BioCentury This Week
BioCentury's streaming commentary on biotech industry trends, plus interviews with KOLs.
For three decades, BioCentury has helped biopharma executives and investors make business-critical decisions and build larger networks with peers across the innovation ecosystem.
BioCentury This Week
Ep. 335 - Neurology's Coming Inflection Point
Voyager CEO and former head of R&D at Biogen Al Sandrock is more optimistic than ever about the prospect of bringing clinically meaningful solutions to patients with Alzheimer’s disease and other neurodegenerative disorders. The threads of progress are finally coming together, he said in a special episode of the BioCentury This Week podcast. From the first disease-modifying therapies for Alzheimer’s disease, to a growing biomarker toolkit, to an expanding set of genetically validated targets in other neurodegenerative conditions — and, crucially, to delivery vehicles capable of broadly and deeply penetrating the brain — neurology drug development may be poised to accelerate. This episode of the BioCentury This Week podcast is brought to you by Voyager Therapeutics.
View full story: https://www.biocentury.com/article/657678
#AlzheimersDisease #AAVGeneTherapy #BloodBrainBarrier #TauTargeting #Neurodegeneration
00:01 - Sponsor Message: Voyager Therapeutics
03:41 - Voyager's Approach to Gene Therapy
15:07 - Alzheimer's Disease
25:25 - Big Biotech to Small Biotech
29:21 - Neurodegenerative Diseases
31:19 - FDA Flexibility
To submit a question to BioCentury’s editors, email the BioCentury This Week team at podcasts@biocentury.com.
[AI-generated transcript.]
Eric Pierce:BioCentury This Week is brought to you by Voyager Therapeutics. Voyager Therapeutics is dedicated to leveraging the power of human genetics to modify the course of – and ultimately cure– neurological diseases. Voyager addresses the challenge of delivering novel treatments to the brain through the company's innovative TRACER™ AAV capsid discovery platform, as well as Voyager's NeuroShuttle™, a non-viral delivery platform designed to transport multiple modalities of neurotherapeutics across the blood-brain barrier. The company's programs address diseases with substantial unmet needs, including Alzheimer's disease, Friedrich's ataxia, Parkinson's disease, ALS, and other diseases of the central nervous system.
Jeff Cranmer:Welcome to a Special Edition of the BioCentury This Week podcast. I'm your host, Jeff Cranmer, one of the Executive Editors here at BioCentury, and today I'm delighted to have my colleagues Lauren Martz and Selina Koch, join me for a conversation with Al Sandrock, he's CEO of neurogenetic medicines company Voyager our sponsor this month. Before joining Voyager in March of 2022, Al spent more than 20 years at Biogen rising through the ranks, to become CMO and eventually EVP of R&D. Given his background, Al can cover any number of topics in the field of neurology. So I'd like to bring in my colleagues now to find out what they'd like to learn from Al. Well, Selina, you, uh, lead our neurology coverage, what are you, hoping to talk about today?
Selina Koch:Thanks Jeff. So I recently wrote about this, so the topic will show my bias, but personally I think Voyager is working on one of the most important challenges in neurology, which is the difficulty of delivering treatments to the brain. At the risk of sounding simplistic, um, you know, drugs don't work if you don't get them where they're needed, right? Which makes CNS delivery kind of foundational, with implications across, you know, all of neurology, well, even the psychiatry. You know, it's an exciting time because there's a lot of activity aimed at solving this problem right now, and I'm looking forward to hearing how Voyager's approach kind of fits into that landscape. But maybe I'll bring up one more topic before, uh, moving on to Lauren, which is, of course, I want to pick Al's brain on up and coming therapeutic approaches to Alzheimer's disease, where he's seeing the most promise in the short term. What might be needed to advance some newer hypotheses.
Jeff Cranmer:Lauren, what are you, uh, curious about?
Lauren Martz:Thanks, Jeff. I'd love to hear a little bit about the transition from a large company to a leadership role in a small company. And I'd also love to hear some thoughts from Al on transitioning the modality focus at a biotech. So we know that Voyager has historically done a lot of work in gene therapies and has used some of the expertise from that work to start moving into delivery of different modalities. So I, I'd love to hear more about how that came about.
