Ep. 338 - Semaglutide’s Alzheimer’s Miss. Plus: Vaccine Policy, Cell, Gene Therapy Funding

Novo Nordisk’s highly anticipated data for semaglutide in Alzheimer’s dashed hopes that the GLP-1 therapy could become a game changer in the disease. On the latest BioCentury This Week podcast, Executive Editor Selina Koch discusses the Phase III readout including what it says about the mechanism’s use in the neurodegenerative disease, Novo’s decision to skip Phase II and enroll a large patient group in a later stage trial, and what other datasets for GLP-1s in the indication have shown.
Washington Editor Steve Usdin explains why FDA’s new vaccine policies, driven by CBER Director Vinay Prasad, could have impacts more far-reaching than expected, including making it more difficult to develop or modify vaccines. And Lauren Martz, Executive Director of Biopharma Intelligence, analyzes the bleak investment outlook for cell and gene therapy companies in the U.S. and why China’s biotech ecosystem offers a glimmer of hope for sponsors of these assets.

View full story: https://www.biocentury.com/article/657721

#Semaglutide #GLP1Therapies #VaccinePolicy #CellAndGeneTherapy #AlzheimersResearch

00:00 - Introduction
01:53 - Novo's Alzheimer’s Miss
13:19 - FDA's New Vaccine Policy
19:53 - Funding C&GT Biotechs

To submit a question to BioCentury’s editors, email the BioCentury This Week team at podcasts@biocentury.com.

Chapters

• 0:00 Introduction
• 1:53 Novo's Alzheimer’s Miss
• 13:19 FDA's New Vaccine Policy
• 19:53 Funding C&GT Biotechs

Transcript

0:00

[AI-generated transcript.]

Jeff Cranmer: 0:01

Novo Nordisk data for semaglutide in Alzheimer's were highly anticipated. But last week's readout for the GLP-1 therapy dashed what may have been long shot hopes for a game changer in the disease, we'll discuss what the data mean in detail on this week's BioCentury This Week podcast. Plus you've seen the headlines, Vinay Prasad is ready to deploy a new vaccine strategy at FDA, the impacts could be more far reaching than has been reported. And cell and gene therapies have fallen off the radar for early stage venture investors in the U.S. Why is that happening and could there be hope across the Pacific. I am Jeff Cranmer. joining me today are my awesome colleagues.

Selina Koch: 1:02

Selina Koch, Executive Editor.

Steve Usdin: 1:04

Steve Usdin, Washington Editor.

Lauren Martz: 1:06

And Lauren Martz, Executive Director of Biopharma Intelligence.

Jeff Cranmer: 1:10

All right, well, I'm happy to be here with you guys. Uh, I know there's a lot of talk around J.P. Morgan every year about the weather we have here in California. I'm just happy to be home after, uh, well, a lot of snow in Chicago. I gotta say, uh, much respect, to the good folks that, uh, managed to get me on a flight, me and my family on a flight back to California. Steve, how were your travels? I know you were on the road.

Steve Usdin: 1:35

Montreal is, people say Montreal is the, uh, you know, it's like if, London and Paris had a child, it would be Montreal, and it lives up to it. It's great.

Jeff Cranmer: 1:44

That's awesome. Alright. Hopefully it was smooth dropping back down into the country. I, I guess they'd let you cross the border, which is always good. All right. Let's talk a little Alzheimer's, Novo Nordisk Alzheimer data, were highly anticipated in last week's readout, dashed what may have been long shot hopes for a game changer in Alzheimer's. Selina for those of us who haven't been following this program so closely, can you tell us about the program and why there has been so much excitement around it.

Selina Koch: 2:21

Yeah, thanks Jeff, well, why is there so much hype? I mean, it's GLP-1, it's one of the hottest targets in the industry, undisputed for its efficacy in diabetes and now obesity. And, you know, big top selling drugs where there's been these tantalizing signals across really a wide range of indications that maybe it's gonna be effective, in many, settings from sleep apnea where it's relatively established, to things like addiction, and Alzheimer's. And of course Alzheimer's is a big financial opportunity for Novo. So in its mandate to maximize, its profits from Semaglutide, it would've been a, a big one. But alas, it will not, it will not be.

