第197期 - 2026年9月25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 leaders and experts. I’m Sam Fazeli. My co-hosts today are Yaron Werber, Brian Skorney, and Matt Gline. For more information about our hosts and guest speakers or to listen to the most recent episodes, as I always do, even when I’m not on, please go to biotechout.com.

1.

Right. We’re going to start off talking, as usual, about the market, policy, and regulatory issues. When you look at the XBI, it doesn’t feel like it’s been suffering or anything. Maybe it’s been down a little bit from its peak over the past 2 or 3 weeks, but it seems like a lot of long-short funds are suffering because of the way some of the smaller-cap names have been performing.

I can’t really think of any particular driver for that, aside from whatever macro stuff is going on. I thought maybe we could talk a little bit about how you guys feel about the current state of the market. Obviously, IPOs are still happening. I’ve counted 22 that are trading, and of course we have another one today that has opened up, or is indicating up, which is great—meaningfully up.

The average amount of money being raised in these IPOs is the highest that we’ve ever seen for the biotech sector. Well, I can’t say ever, because I didn’t go beyond 2019 or so, but it’s still higher than the go-go days of 2021. Those are all pretty good signs in terms of the IPO market, even if the number of deals isn’t going to get anywhere near what we saw in those days. Do you guys want to have any quick comments on this before we move on to most-favored-nation issues and revenue sharing, which Matt is going to help us think through?

If not, we could just go straight to Matt. We could talk about—yeah, go on.

Yeah, I was just going to say, I think it’s been a rough week. Obviously, the sector overall has done very well for the year, and there was a really bad day in the middle of the week, followed by a couple of days of selling.

Is it a trend that’s going to continue? There are a lot of questions about the big de-grossing effect. Long-short funds just seem to be getting squeezed everywhere I look. Is the de-grossing of those long-short books driving the XBI down?

There’s also an interest-rate dynamic. I can’t tell you how many conversations I’ve had over the last couple of months about how impervious the XBI has seemed in the midst of escalating interest rates. Now we’ve crossed a threshold where maybe people are taking it more seriously. Is that an excuse for what’s happening this week? Is it a driver?

It’s a bit of a chicken-or-the-egg question, but certainly I think there’s renewed interest in monitoring and worrying about the escalation of interest rates.

Right. I have 2 comments. First, Roivant has no real basis for complaint in terms of share price over even the medium term. We’ve had a pretty great run. In the last month, we got a drug approved and were down about 8% that day. Then we added a bunch of value on some really great P3 data—I think you guys talked about it on the call a couple of weeks ago—and we’ve given a lot of that back in the sort of relentless sell-off following a negative result earlier this week in CLE.

The moral for us is: never get a drug approved, and don’t bother with clinical data. Take what you can get. It’s been a challenging environment, and my hope is that at least we can overcome it with continued execution, but we’ll see.

2.

As you’re executing that, do you want to move over to the MFN stories that we’ve been hearing? I’m particularly interested in whether you have a view on this revenue sharing. If companies manage to raise the price in Europe, do they have to give some of that back to the administration or the government? Just talk us through how you think about this.

Obviously, what happened here is that a bunch of agreements were accessed through, effectively, a FOIA request. They talked about the Pfizer MFN agreement among them. I’ll be honest: a lot of the juicy bits were redacted, so it’s hard to know exactly what’s going on. But there was some interesting content in there, including a provision that, if prices in other jurisdictions go up, Pfizer has agreed to some kind of net-revenue share, where some of the benefit it gets from that goes to the U.S. government.

I have a few comments on this. One is something I’ve said on this forum before: there’s a lot of appropriate, somewhere between acute and existential, angst in the U.S. biopharma community about MFN. I’ll reiterate my pretty strong view that mechanisms and implementation matter, but it would obviously be good for the U.S. ecosystem, the global ecosystem, and the industry as a whole to see some equalization, where the U.S. became a less disproportionate share of the market and we were less levered to policy here.

I think it’s actually a well-minded policy in terms of what it would mean for all of us if it were successful. This particular piece of it—the idea of a revenue share if prices elsewhere increase—is a good piece of it in the context of encouraging an attempt to create some equalization, versus an attempt purely to lower U.S. prices. I totally understand from a U.S. perspective why there’s a political desire to pay less for drugs. Obviously, that’s challenging for the industry from an innovation perspective if it comes without a corresponding increase in the willingness to pay elsewhere.

I think this is a useful piece of that. I don’t think we have an MFN agreement with the government today. Given what we’re seeing around us, I suspect it’s coming for the mid-caps, and it may be a conversation we have to have at some point. I think we’d be open to one. From what I’ve seen other people sign, these agreements seem constructive.

It seems like there’s a real desire to make it work for the industry, and this reads to me like a relatively creative idea. It’s very, for lack of a better phrase, Trumpian in that there’s a desire to get a deal for the U.S. But certainly, if the government is willing to advocate on behalf of U.S. biopharma companies and is able to successfully push other countries to pay more for drugs, I think it’s reasonable that taxpayers should get some of that benefit if it’s something that accrues to the industry here.

I think it’s interesting. I just wish less of it was redacted so we could understand what was going on better.

