[Music] Welcome to this week's episode of The Readout Loud, a weekly biotech podcast from STAT. I'm Alice in DeAngelus. I'm Adam Forrestine. And I'm Elaine Chen. It's Thursday, March 4th, and on this week's episode, Spire Therapeutics CEO Cameron Turtle joins us to chat about developing new drugs, including combination therapies for inflammatory bowel disease. But first, a recap of the week's news and a word from our sponsor. [Music] I'm Stappren Studio Editor, Jesse McHorters, and I'm talking with Dr. Fred Applebaum, Executive Vice President at Fred Hutch Cancer Center. Dr. Applebaum, how has the work done over the past 50 years of Fred Hutch impacted how we treat cancer today? About 50 years ago, Don Thomas and our team showed that marrow transplantation was possible, which enabled us to cure almost every marrow-based disease. Today, over 100,000 people worldwide undergo a marrow transplant every year. Going forward, we're developing even better immune therapies, antibody-based therapies, cell-based therapies that harness the power of the human immune system to eradicate cancer. For more information on Fred Hutch Cancer Center, visit FredHutch.org/lookbeyond. Adam, how was it with both me and Alice and Gone last week? It was lonely. All I had was Jared to talk to you. God, who wants to talk to Jared for 30 minutes? No, I can't get it. It was very nice to have him on. And as you guys know, Jared and I are friends, so it's pretty easy to just talk, talk, talk to Jared. But yeah, I'm glad you got your back. I hope you guys had a good time off last week. Yeah, I think we both don't want to be back. Yeah, Adam, nothing against you, but I'm not sure why I'm working right now. Glad to hear that you're not going to replace us with Jared any time soon. No, but maybe AI will replace you. I don't know, or replace all of us, I should say. That could happen fairly soon. That could really could. Well, we still have jobs. Should we talk about biotech news? Let's do it. Okay. Okay, so let's start off by catching up listeners to the disagreement between the FDA and Unicure. As you may remember from previous episodes, Unicure had hoped to submit its gene therapy for Huntington's disease for approval, but regulators turned it down. Now there's contention over whether the company will need to run another trial that includes a control group, a group of people that may need to undergo anesthesia and have a mock surgery. Adam, you've been covering the story. Tell us more. Yeah, it's been kind of all I've done this week. It started on Monday when Unicure, which is the company that's developing the gene therapy for Huntington's disease, a regulatory update, which basically kind of repeated what we had heard late last year was that there was this fundamental disagreement between the company and the FDA about the adequacy of the clinical data that they had compiled from a three-year study of this gene therapy. The FDA essentially just told them that the data were not sufficient to allow the company to seek approval. They had several meetings, including one at the end of January, where they went back and forth over this issue. The FDA was pretty firm in saying that you can't file based on the data you have. You need to run another study. That has sparked a lot of debate. Obviously, we had Lauren Holder, who is a Huntington's disease advocate, and she has the disease herself. We had her on the podcast. I guess it was about a month, a month and a half ago, to the Huntington's community. This is pretty devastating news. I did talk to Lauren this week, and she shared that with me again, because there's a lot of promise with this therapy, and they feel like the FDA is essentially being too conservative, too restrictive. We'll review the data that they have. As you mentioned, the issue here that's gotten away here is, the company has run this study where they compared the effects of their gene therapy against a historical control, a large natural history study. The FDA wants them to do a controlled study. It's something that Unicure did initially. For about a year, they ran a study where they had patients who received the therapy, which requires a brain surgery. You have to drill these burls into the skull. The therapy is then infused directly into the brain. For a control, they wanted people to basically undergo a similar sham surgery. They did that for about a year. Those were results were not. The FDA, I think that was a negative study. The company thinks that this study was too short, and they couldn't show enough benefit. At the end of the day, there's disagreement about that, and now the FDA wants them to do another sham control study. The question now is, is it ethical? Is it feasible to ask a Huntington's disease patient to undergo or participate in a clinical trial where there is a chance that they would essentially be treated with a sham surgery and they wouldn't get it? There's a lot of pushback on that. The FDA says, yes, you can do this kind of surgery. It's a sham surgery. It's not that big of a deal. The company, and I would say most people within the Huntington's community disagree with that, and they don't want that. Yeah, because I mean this sham surgery is not