第166期——2025年12月12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. I'm Grace Colón and my co-hosts today are Chris Garabedian, Sam Fazeli, Paul Matteis, Yaron Werber, and special guest John Stanford. For more information about our host and guest speakers or to listen to the most recent episodes, please go to biotech hangouts.com. And as always, for more information about our hosts and guests or to catch up on recent episodes, visit Biotech Hangout.

We have a very full slate today: big policy news, major financing activity, several deals, a huge wave of conference data, and a lot of important updates in some key hot therapeutic areas.

Why don’t we jump in? Why don’t we start with John Stanford, host of the Making Medicines podcast? Welcome, John. I’m glad to have you here. He’s here to help us unpack the latest developments regarding the 2026 reauthorization of the National Defense Authorization Act, or NDAA. The House passed it this week, and the Senate is expected to vote on it next week.

John, there’s a lot to digest here. Can you walk us through some of the highlights and the implications for the sector? There’s stuff on research restrictions with other countries, supply-chain implications, SBIR and STTR—the list goes on. I’ll let you get going on that, and thanks for joining.

Yeah, you bet. It’s great to see so many familiar faces. For those of you who don’t know Incubate, we’re sort of the voice of venture capital and the early-stage ecosystem in D.C., so we watch things like the defense bill, or NDAA, as us D.C. nerds call it. All eyes are on biotech this year.

The first key takeaway is that this isn’t a bill just for warships, planes, and Pentagon funding. This is a clear statement that biotech has now moved into the list of fields, along with quantum, hypersonics, and AI, that are frankly viewed as national-security assets. That manifests itself in this bill in a bunch of ways that I’m going to try to get through without putting everyone to sleep.

I think there are 2 ways to think about it. There’s the good news, and then there are the possible constraints that we need to be mindful of. The good news is more investment through the DoD to build at home and secure the ecosystem.

There will be more money at the DoD. Now, we all know that the SBIR/STTR program remains on pause—we can cover that later—but in the meantime, this bill is going to authorize the DoD to effectively build a similar program to subsidize things that are relevant to DoD goals.

If you’re in the life sciences space and you’re navigating synthetic biology, getting involved in biomanufacturing, using AI to develop new molecules, or working in the infectious-disease space, there are going to be new DoD resources. Most importantly, the DoD is creating a new biotech office. Long story short, out of this new office is going to come a new opportunity for a different type of capital.

You’re definitely looking at different terms and conditions when you work with the DoD, but it’s an emphasis that they are going to fund some research at a time when NIH is facing cuts and SBIR programs are paused. The DoD may become a new place for funding. That’s 1 bucket of this 2,300-page bill: frankly, the DoD now cares about biotech.

So does the intelligence community. For the first time, the intelligence community—including the CIA, NSA, ODNI, and a handful of others that are more at home in Mission: Impossible films—is going to have biotech liaisons and enormous pools of money to begin to draw down on. So that’s the opportunity bucket.

Later in the bill are some things that might not be viewed so much as opportunities, possibly more as constraints. Included in the bill is a watered-down version of the BIOSECURE Act. For those not following it, it’s going to prohibit federal agencies from buying biotech equipment or services from “biotechnology companies of concern.”

This was the big WuXi debate that we saw over the last 18 months. The bill has been moderated slightly. This is more about companies not being able to access federal dollars, but there are some flow-through provisions here. So if you begin to take federal money—if you’re taking SBIR money when it’s turned back on—and you’re using companies that are on this list, that’s going to be a problem.

There are going to be 2 lists that everyone on this call has to pay attention to. The DoD is going to manage 1. It’s actually already existed, called the 1260H list. If a company shows up—if a WuXi ends up on that list—it’s going to be difficult to do business with them.

There’s also going to be a new, more subjective list out of the White House through the Office of Management and Budget. That’s probably where we’ll expect to see more of the companies that are CDMOs or CROs. If they end up there, they have an opportunity with the White House to explain why they should not be designated a company of concern.

Stepping back a little bit, in the defense bill, BIOSECURE is on its path to becoming law, and it is going to prevent companies that in any way are touching federal funding from working with companies of concern. Those companies of concern are probably going to lobby the White House pretty hard on this new list to keep themselves off it.

This is a big one. BIOSECURE was fiercely debated. It comes amid efforts to onshore and nearshore a lot, and there’s a lot more I could go into. I’m going to pause here before I move into something else that I think is super relevant, but in case there are any questions on BIOSECURE, I’m happy to jump on them right now.

Hi, John. I have a question. Just thinking about the funding that’s been taken away from NIH and the funding that’s available here now, can you put those 2 into magnitudes of comparison?

Also, NIH, I think, to a degree, was funding where the scientists decided how to spend it. How are the decisions made here in terms of funding? An interesting one was infectious diseases, where all we hear is that they’re trying to get away, at least from a vaccine perspective, rather than therapeutics, to dilute the effort on vaccines. Could you maybe comment on those?

Yeah. I’ll take them sort of in reverse order. The priorities of the Defense Department tend to have inputs relative to what the rest of the world is doing, because that’s the attitude they’re coming at it with. If China—and we’ll just keep using China as a proxy—is developing something, the DoD doesn’t like seeing other countries advancing in innovative spaces where we’re not.