That’s very good, Matt. Thank you for summarizing that. I would just add that, sitting in Europe—and having a lens, or my aperture, that’s a bit broader than just the healthcare sector—I’m looking around myself at the impact of inflation and energy costs. Europe is in the darkest place in that regard because you might have an increase in diesel and gas prices in the U.S., but it’s even more significant here because there is very little refining capacity here.

That takes money out of people’s pockets. You also have the need for increased defense spending, whether it’s because of the push by the U.S. or not. There’s a war ongoing on Europe’s doorstep, and that takes budget. Growth is being impacted, while AI and AI businesses are mostly U.S.-based and are sucking revenue out of Europe.

The reality may unfortunately end up being that Europeans just can’t afford to pay the extra cash. It sounds awful, because these are advanced, first-world countries with first-world GDPs, but if it ends up in a situation where the only way to deal with it is to limit the number of patients who get access to a drug, that’s a really bad outcome. In the end, if the pharma companies don’t get the same revenue they’re getting here, the only option left is to raise prices in the U.S.

I’m not convinced this is simple math that’s going to work out. Time will tell, and maybe the whole thing changes a little bit. I doubt this would change if the administration were different, but we’ll see. It creates a very difficult situation for quite a few European countries unless they’re prepared to cut budgets elsewhere, and I don’t know where they would cut.

That’s a counterpoint to this whole conversation. I’m not condoning low prices here; I’m just saying that maybe U.S. prices are too high. We’ll have to wait and see how that goes.

I would say 2 things. One is that there’s a separate question of trying to get some normalization globally over the long run, versus the current moment, when prices of a whole lot of things, as you pointed out, including energy, are rising in a way that seems uncontrollable.

Cost control across the board is a topic that everybody is trying to sort out. We’re not the only industry affected by it, and that throws the discussion into relief.

I think, ultimately, US biotech and global biotech investors could get smaller returns on drugs that sell for less money globally. That’s one thing that could happen. Fewer drugs could be developed. That’s another thing that could happen. Or there has to be some equalization. I think 1 of those 3 things has to happen, at least in a world where US prices are going to come down.

Yeah.

So, mechanically, that’s math. The rest is a policy question.

I’ll give you one more. I don’t want to dominate this conversation or the session. I’ll give you one more.

All this China innovation that’s happening—there are endless PD-1s in China, including biosimilars of Keytruda, but ones that are branded. I mean, serplulimab from Henlius, toripalimab, et cetera. You can go on. There are ADCs, there are Nectin-4 ADCs, et cetera.

Is it possible that this might actually—similar to what’s happening with electric vehicles in Europe, and less so in the US—open the door for cheaper, not lower-quality but cheaper, Chinese drugs that do the same thing? Clearly, they have to prove it. But is it possible that over the next 5 years we actually see a shift there, and then there is no benefit for the US? They just lose the market.

It’s an interesting discussion to have. Perhaps we need to just sit on a panel together and beat the hell out of it and see which argument is the one that holds the most water. So, does anyone else want to comment on this? No.

3.

Brian, 1 other thing that’s clearly been a key event this week is the confirmation hearing for Heidi Overton. I’d love to hear what you heard. There were some interesting comments being made, and then other questions that have been raised. Talk us through that, please.

Yeah. She had her Senate committee hearing yesterday. Heidi Overton’s not someone who’s been very well seen in the press. She doesn’t go on podcasts the way her predecessor did, so I think there are a lot of question marks about her and where her opinions lie in terms of MAHA and medical science. That was pretty evident yesterday in terms of the questioning.

Obviously, the role is super important to our industry, given that the FDA effectively serves as the gatekeeper for pharma products. There’s been quite a bit of upheaval over the last year or so. I think we’ve talked about this, thinking that Diamontes, who serves as sort of the acting commissioner, has done a pretty good job of at least maybe cooling the temperature in the room. But there’s always this question of what direction the agency goes under new leadership.

I think in many ways Overton looks like an okay pick. I don’t know that she would be the person we would all choose in the scheme of an HHS run by RFK Jr., but she has certainly opposed some of the more extreme MAHA pushes. She seems more committed to Trump than to RFK Jr. and the MAHA movement.

This is all in the background just ahead of the midterms, which will make whether or not she gets confirmed very interesting. Politically, she needs 11 votes to make it out of committee and go to the full Senate, and there are 12 Republicans on the committee. But some of those Republicans have broken with Trump, and the chairman in particular, Cassidy, has seemed to have some regrets over his vote in support of RFK Jr. After losing his primary, he kind of has not much to lose.

There were definitely some questions, not just from Democrats but from Republicans, that were particularly pointed at Overton yesterday. I think there were a couple of key responses that are positive for industry. First of all, in her opening remarks, she really talked about speeding through innovation and getting pharmaceutical products and cures out there.

Thematically, I think this is good news. Whether or not it’s her own opinion or the administration’s opinion, it does seem like there’s more of a pivot toward focusing on the speed of innovation. She directly brought up the China issue and trying to compete with China.

Going back to the point you were making earlier, Sam, she also didn’t hesitate to answer a question about vaccines and say that the MMR vaccine is safe and effective. She even said every vaccine on the market in the US is safe and effective according to the FDA. It just felt more unhedged to me as a statement than RFK Jr. in committee hearings, or many of the other people who have been put before the committee in HHS.

