第158期——2025年10月10日

You're listening to Biotech Hangout, a live and unedited weekly discussion of all the latest news in our industry with a group of biotech insiders. My name is Tess Cameron and my co-hosts today are Sam Fazeli, Luba Greenwood, and Brian Skorney, as well as Yaron Werber, who's going to be joining us shortly. For more information about our hosts and guest speakers or to listen to our most recent episode, please go to biotechout.com.

We have a lot to cover this week, as usual. I wanted to start with a short pop quiz for my great co-hosts this week: When was the last time we saw the XBI, or had a Biotech Hangout with the XBI dancing around 105?

That's easy for me to answer. I've got Bloomberg right in front of me.

So tell us. I'll let people who don't have Bloomberg in front of them guess. Brian?

That's a good question. Maybe 2022.

It was not 2020. It was not 2022. It was 2021.

No.

Yeah, we have to go all the way back to 2021 to be at a Biotech Hangout where the XBI was around 105. I think it just dropped to under 105, so over 104—let's call it that.

1. Biotech M&A Comes Back

That's obviously exciting: to see more interest in biotech, driven by a lot of fundamentally good news. I think one of the pieces of good news we want to start with today is deals and M&A.

There was a nice analysis I saw from LifeSci Advisors pointing to year-to-date M&A—before the deals announced this week—at around $81 billion, with a lot of deals over $1 billion through September. That $81 billion is a real increase from full-year 2024, although not quite at the highs of 2023.

Looking at the number of deals, year to date, with a couple of months left in the year, we're looking at about 30 deals—more than that now, with a couple of deals announced this week. That's actually pretty in line with full years for many of the past couple of years since 2020. So let's get into some of the deals announced this week. Sam, maybe I'll start with you on Akero and Novo Nordisk.

Yeah, sure. But if you don't mind, Tess, beforehand I want to highlight something. If you look at these deals we've been seeing—Akero and Novo Nordisk, Pfizer and Metsera—think about the story behind them. This is the reason people should be investing in biotech in general, or at least that's the reason we put forward for investing in biotech: Pharma needs pipeline.

We had Pfizer—I mean, I can keep going backwards, right? But let's just think about these 2 examples. Pfizer tried to develop its own asset in obesity, and it didn't work out straight away. So you go and buy it in; you're either in-license or you buy it in. In this case, they bought Metsera.

Novo Nordisk is one of the leaders, without dispute, in the obesity and metabolic disease world. Akero's MASH program, with an FGF21 approach, looked compelling, so Novo bought the company. That is why I think people should be thinking about biotech, and I think that's why perhaps the market is picking up for the sector as a whole. I'm not talking about any specific stock here.

This is what happens: Pharma companies need pipeline, they hit a brick wall, and there are assets out there available. Of course, we all want them to buy the company that we have on our list or in our portfolios, but in the end, it's good for everybody.

In this particular case, we have Novo buying Akero. I don't know—this is the sixth week in a row that we've had an M&A deal, and maybe tomorrow we'll have 2, with the rumor about Johnson & Johnson and Protagonist. This is a deal that Novo Nordisk announced yesterday for up to $5.2 billion for Akero.

Akero's efruxifermin has, based on our analysis, leading efficacy data. There are other things to consider in the MASH space—the metabolic liver disease that often follows obesity, although in some cases it isn't associated with obesity. You don't have to be overtly obese to potentially have MASH ongoing underneath.

They showed some compelling data: 40% fibrosis improvement at 24 weeks, growing to 75% at 96 weeks. There are lots of details we can go into here, but when you look at the entirety of the trial, it was strong—better than what we've seen with some of the others—and it continued to evolve and get better over time.

It looks better on efficacy than what Novo Nordisk had themselves. It looks better on efficacy if you don't adjust for placebo. If you do adjust for placebo, it's slightly different—not that much better than 89bio's pegozafermin.

Then, of course, you come to GSK and Boston Pharmaceuticals' efimosfermin. These are drug names that we all love because they get so convoluted in terms of their structure. But they all show good MASH resolution.

Of course, in these trials you have to be very careful about which patients were included: F1, F2, or F3. With Akero, we've even seen some good results in F4 patients in the SYMMETRY trial. Thirty-nine percent had improvement, et cetera, and MASH resolution was 3 times placebo. These are all very significant data.

Then, of course, you get to tolerability and safety, and you look at it and it's kind of the inverse. You get gastrointestinal effects and side effects with the Akero product that appear to be higher than the data we see from the other drugs. Interestingly, discontinuation rates are all the same across these products.

Which has the best product? Who knows? But these gastrointestinal side effects worry me a little if we're going to be looking at a combination with semaglutide, which is obviously the active ingredient in Wegovy.

Lastly, it comes down to dosing. Currently, the Akero compound is dosed once weekly. You get the 89bio drug twice weekly in a prefilled syringe, as opposed to a lyophilized powder. Then, of course, you have GSK's possibility of potentially a once-monthly dosing schedule.