Jeff Cranmer:Sounds good. Well, Selina, why don't you, jump right in on the, BBB question you wanna ask. Well, just for our listeners out there, Selina has written several pieces now on the blood brain barrier and, uh, the companies, the players, the technology, the deals. So do go to BioCentury.com to check those out. And now I'm just gonna hand it over to Selina.
Selina Koch:Yeah. Well, I have a couple. Um, I guess we could build on what Lauren was saying at the start in the gene therapy space. You know, we have seen a string of safety incidents in the clinic with gene therapies. These are generally, you know, inflammatory in nature. So voyagers working in indications that span neurology right from ultra rare like Friedrich's ataxia all the way to Alzheimer's disease. So I guess al what's convinced you, that you know, if you have a highly penetrant, CNS penetrant AV capsid, that that's gonna be safe enough, even for the larger end, that spectrum for a prevalent condition like Alzheimer's.
Alfred Sandrock:So there's two main reasons for that, Selina. And, and maybe before I start, I'll say thank you for hosting this and for talking to me, appreciate you, and I hope you have a good conversation. There's a couple of reasons why I came to Voyager. And it was because I felt that we can make gene therapy work better, and more safely. And there's two reasons why, I like the approach that we're taking. One is that we're engineering capsids that get across the blood brain barrier after IV delivery, and they're so potent that we can lower the doses, from what's been traditionally used for systemic or intravenously delivered gene therapy, AAV gene therapy. So typically, for example, people give, one E14 viral genomes per kilogram, so one times 10 to the 14th viral particles per kilogram. And that's the dose, in fact, of the approved gene therapy for spinal muscular atrophy called Zolgensma. So a basic tenet of drug development is if you go lower in the dose, it's likely to be safer. So we are dosing in the E13 VGs per kg. So an order of magnitude lower. In fact, we have data that says that at 1.3 E13 VGs per kg, we can get delivery enough into the brain to get the, therapeutic effects we want to have. The second thing is that you may have noticed that some of the issues that have plagued this field is liver toxicity. In fact, we had a couple of examples of patients who unfortunately died from liver failure. So not only do we have a lower dose, but we are det targeting the liver with our capsid. So they're great for getting into the brain better, but they don't get into the liver any better. In fact, they're 30 fold less effective in getting it to the liver. So these are two reasons why I'm pretty excited. And of course, what you want is. Broad brain distribution. You want better efficacy too, and so our capsids, promise to do that. It's always benefit risk, right? It's always the ratio of benefit to risk, if you will. because it's hard to talk about one without the other really, or to consider how good a drug is without talking about both benefit and risk. that's why I bring up the benefit side as well. Selina.
Selina Koch:Yeah. And so you've identified the receptor for the capsid, ALPL , and now, you've developed other kinds of ligands against that receptor, so you can shuttle, not just AAV gene therapies, but a kind of a wider array of biologics into the brain antibodies, enzymes, oligonucleotides. Um, I think you've just kind of released the first preclinical data on that. If you want us to tell us a little. Well, one that's like gonna increase your optionality. I can imagine. You can be in situations where you could have a vectorized gene therapy against to target. Or you could just deliver, say, an siRNA with this ligand. Maybe let's start, let's start there. Like what's your guiding principles for like picking a strategy?
