centers is very close to the number of patients. So presumably, some centers may have had maybe one or maybe none randomized. Again, this is a rare disease. No, no, this to anyone. So the trial had, as far as the design is concerned, there was a 10-week screening period, a pretty long screening period. The 26-week randomized controlled period, where the intervention and the blinded control was given. And this was followed by a 26-week open-dabel period, presumably where everybody got the drug. And then there was an eight-week follower period for patients who did not enroll in the long-term extension. So I guess patients at the end of the 52-week were given the option of enrolling in a longer-term extension so that everyone gets access to the drug. The patients were enrolled in a one-to-one ratio. We've seen a lot of GN trials. Now we're all becoming experts at evaluating GNRCTs. And they're all longer than 26 weeks. Right. The IG is typically nine months and then nine months for a protein Newriah and two years for GFR. So Carlo, what was going on here? Why are we doing a 26-week trial? Yeah, it's a good question. And you all may know that even before these trials were actually created, there was lots of discussion around that. But the problem was, is that our regulatory agencies wanted placebo control, right? Yet when you're talking about a disease that goes to end stage as quickly as this one goes to end stage, and our inability to find who that is that's going to go to end stage quickly, there was quite a bit of discomfort understanding whether you could even recruit to a trial that actually was going to run for 52 weeks instead of a 26-week placebo control. There were subsequent meetings with the FDA to sort of sort that out. But the bottom line is, is that also that we had to tell the FDA what was going to be efficacy at 20. weeks, which, you know, becomes important, right? But even before the trials where we reported out, we had to tell the FDA or the regulatory agencies, not just the FDA, the EMA, et cetera, et cetera. We had to tell them what we thought was efficacy was going to be measured by. So that was the standard and at high risk disease, if you will. You were part of these discussions, I take it. On one side of the table are the investigators. Did not have to work with the FDA. What would have been your ideal leg? Would you have been shorter? I will say to be fair, you know, it was actually where we were all in a room and I won't say one side of the table. We were all on the same side of the table. Okay. I do want to say that. And I do understand where you're going with that. So what I thought is that let's say if you go into a trial in your C3 is 10 when 90 is normal, I personally felt like you had to normalize your C3 if we're shutting the alternative pathway off. I thought that you needed to see. Yeah, but the FDA was never going to accept that as an end point. Oh, no. Of course they were. Yeah, but you asked what I wanted. No, I know. I know. Yeah. A hundred percent. A hundred percent. Yeah. So you wanted you wanted to see biological proof. I wanted to see biological proof and I wanted to see what happened in the animal models. I should have given my bias. I've come from a biomarker lab. So I definitely believe in these biomarkers that can tell us a good story. Anyway, I wanted to see that we could actually normalize the C3. I also wanted, of course, to see what happened to the histology because you didn't mention, but there were biopsies at 26 weeks. I also wanted to see what would happen with histology. Now, you're a hundred percent correct. The FDA is not interested in the, I mean, that's background noise. They are interested in that, but it's not going to get an indication. What they wanted to see is that there was clinical benefit that, you know, either in the urine protein or in the GFR because again, is as a group of patients is losing GFR points, you know, practically daily, if you will. So they wanted to see improvement in prognory and GFR as the major end point. So that's how the discussion went is how are we going to sort of mishmash this together so that we're both kind of satisfied. The open label period, not correct me. I think I'm wrong. In open label period also, they got Pexitaclopan and placebo. At 26 weeks, they transitioned to everybody was on drug. Okay, everybody was on drug. Perfect. And on this point of the trial, I don't want to segue off, but remember if you in the HUS, the TMA, Ecclizimab, they didn't even do a placebo control trial because that disease is so nasty. And, you know, again, my bug is that it's so expensive. They never did a trial and they claim, you know, we can never do a trial. So again, this is not as bad as TMA perhaps, but it's a pretty rapid loss of GFR. So that tension is there. Like, if that is an efficacious therapy, you don't want to deny patients from getting that. So you want an answer as fast as possible. But it was not, it was placebo plus usual care. And they had a lot of patients on immunosuppression. And exactly. I imagine was Michael Phenolite-Mafatil and steroids. I'm guessing. Yeah, up to, I believe they allowed up to 10 of steroids. You'd have to confirm that, but I believe they allowed up to 10 a day of steroids. So yes, Michael Phenolite and steroids. So this was technically an add-on therapy. Yeah. From really close. Exactly. So it's a placebo or intervention on a background of standard of care. Usually care, yeah. Usually care. Okay. So the randomization was stratified according to transplantation status and baseline biopsy availability, which will come to shortly. So in terms of the eligibility, you can already see that transplant patients are in. So the trial was designed by the sponsors. So there is epilys, but there are two sponsors. I think there's epilys and soby, which is Swedish short fund biobitrium. So again, I guess there are two companies involved making this or marketing it in different parts of the world. Yeah. Soby is the European arm. Appelices is the US or slash North American arm. Perfect. And they obviously funded this is going to be an expensive trial to do. So patients, eligible patients where either adolescents is 12 to 17 years or adults more than 18 years with the diagnosis of primary C3GN. So again, this is perfect for med-peeds and this reminds me of the fifth-geist trial with Sparcentan, which was also adolescents and adults. So is this like the new thing? I know Michelle Rowe was very excited about when they got Sparcentan trial done. But is this going to be the new thing in GN, especially if you see adolescents to do kids and adults in the same big trial rather than pediatricians fighting over saying, hey, we don't have an evidence in kids. Is this something that you had to fight for or was this like a logical thing? Hey, you know, this disease