There are other side effects we need to keep an eye on, particularly bone mineral density, which is supposed to be a class effect, although there seem to be some differences between the drugs. All in all, the acquisition Novo Nordisk just made appears to bring what looks like the best efficacy in fibrosis improvement, particularly in F4 disease. On the side-effect profile, though, they have some issues relative to the others.

Of course, time will tell. These are all relatively early studies, dosing needs to be worked out, and if you're going to use them in combination, we need to figure out how to do that.

Again, I want to highlight that Novo Nordisk is one of the key players in this space—the obesity and MASH space—and already has semaglutide, which has good MASH data. Let's not forget that a lot of people got worried when the GLP-1 drugs started reporting MASH data, saying, “Wait a minute, what's the investment case for these companies?”

The folks who had thought about it long enough knew that this is a disease area where combinations are likely to be needed, and that drugs following GLP-1s are not going to be the answer to everything. Here, Novo proves that investment thesis. It's great to see. We have a whole bunch of companies that are still in the space, and it will be interesting to see how that goes. I'll leave it at that.

I think it's interesting, Sam, building on what you said. There are some companies left in the space, but we're looking at such a different picture for NASH companies than we were a couple of years ago—or MASH companies.

So far this year, even just in the past couple of weeks, with Akero and 89bio, and Boston Pharmaceuticals earlier this year with GSK, I'm having a hard time thinking of another independent, clinical-stage biotech with a clinical-stage FGF21 program. They've really been snapped up.

I think the focus on cardiometabolic disease by a lot of strategics has been part of this. I also think all of these companies have Madrigal to thank for really showing that the market is big and that there's a high enough unmet need to support a price point that can deliver a very robust peak-sales number. It's a very different place from where we were looking a few years ago.

Let's have a bet, Tess. What's your bet that in 6 to 12 months there will be a whole bunch of companies coming out of the woodwork—assets that people had forgotten about, with a slight twist on them? An FGF21, or even other mechanisms, are going to end up coming out of stealth, or not even stealth.

I haven't looked yet to see what's happening in China. Are there assets in China that people are going to bring in and create newcos out of? I bet you there will be.

I would not bet against you, Sam.

2. In Vivo CAR T Takes Off

Let's go to the other deal this week, the BMS–Orbital deal. Maybe Yaron, you could kick us off here.

And Sam, I know you have comments on this one as well.

Yeah, absolutely. I hope you can hear me okay.

The next innovation in CAR-T is really going to be an in vivo, sort of bedside, LNP-driven modality. This is a $1.5 million deal for Orbital for a CD19 CAR-T, using its proprietary mRNA platform to deliver it in vivo. We’re seeing a lot of that now, both on the BCMA side and, obviously, with several companies working with CD19, and they’re all early.

There’s been some proof of concept already in the clinic in general in the space. We know that even J&J is definitely looking at some preclinical assets targeting BCMA, as much as they think Carvykti is a winner. Obviously, everybody is looking for something a lot easier that doesn’t require apheresis, conditioning, and, ultimately, processing. That’s definitely a hot space worth following from now on.

Absolutely. And Sam, what do you have to add on that?

Just to add a little bit: remember, this is an acquisition by a company that’s got, pretty much in our view, the leading anti-CD19 CAR-T, Breyanzi.

When you read the press release, Orbital has been focused on the I&I application. For I&I—and I don’t know, Yaron, I’m sure you agree—you can’t go with the standard CAR-T process, right? You need to have this in vivo, off-the-shelf approach to make it a lot easier for those sorts of patients to take value from it, unless you were aiming at the absolute end-stage autoimmune diseases.

It’s interesting that it was Bristol Myers that did it. Any CAR-T company, as Yaron said, if you talk to them, is talking up the idea of in vivo, which, of course, is logical. It just makes it so much easier to deliver these agents and makes it so much easier not to worry about academic versus community, et cetera, particularly in the oncology space.

Yeah, spot on. The AEs of the traditional approach are just nonstarters, and that came out very clearly about a year ago at ACR for I&I.

Yeah, absolutely. We’re seeing a lot of interest in this transient approach. Within the in vivo CAR-T landscape, there are a lot of different ways to think about and look at it. Certainly, one is whether it’s transient or nontransient.

In the nontransient bucket, you have a bunch of different integrating approaches. Interius was one of those integrating CAR-T approaches. I think it’s interesting with both Orbital and Capstan, which shared a similar upfront acquisition amount for very early, either late preclinical or early clinical companies.

I think it’ll be interesting to see how the different applications for these companies really emerge in terms of autoimmune disease. With both Orbital and Capstan, which really had leads in autoimmune disease, the transient approach does seem to lend itself there for these broad patient populations and for dealing with something that is certainly a very severe disease but nonlethal.