Alfred Sandrock:Yeah. So this also gets into some of the questions I think Lauren had about small company, large company. And, you know, look, I think it's important, particularly in a small company, to maintain focus. If you're too unfocused, you're not gonna be good at anything. So we decided to stay focused on neurotherapeutics and not try to broaden into other therapeutic areas. So I'm hiring people and I've collected a group of people who are specialists in neurotherapeutics. But I also said, hey, you know, patients. In my experience, when I used to see patients, they don't care about the modality. They want the treatment that's gonna best meet their needs. and in the case of neurological diseases, we have so few treatments that are effective still, and very few disease modifying treatments. We're in an era in neurotherapeutics where I believe we have a lot of really well validated targets to go after in the central nervous system. The problem is, is that if you only have small molecules, which which has up until now, up until very recently, then the only way to get drugs across the blood brainin barrier when you only have small molecules at your disposal. Your limit there, there are a lot of targets that are considered undruggable. And so that's a shame because we want to help the patients. We have great targets to go after, validated by a lot of human genetics and human biology, but we don't have the ability to target some of these, go after some of these targets. But we do have these newer modalities, gene therapy, genetic medicines more broadly, which would include, I, I believe, oligonucleotide based treatments as well as protein therapeutics, antibodies, peptides. And so the trick is then to get them into the brain better. And so we started with the AAV. We had a platform where we could make, essentially random mutations, millions of variants of AAV and discover only the few that get across the blood brainin barrier. Then we said, well, these viral capsids have to cross the BBB by binding to certain receptors on the BBB. We identified some of those receptors and you just mentioned one of them, ALPL, and then we said, well, maybe then we can then use them as shuttles. Or receptors to make shuttles that cross the BBB and bring in all the other modalities. I was just talking about protein therapeutics, oligonucleotides, for example. So maintaining focus on neuro, broadening the therapeutic approach so that we can go after the highest unmet need diseases and really help patients to the best of our abilities.
Selina Koch:Right. Um, well, I know you have say an, I think it's an siRNA that's vectorized against tau, right. But now that you have this ALPL, like non capsid shuttle, you could also just link that up to that shuttle. So I guess that's where I was thinking like, are there guiding principles to wade through those options? You just have a much bigger option space.
Alfred Sandrock:So we already have at least one promising shuttle approach, uh, the transferrin receptor. But each shuttle is gonna have its own, advantages and disadvantages. The three main characteristics we focus on are pharmacokinetics. Standard things like Cmax, how high a concentration you can achieve, and also the half life, if you will. Uh, the distribution, in other words, where else in the body does that shuttle take drugs to? In some cases we want more broad distribution because the disease may involve more than one organ, more than the brain. In other cases, bringing things into the other organs effects first the pk, but also may cause safety liabilities. Don't deliver the drug to the organs where, where you don't need to, you're just asking for trouble. Uh, would be another way of saying it. And the third thing is, each receptor and each shuttle against the receptor is gonna have its own safety issues. You know, God didn't put these receptors on there just for us to shuttle drugs there. These receptors serve a purpose, and when you bind to them, you might block them from doing their normal function. So having an array of shuttles against various receptors, they give you the characteristics you need for the particular disease at hand, I think is going to be the way to go, and that's why we're doing what we're doing.
Selina Koch:Yeah. What? What would you say right now, based on the data you have, is the key differentiator of your ALPL based shuttle from a transferrin shuttle?
Alfred Sandrock:So right now what we see is we don't see quite as high a concentration in the brain after initially giving it. But what we see is a nice steady exposure in the brain. So the half-life is much longer, and for many drugs, for example, if you want to block a pathway. You wanna maintain blockage 24/7. Having a short half-life is suboptimal. Because if you do wanna maintain exposure, you have to give it very frequently. so that's one difference. The second thing is that, a transferrin receptors, because iron is so important for red blood cells. That there are hematologic adverse events when you use transferrin receptor based shuttles. We see none of that with ALPL so far we've looked carefully at that. Of course, we may have our own separate set of issues because ALPL has a separate function, but we're, we're hoping not, and we're investigating
Selina Koch:How much is known about that function?
Alfred Sandrock:Well, there are humans that have, uh, so that if you've lost 50% of the function of ALPL, you seem to be fine. If you lose 70% or more, you can run into bone mineralization problems. So ALPL is not just expressed on the brain vasculature, but it's expressed in other vascular beds. And there is a disease of severe ALPL deficiency called hypophosphatasia, which is a bone mineralization problem. So we're gonna have to watch out for that. But again, I think in humans anyway. Humans seem relatively tolerant of at least modest loss of function. It has to be severe, so we're hoping we can still use it as a receptor.