Steve Usdin: 3:06

Selina. One of, one of the things that, you know, I wonder, and, and you wrote about this, was the decision to jump right into Phase III trials. What are the consequences of that or the implications of that for the Alzheimer's field more generally?

Selina Koch: 3:20

Yeah, that was the thing that stood out to me most about this program. So the reactions to this negative result have ranged from, you know, what a predictable waste of resources to isn't it so wonderful that we have these robust definitive data now and everything in between. And what stood out to me about Novo's press release, and it's kind of been saying this all along, is that because it had lots of real world data from use in diabetes patients, compelling preclinical data, and it knows some things about the mechanism, the semaglutide, although that is a complex mechanism that's only partially understood that it had a quote, responsibility to explore it in Alzheimer's. And on one hand I kind of agree with that. I'm really glad they explored it in Alzheimer's, but what gave me some cognitive dissidents was that that same release said that it had a very, these studies had a low probability of success, and it's been saying that, acknowledging that all along the way. So if your studies have a low probability of success, do you really have a responsibility to recruit nearly 4,000 patients to answer the question.

Steve Usdin: 4:29

And the, the other thing is you talk about the preclinical data, but wasn't the preclinical data suggestive of a protective effect and the trial was in patients who already had Alzheimer's.

Selina Koch: 4:40

Yeah, so the real world data that was so important for this program is in diabetes patients, and some obesity patients, I guess, but primarily diabetes. And what it shows is that the time, so diabetes is a risk factor for Alzheimer's, right? And the time to diagnosis of Alzheimer's in the real world data is delayed with semaglutide use. And semaglutide seems to be better at delaying Alzheimer's than some of the other treatments available for those patients. But yeah, when it came to testing it in Phase III, they jumped right into a setting where you're not talking about diabetes patients here, you're talking about Alzheimer's patients who are already symptomatic. So it, it's a pretty big leap and I think, patients are just a really valuable resource. And so, if you're recruiting 4,000 of them to studies that you think of a low probability of success when you could answer that, que question with a robust Phase II, like say a 500 patient Phase II, which is what Johnson and Johnson just did with its anti-tau mAb. You can get a, a fairly definitive read on a product with a robust Phase II in Alzheimer's disease.

Jeff Cranmer: 5:51

Yeah. Selina, so you, you wrote that, recruitment and retention are just such bottlenecks for Alzheimer's. Especially at a time when the therapeutic pipeline is, is broadening. So is it, maybe this is naive, but like, is this a super hardship on other companies?

Selina Koch: 6:10

Well, let's see. I mean, we'd have to get data on that to know for sure. Right. Um. But the pipeline has been expanding. It's not that there's a bunch of candidates in Phase III that are highly promising, there aren't. But there's lots of early stage trials going on. Testing, you know, various neuroinflammatory mechanisms, for instance, and just things beyond amyloid and tau. You know, I don't, I couldn't say if for certain that, because 4,000 people were enrolled in this trial and took X number of patients away from trial X or Y or Z. But there is a sense in which you think something as low probability of success, so you're kind of instilling false hope and far more patients than would strictly be necessary to ask your question. That's the part that kind of left me just wondering.

Jeff Cranmer: 6:59

Yeah, are there other GLP-1 programs, for Alzheimer's or other neurodegenerative diseases that you're looking out for?

Selina Koch: 7:08

Well, there have been along the way, liraglutide has been tested. Several of the GLP-1s actually have been tested in different neurodegenerative disease settings. None of them have been a obvious success so far. Now a lot of those studies have been kind of small academic, early stage, right. So I get that you want something more robust than that to be definitive. There was a recent failure in Parkinson's that I think was pretty interesting. And I think right now in terms of like getting the most learning out of this very robust trial that Novo ran, you know, I'm very keen to see that CTAD presentation coming up this week where the actual details of the data will be shared when you do have this many patients. I think one of the positives, right, is that you can, um, do a lot of subgroup analyses and hopefully there was a robust set of biomarkers that were, you know, employed, so we can do some hypothesis generation or learn whatever it is there is, there is to be learned. So that's on the positive side of the ledger.