It’ll also be very interesting to see how the integrating approaches evolve over the next several years, with Interius really being the deal that happened on the integrating side this year. These couple of deals that we’ve seen in the in vivo CAR-T space also go back to Sam’s point about a lot of the M&A this year really being about filling out pipelines and filling out the early side of the R&D pipeline as well, with platforms like these in vivo CAR-Ts that can be applied across a number of different disease areas.

3. Pharma Partners With AI

I think another theme on that early pipeline buildout for pharma that we wanted to hit on is these AI pharma deals. Luba, you’ve been watching those very closely, and we’d love to get your insights and perspectives on a few of those that happened this week.

Oh, Luba’s just being kicked off.

Oh, Luba’s being kicked off. My goodness.

No, I mean—who dares do that?

Who dares kick Luba off? She will.

It happens all the time on Twitter for some reason.

It’s probably Elon.

But never to Luba. Maybe it happens to us, but never to Luba. We will restore that inequity quickly.

While we do that, let’s talk about one side of the ledger: M&A that has actually been returning a lot of capital over the past couple of months to investors, particularly biotech specialists, as well as some of the larger mutual funds that have pretty high biotech exposure, like Fidelity and Janus and the like.

There are obviously a lot of opportunities to deploy capital in biotech. We’ve seen a lot of follow-ons in the market, and we’ve started to see some IPOs on the market. I think there have been 9 IPOs this year. Almost all of those were IPOs that happened in January or very early February, and then there was nothing. Then there was LB Pharmaceuticals.

Now we’ve seen MapLight file its S-1. MapLight is a company that is really looking to improve on Cobenfy, which was the drug that Karuna developed, that was acquired by BMS, and that is currently being launched. MapLight is looking to optimize and improve on Cobenfy, and it is raising money to fund trials in schizophrenia.

I think this is really another great example of biotechs leading the way and showing big pharma where there is a lot of opportunity. Karuna really did that through its data, as did Cerevel, and MapLight is coming out with what it views as a potentially even superior version of that.

They’ve filed their S-1, and we’ll get to see over the coming weeks just how that IPO unfolds. But it does draw on a theme of continued interest and recognition that there’s a lot of really important innovation that we need to follow in neuroscience. I mean, AbbVie acquiring Gilgamesh, a psychedelics company, is another great example of that this year.

These are big markets with a lot of unmet need, and it’s encouraging to see continued investor interest in these areas. I’m hopeful that we now have Luba’s rights restored.

Which is fantastic. So, Luba, why don’t I turn it over to you on the theme of filling early pharma pipelines, including with capabilities and platforms? Tell us about these AI deals this week.

Yeah, thanks so much. AI has had a love-and-hate relationship with pharma. Initially, everybody wanted AI platforms; then everybody was platformed out. Then pharma decided to build its own AI capabilities. Now they realize that they should stick to what they know and partner with AI companies.

We’ve seen quite a bit of AI platform technology partnerships with pharma. What I mean by that is anywhere artificial intelligence is enabling discovery or translation.

First, I’d like to talk about the recent deal that AstraZeneca just signed with a company called Algen Biotechnologies. It’s for $555 million. We don’t know what the upfront is, but it’s mostly a back-loaded deal. It’s still pretty exciting for Algen and shows commitment from pharma, like AstraZeneca, to utilizing AI in drug discovery.

This one is specifically targeting the discovery of new targets in immunology. It’s a multitarget research collaboration, so not just around 1 target. What Algen will do for AstraZeneca is use a platform called Algen Brain to identify and validate novel targets specifically in immune-mediated diseases.

AstraZeneca will get exclusive rights to develop and commercialize any of the resulting therapies that Algen Brain finds for them. Algen is not taking equity stakes. Sometimes in these deals, pharma companies structure it so that they take an equity position; here, that’s not happening.

What’s really neat about it is that Algen’s technology provides AI and combines functional genomics, CRISPR screening, and CRISPR modulation. It maps out basically a causal link between gene regulation and disease progression in human cell types.

If you think about it, it’s a platform that uses single-cell gene modulation, high-throughput screening, and AI models, all to figure out which genes are therapeutically actionable and which ones are not. It will help a company like AstraZeneca with translation from human biology and our understanding into immunology, and with finding novel targets around which they’ll have exclusive rights.

AstraZeneca has been pushing into cell and gene therapy, and they want to expedite discovery in that space as well—discovery and advanced modalities. They also did a multibillion-dollar deal in this space earlier this year, so it's all pushing in the right direction for them. I think it's a great deal and also very good for AI in general.

Even with all this enthusiasm, I think if we step back, we haven't yet seen an AI-drug-discovery-enabled drug approved in immunology. But that doesn't mean it's not going to happen soon. So that's one AI-type drug-discovery, preclinical, translational-biology type of deal that we've seen.