Jeff Cranmer:All right, we're gonna go to a quick break and we're gonna come back and talk neurodegeneration, what's happening in the space, and we're gonna talk a little bit about moving from a big, big biotech to a smaller, more nimble biotech, Al's move from Biogen to Voyager.
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Jeff Cranmer:We are back at the BioCentury podcast. We have a special episode that we're doing right now with Al Sandrock, he's the CEO of Voyager Therapeutics. Lauren, where do you wanna go next?
Lauren Martz:Al I'd love to hear about what you are most excited about within the neurodegenerative disease drug development space.
Alfred Sandrock:Several things. First of all, we, for example, in Alzheimer's disease, we have the first disease modifying therapies that have been approved in recent years. They're drugs that affect that, that bind to amyloid, the anti-amyloid antibodies you know, they're the very first ones. And you know, on average there's a 30% effectiveness slowing the progression. When you look at large populations, it's an average of 30%. So what we need to understand is, well, does that mean that everybody is 30% or does that mean that some people get a 100% effect and some people get zero, and some people get somewhere in between. It looks like it's more the latter. That some people actually can, can actually, have substantial slowing, in fact, maybe even stabilize and not get worse, whereas others seem to deteriorate at the same rate as before. If that's the case, then it would be great to know who can be predicted to be in which category because you'd be there, there'd be a high sense of urgency to put people. Who are likely to be good responders onto the treatment. The other thing that we're gonna learn shortly, because the companies are doing these large studies, is what happens if you treat earlier? there are studies now where people are being treated even before mild cognitive impairment. So these are people who have no outward symptoms of, uh, memory loss or any of the problems associated with Alzheimer's disease. But they're building up amyloid in the brain. So if you treat even before symptoms, can you get a bigger treatment effect? I predict that that will be the case, that we will get a bigger treatment effect on average. And I think that would be hugely important. Of course, what we need now are we need to then recognize who's building the amyloid up, in a more convenient way than we have now.
Selina Koch:Those two different points, I wonder how intertwined they might be, for example. How much of identifying responders to that mechanism, the anti amyloid mechanism is gonna come down to disease stage, 'cause we saw that, tau PET Imaging data from Lilly. That's really suggested to me like you, you gotta be early in tau. You can't have Tau PET really escaping the medial temporal area and still expect to see efficacy or, or do we need other things besides that?
Alfred Sandrock:so there is some data to suggest that if you take people who have a low tau burden. So tau is another protein that builds up in addition to amyloid in the brain of Alzheimer's patients. And there's some suggestion that those with a low tau burden, in other words, those in which the tau hasn't spread that much yet, have a bigger effect of the amyloid treatment. But on the other hand, you know, many of these trials enrolled people with mild cognitive impairment and early dementia. So earlier and later stages. And guess what? The treatment effect side wasn't all that different between those two. So there's some conflicting data there. You would think that mild, mildly cognitively impaired people would have a bigger effect than those who were already demented and there wasn't a big difference. so it's a little, uh, troubling to me. So I think it's a mixed picture. But I do think that, the reason why the heterogeneity of, treatment responses I gonna be is important is that when we think about now tau treatments. Where does that fit in, into the treatment landscape? If somebody is already completely stable on antiamyloid. Well, you don't have to worry about adding any other treatment or switching, but if you're in one of those people who have either no effect or only a partial effect, for the former category, those who have had no effect from the anti-amyloid antibodies, well then you should switch to the tau treatments. For those that have a partial effect, maybe you add so that you get a better effect by combining two treatments So that's another value to understanding the heterogeneity treatment response, 'cause it will tell you how you deal with a new set of treatments. And hopefully they'll come, the tau directed treatments, in the clinical setting. I want to just touch on though the diagnostics piece because, if we're gonna treat early, we have to recognize that somebody is building up amyloid before any symptoms. That's gonna require for it to be feasible in the primary care setting, you're gonna need a blood test. And I'm happy to say that, you know, now that there are treatments, people are now doing more work on diagnostics and so the blood-based diagnostic biomarkers are coming. I think that's gonna make this early treatment feasible if it does in fact show that it's, it's of of high value. I see it very similar to sort of what happened in cardiovascular disease. You know, we don't wait till somebody has a heart attack. We treat the cholesterol or we treat the blood pressure, so that we can prevent heart attacks. Maybe that's where we're gonna be going with Alzheimer's disease. We can recognize early and start the treatment and hopefully maybe we can prevent people from getting demented ever. That would be a, a wonderful dream come true.