affects children. So we should have children in the trial. I think your last point is the major point. I think this is a disease of young patients. You know, the median age is a 16 year old. So you really need to think about moving it down lower. In fact, the next set of trials will be down to the age of two, which we hope will open up, you know, here fairly soon, if you will. Of course, the FDA wants to study children, but there's always going to be this burden of proof of safety, if you will. So there needs to be some hint that this is not, you know, that not all the young patients are going to, you know, die within the first month of study, you know, that sort of thing. There were different things that they did to the adults versus the kids. Right. Exactly. Exactly. We'll come to that and I get the safety is fine, but I think it's a little bit paternalistic because then you end up with a situation where you have no data, just like in pregnancy and sometimes in a previously in CKD. So what was C3G? So C3G, or primary immune complex, GN, it was defined on the basis of either a baseline kidney biopsy done less than 28 weeks before randomization or in adolescence, they were in certain adolescence, you were allowed to have a historical biopsy, but then they needed to have active disease defined clinically. So let's try to understand that. So in the base, people who did have a biopsy, baseline biopsy within 28 weeks, they had to have an active disease which was defined as a score of, you know, C3 being 2 plus or more on immunoforescence. And this was reviewed by a central pathologist. So the, you know, they had a recent biopsy, all biopsy is very viewed. For those who had a historical biopsy, which was, you know, hey, this is C3G, you know, two years ago biopsy and they were adolescents, you didn't want to re-biopsy them, they had to have clinical disease which was defined as one of the following, a plasma concentration of soluble C5B to 9 of more than 207 nanogram per liter, C3 being low less than 90 milligram per decilator or active urinary sediment or the presence of a C3 nephrodite factor. So how easy or how hard is to get these things done? Do I have to send samples, you know, if I had to do this, do I have to send samples to Iowa? In fact, for the trial, they could have been done through the trial, if you will, if you needed to prove that. And I'll go back to say that again, you know, this tends to be a regulatory agency thing that they do not want you re-biopsy in a child, just put them in a study. If they've had the diagnosis and there's no reason to think that their diagnosis is gone or that it's a new diagnosis, then they have generally thought that it was going to be acceptable to use a historical biopsy. I will tell you, from a gomereller disease doctor standpoint, I'd rather have had the biopsy yesterday on everybody, right? It would be ideal to know exactly how much damage is on the biopsy, exactly how much proliferation is there, but that's unrealistic, you know, so they had to settle on some parameters and that was just the, you know, the back and forth, if you will, that got settled on. Perfect. So we've talked about these standard of care already. So what that was was our investigators' discretion. So ACE inhibitors, ARBs, flowzins, and immunosuppression. So immunosuppression could be, you know, a microphenolate morphetal or low-dose steroids, less than 20 milligram equivalent of prednisone. And transplant patients, I assume, could be on, you know, whatever immunosuppression they were, and this had to be stable and there should have been no plan to change it during the trial, except that if they were on transplant and sometimes, you know, at one year, you decide to reduce this. If it was all planned, it was allowed. But otherwise, they preferred them to be unstable by ground therapy. One editorial offer here is both for the native kidney and the transplant kidney, the reason I'm offering this because I didn't agree with this necessarily. Both the transplant and the native kidney patients had to have a gram of urine protein. I struggled with, do we make our transplant patients gain a gram of urine protein even though they've got flagrant recurrence of disease on biopsy to move forward. But again, it was a back and forth decision that, you know, that eventually was settled upon. Moving forward, the application of this, you're not going to be pinned down. I don't think necessarily saying, well, like my patient has 0.9 grams of urine protein, you know, lots of proliferation on their transplant. I can't treat yet, or I'm not going to treat. But I think when you're, we haven't gotten to the outcome, but your primary option is to produce your urine. Exactly. You got to draw some pretty hard, hard rules on who you can control. Yeah. Right. If they're exactly, I was going to say the same thing. If they have very low protein duty, I'd be hard to show a change. Yes. If it is low. You're right. Yeah. So what was the intervention? So adults and adolescents who had at least 50 kg received a 1,080 million ampoule picks a tachylopan or placebo. It was a subcutaneous injection, which was either administered by the patient or a trained caregiver twice weekly. Twice weekly is that like Monday and Thursday or something like that? Most often. Monday, Thursday, Tuesday, Saturday is usual. Yep. And what's a volume of this? I think it was like 20 ml, for instance, you know, would be the. Wow. Wow. So it takes about 30 minutes in a few hours. Wow. Wow. And again, subcute is something they can easily do rather than needing infusion centers to give something intravenously. So that is smart. Yeah. But cows are going to start rolling two year olds. That's a lot of volume. Yeah. So again, for lower, for smaller individuals, you know, there was a weight base like if they're 30 to 34, they got 540 milligram. And you're right. Yeah, 540 was 10 ml. So you know, 20 ml for 1080 and so on and so forth. They did need to have vaccinations for strep pneumonia, [BLANK_AUDIO] series, I'm an engineer, it is and he more philous influence of the more than two weeks before. Again, you know, that's is something that is standard in these kind of therapies. The outcome. So the outcome was the log transform ratio of the urine to protein protein to creatin ratio, not 24 are urine. Urine protein to creatin ratio, but they did like three readings. So the outcome is at 26 weeks. So they did ratio at 24, 25 and 26 and they're an equal weighting of the three to use compared to baseline. And then it was specified, you know, it was again analyzed based on pre specified subgroups, which will come to with the results. And then for secondary outcomes, they had a bunch of secondary outcomes, which were tested hierarchically, the composite, in the land end point, which included stabilization of