We’re seeing the same thing play out with nuclear and small modular reactors. Because China is doing it, we’re going to start thinking about it in the U.S. One way to guess where the DoD is going to put that money is: What is China investing in? To some extent, the money is going to be reflexive of what we’re seeing.

I think there are some obvious areas. Data management is going to be a big one, so I think there’s a data piece here involving how you protect biological data. Synthetic DNA and RNA are going to be another area of focus, but we’ll also hear from the DoD what its stated focus is going to be.

In terms of scale, we’ll see how much funding this actually yields. On the NIH front, I think it’s important to dispel the notion that NIH is facing substantial cuts. As of right now, the cuts to NIH, out of the roughly $45 billion in spending, are pretty nominal.

Now, in some areas, they are existential. They have cut $500 million or $1 billion, but they’re spending it elsewhere. As the administration would be quick to point out, they have pushed out dollars in this fiscal year faster than the Biden-Harris administration had at this point.

Similarly, we expect NIH to remain well funded, to the tune of $40-plus billion, but the priorities, as you laid out, and who gets to say what gets funded are certainly in a process of transition.

John, thank you for that context. I’m conscious of time, and I’m wondering if maybe you can hit a couple more highlights. I know, in particular, I had a question about SBIR/STTR reauthorization. I know that it didn’t make it in here, and I’m curious about your thoughts on that, when the tea leaves say we might see that, if at all, and any other major points to highlight here.

I’m sure we’ll be talking about this again and again over the coming months. There are a lot of policy implications to everything that’s going on.

Absolutely, and thank you for the opportunity to be on here. The last thing I’ll come to—SBIR and STTR—the last thing everyone should know is that there is a new outbound-investment regime built into this bill, and I want to be super clear: biotech, as of right now, is not covered yet.

This is the concept of reverse CFIUS. In the U.S., we have CFIUS. If a Chinese investor wants to invest in U.S. technology, there’s a CFIUS review deciding whether or not that’s acceptable. Recently, people have been talking about reverse CFIUS: Should U.S. capital be able to invest in countries of concern?

That is now going to be in place through this bill for AI, quantum, and hypersonics. Biotech was not initially included, but this is something we have to pay attention to, because I know there are some funds on the call. Imagine having to notify the federal government. The White House can add things to this list over time, and you might say, “I see this really interesting company I want to invest in outside the United States.” You might have to notify the government of your investment and, at times, ask for its permission.

So, more to come on that. But this is a huge deal that we have to pay attention to. On SBIR and STTR, we have a logjam over whether or not foreign-funded companies should be allowed to accept SBIR, and this debate over so-called SBIR mills. We do not see a path forward right now for turning the program back on.

Any number of people are putting pressure on Congress, saying, “Solve your debate here,” really, frankly, between only a couple of members of Congress, and get it turned back on. We had hoped to see maybe a 3-month extension. But as of right now, people are holding their ground, and we don’t expect that to break. The next opportunity for it to break will be the January 30th bill to fund the government. That has to pass, or we’ll have another shutdown.

All right. Well, thank you for that context. I know a lot of companies were working on the January 5th deadline and working over the holidays to hit that deadline for SBIR, and things have changed. So let’s keep our fingers crossed on that one. Thank you so much for the context and for joining, and obviously stick around. We’ll have more commentary on industry sentiment later.

Generally, just a quick industry perspective, and then we’re going to jump into conferences. Earlier this week, we saw a day that reached almost $2 billion in financing. It might have been the biggest single-day total we’ve seen this year, maybe in longer than a year. A couple of examples of that, with exciting data that came out this week, are Turnstone and Wave. Turnstone went out for an upsized offering—I think it was $650 million—and ended up raising nearly $750 million. Wave surpassed $400 million, and a few others.

So, if you pair that with the recent strength in the XBI—I believe it’s up something like 35%–36% year to date—are we finally seeing a real sentiment shift despite some of the policy hiccups and challenges? Is this signal? Is it noise? What does it mean for 2026? I’d love to do a quick roundtable before we jump into the data, and then we’re going to circle back at the end, after we’ve heard from everyone, and talk about some other industry sentiment stuff. So, who wants to start?

Yeah, Grace, I’ll start. These are the best signs we’ve seen in years, right? Follow-ons are really important. We’ve seen valuations start to tick up, with more biotechs having more than a $1 billion market cap and a lower number of negative-enterprise-value public companies. All of those point to really good signs going into J.P. Morgan.

The one area that we have not seen yet is the IPO window really opening up. I think if we see—I’ll just pick a number—10 to 15 IPOs in the first and second quarters of 2026, I think it’s going to be a really good year, coupled with valuations, the XBI, and these follow-ons where there’s definitely money going in. I think part of that is anticipation that we’re going into a hopefully bullish market.

I would just add: most of these, like you said, Grace, are on the back of good data. I would also add Kymera, MoonLake, and Dyne. I think that feels fairly healthy for the space. Investors sometimes balk at it more just in general when things are—when a company doesn’t really have a direct sort of event, and they’re just like, “Oh, it’s opportunistic.”

But I think we were talking about MoonLake specifically: on the back of strong data, a clear use of proceeds, and an opportunity for more people to invest in something that has a lower-risk profile, I think that’s hard to argue with. I agree with Chris. I think it’s a positive indicator, but still very, very different than opening an IPO window, which we talked about last week, and Josh and I had really different estimates for how many IPOs were going to be next year.