We've also seen another one with a company called BenchSci. I'm actually on the board of BenchSci. It's a fantastic company based in Canada, in Toronto, where the University of Toronto is one of the top places for software engineering and that type of talent.

They've just done a 3-year licensing deal with Sanofi, where Sanofi will be using a platform that BenchSci has built called ASCEND, also for preclinical research operations. Think of it as a disease-biology AI copilot: it takes in the scientific literature, proprietary data that Sanofi has internally, experimental metadata, and graphs that out into basically a biological evidence knowledge map.

It can help with everything from triaging your targets to creating a better experimental design and optimizing it, as well as generating hypotheses and new mechanisms of action. So, all good news for those companies and AI platforms that want to partner with pharma.

4. Nelo Targets Brain Body Pathways

Thank you so much, Luba, for that great overview. I think, sticking with the new mechanisms, Nelo Therapeutics is a company that launched on Wednesday this week. They are taking a pretty interesting approach to the immune system. So tell us about that, Luba.

Yeah, thank you. I have been personally obsessed with this type of mechanism of action and the correlation between understanding the effects of regulating circuits in basically brain-body pathways—in the vagus nerve and the nervous system—and how that relates to regulating the immune system.

There's been a lot of research, and I think I talked about this a bit before in some of the other podcasts. I think this is a highly underfunded area. I was wondering why more companies and more funds weren't interested in or looking into it. So when I saw this, I got very excited.

What is Nelo? It's a biotech. They were in stealth for many years. They just raised $101 million in Series A funding, and what they're doing is exactly what I just mentioned: modulating neural circuits to control the immune system and, therefore, inflammatory diseases.

I love seeing what they come up with and learning how the brain connects to inflammation. Their thesis is that if you go after and target central master-regulator circuits, like brain-body pathways, you can coordinate multipathway immune modulation in a much better way and with less resistance.

The science is built from an academic institution, Zuker's lab, and he has shown that there are certain neurons that can dial inflammation up or down in certain animal models. So, again, it's very early—the evidence is in animal models—but I think it has a lot of potential, not just for them but for the whole field.

I wish them luck. They have quite great backing. Column Group, DCVC, Lux Capital, and the Gates Foundation all participated in this round. I don't know, Tess, if you've seen anything that has come across your desk in this space. If you do, that's great. I love it. You should fund it.

Yeah, it's a really interesting approach, and it's great to see them moving forward. Luba, we're sticking with you for a few minutes. This is why we needed to make sure—

Now that my mic is on, you've got to make me work. I like it.

5. Fresh Capital Enters Biotech

Exactly. This is why we needed you to come back. We've talked about money coming back into biotech through M&A. We've talked about where some of that money is being deployed. Tell us about new funds, Luba.

Yeah, I love seeing new funds. I think everybody in biotech—if you're an operator out there—we're all very excited whenever there is a new fund, especially a well-capitalized fund that has a broad investment thesis.

We have a new one, I think I'm pronouncing it as Sante Capital. I think I'm pronouncing it correctly.

I think you are, yes.

Okay. If I'm not, I apologize to the founders. They're two former Moderna leaders, and they just closed on a new fund. They're out of Florida, which sounds nice and warm today. It's a $325 million fund.

What they're looking for is development-stage biotech—things that are in the clinic, in phase 1 or phase 2. They're looking into companies that have multiple assets, so not a single asset but multiple drugs in the pipeline.

I like that they're not passive backers. They're not saying, “Hey, we're going to deploy this money.” They have already deployed, they say, up to $100 million in 6 startups, including some companies that we've covered here, like Odyssey.

I also like that they're reducing the risk by providing and partnering on the technical, operational, and scientific sides. They're also pretty open across multiple therapeutic areas. I think their approach is good, and it's always nice to see new entrants into the field.

Wonderful. Fantastic. Okay, we'll give you a short break, Luba—

From all of that. All right.

6. New Data Tests Biotech Theses

Let's move on to some of the data we've seen come out over the past week. We've had a number of readouts. Let's start, Sam, with one that you've highlighted, which is Arcus Biosciences and their monotherapy data in renal cell carcinoma.

Yeah, sure. So, Tess, Arcus is best known for the story of TIGIT, which is the deal they have with Gilead. That deal is still ongoing, despite the fact that many other TIGIT approaches from other companies have been shelved. But this is not about TIGIT. This is about a drug that targets HIF-2α, where there is already a drug on the market from Merck, and that's Welireg. That's for a very specific group of patients with kidney cancer.

This time, these guys have pulled together the data from their dose-ranging study of about 121 patients—phase 1 data—and frankly, it looks pretty good. It is a dose-ranging study, so that's important to realize when you're looking at the AEs specifically.