Jeff Cranmer: 8:11

Cool. So this, this was last Monday before Thanksgiving, big hit on Novo shares, raised about 11 12 billion, from its market cap. But J&J had some tough data too for its, uh, anti-tau program, yeah?

Selina Koch: 8:25

Yeah, it sure did. So tau, I think we've all seen that there's been several failures of tau antibodies. There's sort of two hypotheses about, tau is just a more complicated target than amyloid in a sense, because it exists in lots of forms. It can be spliced in different ways. It can be phosphorylated at lots of different sites, individually or in combinations of phosphorylations. That it's thought to spread, like misfolded tau seeds are thought to spread extracellularly, but tau aggregates kind of wreak their havoc intracellularly. So exactly what form of tau to target, where and when is just a little, it's complicated, right. But there's really good reason to think that tau plays important roles in Alzheimer's, you know. And so I think this is just a hypothesis that's going to continue to take time to test because it, it's not really a one hypothesis. It has to be tested in the various, all the various ways That kind of makes sense. So what was interesting about this J&J antibody is that it targeted a mid region piece part of tau that people thought was kind of the business end for this extracellular spreading hypothesis. The first, I think it was four MABs that failed in Phase II were all end terminal targeting. And it's just not clear how important the end terminal is for the escape of tau from where it first aggregates and the medial temporal lobe, to it's escaped into the frontal lobe or the parietal lobe, which are very well timed with symptom onset and the character of those system symptoms. Tau it ends up in the frontal cortex, you get different symptoms and if it ends up in the parietal cortex for instance, that's some of that data that makes you think the how it's probably important. Anyway, the internal ones failed. There's a lot of hope that these mid region ones might be more useful. We now have two bepranemab from UCB and now, um, posdinemab from J&J that missed. Their endpoints. Still the bepranemab dataset was kind of interesting because it showed changes on on tau pet. Now we're looking forward to couple antibodies that bind specifically to the microtubule binding domain there's still some C terminal ones, working their way through the clinic. I think the field is most, the prospects have certainly dimmed for blocking just the extracellular piece of tau being effective. I think people are most excited now about Biogen's BIIB080, which is a antisense program with Ionis that knocks, just knocks down tau, right. It's at the mRNA level, you stop producing it. So you're gonna block all of those forms. Biogen was able to show that that could actually reduce some of the tau pathology, not just stop progression of getting more neurofibrillary tangles, but like reverse some of them. Um, that was pretty exciting early data. So I think all eyes will be be watching that next year when they report more data.

Jeff Cranmer: 11:19

All right, well, you can see Selena's story up on our website, BioCentury.com BioCenturypodcast.com. I'll drop a link into the show notes. we're gonna take a quick break and we're gonna come back and talk about what is happening with FDA's new vaccine policy.

Alanna Farro: 11:40

BioCentury This Week is brought to you by The 5th East-West Biopharma Summit in South Korea. An arc of innovation is emerging across Asia, and Western biopharma leaders are taking note-from cross-border deals to newcos. In March, 2026, The 5th BioCentury-BayHelix East-West BioPharma Summit visits South Korea for the first time. Meet the biopharma leaders putting Korea innovation on the global map. Learn why Korea has become a clinical trial in manufacturing hub. Discover if Korea is the next hotspot for NewCo formation. Plus, meet biopharma innovators from India to Singapore, to China and Japan. Register now at BioCenturyEastWest.com.