GFR, which is, you know, less than 15% reduction from baseline, 50% reduction or more of urine PCR. And at least a 50% reduction in urine PCR, change in that activity score in patients who had a paired kidney biopsy. I guess, so everyone could have had a second kidney biopsy. How did that work? No, not the kids. Yeah, not the kids, right? So it was, was it like an optional thing only adults, but did adults have to have a kidney biopsy or was it like, hey, do you want to have a kidney biopsy? I do think they had to agree to it. But I think most centers, you know, brought patients into the study with the assumption that the second biopsy was part of the study. So then again, the decrease in either the activity score, in the C3 staining by two orders of magnitude and the change in GFR, these were sort of the secondary assessments very briefly on stats, because we have already spent more than 40 minutes so far. Nayan is not there, but I am on the clock. I know that for the sample size, I have to look at the supplement. And they are sort of assuming that it's going to be maybe 20% reduction in protein urea in the placebo versus 60% reduction in pexataclo pan, based on the discovery trial in which they saw, you know, a certain degree of protein reduction. And based on that, they had needed at least 70 patients with a 90% power, but then, you know, including attrition and all that, they bumped it up to about 80. But then I see that they actually enrolled 124, which is a nice sample says more is better, but did they do more by design or was it something that happened? No, and I honestly don't know the final answer to that. But I think it goes back to something you said very early, they needed to open so many sites just to hedge their bets that they were going to be able to enroll individuals. And so, and they certainly didn't want to necessarily close down a site before they enrolled if they were still sorting through some of that. So I'm guessing that played a significant role there, but I'm not sure. And the 10 week screening process, right? You're right. Exactly. A lot of people are going to be in screening and if they've entered the screening, you can't stop because you have a lot of patients. Yeah. That is a good point. The other thing that is unique about this study is that second biopsy. So what was the discussion behind there? What was it? Why did you need to have a second biopsy? We'll talk a little bit about that. Yeah. So again, it gets back to what we thought would need it to be signs of efficacy, if you well. And again, if you look at the animal models, I'll use the rat model because that happened to be the one where if you if you somehow blocked the ability to continue cleaving C three in that rat model, then within 24 hours, the C three deposition disappeared. So there was this concept that that could actually be improved based on animal models. Then you go to the activity score, for instance, and it's been said that if you can actually reduce the activity on a Gomerular disease biopsy, you are doing something good for the patients. And then of course, you know, you need it to know what degree of, you know, because again, this is a rapidly progressive disease in general, you need to know the accrual of scarring to know how to interpret your urine protein. So I think it was like multifactorial, but the bottom line is is that I think that the study organizers felt like, and again, you know, Gomerular disease doctors, they're going to want to buy up see there needs to be proof that something is happening. Now, we could argue for sure that 26 weeks would not be enough time for something to happen. And in fact, it did happen in the activity score. But I think that there was at least this general hope that that would be supportive information. And you think those two, those are cooperative the fact that it was a shorter study made you lean more than hey, but we're going to get histology, right? Because I mean, those same arguments could be made for IGA and for loop this, but we're just not seeing those studies being done with multiple biopsy. Yeah, that they should be though. And I will say that something similar happened with eculism at those patients, many patients got better urine protein. Maybe it was only over a year or two years or something like that, but their disease progressed. So we knew based on that sort of limited data that decreasing the urine protein was not the only answer, you know, you had to actually be seeking something a little bit more struck, you know, with a little bit more strength in that. Anyway, that was some of the background noise that was going on at the time. But on this point, if we are when we go to use these drugs, would you recommend doing repeat biopsy in patients clinically as well? I would, but I again, I'm glimicking a disease trained. I think we don't buy up see enough technically. And I know, for instance, I my lupus colleagues, you know, Brad Rhoven, et cetera, et cetera, they believe that if we did buy up seen more frequently, we would have a better understanding of what is working, what's not working, even the natural history of disease would be better understood. So, but again, you have to balance that with the patients reluctance or the patients understanding about what you're going to achieve. But in a clinical trial setting, you should shoot for the stars as much as you can, right? Well said. Calla, can I ask you, what do you think the barriers are to getting more biopsies then? Have you seen the needles? They're really well. And loud. I do my biopsies. And so I'm like, I'm genuinely asking because I don't find that it's been difficult to do them. And then biopsies have become lower risk, right? Like we used to talk about the risk, but unless it's RPG and AK or whatever. If they know that they're entering a trial and there's going to be a biopsy now and a biopsy now, they enter the trial knowing that. And I think that that works fine. But I don't have a patient tell me no, you can't have a biopsy. I do what I need to do to make them comfortable, make them safe and tell them why this is important to me. Yeah. Carla, I can't get my patients to take a flu shot. I don't think it's a good deal. That's the two of us. I can buy. I think it's easier and renal and rare renal disease. Let me say that. Yeah, that is true. That is true. I feel like I could commit someone to get a biopsy over a flu shot days days in this kind of. Right. Probably true. Cap tides, pep tides, giving them my pup tides. It's scary. Well, taking a tumouric. Any, I'm not the big, the big picture here is it's a multi center randomized control trial, usual care versus this add on therapy to sub queue injections a week, 26 weeks sprint with a biopsy, the beginning of biopsy, the end protein areas, you're happy. Yeah, you said that that's a DLD out of ocean. Okay. A C this was some results. All right. So the screen 261 patients from May of 2022 to June of 2024. 