She also spoke about Operation Trailblazer, another research initiative. Overall, whether she’s ultimately confirmed or not, I think you can take away the message that the administration is really trying to calm the chaos at the FDA, whether it’s through Diamontes, who’s been acting again. We also talked about the appointment of the permanent CDER and CBER directors, which I think is a positive, and it’s hard to imagine that Overton didn’t have some say in that, even though she’s not confirmed yet.

My takeaway was that there wasn’t a clear opinion, and I think the press has jumped on the fact that she didn’t really offer a lot in terms of what her opinions on things were. But in general, it did signal what I think would be a positive change relative to what we’ve had in the FDA for industry. There are other things that, on the political side, I think people will debate more hotly.

Brian, I think your dog doesn’t agree with most of what you’re saying. Perhaps we should listen to her too—or him.

I mean, we had a lot of comments from Dr. Makary when he was in charge about trying to create situations, or a setting, where clinical trials can be initiated and tested faster, so that drugs can get into trials quicker. But I’m not sure a lot happened there.

Let’s see if this is definitely something that needs to be done to get at least that aspect of US development. On an innovation front, the US is by far ahead. But in terms of getting that innovation through to the first group of patients, that’s what we need to wait and see.

Now we have Yaron, who also joined us. Yaron, you probably heard some of the conversation we had. Did you want to add anything to all we’ve said?

No, Sam. I think this was unbelievably insightful.

Okay.

I don’t have anything to add.

Great. I’m assuming you’re referring to Brian and Matt there rather than me. But anyway, let’s go on and talk about something else.

4.

Compass Therapeutics had a pretty rough ride this week with regard to having already suffered a big setback, from just over $5 down to $1 or $2 per share back in April, after they reported their trial that did well—or, depending on what you call well, the numbers are low relative to what we’re looking for.

This is the drug for second-line biliary tract cancer, which is a tough cancer. It’s a small indication and a tough one, and there are other drugs being developed. We know that tislelizumab succeeded in China in its Phase 3 trial for this same indication and did have an overall survival benefit, so we’ll see what that data looks like.

Here, they had an ORR benefit and a PFS benefit, but the median overall survival didn’t work out because there was, according to the company, 54% crossover. At the time they had the data, the share price fell. Then they talked to the regulators, and the regulators were saying they might need a Phase 3 trial that gives them an overall survival benefit. Now, of course, that’s actually happened, and the FDA has fed back to them.

So the shares fell yet again. Whether that trial is doable is 1 question, really, in terms of not allowing crossover, et cetera. Whether it’s something the company can afford to do with the cash balance they have is another question. There’s a lot riding on this here, and I’m not sure if I read this as the FDA being tough. They could have said, “We can approve this, given the side-effect profile isn’t particularly onerous, on an accelerated basis, but then you need to do a confirmatory trial that shows the OS benefit,” which would mean you have to not allow crossover, assuming your drug’s working.

That obviously has been a tough week for them. Not quite data, but I’m wondering whether this is a new toughness by the FDA or the right toughness. I don’t know if anybody else wants to comment before we move on to some other data readouts this week. Doesn’t sound like it.

Let’s move on to Vertex. I think that’s Brian, who’s going to be talking to us about Vertex and the APOL1-mediated kidney disease news that we had. Brian, I’m sorry—Vertex. Vertex, not Amgen. Sorry, Brian, are you there? Hello. Is anyone there?

I’m here.

We can hear you.

Sam, what happened to Brian?

I think he’s—

Can you guys hear? I said I’m Jen.

I'm sorry. I'm at Vertex.

Well, I think we'll be talking about both of them, so we can go for it. Let's start with the Vertex one.

Okay, so they announced data this week for one of their more interesting pipeline programs, a drug called inaxaplin, which is a targeted therapeutic for the treatment of kidney diseases mediated by high-risk variants in the APOL1 gene. People with these variants have a really high risk of progressive chronic kidney disease. It's estimated that there are about 250,000 people in the U.S. with these variants.

We've previously seen really impressive data in these patients with focal segmental glomerulosclerosis, or FSGS, with these APOL1 alleles. But there have been a lot of underlying questions about how broadly applicable it will be across people with the underlying genetics, not just APOL1 and FSGS. Maze had data earlier this year across more diverse patients, including diabetics and non-FSGS patients, with its own potentially competitive drug, and it was kind of mixed.

I think Maze went down pretty significantly on its data. The FSGS patients looked really good, in line with what we've seen from Vertex, but the results in non-FSGS patients were a little more confounding. In diabetics in particular, it really didn't look like it was moving the needle. That raised some questions: Would it be competitive with Vertex's drug, and would the market wind up including non-FSGS patients and diabetic patients?

This week, Vertex presented its first data set in a broader range of patients outside of the FSGS population, and it was kind of okay. I think the effect on eGFR in non-diabetics looked good, but they didn't really break out FSGS versus non-FSGS patients other than to say that this cohort was mostly not diagnosed with FSGS. The impact on proteinuria here was more or less the same as the impact on proteinuria in the Maze non-diabetic cohort.