Excellent. And anyone else before we jump into—was it Josh at 100 and you at 50, or Josh was 50 and you were 100?

I had 15, which I felt stupid after Josh said 50. Well, I mean, I don’t know, man. How many were there this year? It’s been a great market this fall, and there have been what, 2, maybe 3? I’m probably low, but Josh said 50, and I felt like that was high. I don’t know.

I mean, we gave a really wide range, so there’s a good opportunity for both of us to be wrong. What do you think the market could digest? Are there 50 good-quality, clinical-stage companies out there that can IPO?

It’s a good question. All of us can speak on it, and it could be interesting to hear what your own experience is, too. I mean, you can speak on my narrow sort of list of companies—I don’t want to talk about specific companies—that I’m looking at and that I’m close with, which are kind of in the later stage. The profile of that list is more of a Phase 2, and sometimes Phase 3, profile than it’s ever been.

I compare that to 2020, when companies were putting IND acceptance as a major value-creating event in an S-1. That’s good, but I don’t know if there are 50 of those. There are probably more of those types of companies than ever, but it might be 20. I’m not totally sure, to be honest. I feel like 50 is a high number for companies that are mid- to late-stage.

All right. Well, ladies and gentlemen out there, place your bets and let’s see what happens next year. Certainly, we’re seeing bigger financings and bigger implications from good data than we were seeing earlier this year, for sure.

So, why don’t we jump into conferences? There’s ASH, ASH Asia, and a number of conferences. Obviously, ASH was huge. Why don’t we start there? You had a couple of competitive readouts that you wanted to highlight in particular: Lilly versus BeiGene and J&J versus Gilead. Do you want to walk us through a couple of those?

Yeah, absolutely. There was a lot. For an ASH that was supposed to be not that busy, we all got slammed, and there was a lot of really great data, too, which is actually really encouraging.

The first one is Lilly against BeiGene: the battle for the BTK inhibitors. Obviously, it’s a huge market, with $12 billion in expected BTK sales. The old one, as we all knew, is Imbruvica from J&J. That’s really losing a lot of share, and BeiGene is now the global leader on a quarterly basis—now the global leader both in the U.S. and ex-U.S.—by virtue of having shown superiority against J&J’s Imbruvica.

Lilly released the anticipated data in first-line and second-line treatment. It’s a noncovalent inhibitor; the other ones are covalent. The noncovalent inhibitor was supposed to be better on mutations. The more data that emerged suggested that each one of these classes has its own sort of unique profile, a little bit more Coke and Pepsi. Jaypirca just got approved in second-line CLL.

To make things complicated, this was one that kind of had a little bit for everybody. What was in the abstract, which looked like shock and awe and potentially like it was going to be the class leader, was definitely a lot more mixed at ASH. The data in patients who were relapsed and refractory really did not beat at all. In fact, Lilly, I think, in the abstract had the investigator-assessed data; in the presentation, the paper actually had the IRC data, which looked dramatically worse.

Then they showed the frontline data, which looked really good and was IRC-assessed, but the data is extremely early. Most of the difference in survival, which was impressive against the BR historical arm, is because BR had very poor tolerability. Out of 10 patients who died, 9 died because of toxicity, and there was only 1 disease progression.

Bottom line, putting it all together, I think there was a lot of sentiment that people will still start with the covalent inhibitors first because Brukinsa did beat Imbruvica cleanly in the relapsed and refractory setting. We know you can use Lilly’s drugs after Brukinsa or Calquence, but you don’t know if you can use them the other way around. Lilly’s data is very early. In general, it’s supposed to be safer, but the safety differences honestly ended up being marginal.

Finally, BeiGene has a monster pipeline in CLL, including a BCL2 inhibitor in combination and a BTK degrader. Frankly, they’ve moved their BTK degrader now to be tested head-to-head against Lilly’s drug. This is going to be fireworks for a while. Bottom line is, you could argue BeiGene is no longer the absolute leader with no competition at all. Lilly will be competition. Lilly says that they’re going to do extremely well. I think other people think they’re not going to do quite as well, but BeiGene really has an amazing pipeline. This is going to be an exciting area to watch.

That’s great. And I know we’ll hear about Lilly later. They have a lot in the bank to spend, and I know Chris is going to talk about that a little bit later. So, they’re probably going to be beefing up their pipeline. Do you want to talk about J&J versus Gilead?

Yeah. So then there’s J&J/Legend against Gilead/Arcellx in the CAR-T BCMA battle. This is a little bit of a tough meeting, I would say, for J&J and Legend. Remember, J&J and Legend are the only—well, they’re not the only; they’re the leading CAR-T for BCMA in myeloma. Their efficacy has been absolutely tremendous. I think it’s actually the biggest CAR-T for any cancer out there right now, growing extremely rapidly, and it had a huge benefit in second-line treatment.

But their capacity constraints are going to end early next year. They do have some noticeable toxicity, including low rates of parkinsonism—let's say 1% to 3%—and neurotoxicity, as well as a 0.5% rate of immune-mediated enterocolitis, which could be fairly bothersome.

There were some deaths initially. I think the deaths have really gone down; they know how to manage it now, but it does require hospitalization. The drug from Gilead, anito-cel, does not cause any of this toxicity. They're going to file early next year for fourth line, while the label right now for CARVYKTI is second line.