Jeff Cranmer: 12:28

Okay, we're back. Yes, we are getting close to the BioCentury East-West Summit in Seoul. I am, pressing Josh, our guru behind our conference is hard to have an event tied to noraebang that is, uh, Korea's answer to karaoke. So you should sign up to be a delegate. If you're interested in presenting we are recruiting companies from across Asia's arc of innovation, from Europe, from the U.S., from Canada. Reach out to me via LinkedIn or go to our website, and submit your interest in being a presenting company for the 5th BioCentury BayHelix East-West Summit in Seoul. Okay. Vaccines have been in the spotlight more than ever since RFK Jr became head of HHS. Now, Vinay Prasad, Head of FDA's CBER wants to change how vaccines are regulated. He claims that a new review has tied 10 children's death to the COVID vaccine. Steve, I know you've been working the phones over the weekend. What are you hearing?

Steve Usdin: 13:47

Yeah. So Vinay Prasad and FDA Commissioner Marty Makary are using disputed analyses that purport to link COVID vaccines to pediatric deaths. To justify a set of policies that would make it really difficult to create new vaccines, and especially to update existing vaccines in response to emerging threats or evolving pathogens. So Prasad, Makary, as you said, they've asserted that COVID vaccines caused the deaths of at least 10 children. That conclusion, they haven't provided the data to support it. It's at odds with investigations that were conducted during the Biden Administration. A Senior CDC Epidemic Intelligence Service Officer and an FDA Pharmacovigilance Staffer reviewed all the pediatric deaths that reported to the agency as being possibly related to COVID vaccines and determined that none were definitively or probably caused by the vaccines. That's what two former senior agency officials told me. I think that what's even more important is that this conclusion about the pediatric deaths is being used as a lever to roll out contentious vaccine policies. Policies that are really gonna change the way that, the way the vaccines are, are developed. So in, in the memo, which

was released at 4: 15:03

21, on the Friday following Thanksgiving, Black Friday, Prasad said that FDA is no longer gonna allow manufacturers to rely on immunogenicity surrogates, and will require pre-market randomized control trials for most vaccines. He also indicated the FDA will revise the framework for approving annual flu vaccines, and that it's reassessing the safety of multi vaccine administration. These are gonna have profound effects on vaccine development, as I said. And some of the concerns are also around how this policies have been developed and rolled out. They've been developed by political appointees, in secret. There's been no advisory committee meeting. There's been no opportunity for a discussion among the scientific and medical community about these changes. And in his memo, Prasad also, basically told CBER staff that it's his way or the highway, that if they don't agree with the actions that he's taken, that they should resign. This is also unprecedented at FDA.

Selina Koch: 16:08

So Steve, what would this have looked like if this had been in effect, in effect in the past?

Steve Usdin: 16:13

Well, yeah, and that's a good way to look at it, you know, to, to understand what it's gonna mean going forward. So for example, the HPV vaccines that are making eradication of cervical cancer a real possibility, wouldn't have happened, if these policies had been in place, neither would Ebola vaccines, neither and the chikungunya vaccines that are under development, all those would be impossible because they all rely to an extent, to a critical extent on immuno bridging studies. So for example, Gardasil, the leading HPV vaccine, was approved, based on a large trial that showed high efficacy against virologic endpoints and high grade cervical pre-cancer and placebo controlled trials in young adult women, placebo controlled trials in early adolescents weren't practical or ethical. So the, licensure was extended to younger age groups to nine to 15 year olds. And dosing changes, approved based on immuno bridging. Regulators accepted vaccination in adolescents because their antibody responses were non-inferior to those seen in adults in whom clinical efficacy was demonstrated.

Jeff Cranmer: 17:21

So, where do we go from here, Steve?

Steve Usdin: 17:23

You know, it, it's really unclear. I think that this is part of a, a broader assault on vaccination. It's not a coincidence that, this memo was sent out just a few days ahead of the next ASIP meeting. The members that were were in ASIP were, most of them were fired, and they were replaced by individuals who were on board with Robert F Kennedy's Make America Healthy again ideology. They're gonna be meeting this week, likely to discuss, and recommend changes to the, pediatric vaccine schedule. Changes in vaccine formulation that will make it difficult to approve new vaccines and could result in, um, removing existing vaccines from the market. Martin Kulldorff, has just been named to a senior position at HHS. So I think we're seeing this, this really broad kind of movement across government to implement policies that are gonna result in reduced access to existing vaccines and a halt, or at least enormous slowdown in the development of future vaccines. Now, there's also gonna be, of course, there's gonna be a backlash against this from the public health community. And it, it isn't clear how it's all gonna be resolved. The other thing I think that's important also is that it's gonna have effects outside of vaccines. The climate of, of fear and top-down management at CBER, isn't restricted to vaccines. And I think it's gonna have effects on, um, CBER's ability to function more broadly.