a simple procedure. The patients who receive the sham will still have to undergo anesthesia, and they're out for like 10 hours, right? Yeah, so let's define what sham surgery means in this case. What it means is a patient goes into the hospital and they're put under general anesthesia. They have an incision in their head, in their skull, through the skin, and then very, very shallow burrows. The company has described to me as two millimeter burrows. So you're not going into the bone. You're not going into the skull, but it sort of simulates the surgery that you would have if you were having this therapy. In order to keep the blind though, patients have to be under general anesthesia for between 10 and 12 hours, because that's how long the surgery and the administration of the therapy for a patient to actually get it takes. So the company's point of view is that that puts these patients at risk. And actually in their in the study that they did originally, where they did have the sham surgery, they did it in 10 patients. And one patient actually had a serious adverse event developed a blood clot following the surgery. So their point is that this is just not ethical. It's not feasible. If we try to do a study like this, we're going to get a lot of resistance from from Huntington's patients who are not going to want to participate in a study like this. And therefore, you know, we really can't do it. And right now, there is no agreement. You know, the FDA and the company are basically have these, there's two sides, they're divesting different viewpoints on this. And at some point, the company and the FDA are going to have to meet and sort of figure out how to move forward. Adam, you made a point in your newsletter this week that, you know, the extremism that we're seeing with Vinay Prasad and that, you know, even we saw with Peter Marx has come with costs. Explain that a little bit further. Yeah, you know, I think all of this debate around unicure is not isolated. Right now, we've been talking about this, we've been writing about this, where we're seeing the FDA, you know, talk a lot about advocating for rare disease treatments and people with rare disease and saying we want to bring, we want to accelerate the approval of these drugs. But yet, the actions that we're seeing the FDA take are vastly different. You know, we're seeing like again, with unicure where they, you know, they're telling the company they can't file. We're seeing rare disease drugs rejected. And it and I think the point I was trying to make in my newsletter is that we really have had, you know, two top regulators at the FDA in charge of cell and gene therapies. We had Peter Marx and now we have Vinay Prasad and they really have vastly different regulatory philosophies. Peter Marx was very permissive. He espoused this sort of flexible doctrine, right, where if there was a chance that a therapy might benefit patients, it's better to approve it now and then maybe find out later that it's ineffective. That's the philosophy he worked under and that's why we saw so many gene therapies and cell therapies approved or developed while he was at the FDA. Now we have Vinay Prasad in that role. He takes a very much more conservative approach. He's setting a much higher bar for these same kinds of therapies where he's saying in the case of a unicure, he's saying, you know, which may seem extreme to a lot of people. I want 100 new patients to go on to a sham surgery in a clinical trial. And I think what the, so a lot of the things with what's happening now is that we're just the rare disease community as I write is being a whip side. You're going from sort of one extreme, this flexible, very permissive environment to run. It's very conservative and very restrictive and that's kind of, you know, like many things in life, the optimal, the best probably way to handle this is somewhere in the middle, you know, where you have some flexibility, but you also, you know, you have some more, maybe more rigor. It's somewhere in the middle. I don't know where that balance is, but right now it does not seem like we're there. So in more news in the gene therapy field, Prime Medicine said this week that it'll ask the FDA to approve its gene editing treatment that has been given to only two patients. Prime Struct is the first to employ prime editing a CRISPR-based tool for making virtually any small change to DNA. So prime treatment is specifically designed to insert two missing DNA letters into the blood cells of people with one form of a disease known as CGD. And this disease leaves patients susceptible to life threatening infections and inflammatory disorders. Prime initially deprioritized the program last year as it was working to conserve cash, but it has been revived following the FDA's rollout of what it has been called the plausible mechanism pathway, which is designed to allow approval of custom gene editing drugs. And this will be a key test for the FDA. On one hand, it's promised to bring new gene editing treatments to patients faster through initiatives like this plausible mechanism pathway. But on the other hand, as we just discussed, the FDA has spurned a string of gene therapies that observers thought