It looks considerably cleaner for anito-cel. There are debates about efficacy. They released their 1-year survival data, claiming that it looks better, but the data is extremely premature. They didn't give the curves, and they have lower complete response rates. J&J has now shown what the CARTITUDE data could be, and the bar is very high on efficacy.

We think they're probably going to be the same on efficacy. But bottom line, what does this all mean? Clinician feedback is that when anito-cel comes to market next year, because it's safer and doesn't have any of these issues, it's probably going to be the preferred drug. It's really going to have a fourth-line label, and that's the issue.

It's going to be very hard, if not extremely hard, to use it off-label because there's no data and there isn't going to be coverage. J&J will grow really well in Europe, and they'll grow in earlier-line settings. About a third of patients are high risk, and they'll take the J&J drug because it showed survival.

But anito-cel, over time, unless J&J can figure out what causes this T-cell expansion and really control it, will continue to get more and more market share as they expand the label. It's going to take time.

Okay, great. Thanks. Sam, I think you were tracking AstraZeneca's CAR-T data. Do you want to talk about that?

Yeah, sure. Picking up from where Yaron left off, it's quite interesting. It's Legend who's most at risk here, of course, because J&J has a whole bunch of other things to talk about. We'll get to what I think was the standout data at the conference, which is the MajesTEC-3 data, and I'll come back to that.

AstraZeneca has come into this space. They're not really in myeloma, but they acquired a Chinese company called Gracell. Two or 3 years ago, data at ASH—I think it was ASCO; I can't remember, because they all merge into one another after a while in my brain—showed some very interesting data. About 6 months later, AstraZeneca bought the company. It wasn't an in-licensed thing; they bought it. This is called AZD0120, and it's slightly different.

Everybody is now talking about faster and faster manufacturing, and I'd love to see it in the market. Manufacturing isn't the issue; it's actually getting the product from vein to vein. I think they'll all end up being around the same in the end—I'd love to hear your view, Yaron—about, I don't know, 4 or 5 weeks vein to vein.

What is different here is that they've got a CAR-T that targets BCMA and CD19. You wonder, “Oh my gosh, what are you going to do with the side-effect profile?” But they've got data presented in 2 groups of patients, which was quite interesting, particularly the second set that came, I think, after the later-line setting.

The idea here is that BCMA does the job for the plasma cells, while CD19 should go after some of the progenitor cells in the bone marrow. That's the idea, or generally some of the progenitor cells, and therefore you should get a deeper, longer duration of response, or a deeper response, with more patients potentially being—I don't want to use the C-word—but potentially cured, depending on how long these things go.

Of course, they first presented the data in small trials. But let's not forget that Johnson & Johnson did the deal with Legend on the basis of a very small trial data set. In CAR-T, I think you get a good feel for what you're looking at; what you don't get is the duration.

Here, we have data that showed really strong efficacy and a manageable safety profile in newly diagnosed, high-risk, transplant-eligible patients and frail, transplant-ineligible patients. It's a slightly different subgroup than just the standard newly diagnosed patient group. The follow-up was 36.5 months, and of course it's a China-based trial. What we ended up with was a 36-month overall survival rate of 89%, which is pretty impressive in my view.

There's really not much to compare it with because not a lot of these CAR-Ts have gone that early. When we had the audience—the chair of the session—ask whether this is something that could potentially displace ASCT, or autologous stem cell transplantation, it was too early to say. But there are real trials ongoing with CARVYKTI that are literally asking that question: Can you displace ASCT? Do you get a better outcome?

I don't know; my gut tells me that that's the scientific one, right? My gut tells me that it's going to do better, and I think this therapy is going to come earlier. AZ is out there with this data, and I think they're in late-stage development. The cytokine toxicity profile wasn't particularly worrisome, given the relevant data that we know and this small patient sample.

Of course, then they had the later-line data, where we can start comparing with CARTITUDE-1. Again, I think they showed a complete response rate rising to 78%. This is at 39 months here, right, versus 33% at 15.4 months, and it's trending toward the early sets of data that we got from CARTITUDE-1 and looking very, very good.

Again, is this another thing for Legend to worry about? Of course, it's a while away yet, and you end up in a situation where Legend and cilta-cel might be much earlier. The dynamics in CAR-T are going to be quite interesting. Just before I go on to Johnson & Johnson's MajesTEC-3, I wanted to hear what Yaron had to say about any of these.

No, I totally agree. Then, of course, there was also the BCMA-GPRC5D CAR-T, or the GPRC5D CAR-T from Bristol. But one of the stars of the show was EsoBiotec. It's an in vivo BCMA CAR-T, with early data. Because it's in vivo, there's no need for leukapheresis and no need for conditioning. Literally, you just put an IV in the patient and give them the lentivirus and the fusogen.

It was 4 out of 4 MRD-negative very quickly, with essentially no ICANS and very little CRS. There was no infection at all on the T-cell side, the macrophage side, or the cancer side. It's really, really interesting early data, which obviously needs to be followed. This is going to be a hot area, and there will continue to be innovation with that approach.

And of course, Yaron, that's licensed to Johnson & Johnson.

Yeah. So J&J, you're right, has a broad collaboration but doesn't have rights to that drug.

To that particular one, remember?

Yeah, yeah. And so what's going on here? Look, I loved the data: 4 patients, and we went from 3 to 4 and got another 100% essentially in ORR. That was good. It was nice to see that from the abstract to the actual presentation.