It's a $5 billion addressable market based on our modeling. They've shown what looks like better progression-free survival and response rates than we've seen with Merck's Welireg, although obviously we're doing cross-trial comparisons. One study is 121 patients, and the other is 374 patients, but 121 is still respectable. We find that, at least preclinically, there was some reason to think this difference might exist, and now this suggests that you might be seeing it in the clinic, too.

What are the differences? It's 12.2 months of median progression-free survival versus 5.6, which is a big difference. Median follow-up is pretty decent for the casdatifan data. Remember, Welireg is belzutifan. Median follow-up is about 15 months, so we'll see how this progression-free survival evolves as time goes by.

Then you've got a confirmed response rate of 31%, which is better than the 20% to 30% that we've seen with Welireg. Side-effect profiles seem about the same: grade 3 or 4 AEs were 60% for one and 62% for Merck. Discontinuations aren't available for these guys, but they were 6% for Merck. We saw some grade 5 events in the Merck trial, but they weren't necessarily related to the drug.

In general, it looks pretty decent. None of the anemia events, which are of course part of the package with this approach, led to discontinuations. The data looks quite good. We think there's room for this, and the share price duly responded on the day the data was released.

It jumped from a close of $13.35 on Friday, October 3, to a peak of $16 and a bit, and it's now settled down a little higher. Of course, it's a bunch of patients from different dose groups put together. It's a phase 1, single-arm study, and we need to see how it progresses. But it's nice to see this happening.

It's interesting that this was a drug Gilead backed away from, while they stayed with the TIGIT program, for which we're going to get some more data from AstraZeneca at ESMO. We'll see how the ARTEMIS-1 trial pans out.

These guys' TIGIT is based on the same sort of idea: it's not Fc-active. That's something that the couple of companies left in the space tout as a key element of why they're able to continue, whereas Roche had Fc-active approaches. Sorry—the Fc-silenced and Fc-active approaches.

Great. Thank you very much, Sam. You were talking in the topic that kicked us off, which was the AstraZeneca acquisition. We were talking about activity in the metabolic space and just how much activity there is.

I think we’re actually at a pretty interesting time. In the next 6 months, we’re going to start seeing a lot of readouts on new mechanisms for obesity and new mechanisms that could potentially be applicable across a few different disease areas.

One of these mechanisms that there’s been interest in, and then concern about, is CB1, right? CB1 had historically shown some weight loss. Novo acquired Inversago, which had a CB1 program, and they came out with some data at the end of 2024 that I think underwhelmed a little bit in terms of weight loss. There were also concerns about the neuropsychiatric side effects, and I think those concerns were recapitulated in a diabetic kidney disease trial that came out this year.

There was a lot of interest in Skye’s molecule. They also have a CB1, and maybe, Sam, you can tell us why their drug was a little bit different from Novo’s, what the hope was, and then what we saw this week.

Yeah, sure. Skye Bioscience is not one that really shows up very often when people talk about obesity, but I always found their idea interesting. As we know, CB1 is an old-new mechanism, right? It’s something that has been postulated for a while. But, of course, as you rightly said, you get these neuropsychiatric problems when you’ve got an oral drug that penetrates the blood-brain barrier.

Here, they thought, maybe we can deal with this by using an antibody, which shouldn’t distribute as much, as we well know from the Alzheimer’s world. They all need a brain shuttle to try to get that concentration up with antibody drugs. Here, they’re trying to just use a standard antibody, nimacimab, that binds CB1 and should be peripherally restricted, essentially.

They did a single-agent Phase 2a study with 26-week data, and the weight loss underwhelmed. So what’s the way forward? Is the weight loss underwhelming, or maybe it’s because it’s not dosed sufficiently? It is a bit complicated to dose this. They suggest one way of combining it with semaglutide, and when they combined it with semaglutide, they saw better efficacy than in the semaglutide-alone arm. That’s something they’re going to focus on and possibly increase the concentration that they deliver.

That makes sense. If you put more antibody in the bloodstream, subcutaneously or whatever way you’re going to do it, you should get more target engagement. Let’s assume that works. The only worry I have is, if you increase the dose, are you going to get sufficient penetration in the brain that might cause these neuropsychiatric side effects? They’ve seen none with the drug so far at the doses that we’ve seen.

Maybe the future for this is a combination with semaglutide. Of course, you’re dealing with a completely different mechanism, so you don’t keep getting additional nausea and vomiting, et cetera. Where this really fits in the future, who knows? There is some logic to the approach, which I’ve always liked, and we’re going to have to see how this data reads out. We do have some more data coming in Q1 2026, when they report the Phase 2a extension study.

That’s it. Great. Great. Thank you. Thank you for sharing. I think there are open questions on that mechanism, and we’ll really need to see positive clinical data that shows really competitive weight loss for there to be renewed enthusiasm in that mechanism.

There are many other mechanisms for obesity that should be reading out over the coming months, including quite a bit on the incretin side. Let’s go over to muscle and Brian. I think maybe if we could have you comment on Dyne’s data in DM1, as well as the World Muscle Society’s DMD presentations.