were on track for approval, much like unicures, Huntington's disease therapy. In other news this week, Moderna agreed to pay Roivant up to $2.25 billion to settle claims that it infringed on Roivant's patents on its COVID-19 shot. The dispute centers around the use of lipid nanoparticles, the delivery vehicle that carries mRNA into cells. Roivant will receive $950 million, and then another $1.3 billion if Moderna's attempts to have parts of its liability offloaded to the federal government fail upon appeal. If the full amount is paid, it would be among the largest patent settlements in history. And this will come really shortly before the two companies were set to go before jury trial, where legal experts said that Moderna may have faced an uphill battle. And let's pour one out for our colleague, Jason Mas, to wrote a great story, sort of kind of previewing this trial, which can be really unusual. I mean, this was going to be a jury trial in Delaware. Really interesting, very deeply in the weed science stuff and legal issues, but still obviously high stakes and and then right at the eve of the trial start, they settle and Jason's story will never see the light of day. Hmm, every journalist knows this feeling very well. Jason, we salute you. You've likely seen the barrage of ads on TV promoting medications like SkyRizzy, Antibio and Trampaya for Crohn's disease and Ulcerative Colitis. When you live with moderate to severe Crohn's disease or ulcerative colitis, your day can be full of reminders of your condition. There are several options for patients, but the majority of people with these forms of inflammatory bowel disease struggled to find relief. Researchers have found that, no matter the drug, only about 30% of patients with IBD interremission. A new way of pharmaceutical development, though, hopes to change that and we're going to start seeing results this year. Joining us to discuss these developments is Cameron Turtle, CEO of Spire Therapeutics. Spire is a spin-out of Paragon Therapeutics, the rising biotech R&D engine created by investment firm Fairmount. Spire is also wrapping up a mid-state trial, testing an array of combination therapies for Ulcerative Colitis. Cameron, welcome to the podcast. Thanks so much for having me. So, Cameron, can you start off by telling us a little bit about the IBD field in general and why there's been so much activity of late, particularly in combination therapies? Sure. So I think you hit it a bit in the introduction here, which is that there's over 2 million people in the US that have either Crohn's disease or Ulcerative Colitis. And despite a few decades of advances and about a half dozen classes of drugs that have been approved now, none of them get patients into long-term stable remission or at least the majority of patients into long-term stable remission. And it's important to recognize these are costly diseases to these patients and their physicians. When you have a flare of IBD, you can have hospitalization surgery, you can have part of your GI tract removed. And obviously that's a permanent problem. And so what we found is that instead of blocking one pathway at a time, a very promising approach is in this heterogeneous multifaceted disease that hitting more than one pathway at a time seems to provide substantially improved efficacy without apparent safety effects so far. So I think this is really the next opportunity here, which is to see if we can move up these efficacy levels from 25-30% where we get with each individual therapy and potentially break what the physicians call the therapeutic ceiling in this space by hitting more than one pathway at a time. So Johnson and Johnson has garnered a lot of buzz for clinical data that had reported back in 2022. Using this combination therapy approach and we're waiting for later stage results from them. Cameron, tell us a little bit about Spires approach to IBD inflammatory bowel disease and kind of the drugs that you guys are developing. We really are standing on the shoulders of the work that J&J has pioneered in this space. I think it's been pretty likely for a long time that combinations would advance this field because we see physicians using them in the real world. We have animal evidence and human genetic evidence that you can get additive efficacy between multiple mechanisms in this space. But J&J with that Vega study was the first to run a randomized trial and test their two things together and see basically additive efficacy between their drugs. So when we're putting Spire together about three years ago, initially we were really looking at a pretty simple approach which was just to make long acting more convenient versions of the best biologics in IBD. So that was in Tivio, SkyRizzi and then this new target TL1A which we thought looked like the three best mechanisms in the space. But as soon as the Vega results came out and showed that you could get additive efficacy by combining drugs together, we saw that that was very likely to be the future of this field and set out immediately to work on those as well. So we're now working on these co-formulations of long acting optimized versions of what we believe are the best biologics in this space. And