The one thing was the infusion reactions, which I'm assuming they can manage. You essentially have a gene therapy here, so everyone's going to worry a little bit until this gets through to a lot of patients and we see how it looks. Durability is the key here, right? We don't know what the durability of these in vivo CAR-Ts is like.

This just proves that we're going to keep having to go to ASH and keep following these data, which is really great to see in the myeloma space. So, Chris, do you want me to move on to J&J's—

J&J, and the broader area—the bispecifics, trispecifics. I think you were also going to talk about infection risk in this whole field.

But, yeah, start with the great J&J data. It was pretty impressive. Even before, you could take the CARTITUDE-4 CAR-T data and look at the overall survival at 30 months—or the progression-free survival—and here, sorry, the OS data was way above that.

This is Darzalex plus teclistamab in patients with a median of 2 lines of therapy. It's very similar to the CARTITUDE-4 data, which is also Johnson & Johnson's. The control arm was very similar, and it actually performed really similarly: 26% PFS in CARTITUDE-4 at 30 months, and here we had 30% at 36 months. Overall survival was in line.

It was a well-controlled study, and it's quite large. This is not some phase 2 or phase 1 trial—roughly 290 patients in each arm. It compared teclistamab plus daratumumab versus a daratumumab-based triplet, either pomalidomide and dexamethasone or Velcade and dexamethasone.

What did we end up getting? Phenomenal overall survival rates: 83% at 36 months versus 65% on the triplet. That OS rate compares with 76% at 30 months in CARTITUDE-4.

And then, the greater-than-CR response was fantastic. The MRD response was similar again. So really, you've got something here that could stand up to the CAR-Ts, if you want to, for want of a better phrase.

The side-effect profile is different, right? We get CRS for both, and we get ICANS to a degree for both. What we don't really get is lots of very serious grade 3 issues in terms of neurotoxicity. But what we did get—and you could see that in the Kaplan–Meier curve for OS—was that a number of patients died early because of the infections this causes. Not a lot, but a few patients.

Why is that? Because you're essentially chronically getting rid of your B cells, right? Those are the ones out there trying to deal with your disease, and if you get an infection, that is what they need to address. Of course, this started during COVID. A lot of the patients died of COVID, but of course that's still possible now. IVIG wasn't necessarily part of it.

I suspect that when you talk to physicians—which we did, quite a few of them, because the excitement was quite high here—their view was that with decent IVIG, which is now available subcutaneously as well, you should be able to manage this toxicity. So let's see how this goes.

This is up for FDA approval in 2026, if I'm not wrong, and it's going to be very interesting to watch this dynamic. Then Arcellx, which of course is later-line therapy, at some point is going to have to come and compete in this space, or the CAR-Ts are going to compete in the same space. It's going to be very interesting to see how the patients and physicians end up putting their patient groups on different types of therapies here.

One last thing I would say is that if you're treated with a bispecific, your probability of responding well to a CAR-T afterward is lower because you end up with pretty much exhausted T cells—unless you have a big break between the last bispecific therapy and the need to go to CAR-T again. Yaron, anything to add?

No, that was a tour de force, my friend.

It was fantastic. Yeah, AML patients, we had some triplets, etc., but I think we should leave it there because they already have posted. So clearly, we're going to be looking at this field very, very closely because so much data will continue to come out, and it'll change the treatment paradigms, right? Like you were saying, in terms of which order you can do things and how long you have to wait. But very exciting, and thanks for covering it so thoroughly.

Yaron, you want to talk about the Genmab data? Do you want to jump into that?

I can be quick because we have so much to cover. Epcoritamab, or Epkinly, is a CD20/CD3 bispecific from Genmab and AbbVie. It's given subcutaneously, mostly in the outpatient setting; they're really trying to remove any initial hospitalization, which will really open it up to the community.

Of course, the competition is Roche's Columvi, which has been doing better for a variety of reasons in terms of the data and ease of use. Remember, the standard of care has always been R-CHOP in the first line. This is for diffuse large B-cell lymphoma, approved right now in the third line. They'll have data next year in the second line and then in the first line, and that's the point.

The data that came out at ASH are updates of up to 3 years, so we can really now look historically against R-CHOP and even against, let's say, the standard of care technically now, which is Polivy with R-CHP. Next year, Epkinly will have data in combination with R-CHOP, and the bottom line is that we're really at a point where we think they're going to be the best regimen out there. That's based on the data that we saw and our consultants, and that's going to be important, obviously, for the companies.

It will really provide amazing innovation for patients, especially if they could move the whole thing to the outpatient setting with no need for initial hospitalization. A year later, Roche will come up with its new data, which is now going to test everything together: their Columvi, basically their bispecific, on top of Polivy with R-CHP. At that point, we're talking about a cocktail of 5 or 6 drugs together, and we'll have to see whether that could look better than the new Epkinly regimen.

The innovation now is absolutely amazing, and increasingly, there's less and less chemotherapy. I mean, chemotherapy is really going away, thank God. There was a standing ovation at ASH. The data was really good, including in elderly patients. It's hard not to get excited, a little emotional, about how good things are going.

That is exciting, and it's great to hear you're passionate about it, because you're right. This is going to be huge for patients on a number of levels. And now, back to Sam. I know one of the other big stars at ASH was Terns Pharmaceuticals, where they had impressive data in CML with their novel allosteric inhibitor. Do you want to tell us a little bit more about that?