124 were randomly assigned to receive either pegs at a co plan, which was 63 patients or placebo 61 patients. And we're included in the intention to treat and safety populations. Six of those 124 patients discontinued to in the pegs at a co plan group, which were for adverse events. And then four in the placebo group. And those discontinuations in the placebo group, one was an adverse event, one was withdrawal of consent, one was pregnancy, and then one was patient non adherence at the data cut off date. Two in the pegs at a co plan group had completed 26 week assessments, but not started the open label period. So ultimately 59 patients in the peg group and 57 in the placebo group completed the 26 week randomize control period and continued on to the open label period. And all patients in the safety population received at least 80% of the doses of either peg or placebo. Two patients in the trial needed glucocorticoid rescue treatment, both of those were in the placebo group. And then eight patients had intercurrent events to in the peg group, six in the placebo group. Carla, how good is steroids for this disease? It's not okay. It's not working. This is a podcast. It's not a video. You got it. Yeah, it's an anti prognoric to a degree, meaning if you're if you have a child who's severely nephrodite syndrome, you might be able to take the edge off with steroids, but you can't possibly continue them enough, keep the nephrodite syndrome gone, et cetera. So I would say it's not effective. But but do we all use it in it? Yes, we do acutely. Okay, okay. The characteristics between the two groups were similar. So similar ages, similar number of adolescents in both groups, there was a slightly higher age of the adults in the peg set of Copeland group. So 39 years versus 30 years. And there were slightly more C3G patients in the peg group 51 versus 45 in the, but it's almost all C3G. It's always yeah, exactly. And then slightly more primary immune complex MPGN, but that was 16 versus 12. So mostly C3G, the peg set of Copeland group had a higher urinary protein to create an in ratio. So that group for the spot urine protein to create an in ratio, the mean was 3,123 milligrams per gram versus 2500 40 in the placebo group. And then the median for the peg group was 2389 milligrams per gram versus 1,815. Carla, in my career, I've had one patients with C3GN. When you look at this table one, does this look like typical patients with this disease? Are they sicker than normal? Less sick than normal? there's this kind of usually what you- The problem is, is this incredible heterogeneity. I mean, we all have had patients that walk through the door with 10 grams of urine protein. And that happens quite a bit, actually, frankly, in children that really high urine protein. But I would say, once you sort of start putting meetings on things or averaging things out, you know, it's probably a reasonable group of patients, as far as I'm concerned. But the last difference between the groups was that the Paxedico Blanker, Patastately Lower, starting EGFR, so 78 versus 91, and then 9 of the 124 had a kidney transplant. The other thing is that the authors know that the demographic characteristics align with the reported data on this population. So they felt like this is overall fairly representative, which demographic wise. The number of transplant patients are a little bit on the lower side. Is that because that protein urea number was hard to get? Or is it because of a reluctance for transplant patients to end the role? Or is it just not very common? No, it is common. It is common. Yeah, it's common to recur. But I think it's both of what you've said. You know, hitting the one gram without wanting to do something before you get to that gram. But also the risk of placebo might have played a role. But again, we're early on in trials in this setting. So it's possible that that even affected it. You know, people weren't sure whether they wanted to jump in just yet. So in terms of the results of the Pag treatment for 26 weeks, the results in a significantly greater reduction in proton urea as measured by the log-transformed ratio in the baseline urinary protein to creatinine ratio when compared with placebo. The geometric mean of the urine protein to creatinine ratio was negative 67.2% in the Pag group versus 2.9%. So a relative reduction in the Pag group of 68.1%. And the pro-nuria reduction happened as early as four weeks and was sustained through week 26. And the pro-nuria was largely unchanged with placebo. Starlight, four weeks to see that reduction in proton urea. Is that faster than you expected? That seems really quick for that degree of proton urea. Yeah, I agree. I agree. I think, yes, I agree. It was fast. Cool. Which I think represents the targeted piece of this, if you will. It's not going to be that you've suddenly fixed your split basement membranes in four weeks. It's going to be the other pieces of this, whether it's the deposition or whether it's the inflammation, et cetera, et cetera, that you may have impacted. We honestly don't know, obviously, because we don't have biopsies at four weeks, which we could have. No. Which we should have. Which we could have. I can too, as biopsy management. I'm asking this question on behalf of SWAP because I feel like you'll appreciate this. Why pick the log transform ratio? Why was that a really important marker? You know, I apologize. I do not know. Yeah, that makes me feel a lot better. Usually it puts it into a normal distribution. It allows you a wider acceptance of statistics. Exactly. From 1 gram to 10 gram, any other mean, maybe you know, dried up because it's a just cured number. So it kind of transforms it into a more normal distribution. So, yeah. So you weren't meant to know the answer to that. Okay. So, significantly more patients than the PEG group met the composite renal endpoint at 26 weeks than the placebo, so 49% versus 3%. So, on minor, that's a 50% reduction in protein area with stable kidney function within the percentage. Correct. And the difference was mainly driven by the reduction in protein area. So, 38 of 63 patients in the PEG set of co-planker had at least a 50% reduction in protein area versus only 3 of 61 in the placebo group. Then they did a post-hoc analysis that found the protein area reduction corresponded with an increase in those with a UPC of less than 1 at week 26. So, a percent baseline versus 61% at week 26. And a decrease in those with nephotic range progenuria, so of 3 or more 38% versus 14%. And more patients in the PEG group had a stable or improved GFR, which as you mentioned, was defined as a less than or equal to 15% reduction in their EGFR. So, 43 patients or 68%. I