Of course, there were cross-trial comparisons, but I think it did recapitulate the Maze data in a certain way. It probably strengthened the argument that these are going to work outside of FSGS, but maybe also highlighted that diabetics are going to be a much harder hurdle to move the needle in. My guess is that the stock move on Maze this week is really due to its being seen as back in the competitive running in this market.

Both of them are at similar stages of development, and the next data we should get from Vertex will include an interim look at a phase 3 study of this drug in APOL1-mediated kidney disease. That should be over the next 6 months or so.

So, while we've got you on the phone, we might as well go to Amgen. I'm looking at Amgen's share price, and it's performed particularly well during 2026, or at least over the past 12 months. Over the past 12 months, we've gone from just shy of $300, or below, up to where we are now, just over $400, having been up to close to $450.

Talk us through this particular Sjögren's data that they had. Then I think Matt and Yaron want to speak to this and maybe just frame for us the current Amgen story. Is it getting away from being a biosimilar story? Is that too provocative?

I don't know that anyone would ever describe it as a biosimilar story specifically. It's a pretty broadly diversified company: It does biologics and small molecules, and it does have a pretty meaningful biosimilar franchise.

I know Yaron has opinions on this, too, so feel free to jump in at any point here. They're sort of a company where the question is whether they have a pipeline that's going to grow beyond the very meaningful P&L that they put forward today. They have a lot of LOEs coming over the next couple of years, and they have a couple of things that are really interesting.

It had a big sell-off the other week when the Lp(a) study from Novartis failed, because Amgen's own Lp(a) drug is one of the pipeline assets that has had a lot of enthusiasm for it, certainly on the generalist side. We've all talked about MariTide, their potential monthly or even less-frequent GLP-1/GIP drug, and they have a number of other programs in the pipeline.

This is also one of the more interesting ones. They had positive phase 3 data for a drug called dazodalibep, which is a CD40 ligand antagonist. This data was in Sjögren's. Sjögren's is interesting because it's been a pretty tough nut to crack. It's a very heterogeneous disease, and there have been a lot of failures.

We've had 2 pretty meaningful successes now. One is from Novartis, which is expecting approval for its own BAFF-targeted drug, ianalumab, and it should be able to launch in the next couple of months here in the U.S. It had 2 positive phase 3 studies there. This is going at the disease in a slightly different fashion in terms of its target, but what we've learned is that at least this phase 3 study is positive.

I think a lot of the questions are how positive it is. There have been hits and misses among CD40 ligand-targeted therapies, and even in Sjögren's there have been a number of failed phase 2 studies with different targets. The question is whether this is really going to be needle-moving. Have they just designed a smart study to get it across the line?

That's a little bit of a debate here. Is it going to be a nice billion-dollar product, or is it going to be something more because the clinical effect size is going to be much more robust than Novartis', which is more or less a point on the scale that's being used in these studies? But it's certainly a positive for Amgen. It was up on the day.

I think, Sam, you're also going to talk about some of the Viking data, which was one of the other things people had questions about with Amgen, going back to MariTide and the monthly dosing, because Viking had some pretty nice monthly maintenance dosing. But on Sjögren's, I don't know if Yaron has other thoughts on that data set.

Yeah, absolutely. I'm going to take a much more constructive view on Amgen, definitively. We've done a huge amount of work on Sjögren's. I do think that's one of our strengths as a team.

This is a huge market. Amgen, recall, is the only company that had positive phase 2 data in both symptomatic and systemic disease. Most companies out there—essentially all of them—are doing studies in systemic disease. That's about a third of the market, although I do admit that the lines are a bit blurry. Amgen showed activity in both, in 2 studies: systemic and symptomatic. This is the systemic study.

The press release is rather prescriptive in a very positive way. The data is clinically and statistically meaningful, with a very rapid onset of action. There were no differences in opportunistic infections or thrombotic events.

Brian, of course, as usual, is 100% correct. There have been other CD40 mechanistic drugs that have shown thrombosis. Those were because of the Fc portion of the drug. This one is a fusion protein that does not really have an Fc portion, so it was completely engineered out a priori because of that. That's why we've really not seen these issues with this drug.

We're expecting the second data from the symptomatic study by the end of the year. Just to level-set the market, even though it's a huge market on paper, let's be very strategic and use the scalpel very surgically. A third of patients are moderate to severe based on symptomology, and it's still $250,000 per year. It's a $5 billion opportunity in the U.S. for systemic disease and another $20 billion for symptomatic disease.

This is a big market. You're correct that Novartis will be first with data that is fairly lackluster but hopefully approvable. Now we need to see Amgen's data. Its phase 2 data was definitively more encouraging.

There's also FcRNs, which we shouldn't forget. We believe argenx will have data in the middle of next year. Then, of course, our good friend Matt and Roivant are in hot pursuit thereafter. I know they haven't given full guidance necessarily, but we think the data is probably around the middle of 2027, or maybe the second half of the following year, in 2028.

We think both of those should be positive. We think Sjögren's is going to be a huge market. We are the Amgen bulls on the Street. We do think they have LOEs, which we all know about, but they have an underappreciated pipeline.

They're doing extremely well commercially, and they have a very robust pipeline beyond biosimilars. They also have xaluritamig in phase 3 for prostate cancer, with very good data, now that, frankly, the PSMA drugs have kind of fallen a little by the wayside.