we're hopeful that we can kind of build off what J&J has shown with we think superior mechanisms and molecules for our own combinations to really move the field forward from there. Cameron, an executive at AV told staff that combination approaches hold the best shot of really breaking through this efficacy ceiling and improving standard of care. But the market has also gotten really excited about some of the new mechanisms of action that are being explored with mono therapies like ABBAVACS's drug. Do you think that all bets should be on combination therapies over some of these new mono therapies? Well, I think what's important to recognize about IBD is that because how serious this disease is and that many of the effects of IBD are irreversible. Once you have a surgery to remove part of your GI track, you don't get it back. There are kind of a number of disease pathways that really you can't improve once you've lost in terms of the function of the GI track. And so what that has led to, the physicians do what they call top-down therapy, meaning use the best drug first in terms of it's really important to get patients into remission as quickly as you can and keep them there to avoid those irreversible consequences. And so what that means is we're going to look for the most efficacious drugs first. And I think we have a pretty good idea that that's going to be combination therapies. We've already seen that they can provide additive efficacy. And so if that occurs, those really are going to come pretty early in the treatment line. And then I think you may see mono therapies get used afterwards when in patients once they don't see kind of the effect of the combinations. I wanted to get your thoughts. Black stone life sciences recently just put $400 million into a drug being developed by Tava and Sonofi. It led to between 47 and 58% remission and ulcerative colitis. What are your thoughts about that? What does that result mean? Yeah, I think the TL1A, this is the TL1A deal recently announced. And I think TL1A is one of the most exciting targets in I and I more broadly. It's why we started working on kind of a next generation TL1A when we saw the the Tava Sonofi, the Merck Prometheus, and the Pfizer Roche molecules, and the value that those accrued. And the value is not just an IBD either. We've seen great results from each of those three drugs, as you just mentioned in IBD specifically. But actually this year we could see up to seven different indications for TL1A being read out as well. We're running three rheumatic disease trials. So rheumatoid arthritis, psoriatic arthritis, an axial spondaloarthritis. But we may also see redouts in atopic dermatitis, SSCILD, MASH, and HS as well. So there's really this really pipeline in a product potential for TL1A. And that's what garners such high interest that you can have potentially a humeral like product profile where you don't just get approval in a single indication, but many. And that's what justifies these very large investments. I'm curious, given that you guys are working on your own TL1A program that's part of, you know, you're developing it and testing it as a monotherapy, but also as a combination therapy. When you look at that Tava Sonofi data, that's, I mean, 47 to 58% remission, what does that then lead you to anticipate for your own trials? At Spire, what kind of remission that you can put patients into by doing it as a combination therapy? Yeah, I think our fundamental hypothesis here is that better components are going to lead to better combinations. And so when we look at that J&J combination initially that delivered such exciting results in terms of additive efficacy, Gacelcomab or Trumphia is obviously a great drug, but the other one that they're using is Glimmumab or Symphony, which is even within the TNF class, not the best TNF, and we've seen multiple classes be superior to TNF as well. And so we think it's pretty logical to replace the TNF component in combinations with something that is superior, specifically Alpha4 Beta7, which has been shown to be head-to-head superior to TNF. That was to Cata's varsity trial, or TL1A, which as you've mentioned some of the results for that mechanism individually are far better than what we've seen from the TNF class overall. And so we generally think replacing TNF in these combinations with an optimized TL1A or an optimized Alpha4 Beta7, if we see additive efficacy from those higher baseline numbers, you're really talking about kind of a much different result than the historic kind of 25% clinical remission levels that you get from monotherapies to date. What do you think though if you were to put an estimate on it, what kind of remission that we can hit, whether it's spire or whether it's like the field at large, feasibly? I mean, I think we've gotten, you know, I think J&J was just under 50% in terms of clinical remission with their drugs. We're replacing one of those two components with something that does 10 percentage points or better in terms of clinical remission individually. No one's sure if you're going to get one plus one is two for every different combination, but if you do, you could be adding 10 or more points of clinical remission on