didn't quite follow what you meant by that post-hoc analysis. That second analysis you were just talking about with the protein area. Yeah. Basically, when they looked at the PEG set of co-planker, what they found was that, so in addition to this progenuria reduction, when you look at actual kind of more categories. Yeah, more like categorical endpoints. There were more patients who were brought down to a urine protein to creatinine of less than 1. So, yeah. So, more dichotomize, your continuous variable, it also works out. Yeah. And the two kind of dichotomies that they used were less than 1. And then no longer having nephrodite range progenuria. There was a change in the activity score, histologic index that was numerically greater with the PEG set of co-plank, but the between group difference was not statistically significant. And so then the subsequent endpoints were not tested. I got to say, there's a figure two in this study. And it is the most dramatic figure two. They have the C3 staining and it goes from lit up like New York City. It's like the middle of Broadway to the main street USA at two in the morning. It's completely dark. I can't believe that the histological findings were not significant. And it makes me think that we should dump the histological system. You have this drug that statelessly can function reduces the progenuria and proves all the biochemical findings. And this pathological system that was created long before we had any effective treatments that didn't work. Well, maybe it doesn't work in 26 weeks. I think that's-- Oh. I mean, it just looks like product remodeling. Yeah. And to be clear, the C3 deposition-- yeah, the C3 deposition change was statistically significant. But when I've asked what the heck happened with the activity score, maybe it writes with me, and maybe it doesn't happen in 26 weeks. But I also have sort of poked at the people that created that score. And they said, you know what really wasn't meant to do this. I mean, it wasn't meant to be a clinical trial score. That's number one. This is bomb back at Columbia, right? Yeah. And number two, it sort of mishes and matches some things together. For instance, Terry Cook out of the UK would say that, you know, technically, we're double counting some pieces of this. And so maybe that's why it didn't change. The point is, really, it wasn't meant to be a tool for this particular setting, perhaps. Maybe that's the real reason. Because I was actually surprised by that as well. Why didn't it change? Or why wasn't it statistically significant? No offense to the designers of the trial. I know you are part of this, but I feel like that totally threw off the higher article. I mean, it's particularly if it's not utilized for that, why select it? Because it really is then going to mute some of the other really great outcomes that we see. Now they get to say, oh, the descriptive viaps who signals were strong. Joel says they're incredibly compelling to look at that from the immunofluorescence perspective. I agree. Yeah, but you have to live and learn, right? Like you. Next time. Well, we need is a new score that is designed for this. And then you do get to name it after yourself. Right. Right. Right. Which is totally cheating. Now that we have the results. It's going to be the nest of school. Yes. The nest of activity index. And we're doing a lot of complement study at your doctor nest. You will have all the biopsies after that. I will say the same thing happened in the other phase three trial. And these trials were just tagged on together close enough that when the second one came along, it thought, oh, we'd probably not include the activity score. I'm being a little bit dramatic about that. But I think the second study felt like it had to include the activity score as well since the first study hadn't been fully reported out yet when it was being repreated. But you're right. We need to figure out a better way to really understand when we've gotten histology response. Is it going to be as simple as C3 deposition or does it also have to be the proliferative piece because it feels to me like it should be, but we need to figure out a better way to quantify that. I'd be interested to see the biopsies from that bail extension cohort down the line and the comparisons then. And maybe that's when they can include that activity score in the comparisons. Are they going to be biopsies then? I'm sure there will be biopsies in some of those open labels because people are moving towards doing more biopsies in this group of patients, but we'll have to see. I should look and see how many flu shots they also get. True. How many are on petal spikes? And they see mentioned this, but the change in GFR, which was, I think in placebo, it was about 8 ml and it was only 1.5 and picks a tackle upon. It just shows you, which is figure S10, Joel, I think you're not rating the supplements these days again. You've got a bad habit. But old habits, rather, you've got into old habits. And this goes back to the point that these people are losing GFR very fast. This is six months and they've lost 8 ml of GFR. This is bad. One month. So you cannot keep them on placebo for long. It's right. It clearly justifies the IGNF property trial. They need it 24 months to show a significant difference in GFR. You see this already. Yes. Yes, absolutely. So in terms of other things that they saw, so that was one of them. There was also, as you guys have kind of alluded to, there was a decrease in the C3 staining at week 26. And that was in 24% of the pegs at a co-plan group versus only 12% of the placebo group. And 71% of the patients in the pegs at a co-plan group, the staining decreased to zero in intensity versus only 9% in the-- placebo group. And then as you mentioned, the baseline to week 26, least squares mean change in EDFR was negative 1.5 in the pegs at a Copa Ingrid versus 7.8 in the placebo. So the least squares mean difference with 6.3. So it really does seem quite impactful when you look at those things. That's huge. In addition, they looked at the serum C3 levels that appear to be higher and the plasma levels of soluble C5B through nine, which were lower after peg treatment compared to baseline. And C4 levels were similar before and after. So can ask our C3 levels because you know, many centers may not have access to fancy tests is like just C3 enough of a biomarker. It came up so nicely. That's why I'm curious. Yeah, I think that you can tell whether your patient is in theory shutting off alternative pathway, you know, cleavage of C3, if you will, because those patients in the pegs at a Copa Ingrid study got super normal C3s. And that's a very easy lab. You can order locally. There, there may be some fine points that you don't able to pick up by just looking at the C3, but honestly, since regulatory agencies