We are actually very constructive on MariTide. You're right on the Viking data on maintenance, but remember, they're starting with weekly dosing. Amgen is monthly, moving essentially to every 2 months and every 3 months, and we are actually fairly constructive on that data next year.

So, lots to talk about on Amgen, but they have a lot going on.

And did you want to add anything?

Exactly.

If you're back—no, it doesn't sound like he's back.

Well, let me jump in. The FcRn data—and I'm going to be quick—from argenx and, frankly, J&J: J&J actually had a little bit more data than argenx did, but the data was essentially identical. Both of them are FcRn inhibitors, and they're both in phase 3. Argenx technically is first. J&J started the study earlier, and, of course, Roivant started theirs, but they're not that far behind. Roivant typically moves extremely rapidly because they're so focused.

The data with FcRn inhibitors looked very compelling. We know there's a big autoantibody component to it. The CD40 ligand we just talked about is more of a B-cell, T-cell, dendritic-cell function sort of axis, so it's definitely broader. There's also BAFF, which Brian mentioned, and then there's the BAFF/APRIL data from Vera, which is atacicept. That also looked very strong, and they're in phase 3 now. That data was from China, so there's a lot going on.

We think autoantibodies are really promising. They're being tested in the systemic portion of the market. The one area where we don't know how things will work out is that Novartis will be first out with ianalumab. As Brian said, the data is positive, but it's not incredibly strong, so they're probably not going to price it too high. For an orphan, they'll probably price it at around $200,000.

As we all know, with the FcRn inhibitors, the gross price of weekly Vyvgart is around $870,000. That's the gross price, and so there's obviously a big delta. We'll need to see where FcRn inhibitors fit in, just because of pricing, but we obviously like that mechanism alone.

Matt.

No. Oh, well. Zoom isn't the best or least troublesome platform for these things, but I hope we're getting back to him. You guys did a fantastic job here. I'm a bit jealous of the modeling. This must actually be quite fun because of all the little segment competitors.

I'd love to see how this all pans out. You guys have talked quite a bit about the Viking news, so I'm going to just go through it.

Can you hear me now, or you can't hear me?

Ah, here you are. Yes, we can hear you. Go, go, go, Matt. You want to add anything?

My only 2 comments: One is, Yaron said so many nice things about us. I've got very little to add other than that we're excited about Sjögren's, and we think it's a big opportunity. We're obviously running a study there and trying to nip at our competitors' heels. I think that's going to be a huge indication commercially. I think there's a ton of unmet need. I think it's great that there are a bunch of mechanisms coming, and I'm hopeful that FcRn can play a role.

The only other thing I wanted to say, which was more general, is that Amgen bought Horizon, and I feel like the entire narrative at the time was about Tepezza. But I think this drug and Uplizna were also both Horizon carryovers. I just think it's a reminder that sometimes the second, third, or fourth drug in an acquisition can matter in the long run. I think this is going to be a big drug for them as well. That's just an interesting little side note about Amgen.

That is interesting because, at the end of the day, a lot of these acquisitions actually quite frequently end up being about the second and third drug in the pipeline, assuming that there is one. Thank you, Matt. Glad to have you back again.

5.

So, Viking's phase 1 maintenance data for VK2735 injection, a GLP-1/GIP—think tirzepatide or Zepbound—and its oral version could be the first oral GLP-1. When they do the oral version, it could be the first oral GLP-1/GIP to market. There was strong efficacy in phase 2, but they need to improve tolerability in phase 3. This is my key takeaway.

We were excited by the data that we saw: 19% placebo-adjusted weight loss at 21 weeks for the induction phase, which beats the tirzepatide data in cross-trial comparisons. Then, 97% of the reduction was preserved in patients who switched to the lower maintenance doses administered every other week in the subsequent 12 weeks, and 90% in those transitioning to once-monthly dosing. That's pretty good, especially when you're looking at a situation where patients are having a tough time staying on the doses that they're starting with.

We think this is supportive of a—I’m going to dare call it—a best-in-class profile. It clearly sets up the dosing decision to be made for the VANQUISH trial, which is the extension study in phase 3, and that's due to start early in 2027.

The result, as I said, was achieved with what I would call a clean safety profile. I think the other thing that we have to bear in mind when doing these cross-trial comparisons is that folks have learned how to manage some of these side effects, or think about them. We think this was a pretty good safety profile, with very low discontinuation rates, and it could support exploration of the higher doses, which could again give you a further bump in efficacy.

The GI rates during the induction phase were broadly in line with what we've seen in the VENTURE phase 2, even though the titration schedule was quite compressed. We think that partnering is still needed here to optimize the asset's potential, in our view. We have $5.4 billion in risk-adjusted 2035 sales for this drug, which is about 20% to 25% above consensus.

The stock was up 35% on the data, then it settled back. Looking at the 12-month and 2-year price charts, it's doing the right thing. It's going up after the hoo-ha of 2024, when all the obesity excitement was taken out of the stock. It's on a gentle upward trend. They've just raised $500 million, and the story is that one particular investor took 33% of that equity portion, which sounds like a pretty big bet. Of course, this is against the background of some other companies potentially looking for M&A deals or partnerships in this space.

