Episode 189 - July 17, 2026

We have an action-packed agenda. I think we'd be remiss if we didn't start by talking about the most important news in the world, in the opinion of Enovan, myself: the upcoming third- and fourth-place match in the men's World Cup tomorrow, and then, of course, the World Cup final on Sunday.

We're very lucky to have Sam, who is very close to both England and France. Sam, what's your prediction, first of all, for that game? And I don't know if you want to share with us who you're actually rooting for.

Yeah. Well, I'm kind of perfectly hedged here because I love both countries very much and I live in both countries, so I can't lose. However, if England play the same way they've played in the Argentina game, I don't think they have much of a chance of surviving this particular one tomorrow night.

But it could be close because France didn't do that well against Spain either. I mean, there was a pretty abysmal performance, with France being really solid and tight. So it's very hard to call. I don't know—I really can't tell. And to be honest with you, a whole bunch of people are saying, “What's the point? Who cares?” Right?

Well, I gotta be honest. Some of my family members—my daughter—were asking me, “What's the point of the game?” And I was like, “Well, you clearly don't live in the UK or France.” This is still a very important game.

Matt, what do you think? I don't know if you have a view—UK or France?

We have a close family friend who's Senegalese and rooted for Senegal, then France, and then England, so I don't know who to bet against on the basis that maybe I could make some money that way. I don't have a dog in the Argentina-versus-France game.

My son, who's 4, has decided he's for Argentina. I'm not sure why, but I guess I'll support his judgment.

Yeah, he's very smart. He's going to be an amazing biotech investor if he's supporting Argentina. I think he's, as with many biotech investors, alighted on the right answer at random.

For the third-versus-fourth-place game, I think it's going to be France. I think they've just got a stronger team, although I'm sure England wants to do it more than France. I think Argentina is going to take it 3–2 on Sunday. That's my prediction.

I love the accuracy there. Well done, John. This is why you're a successful CEO and we're still here judging biotech companies.

Sam, what you're looking for is precision, not accuracy. Precision.

Precision. Yes. Sorry, sorry. Because accuracy is only after the event, right?

Exactly.

So, 3–2. Is it going to overtime or not?

Oh, yeah. Overtime for sure. Totally overtime. 3–2.

Sam, what do you think for the final?

I do fancy Argentina. But my close colleague Javier is from Spain, and we have a Spanish flag hanging off the back of his chair next to me. I have to bear that in mind if I want my life to be worth living for the next year.

And Matt, who are you picking for the final?

Well, like I said, I've got to follow my son. So I'm for Argentina and have no idea of the score.

Yeah. Okay, so I'm going with France. They've looked way too good. I don't know if you saw the statistics. We probably all watched the last 20 or 21 minutes of the Argentina-against-the UK game. Literally, there were 8 shots on goal from Argentina. They controlled 93% of the possession and completed about 180 passes versus 7 for England. It's mind-boggling how well they did. I think it's a function of the UK's strategy.

Yeah, Yaron, can you bet on the games through Kalshi as well? Is that the topic we're going to talk about?

Probably.

You can. Well, I'm bad enough at doing my day job, and I don't bet on anything.

No, not you specifically, but through that, because that's the topic that I think we might touch on later.

Yeah.

Anyway, I'm picking Argentina 2–1, and I'm worried about that game. I think France looked extremely good.

1. The Market Volatility Mystery

Okay, well, let's now shift over and do macro. We're going to start from the top and dive in. Matt, maybe give us a little bit of a sense of what you're seeing. There's been a lot of volatility in biotech. What kind of questions are you getting from investors?

Obviously, you're running a pretty stable, promising company at this point, so the whims of the markets are a little bit less important to you right now. But how does that impact your ability to execute?

Stability is all relative. I was sitting around last Friday, and you're a CEO; you check the market at some point and realize your stock's down 4 or 5%. Your first thought is, “Shoot, what did I say?” Then you wonder, “What did a competitor do?” Something like, “What happened that I'm missing?”

Then you realize the index is down and everyone's down, and you're like, “Okay, this is a Hillary Clinton tweet situation. Some public official said something about MFN pricing or whatever.” Then that's not true, and you're like, “Okay, it must be the Fed or interest rates.” And that's not true.

Finally, you throw up your hands and call an investment bank. You're like, “What's happening?” And they say, “Oh, it's factor-driven.” I said, “What does that mean?” They said, “It's Jane Street. Blame Jane Street.”

So I called my friend at Jane Street, and he was like, “It's not us.” I was led to believe that. This is an interesting lesson about the markets at this stage: I think my team and I are probably the people who know the most about the trading dynamics in Roivant's stock. We talk to all the investors and so forth, and I think it's just impossible to know some days.