don't accept biomarkers anyway, you know, I think you're fine, you know, monitoring with the C3. Interestingly, in my other life, I also use the C3 to help me think about compliance, frankly, since this is a drug that's used down to the age of 12. If I have a young patient who's C3 is 280, and then, you know, three months from now, it's now all of a sudden 20 again. They're not taking the drug. You know, that's, that's not an official, you know, response related thing, but it's definitely worked for me at least a couple of cases. In your experience, do you know how quickly that sort of changes? Like in the sense that we see a relatively quick change in almost everything in this study, but in terms of patients who are kind of, you know, now compliant with their medication, like how quickly do you tend to see that change? Yeah, I don't know for sure because we haven't been testing in these patients that are now on prescribable med, if you will. We haven't been testing them every 30 days or something like that. But I have recently taken a patient off a pegside co-plan, and within 60 days, her C3 is back down into her baseline level of C3. So it does potentially happen quickly. Now that's an end of one, you know, so I don't know if that's what would happen with many of them, but it can happen fairly quickly once you clear the drug. You know, you supposedly make five grams. I don't know if you know this, but five grams of C3 a day, your liver should do that. So if you have an undetectable C3, that's five grams of C3. You're chewing up every day. Wow. Can I donate mine on the black market? You probably can. And maybe then patients will be like, yeah, okay, this is a value of commodity. And then you can sell it as a peptide, just for this patient. Yeah, I think we're on to something like I think for the people that don't want vaccines, you can sell it as like kind of like a alternative. If you will, more fuel for the fire. So to say, not a good idea. Okay, that's is not a good idea. A lot of people are walking around with the big long black jacket. You know, the part of the model I'm going to say this is not medical advice. That's what it's for. This is definitely not medical advice. So in terms of the adverse events, the incidents of adverse events were similar as were the events considered by the investigator to be related to the trial regimen. So I have 40% versus 43% and then serious adverse events were six per group, so 10%. Infections accounted for adverse events in three of the patients in the paxetical plan group. And in terms of what those adverse events were, they were COVID pneumonia and influenza, one of each. And then in one patient who received the placebo and that was a viral infection, there was one death. So one patient in the paxetical plan group died from respiratory failure that was associated with COVID-19. And there were no serious infections caused by encapsulated bacteria, which is obviously kind of the big one that we're all looking for and no cases of allographed rejection or loss. But all these patients were all these patients were it. Yes. Yeah. That to be immunized. Yeah. Yes. And that's that's what I have. And Carla, can you just, can you talk a little bit more about the infection risk? What have you seen? I mean, it looks really good here. Looks like almost impossible. You're good in this list. Yeah. You are exactly correct, though. We're going to need real world data. The same thing happened with ecuilizmab therapy when it first became available. There weren't, you know, infections. But then once you start accruing real world experience, we may see more. But I agree with you. This agent is appeared to be quite safe, infection wise. Again, as long as you follow the rules, you immunize your patients, some patients were placed on antibiotics. If the local provider wanted to, I don't happen to be a big fan of that. So none of my patients have been on or are on, if you will. It seems to be fairly safe. But it does require in my mind a fairly nice surveillance plan. You know, I live in a rural state. My patients may be five, six hours away from me. They need to know what they need to do and how quickly they need to do it. If they have fever and it's not an obvious conjunctivitis or, or, or, you know what I mean? If they've got a fever, they need to know what they need to do and they need to do it quickly. But I would say that my experience has also been that that it's been a fairly safe treatment approach for these patients. Right. Going back to, we have two medications available now for these entities. What do we select in for whom and why? Yeah. So the simple answer is is that you've got a pediatric patient. Now you'll have to use a pegside a co-planned. The Epitokopan pediatric trial down to age of 12 is ongoing, you know, eventually they'll report out. And Epitokopan is also the agent that will go down to the age of two here, fairly soon. So point being is that you've got a pediatric patient in front of you. You're going to shoot for the pegside a co-planned now. Then honestly, you know, it's it's balancing efficacy. Okay. Is efficacy going to win out over patient choice? For instance, maybe your patient is averse to needles and on there's no way I'm giving my own medication at homes, et cetera. I will say that there were clearly in the Epitokopan trial, there were home run patients, meaning they normalize their C3, their nephrotic syndrome went away there. Your protein is completely normal. Now their inflammation is shut off. Their biopsies look exiled, et cetera, et cetera. So you do have the possibility of making that choice based on some patient driven reasons if you want or or not. You know what I'm saying? Obviously, if you're going to go straight for efficacy, you're going to choose this agent because that's what we're seeing. And then what we need to do is moving forward is see if any one of them has real world data that ends up being important to us. But right now there's nothing. There's no hints in terms of which patients may have that home run response. Unfortunately not. You can't predict it. Unfortunately not. And that's on us, those of us in the biomarker world. We should we should be able to figure this out, but we have not yet. I will say that patients with really low C3s tend to respond to both drugs equally, if you will. But there are, you know, there are flavors of that that the answers no. It's tough right now to tell her dick to is going to respond. And are there, again, we're looking at this data from 30,000 feet. Were there people in this cohort that were non-responders? I assume so now you may know that in clinical trials, there is one of the investigators, if not two of the investigators that is exposed to the entire data set. I was not one of those investigators for either trials since I was one of the