Yeah, thanks. The World Muscle Society is ongoing as we speak. I think they had the late-breaker sessions earlier this morning. There’s a lot of data coming out of here.

Dyne is one of the names I cover, with some updated data in their DM1 Phase 2 study that I think is interesting. Of course, there are a lot of discussions around Sarepta, REGENXBIO, and the DMD gene therapy space, all being addressed to some extent at the World Muscle Society.

Maybe just to start with the Dyne story, this name has been a little bit of a hot-button topic, obviously in competition with Avidity for reasonably similar DM1 programs. Avidity is ahead with a bigger program. Dyne is looking at a smaller pivotal path. Maybe next year, both of them are going to be reviewed at the same time, pending positive results.

Dyne had pretty extensive 1-year data from its Phase 1/2 study, particularly with its pivotal dose, this week. What I would say looks impressive about it is that, almost across the board in its slides, it’s showing continued improvement. vHOT is the main endpoint that the companies are looking at here, which is a measure of how quickly it takes to open your fingers. It’s a little bit better at 12 months than it was at 6 months, which was better than placebo in this study.

When we start looking across a bunch of the other timed function tests, you see more improvement from 6 months to 12 months, which I think reinforces the mechanism here. You’re seeing continued improvement—not just stabilization of disease or an initial improvement, but continuing to improve. I was most impressed by the quantitative muscle testing total score, which basically doubled in effect size from 6 months to 12 months. It’s really showing a pretty nice curve up and to the right in terms of benefit here.

They are enrolling the pivotal cohort right now in DM1, and hopefully we’ll see that data around the middle of next year and should hopefully see a filing after that. Again, Avidity is a little bit ahead with a larger study, but I think it’s going to be one of these situations where we’re going to get 2 data sets from 2 different-sized studies and compare things like vHOT across trials.

Dyne trades at a pretty significant discount to where Avidity does right now, but practically speaking, they’re not that far behind timewise. They could get on the market in a similar time frame, so I thought that data was interesting.

Moving on to the DMD side of things, there was a big run-up in Sarepta last week. I’d characterize that as people maybe being less negative. I certainly haven’t seen a big change in sentiment on this name after the controversies around the gene therapy, which have led to 2 deaths due to liver toxicity in nonambulatory patients, and then the back-and-forth we’ve seen with the FDA over the summer.

Since then, things have quieted down a little bit. They have a number of posters showing more long-term data, including more 3-year data from a number of their studies, as well as more data in younger kids showing what I think is a pretty diminished liver toxicity profile relative to the older patients.

There’s also a single-center experience of prophylactic use of sirolimus presented at the World Muscle Society. This is the tack that Sarepta has taken to try to mitigate the liver toxicity occurring with Elevidys. Interestingly enough, REGENXBIO also has data for its DMD therapy. Sirolimus has been part of the prophylactic protocol that REGENXBIO has been using since the initiation of its studies, and it also shows very diminished liver inflammation as a result of sirolimus.

Talking to doctors, it was a little bit less of a concern and maybe more of a hope that using a different methodology for trying to control this liver inflammation with sirolimus might mitigate some of the effects. A lot of people debate the overall efficacy of gene therapies in general and how much evidence there is of a true effect, but I think there is generally a belief among physicians that there is an effect size here, even if it’s not something that can easily be quantified.

If the safety profile can be secured a little bit more, it may get back to a point where they can start growing sales again.

Great. That’s about it. Great. Well, thank you, Brian. That’s a great overview. I think it’s really important to note because it ties into one of the companies, Brian, that we’ll have you talk about next. It’s just how important it is that we have so many big companies now that are really founded on RNA technology, right?

You were talking about Dyne and Avidity. These are really important companies in our ecosystem, obviously, and we’ve really seen a pretty big transformation this year in investor sentiment for Ionis, another company with a rich history in this space. It was one of the first companies to really be doing a lot of work on ASOs, together with Alnylam and some others.

Its stock price has more than doubled this year, and it’s had a number of readouts. I think what we wanted to spend a bit of time talking about, Yaron, was its Innovation Day, which I believe you attended.

Let’s hear your thoughts on that.

Yeah, absolutely. Peter Lynch used to say, “I’m an overnight success 25 years in the making.” Well, Ionis is now, I think, becoming an overnight success. I don’t know if that’s been 25 years or 30 years at this point, but they’ve finally gotten to a point where the pipeline is really productive. It’s late-stage, and they actually have a combination of their own products on the market that are doing well.

At this point, they have Spinraza, on which they get royalties from Biogen. They have Wainua doing pretty well in polyneuropathy due to ATTR with AstraZeneca, with an autoinjector. They took 40% share within a year from Alnylam. They have Tryngolza for severe hypertriglyceridemia, which was approved for FCS, familial chylomicronemia syndrome. But much more importantly, to your point, Tess, the stock doubled really on the heels of this sHTG data—severe hypertriglyceridemia—that is now leading Wall Street to awaken and realize, “Oh, my God, there’s actually a big drug here.”