We've heard Novo talk about needing to build through M&A. Whether they can possibly, even from a competitive perspective, do this kind of deal with this kind of company, who knows? But the data was very, very strong, so we were pretty excited by that.

You also mentioned the Amgen asset. Not a ton new on MariTide; it's enrolling currently, and data is expected early next year.

Okay. I'm pretty sure that this is a constantly evolving segment, even with the existing drugs. It's interesting to see how these all pan out. While you're there, could you just talk us through the phase 3 HARBOR at Celldex?

Absolutely. This was, recall, the next big readout in urticaria. There's a lot of confusion as to what chronic urticaria is. A lot of people on Wall Street think that it's very mild and not a big deal, but the reality is that there's actually a lot of angioedema with it, a lot of baseline hypersensitivity, and about 20% to 35% of patients actually have pretty severe skin disease and severe angioedema. This is not just a cosmetic or mild disease at all.

There's historically also been a lot of questions about whether this is a big market, because the only approved drug really is Xolair, and its numbers were hidden in the global number. That drug, as you remember, sold more than $4 billion. Half of that was actually in urticaria, so that was not a small market at all for a drug that was essentially not marketed and had a black box for anaphylaxis.

The next drug that was approved is Novartis' remibrutinib. It's going to do very well and grow the market. Dupixent obviously just got approved. It's very safe, physicians like it, but the data was really lackluster, and it doesn't really work in advanced patients.

That brings us to this data from Celldex, and this is one of those super-controversial, contentious stories. The drug is called barzolvolimab, and it's basically a mast-cell depleter. The thinking was, do we really want to deplete mast cells so profoundly? It's a very effective mast-cell depleter, and is this going to be safe?

The data has always been very good on the efficacy side, and the phase 3 absolutely did not disappoint. The concerns were about, I would say, probably 3 things. First, would it cause anaphylaxis because you're playing with mast cells, which could degranulate and cause massive anaphylaxis? The other concerns were a little bit of white-hair change, a little bit of skin change—all very subtle and reversible—and some neutrophil counts going down. They would go down very quickly, and grade 3 events were in the single digits, so really there were no infections, and the counts would come right back.

Those 3 things really led to a lot of concerns and very widespread debate, and because of that, the stock frankly wasn't in vogue. The data came out, and I think it was a pleasant surprise. It was better than expected. Safety looks really, really good. The data on skin clearance and angioedema is really, really strong and clearly is going to be in the label. It is clearly going to be a differentiator.

There were 2 cases of anaphylaxis due to the drug out of 1,500 patients, so way, way less than 1%. There were 3 cases of anaphylaxis in the placebo group, with half the amount of placebo patients. This speaks to the fact that these patients have a lot of hypersensitivity in the background anyway. We really think that the label is not going to have a black box.

The side-effect profile was really not bad at all. Even the hair-color changes were very subtle; they were all reversible, as were the skin-color changes. There were no infections at all. The data is probably going to be presented at the AAAAI in February.

There are 2 big phase 3s. This was 24-week data. The data got better from 12 to 24 weeks, and they need to continue to 52 weeks; then they could file next year. We think, based on the phase 2 data, that it’s going to continue to get better. We’re very constructive.

The stock was up 30% premarket, then it was down 30% premarket because there were concerns about whether there was going to be anaphylaxis. That came out during the conference call: The anaphylaxis really wasn’t bad. So the stock only ended up being down 4% and closed down 10% in a bad market. We’re getting a lot of questions now, and we think the target profile is actually going to look pretty good in a pretty big market. But this is a controversial one.

Thanks, Yaron. We’re never scared of a controversy, are we? Let’s move on to Matt to talk about orexin. I just want to remind everyone that orexin, or targeting orexin, was initially thought to be a good way of trying to deal with obesity or weight loss, and then, of course, it moved over to the treatment of insomnia.

I’ve actually personally tried Quviviq. I find it quite a good drug for when you’re traveling and need to deal with jet lag. I’m not pushing the drug, by the way, but the story of Quviviq is that it’s an agent that helps you keep your sleep architecture relatively intact. But, as with most of these neuroactive agents—or peptides, in this case—they seem to have other uses and activities. In this particular case, it’s in the ADHD space that we’ve had some news. So we’re going to ask Matt to talk us through this and what he thought of the data and the news.

Yes. This week, Alkermes, which is one of the furthest-along players in the orexin space, put out some data on ADHD. Most notably, I think, the orexin study in ADHD succeeded. The market was mixed on the data, to be honest. I’m not super involved in the Alkermes stock discussion, so I don’t know exactly what disappointed the market, but overall, I think it’s pretty interesting to see these drugs succeeding in an indication like ADHD.

I’ll say the orexin class, to me, is one of these classes where you can see—like with Lilly acquiring Centessa—it’s like the GLP-1 class. There’s going to be a groundswell of information about this class coming almost up through the floor, like water seeping in during a rising watershed. I think you’re going to start hearing about people using these drugs in all kinds of different settings because they seem to have an impact on cognition, sleep, wakefulness, and energy levels.