The drug's called TERN-701. As you said, it's an allosteric modulator. The trial is called CARDINAL: 85 patients. I think the fundraising tells you the story. They went out looking for $400 million; they closed at $650 million, right? So that's the way it goes. And of course, it's for CML.

I'm going to summarize it. We've got a once-daily drug, which is better than the standard of care, which is asciminib from Novartis. You can have it with or without food—again, better tolerability, looks better. No DLTs, no pancreatic toxicity. Efficacy looks better. That's obviously not in a head-to-head; as we always do with all of these things we've been talking about, it's cross-trial comparisons, of course.

The efficacy measure here is MMR. In this particular one, what was nice to see was a 43% MMR response in patients who had prior asciminib, either dropping off because of lack of efficacy or tolerability, and then 50% in prior TKI-exposed patients. So really, not much else needed to be added here.

The market's already there. We know what the market's worth, given what we see from Novartis. They created the market. So let's see where Terns goes. Is this the market?

Sorry about that. The next phase is phase 3, but are they going to take it alone? I wonder whether CML is a market you can market yourself in. Will they, or will they even have the option, because the data is maybe so good that someone else might get interested?

Yaron, did you want to add anything? All right, we'll continue the conference tour de force with this dynamic duo. Sam and Yaron, I know we want to hit some highlights from ESMO Asia and a couple of other conferences. Who would like to start? Yaron, unless he doesn't want to start.

No, happy to. I can be very quick. One of the original immuno-oncology drugs was Yervoy, a CTLA-4 drug from Bristol Myers Squibb, which was supposed to be one of the hottest areas out there with Opdivo. Of course, what we've learned is that CTLA-4 does have efficacy, but it's got a lot of toxicity.

BioNTech has a gentler version now in phase 3, and they showed the first part of a phase 3 study in second-line lung cancer, head-to-head against chemotherapy, docetaxel. Docetaxel is one of those old drugs that always seems to do pretty well when you go head-to-head against it. Everybody thinks it's the weakest drug out there and everybody's going to beat it, and then they all get knocked out one after the next and can't beat it.

In Part A, the data looked very good. It's actually in lung cancer—squamous or nonsquamous. The nonsquamous histology is far bigger; squamous is smaller. Squamous typically has poor outcomes and is harder to treat. In phase 3, they were testing both. They actually got into a clinical hold, a partial hold, with the FDA because we think there's probably some toxicity in nonsquamous, which is the bigger part of the market. The FDA agreed not to advance that further and just went with the smaller squamous group.

This is early data, Part A, but it looked really good—definitively better on efficacy so far than docetaxel. So now they're going to completely enroll the rest of the study. It's a CTLA-4 antibody, so it is a little bit more pH-mediated, and it does seem to be better tolerated than the Bristol one. Of course, you expect there's going to be a price to pay in more toxicity. We are seeing more toxicity, but good efficacy. That's encouraging, and that's moving into the next part.

BioNTech's got a fairly robust pipeline now in general, moving into late stage. This is going to be part of the future, and we'll continue to watch this, but it's nice to see something finally working in that segment.

Great. Thanks, Sam.

I'll pick it up from there. We did have some data from a couple of newish targets. This one, B7-H3, is one that's caused trouble for some people in other settings, and these are the ADCs. BioNTech's got one, and of course GSK had some data at ESMO Asia.

Remember that a lot of ESMO Asia data is China-focused—patients, because that's the whole point of it—but some of it is not.

So GSK here showed some data with its B7-H3 ADC, GSK5764227, for want of a better name. The response rate is quite good, with encouraging activity in Chinese patients with nonsquamous non-small-cell lung cancer. We’re still in the nonsquamous setting, so responses in the squamous and oncogene-driven cohorts were a bit muted. We still have an opportunity in nonsquamous disease, and of course the endgame will have to be: how do you sequence these patients, and what do you choose to give them?

The data, in terms of a 33% objective response rate, are similar to what we’ve seen with Amgen’s AMG 994 and BNT324, perhaps not as good, but it’s very hard to compare these numbers. Merck and Daiichi Sankyo have another similar product in development, so it’s complicated, and there are a lot of comparisons to be made. The early data sets are small, with small patient numbers, and they’re all trying to go out there.

The only other one I want to highlight is a trispecific DLL3 in small-cell lung cancer. It’s called ZL-1310, and it’s from Zai Lab. I have to say that, again, in a very broad-brush comparison, the response rate in the China-only small-cell patient cohort looked very decent.

Let’s remember that patients in China tend to get lung cancer that is not necessarily driven by smoking; the etiology is mostly pollution. We have to accept that the biology is different, so it’s hard to do cross-trial comparisons. It’s even harder to do cross-trial comparisons here unless you have a China-only cohort. But the data in this patient population set the bar, at least from a China perspective.

What it does is give us one of those antibodies with 2 binding sites on DLL3, which often seems to change the way things work, as we’ve seen with Zymeworks’ zanidatamab. This is a DLL3/CD3 trispecific, if you want to call it that. It looks quite exciting and is another addition to the large list of DLL3-targeting agents, both ADCs and bispecifics. I’ll leave it there.

Great, thanks. Do either of you want to quickly address the CG Oncology data at SUO?