Selina Koch: 19:00

And very recently, we asked you all out there on your views on how things are going at FDA, what you like, what you don't like, where things are headed across various domains including vaccines. So we are busy analyzing that now, and stay tuned for the results probably next week.

Jeff Cranmer: 19:21

And we should note that Prasad's memo does not name any specific company, it's just the vaccine that allegedly caused these kids deaths. That said stocks of vaccine companies are down today. Uh, a few notable ones, Vaxcyte down eight, as we recorded, Moderna six, BioNTech five, we'll see how this plays out. And keeping with the upbeat news, Lauren, uh, you've got a story coming out on funding for cell and gene therapy companies. It doesn't look good for early stage investments in these plays in the U.S. what's behind the negative sentiment?

Lauren Martz: 20:08

Yeah, this won't be very up uplifting either, and it's not just one thing, but it's behind the negative sentiment. So there have been patient deaths this year linked to AAV gene therapies. The ongoing manufacturing logistical access problems around cell therapies, CAR T cells in particular. You know, have just made a difficult business case for advancing some of those, the challenges of moving CAR Ts beyond hematological malignancies. And some competitive dynamics that we've talked about recently between some of the gene editing technologies and, different modalities are also just contributing to general negative sentiment for cell and gene therapies. I took a look at the number of seed and series A rounds closed this year relative to recent years, dating back to 2020 to see how all of this is reflecting, you know, new company formation and that early stage venture funding that's going into these technologies. And in terms of the absolute number of rounds it's very few have happened this year. So, you know, the year's not over. Of course, venture funding has been down overall this year, so that's maybe not surprising. But there were almost no AAV gene therapy seed in series A rounds in the US this year, for example. And then looking at these as a percentage of the number of overall seed and series A rounds for biotech, it was pretty striking, so each of the last five years have cell and gene therapies have captured like 17 to 20% of these early stage rounds. It was 12% overall based on the data that we have in BCIQ for 2025 so far. And then when you look just at the rounds in the US it was a little higher, historically, cell and gene therapies were about 17 to 21%, and it was only 7% this year. So there is a, a big drop off in, in what we've seen over the past year is when these two modality classes have just been exploding, but, um, interest is definitely way down.

Selina Koch: 22:21

I'm wondering if the ones we are seeing this year, this is cell and gene, I'm wondering if they're mostly in vivo CAR T, or if they cluster in certain areas, like the ones that can make it through to actually get funding right now.

Lauren Martz: 22:34

Sure. So there are, I was actually surprised that in vivo CAR T didn't necessarily stand out as like the modality that's, that's getting funding. It's been pretty consistent over the period that, that I was watching with the number of rounds for in vivo CAR T cell companies. So this is actually something that's been funded back to like, uh, 2022. There were a few this year. The number of rounds was so small that it was hard to pick out trends of what exactly is in the funding. But some of the things that were notably absent were AAV gene therapies in the US in particular, and immune cell therapies were down. CAR T cells in particular were down. And so all of the CAR T cell funding that we saw in the past, uh, season series A funding in the past, two years, 2024 and 2025, was really focused on new indications and expanding access for that modality. So it's all allogeneic, gamma deltas, um, you know, ways to make these more accessible. And then tweaks to the design that may make the cell therapies work in solid tumors, which is something that we haven't really seen yet. So, multiple targets, or armoring the cells with cytokines and things like that.

Jeff Cranmer: 23:55

Alright, Lauren. That's all in the U.S. is there hope overseas? We know we've been following China closely. Uh, what's it, what's it looking like in China?