You know, it’s already the case that if you walk around San Francisco listening to longevity and life-maximizer people, they’re talking about this class in hushed tones as something they’re going to care about. So I think it’s really interesting, against that backdrop, to see a successful study in something like ADHD. I think there’s a version of the world where the orexin class becomes a future successor to something like Ritalin, used in lots of different settings and approved in a variety of indications, but also a drug with a complicated social presence.

The ADHD data is obviously super encouraging for ADHD as an indication. Again, something about the data may not have been perfect from a market perspective, but to me, it’s just the beginning of what we’re going to see. There are a bunch of these orexin drugs, and they have different profiles. Some of them have more or less activity in different directions, but overall, I think it’s a class you’re just going to hear a ton about.

I think this exact property of orexins—that they have a consumer-y, broad base of interest—is probably related to why Lilly seems to care about it with Centessa as well.

Yeah, that’s interesting. Matt, one of the things is that these neuroactive peptides are a nightmare from a biology perspective, as is clearly the case here. If you think about it, you use an antagonist to promote sleep, which would obviously suggest that an agonist promotes wakefulness, and then you use an agonist to treat ADHD, which somehow just seems counterintuitive.

Listen, I haven’t looked into this in depth, but it’s just like the GIP story. When we had the GLP-1/GIP combination at the time, in 2017 and 2018, I think most people assumed that GIP agonism would not be a good thing for you. Of course, it turned out to be the opposite, and all the jaws dropped when Lilly showed us the phase 2 data. So I’m looking forward to seeing all the developments here.

6.

I want to ask Yaron to talk to us a little bit about Ionis’ recent trial successes. The company has had some tough times these days, with the continued conversation about antisense oligonucleotides versus siRNA, Lp(a), and the story with AstraZeneca. Talk us through what’s going on here, and maybe, Yaron, bracket the Ionis story as it stands today.

Yeah. It’s a great point. One of the challenges for Ionis is that the conversation—and I’m not faulting it; I’m just pointing it out—is still siRNA versus ASOs. I don’t know that we agree that should be the conversation, because each one of these studies did well or didn’t do well by virtue of its own design and where we are in the treatment paradigm in this area. Comparing data to historical data across different populations is challenging, and now we can actually compare the ASO to the siRNA in sHTG, and they actually look very similar.

This is totally correct, and that’s still sort of the headwind facing Ionis day in and day out, even though, frankly, the next platform from them is a very potent ASO—now once a year or twice a year—that’s as good as siRNA. Frankly, they even have siRNA now in the clinic.

You’re totally correct: The reason the stock has struggled is really 3-fold. What was very unexpected was that the TTR cardiomyopathy data failed. It failed despite showing the same reduction in TTR as the siRNA showed in the past. The reason it failed is that, in the current populations, they’re a lot earlier. They’re either a lot healthier or, frankly, more advanced, and they actually went on top of the stabilizer—the oral drugs—which, back in the day, they didn’t have to do because they weren’t around.

It turns out that adding an ASO to a stabilizer doesn’t work. We’ve covered that many times, and so that failed. That was very surprising, and it definitely hit the stock.

Then Lp(a) did not work, despite showing what probably looks like an 80% reduction in Lp(a) levels. We’ve collectively covered that, and we’re going to see the data. At AHA, Brian, you alluded to it. Amgen went down. Amgen’s drug reduces it by 96%.

It’s unclear whether Lp(a) is maybe not such a great target in a current, modern population that is extremely well controlled for blood pressure and LDL. Frankly, the historical data back in the day suggested that Lp(a) would be a great target, but these were patients who were not otherwise controlled on the other parameters. The more recent epidemiology-based data showed that if patients are extremely well controlled, Lp(a) might not be such a great risk modifier. That failed. It wasn’t shocking, but it obviously removed a potential upside to the stock.

In sHTG, they continue to look as good as Arrowhead. I think there’s a lot of bullish sentiment, and we think it’s appropriate. Both of those drugs have launched, and we’re expecting to see the numbers shortly for the first quarter on the market. Arrowhead’s is coming next year. Arrowhead’s is every 3 months, and theirs is monthly, so there’s still some positioning: Is Arrowhead going to eat their lunch when they come in around the middle of next year? We think they’re probably both going to grow the market based on historical precedents.

Finally, what you’re mentioning is that they finally, quote-unquote, registered a win this year on phase 3 data. This is factor B with their partner Roche for IONIS-FB-LRx. It’s an injection every month. There is an oral drug out there from Novartis, which is oral twice a day. We’re expecting to see the data at ASN, and in our conversation with Ionis, they’re hinting that they expect their data to be best-in-class among complement inhibitors.

This is factor B and C5s, and it’s even competitive enough to go up against the BAFF/APRILs, like Vertex, Vera, and Otsuka. There’s a lot to keep our popcorn warm and pay attention to. It’s going to be at ASN.

The big argument is that inevitably the data will come out and it’s going to be disappointing. They gave us a lot of body language. The phase 2 looked pretty good, so we’ve got our fingers crossed, and that data is coming at ASN. We think it’s probably not going to compete with BAFF/APRIL in the frontline, but it will probably end up getting used as salvage thereafter—as an add-on or as a switch—because they won’t get to the market for probably another 1.5 to 2 years.