They showed a 72% reduction in triglycerides and an 85% reduction in acute pancreatitis—literally mic-drop-type data. It’s the first time ever you’re seeing an acute pancreatitis risk reduction. They’ve now launched Dawnzera, which is an autoinjector every 4 weeks or every 8 weeks, with switch data from other prophylactic hereditary angioedema drugs.

They’re just getting started. Next year, there’s going to be Phase 3 Lp(a) data with Novartis. There’s going to be CARDIO-TTRansform data for Wainua, the biggest study ever in TTR cardiomyopathy. There’s going to be Phase 3 data from their competitor, Ultragenyx, in Angelman syndrome, and of course they’re 6 months behind. Neither company is getting any credit for that.

Then there’s going to be bepirovirsen, their hepatitis B ASO, in Phase 3 with GSK, with data next year. There’s going to be Phase 3 factor B data for IONIS-FB-LRx with Roche. Finally, with Biogen, there will be MAPT data in Alzheimer’s and early Alzheimer’s from the CELIA study—436 patients at a year—probably coming next year.

At the innovation day, what was new? Three things. 1, guidance to profitability in 2028: peak sales of over $5 billion, $3 billion from their pipeline and $2 billion from collaborators. 2, the knock on Ionis was that everything they’re doing is cool and all, but there’s always somebody behind them who’s better with siRNA. Well, they have their own siRNA platform now, and they’ve unveiled, out of nowhere, Phase 1 data for their APOC3 program.

It’s their own competitor to their own Tryngolza, which is monthly with an ASO. With the siRNA, you’re getting a 90% reduction, the same as the monthly dose, except if you look at the pharmacokinetics, it supports dosing every 6 months or once annually. That came out of nowhere, and it’s going into Phase 2.

Finally, they’ve rolled out a whole new chemistry with an siRNA platform, now even targeting muscle, and they’re going into HFpEF and heart failure. I haven’t even mentioned a host of other, smaller drugs, including Alexander disease, which just hit in a pivotal study. It’s going to be a small drug, but they’re launching that probably next year.

The bottom line is, they used to say—I’m dating myself—“This is not your grandfather’s Oldsmobile.” This is not old-school Ionis. There’s actually a lot going on there.

All right. Well, thank you, Yaron. It’s always exciting to see companies really reinventing themselves and capturing a lot of investor interest and innovation. It’s amazing to think, just winding back a couple of years, when Ionis said, “Hey, we’re not really going to commercialize our own stuff. Let’s spin that out and really focus on R&D, pipeline stuff and doing deals,” and now they’re bringing that back in-house and turning themselves into a commercial company that has many more wholly owned programs. That’s a real shift for the company.

Let’s move on to some regulatory updates that we got this week. Brian, why don’t you kick us off with Lexeo?

7. Gene Therapy Finds Regulatory Flexibility

Yeah, so Lexeo Therapeutics is another gene therapy company. They’re working in the cardiac space. Their lead program is in cardiomyopathy due to Friedreich’s ataxia: LX2006. The company has gone through a Phase 1 dose-finding study in cardiomyopathic FA patients, and we know the history of some of these FA drugs. I think a lot of people think of it as a neurological disease, but most of the patients ultimately die of cardiovascular issues. There’s a huge cardiac component to it, and that’s really what they’re targeting here—maybe more slanted toward the older side of patients who have more progressive disease.

FA is a very interesting disease because it is monogenic. Patients have a diminished capability of producing functional frataxin, and this is a frataxin replacement therapy. They’ve shown a very good ability to increase frataxin expression in cardiac biopsies. It does seem to have a dose relationship across the 3 doses that they’ve tested.

A big question here is around the flexibility of CBER and gene therapy. Obviously, the last iteration of the CBER administration under Peter Marks was extremely flexible and offered a lot of flexibility to gene therapy companies in orphan disease in general. With the changing of the guard, there have been a lot of questions about how much of that flexibility will still be applied, especially given that the current head of CBER has been very critical of the Peter Marks flexibility dynamic.

Lexeo offered 2 updates earlier this week: a regulatory update, as well as some additional long-term clinical data from its initial study. I would say the overall picture looked really positive on the clinical-update side of things. The primary thing we’re looking at here is left ventricular mass index, or LVMI. This is a measure that had already been blessed by the prior iteration of the FDA in Rocket’s Danon disease program.

They’re trying to make the case here that statistically significant reductions in LVMI of 10% or greater over a certain time period would be an approval endpoint—a surrogate endpoint. The FDA had already said yes to this earlier in the year. They had an additional meeting and announced that LVMI would not just continue to be one of the co-primary endpoints in a pivotal study, in addition to frataxin expression, but they also offered hints that the flexibility was leaning even more flexible than we had previously expected.