Selina Koch:it sure would. But to really go into that preventative medicine space where, okay, they might, patient might have amyloid in their brain, but they're otherwise healthy. Right? Uh, you gotta be very safe and low burden with the tone of treatment modality. Where do you see that? I mean, I know right now it's these leading MABs that are being tested, but where do you think ultimately is the right kind of, product profile there?
Alfred Sandrock:Yeah. Maybe, if the earlier treatment with an antibody works, maybe we can treat earlier with other ways of effect of lowering amyloid that could be less expensive and maybe safer. I'll also say that one thing we don't know is how the safety will be affected by going early. So if you have less amyloid in the brain, it's still, it's building up, but if you have less. Is it possible that the treatment would be safer because the antibody doesn't have as much to interact with, then we don't really know what causes ARIA, which is the main side effect that you're referring to, Selina. But it could be that if you have a lower amyloid burden, the safety could improve. That would be a, the hope anyway.
Selina Koch:Totally, and these new shuttles could potentially help with that as well?
Alfred Sandrock:That's a great segue into the fact that, you know, uh, there is an antiamyloid antibody that a company actually discontinued because it was modest in efficacy, but still had all the safety issues, very modest in efficacy, so that in fact, they terminated the program. They put a shuttle on it, and guess what? The efficacy improved and the safety improved. Another example where fixing the delivery really can broaden the therapeutic window, increase efficacy, and, uh, make it safer.
Selina Koch:I wanna talk tau for a little bit, cause I remember a time where I'm pretty sure, correct me if I'm wrong, you were kind of skeptical that tau would make a really, good therapeutic target. But clearly you've come around, Voyager has multiple programs. You've got both the antibody intercepting extracellular tau, and then the RNA silencing getting at the intracellular form. So I mean, what brought you around on that? And also both of those are worth testing, but like as the data stand now, do you think one of those is a stronger hypothesis?
Alfred Sandrock:Well, so, uh, skeptical might be a strong word, but, well, we decided, uh, when I was, at Biogen to go after amyloid first. And of course we did have multiple programs in tau eventually. But the reason why we went after amyloid first was the strong human agentic evidence pointing to amyloid. So, as you know, when you have familial Alzheimer's disease in the early days, we had these cases, we had families that had single gene mutations that increased the risk of Alzheimer's disease. They often developed Alzheimer's disease as early as in their forties. and they had often had ra more rapid progression. After we figured out the genes, it turned out they were all in the amyloid cascade. Either they were encoding for the amyloid, amyloid precursor protein gene itself, or enzymes that process that big protein into the 42 amino acid peptide, which is the toxic species, if you will, after it aggregates and misfolds. So, the genetics strongly pointed to amyloid as being causal. Also APOE, the most common among, not in familial Alzheimer's, but in sporadic Alzheimer's. The most, important genetic risk factor for Alzheimer's disease is APOE. And if you're homozygous for E4, you have a 90% likelihood of getting Alzheimer's disease again at an earlier age, typically in your fifties and more rapidly progressive. But APOE also affected the buildup of amyloid in the brain. So even APOE pointed to, amyloid. So that's why we targeted amyloid first. But I do think that the evidence is growing that tau is responsible for neurodegeneration. In fact, there are mutations in tau that cause a different disease called frontal temporal dementia. So clearly mutations in tau can cause neurodegeneration, but the, uh, human biology also very strongly shows that after the amyloid appears, then the tau starts to spread. And a lot of people, including myself, believe that amyloid actually triggers the spread of tau in the brain. That a little bit of tau misfolding in the brain is actually part of normal aging. It's just that it's localized to a very small part of the temporal lobe unless amyloid is present. Once amyloid appears that tau now spreads, and that misfolded tau spreads throughout the brain. And so, we need to address that.