Lauren Martz: 24:05

So in China, the proportion of seed and series A rounds that we have data covering is really exploding for cell and gene therapy since about 2021. So I mentioned that it was only 7% in the U.S. It was 29% based on the data that we have, which may not be entirely complete. So a big difference in the level of focus that these modalities are getting in China. And something that I found really interesting was that the specific technologies that are getting funded at Chinese biotechs are not what I was expecting. So NK cells were a very hot area, this is a type of immune cell therapy that has had a lot of negative sentiment in the US in particular and in Europe in the past couple years, just because there's been some evidence that an NK cell, a CAR NK, may not be as effective or as durable as a CAR T cell. We've seen deals that are dissolved, we've seen programs dropped, but it seems like some biotechs in China are sort of taking on the challenge of figuring out how to make this cell type work. There's also a lot of development of AAV gene therapies, which I mentioned we're not seeing a lot of early stage funding for companies that are specifically working on that in the U.S. They're a lot working on it in China. So, you know, the regulatory environment obviously is different there than here. One of the contributors the negative sentiment in the US that I didn't mention is all of the uncertainty around how FDA will handle rare and ultra rare diseases, going forward. So that may contribute to the fact that we're seeing a lot of innovation there in other regions.

Selina Koch: 25:47

Lauren, with the commercial challenges in the US for cell gene therapies formidable, what does the path look like for these Chinese companies?'Cause I would think a lot of them would be hoping for overseas partners to really, you know, take these therapies into lucrative markets. I know pricing pressure within China is pretty intense. So what's the commercial dynamics in the poll look like over there?

Lauren Martz: 26:12

That's a good question. I don't think we have the answer, but I know that what we've seen with cell therapies, I think is what we may see with gene therapies. So it is possible to get clinical proof of concept for a cell and gene therapy in China through an IIT in a way that's, you know, potentially faster and less expensive than what may be possible to do in a US based Phase I. I think ultimately at the hope may be a US based partner and de-risking. An asset for a rare or ultra rare disease in a, in a way that changes the economics enough to make Western companies willing to take on the risk.

Jeff Cranmer: 26:53

All right. Well any hope of this changing in the near term in the U.S. Lauren, well, what's it gonna take? Are there any products you're watching that that might give a much needed win?

Lauren Martz: 27:04

We've talked about this before too, but as we, we mentioned earlier, on this podcast, I think the in vivo CAR Ts are something that everyone's watching because there's good early proof of concept data from a very small number of patients. But this is a potential to solve the access issues of a really effective modality for cancer and potentially autoimmune diseases too. That could bring this cell therapy product into more patients, more indications.

Jeff Cranmer: 27:33

And, and one company, I'd just say, uh, maybe have a look at, Immuneel, founded by Kiran Mazumdar Shaw, she's the founder of Biocon most successful biotech company in India. She partnered up with a couple of other Indian KOLs and, and launched Immuneel, which aims to bring CAR T to patients at a fraction of the cost. I've had the CEO on a couple of my East-West panels lately. And, you know, he says that they're making progress, so that's one to watch as well. Steve, you, you spoke to them back in the day? Yeah.

Steve Usdin: 28:13

Yeah, and they have a, an interesting model for developing CAR T and for providing them to patients. Basically looking at producing CAR Ts in hospitals, something akin to the way that transplants are handled in the United States.

Jeff Cranmer: 28:30

Look, you know, a lot of this stuff doesn't work until it works. And, uh, hardworking people like, uh, many of our listeners, you know, they brought you KRAS after how many years? 40 years. And, uh, just gotta keep going at it. All right, well don't miss our sister podcast coming out later this week, The BioCentury Show, Selina will be sitting down with the CEO of Fore Biotherapeutics, that's Bill Hinshaw, And also on biocentury.com BioCentury.com we have our colleague Lindsey Martin's analysis of series A rounds, worth checking out. And we will catch you next Monday. Don't forget to like and subscribe. Send us a question and we will see you next week. Kendall Square Orchestra provides the music for BioCentury's This Week. The group connects science and technology professionals and other members of the Greater Boston community to collaborate innovate and inspire through music, while supporting causes related to healthcare and education.