The FDA is apparently letting them pull data from their Phase 1/2 study and the planned pivotal study. This could potentially lower the overall sample size for the pivotal study that they’re planning to start in the first half of 2026. They’re offering some statistical flexibility that we don’t normally see—the pooling of data across 2 clinical studies for a primary analysis.

The other thing is that I think everyone expected the time frame for LVMI measurement to be 12 months. While they haven’t specified what the actual time frame for LVMI measurement is going to wind up being, they said it’s probably going to be less than 12 months, with the FDA offering an earlier time frame for analysis. When you look across the LVMI data they’ve seen so far in patients who had impaired baseline LVMI, they’re crossing that 10% threshold pretty rapidly, by 6 months.

This might wind up being an evaluation period that is almost half of what was expected. The sample size coming down will certainly allow them to run a more rapid pivotal study. Overall, in my view, it gives me a little more encouragement that CBER isn’t really moving into a much more conservative methodology for evaluating gene therapies in orphan diseases. It’s continuing to, if not totally carry on in the Peter Marks tradition, at least offer a high level of flexibility for diseases that are major unmet medical needs, with not a lot of options for FA patients.

Great.

Again.

Great. Well, thank you. Thank you, Brian. Certainly encouraging. You mentioned Peter Marks. What about Peter Marks?

So, Sam, you want to take that?

I mean, what do we say? It’s funny—Adam was saying on the podcast the other day that he thought he’d be at CBER, and that would have been so much more fun for him, which of course it would have been. But look, it’s not going to be helpful, is it? At the end of the day, an FDA regulator who was potentially a little bit controversial did go to a pharma company, Eli Lilly in this case. What is he going to be doing there? Who wants to take that? I mean, the title doesn’t really tell us much.

But I can't sit here and criticize people who come out of a job where they were essentially—I don't know, do you want to call it pushed out—to take a job to carry on doing what they believe is value-added for the future of drug development. But it's just not very helpful for the cause at the minute. That's all I can say, to be honest with you.

Can I—so, I'm going to take the other side.

I will definitely take the other side here. He has an unbelievable skill set that is going to be put to use in a very valuable company, and he's by far not the first one in any industry or from any government job to then go into industry. We see this over and over again: people coming in on the finance side, people going into consulting firms, people becoming lobbyists. This is just a natural extension of what's next.

I don't know that he's going to work—presumably, he's going to be an academician? I don't know if that's really where his skill set necessarily is. His skill set is in drug development, and if you think about doing good for humanity and for patients, it's a perfect role. I honestly don't look—

Back in the day, they used to say if you left medicine and went into industry, it was sacrilegious. I think over time people realized that an ecosystem is built of many partners, and this is a great example. I think he's going to do amazing work next, and I'm very happy he's doing that.

I agree with you. I didn't want to, for a moment, sound as though I was critical of him. So, just to be clear about that, it's just: what are you going to do? It's not going to look great, and the folks who want to use this as an example of the—what's it called?—the swinging door, or I can't remember now, revolving door, are going to use it. But again, as you rightly say, he's got a lot to offer, and he's gone somewhere where he can do it. So, great.

I didn't mean to come at you in any way.

No, but it's more of a broader conversation about what the public should maybe expect. Look, there's always going to be naysayers. There's always going to be critics, right? It's very easy to be a Monday-morning quarterback, and I'm guilty of it. I scream at the TV, as my kids tell me, “They can't hear you.”

But at the end of the day, I think the average person maybe needs to not be so critical.

Before you wrap up, I think we need to stay on for another five hours because apparently AstraZeneca is going to announce its deal with the administration.

My goodness. Okay. Well, everyone who wants to stay on until 6:00, you're welcome to. But I think this point is a really important one around—yes, you can talk about the revolving door, and certainly I think it's important that you don't have people making decisions in regulatory positions where they're favoring a company because of certain economics or a certain relationship. But what are ways to resolve that? Disclosure is one, and recusing yourself from certain decisions are others, right? We have so many ways of managing conflicts of interest.

I think what's much worse for our sector is if people aren't talking to each other and we're not getting expert opinions on the right things, right? I mean, how much are you really going to learn from an advisory committee related to, say, a multiple myeloma drug, where you can't find a multiple myeloma expert who maybe hasn't been involved in a trial that has involved some kind of industry compound? I think thinking about the mechanisms to manage those conflicts is way more important than just saying, “My gosh, there shall be no connectivity or discussion or knowledge of what the other people are doing.” That really leads to suboptimal decisions.

So I think we will leave it at that. Just an exciting week for continued interest in biopharma, both from strategics and from investors, and a lot of fundamental progress that supports that. And thank you so much, Brian, Yaron, Luba, and Sam, for sharing your perspectives. See everyone next week.