I can do that very quickly. You’re absolutely right: good data. It’s an interesting setup coming up in the next few years with regard to non-muscle-invasive bladder cancer, where Johnson & Johnson’s TAR-200 is already approved. That’s the gemcitabine-eluting pretzel; it’s an intravesical device.

We’re looking at the data that CG Oncology presented and, again, at face-value cross-trial comparisons of the BOND-003 trial, which is a Phase 3 trial, versus the SunRISe-1 trial, which is the comparison we made. Both were presented at the urologic oncology conference. Similar efficacy can be seen at 6 months in the event-free survival rate, and the side-effect profile of CG’s drug looks a little bit better, again in this cross-trial comparison.

Of course, they’re completely different modalities. What’s going to be interesting is how physicians decide between these 2 options. One is marketed by Johnson & Johnson, and the other is marketed by CG Oncology. Let’s see how this all pans out, but it was good data.

Great. Thank you. That wraps up some of the conference material. I know we have a couple more data points to go through. One is Paul, and I think Chris was also going to comment on Dyne’s positive DMD data. Paul, do you want to start with that?

Yeah, sure. Thanks. It’s a good segue into the conversation we always have to have each week, it feels like, on what’s going on with the FDA. Dyne reported positive data from the registrational study of its DMD exon skipper, DYNE-251, for exon 51. For context, these guys have a muscle-delivery platform using the transferrin receptor. This has been a hot space, with delivery to muscle and brain, and there are a number of companies in this area.

Essentially, what they reported was that they made close to 3% of normal dystrophin at 6 months. That’s an apples-to-oranges cross-trial comparison, but it’s about 10× what you see with the standard of care at that time point. They also saw pretty compelling separation on a number of functional endpoints versus a placebo arm.

A lot of the questions I was getting from investors were really around the statistics and these comparisons in small sample sizes, which is fair. I think people are asking the right questions. But in the backdrop of some disappointing confirmatory data for other exon skippers that make less dystrophin, these data were really promising and better than expectations.

The question here is: if we were in the FDA environment that we had been in for the past 10 years, I think it would be perceived as an absolute no-brainer that this would be highly likely to get approved. I do still think that most investors think this is likely to get approved. I agree with that. These data clearly seem to be above the bar for what they’re going for, which is accelerated approval.

The stock traded up, although it was a little bit sideways. They also financed. I think part of that is really just the broader discussion around the FDA, and investors being a little bit confused about what exactly this FDA stands for philosophically from a regulatory perspective in rare disease. You’ve got comments from Marty that are so bullish, certain actions that are confusing, and comments from Dr. Prasad. We don’t have to rehash the whole thing, but Dyne has become intertwined with the regulatory debate that I think we’ve talked about pretty much every week I’ve been on the show this fall.

Yeah, no, good assessment, Paul. Look, I think at the end of the day in DMD, all roads lead back to Sarepta. Sarepta set a low bar, especially for Exondys 51, and I think a lot of people in the industry thought, “If we can just clear the dystrophin biomarker,” which Dyne clearly did, and obviously Avidity did this with exon 44 in compelling ways. But I still struggle with the fact that we have not seen a strong clinical data set that correlates to the biomarker.

You bring up the issue with the FDA. If we were looking just at the precedent of Sarepta, I think absolutely. What are their true feelings about the exon-skipping data at Sarepta? Would they revisit the strength of data they want to see for approval? If that’s the standard, I think they’ve clearly cleared it.

But it’s frustrating, just for someone who’s done this and followed DMD, that we just don’t have the real robustness of the statistics. Part of that is sample size, but part of it is effect size as well—how much of an impact you can make in 6 months or even 2 years.

Yeah, 6 months is such a high bar. Hey, Chris, can I ask you a question? Investors on the Dyne side are trying to figure out how Dyne is exposed to the outcome with Sarepta, with a couple of these confirmatory studies failing. I know Sarepta has perhaps a different depiction of the data and is going to talk to the FDA.

From my perspective, Exondys hasn’t failed in a confirmatory study. If it hasn’t, I don’t see how that drug could get pulled from the market based on a different exon skipper failing. If it’s not pulled from the market, what would you see as the path for the FDA to reject something that is clearly making more protein and looks like it’s safe?

No, I think you’re exactly right. If you go back to the original Sarepta controversy—and I lived this from a front-row seat—they rejected our path to an NDA because Prosensa’s trials failed and PTC’s trials failed, and they tried to extrapolate that. We called foul on that, and we said, “You should look at our data, even though it’s a smaller data set.”

So I think the meta-question is: are we going to see different criteria coming out of this new FDA that would throw everybody off? But based on precedent and how you’ve described it, I think the conventional wisdom is that it’s going to get approved.

I think it’s really hard to tease out where the market sits on this, and you’re closer to it because of the $3 billion market cap. A lot of that is driven by the DM1 program, so it’s really hard to tease out what this DMD program is driving in terms of the stock price.

Yeah. I think it’s a polarizing topic. There are people who totally agree with our conversation, and there are investors who throw their hands up and say this FDA is untenable.

Well, on that note, I know we’ll continue to monitor that topic in the coming months and years. On the other topic that we always hit on—we only have a couple more minutes today—which is obesity, there was a Pfizer-Fosun deal for a Phase 1 asset worth up to $2 billion in deal value, with $150 million upfront. Then there was some data from Structure, Wave, and others.

I know, Paul, you wanted to cover Wave. Sam, I don’t know if you want to start with the deal, then we’ll jump into the data real quick. What are the top highlights?