Jeff Cranmer:I wanna get back to Lauren's initial question now, uh, years at Biogen. Really just moving up through the ranks. And, and then you made the jump to Voyager. I'm sure a lot of our listeners, you know, may have done something similar or contemplating such a move. How has that been for you and why, why did you make that move?
Alfred Sandrock:Well, look, I kind of grew up at Biogen. When I first joined Biogen, it was about, I think it was five or 600 people, so it was still a relatively small company. And, uh, we had just gotten started in multiple sclerosis, actually, as a commercial company. And we were able to develop multiple treatments for MS. And, uh, boy, I, I grew up, like I said, I literally grew up there and, loved it. And I loved it right up until I left, actually. still loved it when I left. But I felt that, it had grown to the size where it was kind of too large for me. I'm not really big on kind of bureaucracy, if you will. Not that Biogen's terribly bureaucratic, but there are a lot of committees, you know. when it gets to multiple, like I think we were close to 8,000 people by the time I left. So from 600 people to 8,000, big difference. And it's hard to make decisions kind of because there's a lot more people involved and, I like smaller companies that are, as you said it, you said it yourself, Jeff Nimble. Like I can walk down the hall here and really talk to all the people I need to, to get the input I need to make a decision. You know what I mean? And I don't need to even schedule a meeting, which is wonderful. I'll tell you the downside though is that we don't have as much cash. Um, you know, at Biogen, there was a little bit more freedom to explore areas that, uh. May not immediately lead to a product. Which was great, because it allowed for exploration into highly sort of risky Innovent territories. Of course, we do do a lot of innovative stuff here at Voyager. But I don't have as much cash and I don't have as many people, here, so I have to be a little bit more cautious. In fact, I have to restrain myself, because, some people say I have too many ideas. and so, so that's the, that's the difference.
Selina Koch:Well, one important, oh, sorry. Uh, one important source of cash for you all I think has been like just partnering out your capsid. Now that you have this other shuttle coming online, is you going to tap into that similarly, or?
Alfred Sandrock:Oh yeah, I'm, I'm a big fan of partnerships. Not only do they bring in, revenue, but you learn a lot from your partners. You know, when, when it's a great scientific collaboration, you know, the interaction scientist to scientist really does increase, um, just accelerates everything and also increases the learning. And then look, there's, there's so much to be done. Once you've solved delivery for gene therapy, there's no way we could prosecute every single target or go after every single disease, and so why not partner? Yeah, you give up some of the upside later. But there's, so there's, you know, if you're successful and you can help a lot of patients, there's no problem in giving up some of the upside. And then, you're right, the, the shuttle program that we just launched, there's a lot of interest, a lot of interest out there in shuttles. And so yeah, I'm open to partnerships.
Selina Koch:Should your tau antibody, do well in the clinic, and I think you've got a readout coming next year. Um. You know, as a smaller company, probably not gonna go the Biogen route and think of commercializing yourself, right? Like when, when would you think about partnering? Assuming you're partnering.
Alfred Sandrock:Well, not only will we not commercialize, we wouldn't want to be doing the big Phase III trials either. Those are usually massive trials and global in nature. And so we'd want to partner, before Phase III.
Jeff Cranmer:So, Al uh, back in the day you were at Mass General, you were a neuromuscular physician, ALS any other neurodegenerative neuromuscular diseases you'd like to, uh, talk about?