Thanks for that, Yaron. Very nice summary. You know, it’s one of the themes of this Biotech Hangout that we usually comment on—the siRNA versus ASO—but data is what we need. I think everyone has agreed that these cardiovascular trials, especially when you’re looking for MACE, have a lot going into MACE, and it’s not just one particular element.

So, nice summary there, Yaron. Before I pass it on to Brian to talk about Lexeo, I want to talk very quickly about Moderna. It's a stock that has been problematic for quite a lot of specialist investors who have not been invested for one reason or another.

The stock has been doing phenomenally well. Obviously, they had the news that their cancer vaccine for melanoma with Merck had succeeded. The data is coming at ESMO in 3 weeks' time, and then you've got the share price, which has pretty much gone up from about $14. Today, it's trading at just over $20. It hasn't been at this level for a long while now. What's driving it?

Well, their presentation for the melanoma data is the number 1 presentation in the first plenary, and I think there's a lot of excitement around that. We'll have to wait and see what the details are, but clearly, the people who are buying into the name are excited by the fact that it is number 1.

I've looked high and low for any other reason why this could be going up, because a lot of the story now, at least from an analyst perspective, is the next news readout, which is the renal cell carcinoma data. There are a lot of questions about whether that can succeed as easily as the melanoma trial, but let's see. People, I think, are expecting a hazard ratio of about 6 for the data set that we're going to see at ESMO.

There's a lot of excitement there, and it's one of the 3 big cancer stories of this year: Summit Therapeutics, Revolution Medicines, and Moderna. Summit also has some overall survival data from Akeso—it's not their data, but detailed data from Akeso—in the biliary tract cancer, or BTC, indication. That's also being presented at the same, I think, plenary session or presidential session at ESMO. That's going to be interesting to watch.

Although, of course, everyone at Summit is more interested in seeing what happens in the ongoing trial they've got called HARMONi-3, which should be reading out in the next few weeks. Moderna has been interesting, moving up, and let's see what the data actually shows.

Now, Brian, unless anybody else wants to comment on either of these, please do. Or Brian, you can take up the Lexeo conversation. Go for it, Brian.

Cool. I'll jump on. Lexeo had an interesting press release this week. This is a company working on a gene therapy for Friedreich's ataxia cardiomyopathy. FA is an indication that we've followed for a while—a severe, debilitating disease caused by deficiencies in a protein called frataxin. We've always felt like it's a very sensible indication for protein-replacement therapy through AAV, and that's why we've liked the story.

They have a program, LX206, which is in a pivotal study right now, following the FDA's blessing on an endpoint. Hopefully, we'll see positive data there next year. But the announcement they made really expands their efforts in FA in multiple ways.

They acquired a company called Mantle Therapeutics, which has a number of early-stage drugs in development for Friedreich's ataxia, highlighted by a combination product of an HDAC inhibitor and an NRF2 modulator. There's an approved NRF2 modulator in Skyclarys, the Biogen drug that they got through their Reata acquisition. HDAC inhibition has shown some interesting preclinical evidence of benefiting frataxin production, and evidently, this combination drug that they've acquired does have some clinical data showing interesting increases in frataxin expression, as well as functional improvements on the mFARS endpoint, which is the standard endpoint used in Friedreich's ataxia studies and is what Skyclarys is approved on.

In addition to that, they're also targeting a number of ways of getting frataxin across the blood-brain barrier. They have a preclinical TfR1-conjugated recombinant frataxin, as well as a discovery-stage TfR1-conjugated ASO that's intended to stabilize frataxin mRNA.

In addition to the Mantle Therapeutics acquisition, they announced a number of collaborations on better administration of gene therapy. They have a program with Cornell looking at sequential dosing in FA patients to provide systemic benefit through the cardiomyopathy portion of LX206, but also a second intrathecal administration. They've also done collaborations with Apertura Gene Therapy for a blood-brain barrier-crossing capsid, as well as Vivet Therapeutics, from which they're licensing VTX-P, an IgG-degrading enzyme that might be able to complement their immunosuppressive regimen.

We see this as a pretty impressive effort to target Friedreich's ataxia through multiple pathways. In our view, Lexeo becomes the FA company with the most going on. There are a number of other companies pursuing Friedreich's ataxia, but it's really been an underdeveloped—certainly undertreated—indication, and it's been a tough nut to crack clinically.

Skyclarys was approved, but I think people would say it's not the most effective drug out there. There would be room for very ample improvements by getting better frataxin expression and better frataxin into the cells that need it. We really like Lexeo's efforts to take what started as just a gene therapy and expand around that program to better address the problems these patients have.

Thanks a lot for that, Brian. We're very close to the hour. We've pretty much covered most of what we wanted to cover.

There's the EASD conference—the European Association for the Study of Diabetes, which of course now also includes the study of obesity—coming up next week, with a whole bunch of data sets coming out. AstraZeneca, AbbVie, Gubra, Lilly's amylin data—we have Hansoh's GLP-1/GIP that will be presented, some cardiometabolic data of particular interest next week, and also, of course, Regeneron's longer-term follow-up with trevogrumab, with the idea being to combine it with Wegovy to spare muscle loss.

There's a whole bunch of data coming, which of course all of the folks on here, at least others on their teams, will be writing on, as we will. Just to do a quick round, if anybody wants to finish with any specific comment before I close out.

No, everyone's had enough.