main PIs, if you will. But I have to assume that there were non-responders in both. And I will say, you know, honestly, since the drugs can be prescribed or even since I've been using them compassionately, I do have non-responders in both sides. Okay. There's different phenotypes in this disease. We just got to be able to tease it out. Particularly in the ICMPGN, since that was part of our, you know, this trial, particularly in the ICMPGN group of patients. There seem to be a lot of the phenotype that we still don't understand or can't use predictably. Did they call out the responses of the transplant patients? I know there was only a few of them, like seven of those patients. And I think they were pretty closely balanced between the two arms. Let's see. Yes, they did. So in terms of the transplant patients in the group who had a post transplant recurrence of their C3G. So in the Pegsedico Plan group, there was a negative 49.2% change in the UPCR from baseline to week 26. So 49.2% reduction versus the placebo group where the change from baseline to week 26 in the UPCR was 44.7%. So the relative reduction in the UPCR and the Pegsedico Plan group versus the placebo was 64.9% in terms of the group with post transplant recurrence. So very similar to the whole. Very similar. Yeah. Just as effective in the transplant patients as it was in the transplant patients. Yes, absolutely. Which is wonderful and amazing. Yeah. Yeah. All these subgroups line up very nicely on one side of, you know, for such a small sample size and when you're slicing and dicing, it's not unusual to see some groups cross one. But in this case, you know, they're fantastically aligned. So it's like a really powerful drug with a with a big effect. Yeah. Yeah. The Pegsedico Plan, that's the infusion. And then it's a monoclonal antibody. Is that right? No. No. It's a it's a pegelated. Yeah. No, it's not monoclonal. Never mind then. It's like a pegelated small molecule. Twice week. It's not pegelated enough. Yeah. So is that is there any movement to try to make it even longer acting? Like, you know, we've got from Ecculismab to I don't know, Raveenu's Imab or whatever. Yeah. It doesn't surprise you there are places in the world that are experimenting with that. Once a week, there's even been at least one publication in that direction that there may be some efficacy that way. But again, pharmaceutical companies do. They do their baseline pharmacokinetics, and this is what they decided needed to be done to maintain what they thought was in vitro efficacy, obviously. But anyway, I'm sure, just as we did with Ecculismab, we'll be finding all kinds of creative ways to use the drugs. Yeah, exactly. I mean, to me, this is as good of a result as I've ever seen in a G-ED trial. I really can't remember results as much of a home run as this is. That's really pretty amazing. Very exciting stuff. I'm curious to you see in the patients that are non-responders in your experience if you have checked C3G levels in them. Do the C3G levels change, but they don't respond or do they not change at all? Yeah, in general, they have had what I would have classed as a biomarker response, meaning their C3s go into the supernormal range, yet they don't appear to have a clinical response. And obviously, I was placebo controlled, so I was blinded for part of the study, but I did have one or two of my patients that did progress quite nicely during the pegside of co-plan treatment phase, if you will, even though I thought that their biomarkers did look improved. Now, the problem you run into is that, meaning compliance would appear to be good to me. So it was true not efficacious for that particular patient. But again, that's also not a surprise. We never have a medication that is 100% effective in all individuals, right? So the onus is on us to go back to the drawing board and figure out what happened or who is that patient? What marks that patient? Is there something more, not just complement mediated here, that sort of thing? Yeah, so we have, in Canada, I don't think they've got full approval yet, but we have got compassionate access, and we are using it in the few patients that we have seen. This is one area where even if they are expensive, it's something that we should fight hard to get access, because if the kidney fails, there's transplant, but these patients, even if they get a transplant, there is such a high risk of recurrence that it's not like, hey, just get a transplant and whatever, it's not like that. Yeah, you haven't changed the underlying complement problem. So it is going to come back in the transplant if you've got ongoing complement dysregulation at the time of placing the new kidney. And what is your practice now? If some of these patients do get a transplant, do you wait for recurrence or do you give it prophylactically? I know there are no studies here, but what do you do? It's a great question, and it's a publication you'll see from us coming up here fairly, and we think we can predict too, or we'll recur. So if we have low inclination that they're going to recur, we don't do anything. We wait. If we have classically not been a prophylactic program, though I will admit, I've put my first patient on prophylactic just recently, but it's because she lost her native kidneys with chryscientic GN, and she lost her first transplant with chryscientic GN. So nobody would even take her, would even consider retransplanting her. So I'm playing that game of, can I block her? You know, can I get her to a point where somebody will agree to put a new kidney in or that sort of thing? You know, there's a certain percentage of these patients that don't recur. So if you do put them on prophylactically, what's your stopping point going to be? How are you going to know whether you had efficacy there or not? Because maybe they weren't going to recur anyway. And how soon, how does that timeline work? And if you are monitoring for recurrence, it's like it's protein media the best way, or can I do weekly C3s? What happens first? Press historically, we've used hematuria. Once the stint is out, if they develop hematuria, the presumption is that they're developing proliferation again. And again, that's a soft call. But so once we see hematuria, then we start watching closely. We may be even though this is very unusual in C3G to trigger a biopsy for hematuria. In a transplant, you may want to reconsider that because there has been a recent Columbia study that said that 89% of their patients recurred within two, I don't remember the exact details, but it was something like within two years. And the vast majority of them did it within 33 days. That's crazy. Yeah. So the recurrence is high in a certain group of patients. So it probably means all of us to consider protocol biopsy. But hematuria is fair. If you're monitoring for