Alfred Sandrock:Yeah, so ALS for sure. I mean, you know, I, I was at Mass General right when Bob Brown discovered the first gene tic cause of ALS, which was superoxide dismutase, SOD. And so we were getting a lot of patients from all around the world coming to Mass General. And since Bob couldn't see them all, some of 'em had the same me, you know. And I'll tell you, it is one of the worst diseases around. I used to see people that reminded me of loved ones you know, some, sometimes the patients, they were always very, very nice people. For some reason it seemed that ALS patients and I couldn't help them, and that could be why I came to industry. So at Biogen, they had a drug called tofersen, which is an antisense oligonucleotide that got approved recently. Actually, uh, we hired Toby Ferguson, to Voyager, and by the way, tofersen is named after Toby Ferguson. But anyway, I digress. I wanted to bring up tofersen because for the first time we see a drug that can not only stabilize some patients, but actually some patients are improving. So imagine that ALS patients who are putting aside their walker or getting out of the wheelchair. This is happening, is just like a, you know, the fact that I'm even saying it now is almost hard for me to believe. You know, it's a great indication of how far we've come in treatment of neurodegenerative diseases. So I'm very hopeful that we can do even more. Unfortunately, only a few percentage of patients have SOD1 mutations. So the vast majority of ALS patients need something as well. And by the way, we are working on ALS at Voyager too.
Selina Koch:Okay, I have to ask an FDA question. So tofersen, to get across the finish line, required some flexibility over there at the agency. You know, they took neurofilament light chain as the biomarker called it a surrogate, and they used open-label efficacy data, right? Because really if you just look at the primary endpoint, it, it on a population level failed rather spectacularly, if you look at that P value. Um, yet that has really, it seems like more to do with the trial design than the therapy, right? And it's just hard in these rare indications where things aren't well standardized, where you only kind of understand the natural history. And right now we're just getting all these, I feel like mixed signals out of FDA. We all saw what happened with uniQure, who was gonna have a natural history comparator, and then FDA agreed to it and then changed his mind. On the other hand Lexeo got some, good news that its program might have some endpoints that could work for accelerated approval. I mean, how do you look at these, I don't know what seemed like mixed signals to me. And what's your, what's your view of them?
Alfred Sandrock:Well I do think that, flexibility is very important. I do like the idea of accelerated approval, that the use of biomarkers, perhaps even with uncontrolled trials to basically accelerated approval is saying, you know what, there's a chance we could be wrong, that the drug is safe and effective, but it's such a terrible disease. There's so few options for these patients. Why don't we approve it? And then let's see the confirmatory trial. And if the confirmatory trial is positive, then we know we've made the right decision. You know, I'm very proud of the fact that Amylyx, for example, there was another ALS drug that had been approved, accelerated approval, the confirmatory trial was negative and the CEOs at Amylyx pulled the drug off the market. See, as long as I think industry leaders are responsible and do the right thing, if the confirmatory trial doesn't confirm, then the drug should come off the market. But in the meantime, having these accelerated approvals allows patients who are have very few other options. These are often deadly diseases. And I think it makes sense to grant approval in an accelerated manner. Look, FDA is in some flux. I still believe, that if you have a great drug for for a bad disease, that we're still gonna be approved. And the companies and the shareholders will be rewarded. If I stop believing in that, then I may as well quit. But I, I firmly believe that we'll figure out a way to help patients with bad diseases.
Selina Koch:Yeah. And is is, are you saying it's not really changing any decisions that you're making over there, that kind of uncertainty right now? You're just.
Alfred Sandrock:No. And, and, and look, we, we are, we are sticking to our convictions that, as long as we make transformative treatments for patients with bad diseases that we will be successful.
Jeff Cranmer:That is excellent to hear Al and, uh, I'm sure you're joined by many of your fellow CEOs and other folks, working in the trenches and even in FDA, uh, as we've talked about on the podcast previously, a lot of great people there, a lot of hardworking people. Got Pazdur at the top of CDER now. Let's get those drugs approved. Selina, we got time for one more question. I'm gonna give it to you.
Selina Koch:Ooh, there are so many. I'd love to ask. Um, but I think I have to ask about neuroinflammation, just because we're thinking about like up and coming therapeutic hypotheses that have some genetic backing. And might be useful across a wide swath of neurological indications. That's certainly one people are talking about a lot. I noticed Voyager doesn't have any neuro inflammation targeting programs disclosed in its pipeline. So I guess I'm wondering, you know, where you think the field is at when it comes to understanding what neuroinflammation is, how it contributes to disease such as Alzheimer's, and I think importantly like, how you can measure it?