Yeah, top highlight is that it’s an asset that comes out of one of Fosun Pharma’s subsidiaries.

This is YaoPharma, and it’s a proprietary small-molecule GLP-1 program in Phase 1. I’ve tried to squeeze some data out, but I can’t. There’s no data yet, but I think we might get some by the middle of the year.

It’s $150 million upfront and up to $1.94 billion in milestones, plus tiered royalties. What would be interesting is to see if this ever gets covered by what we were just talking about right at the start, in terms of U.S. companies buying, financing, and putting money in. I don’t know how this would pan out with that biotech—I can’t remember what the name of it was—but anyway, that was a good deal that came out.

Then we had some data pretty much every day, I think, right? Did you want me to cover the data?

Sure. Why don’t you hit the highlights? I know we only have about 5 more minutes. And then I know Paul wanted to cover Wave. Go on, Paul. Do go ahead first.

Sure. I mean, it’s a fun topic, right? I can be really quick and throw it out to the group because Adam Feuerstein, a friend of the podcast, had a pretty interesting, provocative, and funny headline on the data.

Wave reported single-dose data for its WVE-007 program. This has been a target of interest in the obesity space. They reported a 9% reduction in visceral fat, almost a 5% reduction in total body fat, and an increase in lean mass.

At a high level, I think this is directly addressing one of the issues people have with the GLP-1 drugs. They have this benefit on outcomes and body fat, but also maybe a negative effect on muscle, exercise capacity, and things like that. Conceptually, this looks super, super interesting.

It’s very early data. The stock went up a couple hundred percent. But what Adam pointed out in his article was that total body weight did not go down. I think it actually went up a little bit, right? These are small sample sizes, and there’s also a certain wonkiness with the placebo.

I think it was a thought-provoking point that these data are really interesting, but what is the actual regulatory path here? Is this early data set ultimately replicable? I don’t cover Wave. The tone of his article was probably a little bit more negative than how I feel about this initial data, but it’s an interesting debate nonetheless, right?

On the one hand, you could say this is directly addressing a deficiency in the standard of care. On the other hand, you could say it’s a small data set, and maybe there has to be a different type of regulatory path teased out here.

See, Paul, I’ve looked at Adam’s piece, and you know I’m a big fan of his. I think our headline was better: “WVE-007 early obesity data has license to thrill.”

I like that. I like that. It’s pretty good. I mean, he called it a gym-bro drug, which I thought was kind of funny.

Yeah. No, I mean, look, what do you think, Sam? I read everything that Adam writes, and I read a lot of your guys’ stuff, too. Are you bullish on it?

It’s early data, with no weight loss observed, which of course you could argue with the fat versus muscle, et cetera. But it’s early data, and I think its safety profile seemed clean. Let’s see how this pans out and how it fits in with the current massive obesity pipeline, right?

Of course, then we had Ascletis from China with some weight-loss data with its GLP-1, and then retatrutide, the triple agonist, came out, which people got a bit confused about because of the dropout rates and all that. But a whole bunch of the dropouts was because people were losing too much weight, and we knew that already.

I think the Lilly data for the triple agonist came out actually better than I thought they would. Lilly has always positioned it for patients that are very obese. It would be interesting to see how this pans out overall, but certainly no day goes by that obesity doesn’t have some news or something.

All right, guys. Thank you so much. There’s a lot to unpack there, and I know we only have another minute. I need to wrap up. Let’s go around the room. I’d like to ask you guys each, from 0 to 10, how optimistic are you for biotech next year? Don’t condition it. Just give me a number. Chris, you want to start?

Yeah, I’d say for next year, I’d give it a 7.5.

Oh, okay. Sam?

Hang on. I was going to say—I hope he doesn’t say 8, which he kind of did, right? But I’m going to go with 8.

Okay, Paul.

I was going to go with 8, too. But you know what? I’m going to go with 7.7, just to split the difference.

Interesting.

5. The price is right.

You’re wrong.

He’s given up.

He’s given up. Oh, I think he had to step off. Okay, that’s fine. Well, that’s—

He’s asking ChatGPT.

Yeah, exactly. We didn’t have time to go into, along these lines, the Endpoints 100 survey and the new BioPharma Sentiment Index. I know, Chris, you wanted to cover that. Can we catch the panel replay somewhere?

Yeah, I think the archive is available. But the basic quick summary is that investors are the most bullish, followed by biotech professionals, then pharma, and lastly academics, obviously because of the NIH cuts.

Overall, it’s moving in the right direction, consistent with what the whole panel has said. It’s looking brighter for 2026. Let’s hope that’s true.

Awesome. And it turns out that the BPSI, I think, out of 100 was 78, which aligns very well with what you guys predicted. So I think we’re going to have to wrap it up now. Thank you to all of our hosts, co-hosts, special guests, and everyone who's listening. Before we wrap up, it's that time of year again, and Biotech Hangout will once again be hosting the in-person networking event at JPM on Tuesday, January 13th from 7 to 10 at Persona, same location as the past couple years. Hope to see you all. Thanks to our gold badge sponsors, CFGO and Incubate Coalition, and our blue badge sponsors, FTI Consulting, Catalytic Agency, and Mispro. Be sure to RSVP. We'll reshare the registration link in case you missed it. We're back next week for the last show of 2025.