hematuria and you're not getting hematuria, you're probably not getting the proliferation. But again, that's my bias. Thank you. Awesome. Any other final thoughts? Okay. Tubular secretions. So this is the part of the podcast where we unwind from the fr脏ji, talk about any kind of other media that we've been absorbing as traditions. Do I go first? Yes, I'm so happy Anna is not here. So I am making sure I'm reading BG rated stuff. So this is science fantasy again. It is fantasy. There's no romance in there. It's an author called Adrian Chikovsky. He's written many famous series, Children of Time. I think he's more famous. The one I'm reading is called City of Last Chances. It's a very weird kind of science fiction fantasy. It doesn't fit either of them. So Chikovsky like the composer. But this guy is British. But his face looks very Russian. You should, if you, if you, any get his book, you know, turn to the back page, look at the book jacket. He's got such a fierce looking face. But the books are not like that. They are very gentle and very, very interesting. Highly recommended. It feels suicidal at the end of reading his books. You don't feel suicidal at the end of reading his books. Sophia, what do you got? I don't have too many exciting things from what I'm watching or reading because I'm still reading the whale of time. That's a lot of books. That's okay. You're allowed. Did you watch the TV series? Yeah, until they canceled it. Yeah. Yeah. I mean, I'm really enjoying that. I'm finally discovered. I don't know why I wouldn't have discovered this until I made the drive out to Boise, listening to book on tape, which is pretty magical. And that's sped up. How quickly I'm reading my books because I'm listening to them. But I now forget to make phone calls. And I usually use my car to call it windshield time to call people and get caught up with them. And now I'm not talking to anybody because I'm just listening to my book in my car. So I'm more isolated and secluded now that I've moved away. Anyways, Wheel of Time is actually a great book series. There's like 13 or 14 books and I'm on book 11. I think I'll be done when I'm 60. And then at that point, I'm more than happy to talk about something else on my tubular secretions. Yeah. So they just so long that the author died before he could finish, right? And they had to get another author to finish it. So but Brandon Sanderson's done a great job. The last book is fantastic. It comes down for short books. He's not known for short books, but he did. He compressed it. The last book comes together very, very nicely. It's very well done. That only what you got. So last time I told you that I was watching Heated rivalry. I may have watched it multiple times and I finally moved on from the show. The tub books. I have a lot of small, three books and I'm waiting for the fourth one to come out of the library. It's the Heated rivalry books. Yeah, it's standard off as the books. It's a Canadian author. So I thought, yeah, I thought I could read it to my nine-year-old daughter. And I now realize that he's a terrible life choice. You should never get ahold of those books. See, you watched the TV show before. I was expecting the books to maybe be less graphic. Oh no, they are so much more graphic. They're wonderful to read. [LAUGHTER] My, don't you all shame me. I know you're all loving it. My sister, who I've been reading the Martian and that literally opens with, I am fuck. Fuck, fuck, fuck. Yeah. And he literally goes right into it. Like, so excited. Maybe Kate thinks books away from him too. What do you got in a Carla? Well, I guess a couple of things, but I've always worked with fiber arts my entire life. But my new thing is I'm learning to embroidery with gold thread. Oh, wow. Which is often done, you know, for ecclesiastical things or, or, or, but you can do it in small portions. And it's, it's a lot of work, frankly, but I love the way it looks. I'm maybe a little frustrated right now and now how it, how easy it is for me. So that's number one. The second thing is, is when I was in college, I was on the rowing team. And I have just recently started training as if I'm going to join a senior rowing, a rowing team, a rowing group, if you will. So if you asked me a getting a month, if I gave that up, you might not be surprised. But for now, at least that's the plan. That's awesome. That's great. Yeah. Rowing and gold fiber embroidery. That was, we, not just a lot of work, but it was a lot of money. Is it like really thin gold? It's a real gold. Yes, it's very fine. It's thread, only it's gold thread. Is it considered an investment because it's gold? No, I don't, yeah. I don't know. AC, what do you got? I have been doing a lot of gardening lately. And then in terms of media consumption now that I have a much longer commute to work, I've been commuting with Madeline, which for those of you who don't know, that's my two-year-old. And so we have also been listening to a lot of books on tape, but I have been listening to appropriate books on tape. Not, not he did that. She could get it right education now. Mother of the year and mother to be in bed. So we just finished the giver and tuk-everlastic, which she's been loving. You know what, when your kids get a little bit older, greaking out is a really great podcast. And this guy's done a really good job converting it over. And my kids have listened to me. through it time and time again. And they're really into Greek mythology now and they can talk circles about it around me and they go to school and they can answer all the questions, right? But it's a really interesting podcast. I guess I could have used that one, but as my tubular secretion. But-- >>Greaking out from the one from National Geographic Kids, you're about to make me out numbered in this household. >>Greaking out was the true origin fold. >>Of course. >>One of my buddies got to go play board games with Andy Weir, the author of The Martian. And when he was playing board games with him, he asked for some book recommendations. And one of the book recommendations is a book called This Is How You Lose That I'm More by Amel El Morta. >>I was saying it's two authors. They have come together to write it. And Max Gladstone. >>It is a really interesting book. And I'm about halfway through it. It's not very long. And I would-- I'm giving it a recommendation. I've done with it, so I can give it a full recommendation, but it's good read. Recommended not only by Joel Koff, but by Andy Weir, so you got that. >>Is it science fiction or what is it? >>Absolutely. It's science fiction. It's about-- >>It's hard science fiction. >>That is my thing. And it's the science fiction. I'm moving on to my track. >>It's the science fiction and time travel. It's got everything. >>Yeah. Awesome. [Music] [Music] [Music] [Music] [Music] [Music] you