Alfred Sandrock:Yeah, so, um. if you thought I was skeptical about tau, I was even more skeptical initially about neuroinflammation. Look, the thing is you definitely see evidence of neuroinflammation in virtually all these neurodegenerative diseases, certainly in Alzheimer's disease. But the question is always is when you see it in the brain, is it cause or is it effect? And you know, a lot of dying cells will cause neuroinflammatory type cells to come and do the cleanup, if you will. and so, uh, I was a little bit skeptical, but then when we found that there are certain genetic variants that increase the risk of Alzheimer's disease, such as TREM2, I said, okay, it's gotta be in the causal pathway. Unfortunately, the early the first attempts at making drugs against TREM2 have not been successful. But TREM2 is complicated, their membrane bound, soluble forms. So maybe we haven't targeted the drug in just the right way yet. So I'm still hopeful. I think the complication of neuroinflammation is that there's sort of neuroinflammation that occurs from the cells that are innate in the brain, such as microglial cells. There's sometimes inflammation from cells that come from the outside, from the immune system that come in and invade essentially the brain, or come into the brain and cause inflammation. So it's complicated. And then if you take the microglial cells, the innate cells in the brain that show inflammatory changes, sometimes there's good inflammation and sometimes there's bad inflammation. In fact, there's some forms of neuroinflammation, if you will, or microglial activation that we think are protective. And so I think measuring it in the right way, we'd hate to decrease the protective forms of neuroinflammation, if you will. We wanna dampen down the harmful ones. I think we're still at the very early stages of measuring it properly and figuring out the complexity of neuroinflammation.
Selina Koch:Do you think there's anything to learn from multiple sclerosis here? Because we did recently see a BTK couple of BTK inhibitors slow the secondary or primary progressive form of that disease was just kind of like neurodegeneration, you know?
Alfred Sandrock:Yeah. So MS is a great example, Selina. There's a heavy, contribution of cells that come in from the outside, the adaptive immune system. So we see T cells, B cells, and in fact, all the drugs that work for MS now affect that adaptive immunity, if you will. The B-cell, drugs, BTK being one of them has been among the most successful. The issue there again, might be delivery. There are these B cells that sit in the brain, in the sub meningeal space and they're not affected by the current B cell lowering treatments, certainly not by the antibodies against a B cells. You'd have to be sure your BTK inhibitors, brain penetrant, not all of them are. There are these B cells that sit in the sub meningeal space that I believe is responsible for the worsening that patients still have, despite the best immune modulating treatments that we have on the market today. And I think that's gonna require going after those B cells in the, in the sub meningeal space. By the way, frequently they're infected with Epstein-Barr virus. So, people are starting to think about how to target those as well.
Jeff Cranmer:All right. You've been listening to Geeking Out with Selina, uh, with Al and Selina. Al thank you for joining the BioCentury This Week podcast. Appreciate you giving us so much of your time. I now can see you, uh, just wandering down the halls, uh, putting people loose on new projects, every day. It's a great, great vision and, uh, we're very grateful to Voyager for sponsoring the podcast. And, uh, thanks to Selina and Lauren for joining me today.
Alfred Sandrock:Thanks for having me, thanks for geeking out with me..
Jeff Cranmer:Alright, well, hopefully you two can connect at J.P. Morgan, uh, as you usually like to do, in sunny San Francisco and you've been listening to the BioCentury This Week Podcast, a Special Episode. We will have another special episode this week or early next, coming. direct from Jefferies and then we will of course be back, with our regular episode. Uh, I'm escaping for a few days, so Stephen Hansen will be your host, and we'd like to thank Kendall Square Orchestra for making the music for all of BioCentury's podcasts.
Eric Pierce:BioCentury would like to thank Voyager Therapeutics for supporting the BioCentury This Week podcast. To learn more about Voyager's programs advancing transformative medicines for neurological diseases, visit voyagertherapeutics.com.
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