pop of what J&J has seen. That has led to massive shifts in IBD in terms of treatment patterns. So as I mentioned, in that varsity study, Intivio beats Humera by just under 10 percentage points, and that has led to Intivio being a $6,6.5 billion drug today, because physicians want to use the best thing first. So if we can come out and deliver that type of improvement over the existing standard of care, I think that is what opens up the opportunity to be really the new treatment of choice in these disease area and really change the treatment paradigm and hopefully get a lot more patients into remission quickly. Cameron, what are the criticisms I hear about spire and also your sister company, Apigee, which is also developing long-acting antibodies, you know, for other diseases like atopic dermatitis? Is that you're essentially just a B2 company, that you're taking these well-known targets that are part of blockbuster drugs already from J&J and the like, as we mentioned. But you're just adding the long-acting component. So maybe it's a little bit more convenient, but that's really the only value that you're bringing to the table. Is that a fair criticism or do you really feel like your drugs, the formulations and the technology that you bring to this are going to create like better therapies for patients? I would say it's partially true and kind of I would say, you know, step one and actually what spire was initially proposed to be, which is, you know, a long-acting interview, a long-acting skyrizy, etc. And you know, we're adjusting the dosing to hopefully get incrementally improved efficacy as well, kind of greater target coverage, improving the efficacy and convenience of these drug simultaneously. I think that's somewhat interesting and, you know, if you're in a relatively mature market where you're kind of making the next best product, those still could be big blockbuster products in these spaces. And, you know, maybe it's fair that this is not the most exciting, innovative science, but, you know, you make better products for patients and they get used. And I think that still is important. However, I actually don't think spire stories really kind of incrementally improved monotherapies as the main thesis of the company. It really is these combinations, which I do believe are pushing the science and pushing the field forward quite a lot. When you compare kind of the combinations that we're developing that are actually optimized and able to be dose together in a quarterly co-formulation or twice annual co-formulation, the product profile that we're looking at here is dramatically different than what others are testing where they're combining basically what they already had in these spaces. And you see a whole, I would say, hodgepodge of different combos where you're combining oirls and injectables, injectables and IVs, different dosing intervals into combinations. Just the product profile that you're looking at there is very different than what we're proposing at spire. So I do think it's more than just kind of these incremental improvements that we're looking at. I also think for our TL1A outside IBD, we're first in class there. I mean, we have these the kind of what we believe is an improved TL1A relative to the first generation TL1As. They were multiple years ahead of us in terms of having those molecules from those original acquisitions. And yet somehow we're ahead in terms of rheumatoid arthritis, psoriatic arthritis and ax spa. And we'll be reading out phase two proof of concept data before anyone else. So again, I would kind of push back on this being a not that innovative. I think we're actually are pushing and leading the field in a number of ways with the development strategy we're pursuing here. Talking about innovation camera and spire has been, you know, doing its own work, developing its own like components in house, obviously. We would look at the industry at large in what's happening with compensation therapy approaches. There are cases, you know, several cases where you see pharmaceutical companies combining things that are already in their portfolio. Sometimes things that they've gotten through, you know, some of the acquisitions that have happened in the last couple of years. And we are seeing examples where things that are being studied in combination therapies. When you test them alone, they're not really looking that strong or they're disappointing clinically. And I wonder, like, is the industry scraping the barrel here on I and I and you know, when we look at combination therapies and IBD? You know, some of the combinations there being advanced surprise me a bit. Again, we come back to the hypothesis that the best combos are likely going to come from the best components together. And one of the challenge with combos is the profile of your combination is dictated by whatever the weakest component of your combination is. So if you are using a drug that doesn't work that well on its own or has a pretty inconvenient dosing profile, your combo suddenly needs to have that profile. I mean, when we look at even the J&J combo, they have one drug that's dose monthly and one that's doseed every two months. The combo is now dose monthly. If you look at the lily combination, they're combining a twice daily oral with a monthly injectable. I mean, these are kind of product profiles that don't look nearly as good as, you know, one shot every three months, which is something that that we're proposing here. So I think everyone in this field realizes the next level of innovation is going to be these combination therapies, hopefully seeing additive efficacy without additive safety issues. But it is harder to do this than I think people appreciate unless you plan to do it from the outset. That has been something, though, when I've asked clinicians about when you're witch drugs, they're most excited about her, which drugs they would use most. Basically, the response that I get is whichever one we can get insurance to pay for. There's kind of the question of what data you need to get FDA approval and then what data you need to get insurers on board with this medication. How is the coverage market for these drugs looking? Well, combinations for the vast majority of physicians are not covered, because you're largely asking payers to cover two branded drugs together when they have not been studied together and we have no data and it's not unlabeled for them to be used together. And we're talking about twice the price. So I think it makes sense, actually, that payers are saying, no, no, we can't approve that today because it's twice the price with no evidence. I suspect combinations like ours are going to be dosed and priced like one drug. It's going to be one branded product that is two antibodies together. We're talking four shots a year. There's no cost of goods reason why these two need to be extraordinarily expensive drugs. I think you can make a very compelling case that if you price it comparably to a single branded drug, you have additive efficacy and you don't have safety downsides. It should be the treatment of choice. It's very different than today. Physicians are used to trying to get one drug approved for their IBD and then say, hey, do you have some psoriasis on your arm and try and get, you know, SkyRizia approved for that. So kind of getting payers to approve a combo without knowing they're approving a combo. I don't think that's the future. I think we're going to see real combo studies like the ones we're running. We're going to see real combo products with the data unlabeled and they're going to come out as one brand with one price and I suspect they're going to be very cost effective for everyone involved. Hey, Cameron, we mentioned at the top that Spire is a spin out of Paragon. There are putics, you know, bunch of sister companies, we're brother companies, Apigee, Aruka, Jade. Tell us a little bit about Paragon and kind of how this model works. Yeah, I mean, I think I'll credit to the the fair amount guys who originally put Paragon together. I think they saw this, you know, this intellectual property around half-life extending antibodies and said, you know, why hasn't this been used more broadly? Once you know a target has a pretty safe profile, you know, there's a lot of advantages of extending the half-life. Convenience obviously, but we can also narrow the peak to trough ratio in terms of the concentrations of drugs on board. You don't have to give as much at peak, which sometimes cause safety issues, to have the same level of trough coverage, which is, you know, usually thought to drive efficacy. And so these half-life extending antibodies are kind of a really nice and obvious way to make a, you know, a bio better, an improved version of the existing drug. And we can often learn from that first drug too in terms of how to dose it to actually get maximal efficacy. So I think, you know, the Paragon team was pretty aggressive and said, you know, there's all these great biologic targets out there that we can make better versions of and went systematically and said, let's make a new topic disease company and IBD company, a psoriatic disease company, kind of across the whole landscape. And I think, you know, I think it's likely to lead to better products in a lot of these spaces. I'm biased here, but I think the spire effort here in terms of advancing combination therapies and then testing new biology and new disease areas also gives come true first-in-class opportunities, which, you know, you usually have to be first or best to have valuable drugs in this space. And I think we have the opportunity to be both actually. Cameron, thanks so much for joining us. That does it, print out another episode of The Read Out Loud. Thank you to Hyacinth empanado for producing this week's episode. Our senior producer is Alissa Ambrose. Our executive producer is Rick Burke, and our theme music is by Brian Joel. We'd love to hear from you, Tell us what you like about this week's episode, which you didn't like, and how many of these IBD television commercial jingles can you sing along to? You can do all that by sending us an email at
[email protected]. And if you like what we do, leave a review or rating on Apple podcasts or whichever platform we use to get your podcasts. We'll see you next week. I know them all. Intivio, Intivio, Intivio.
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