I found that to be an almost Zen thought as I went around my job. That's been my experience over the last week. Investors all have pat explanations, like SpaceX is down or whatever, but I think the honest answer is that sometimes you just have to throw up your hands.

Yeah, there's so much of it that's momentum and RSI indicators, right? A 4% move is nothing these days, obviously. But in general, are you seeing anything in the macro environment that you're spending time on or that the board is thinking about?

For us, not really, honestly. Our view is that we've been on a good run and have a lot to do, so we're mostly focused on things that are specific to us. I'm interested in whether the market dynamic around companies like ours is going to change at some point. That could have sort of read-through effects on strategy, but there's not much for us to do about it in advance.

Okay, makes sense. We'll come back to you because you're uniquely suited. Hopefully, knock on wood, you should be launching a drug pretty soon—literally over the next 2 or 2.5 months or so. We'll come back to you in a minute.

2. Eli Lilly Reinvents Pharma

Maybe, John, let me go to you next. We're going to shift over and talk about Eli Lilly's continuing—I’m going to mispronounce it—the Amazonification of pharma, acquiring a variety of different companies. They just literally bought atai Beckley for $2.8 billion upfront plus a $1 billion CVR. That's a psychedelic company.

In general, there's also an Economist article where Lilly is now really reinventing the pharma business. What are your thoughts on that?

I think Lilly is just a fascinating story right now. We've heard a lot from Dave Ricks on a number of podcasts that he's done and so forth. They're really paving completely new territory as our industry's first trillion-dollar business. It's fascinating to watch what they're doing.

The Economist article that came out this week was really interesting. It was about Eli Lilly reinventing the pharma business—I think that was the title of the article—and it talks about Dave's real conviction to remake Lilly, to go from something that's a traditional drugmaker to something that's frankly closer to a tech company at some level.

A big part of that is their shift to focusing on prevention of disease as opposed to treatment of disease, which I think is absolutely the right direction for them and for others to take as well.

They're borrowing a lot of playbook ideas from Silicon Valley, which I think is super interesting. One dimension of this, of course, is that they're getting a lot closer to the patient and the consumer. They've launched a really interesting effort for commercializing their medicines with LillyDirect, which integrates telehealth and a direct-to-consumer-based strategy, effectively going around the PBMs in that regard.

And it just shows how they're thinking about digital in building their business. So that was the one thing, the one article this week that I thought was super interesting. People should take a close read.

But the news this week for Lilly was around the atai acquisition. Again, a $3.8 billion acquisition: $2.8 billion upfront and $1 billion linked to a CVR. atai is one of these psychedelic companies. They've arguably been on the fringe of some of what we all think is biotech because it's psychedelics. But, of course, it's a category that's proving to be pretty important for people with treatment-resistant depression, which is a major, major, major, major problem.

The lead asset here is a nasally administered treatment for depression. It's currently in pivotal trials, so they're buying ahead of the readout, which is a strong and aggressive bet on their part, but arguably would be the right way to do it if they have conviction in the mechanism and the pathway.

The other thing about the deal that I find interesting, because I know her personally, is that it's one of the first deals under Carol Ho's leadership of Lilly's neuroscience franchise. Carol is a terrific physician-scientist leader and somebody that Lilly poached out of Denali, where she was the chief medical officer. I believe it was earlier this year.

Anyway, it's good to see Lilly continuing its remarkable transformation and its continued buying spree in the industry, looking for innovation consistently in many different places. At a personal level, it's great to see Carol taking the lead on this acquisition here from Lilly. But Lilly is, I'm sure, going to be a frequent topic for this hangout.

Yeah. Sam, what do you think?

Yes. So that Amazonification comment came partly from me, and I think the reason I used that is that they seem to be going in every possible area of pharma. Now, I'm pretty sure they're not in every single therapeutic category, but if you remember, a couple of months ago they did 3 deals almost back-to-back in infectious diseases. And now here, this is their third CNS-type disease that's outside of, let's call it, neurodegeneration.

I think it speaks volumes to how they're thinking about the future, which will inevitably include some kind of plateau or pressure on their obesity franchise. Plateau if they continue to keep innovating and replacing, or pressure if someone else gets a meaningful position in here and, at some point, there's some patent expiry or something. I'm talking 10 years down the road here, right?

I think the more I see this, and John's comments were really fantastic on this, particularly his insight on who's in charge in the neuroscience part of Lilly, that's the way I see Lilly going. I think that probably is the only way to manage such a massive future dilemma that will come. I don't know what else to call it—potential risk that will come up.

What I love is that they're just being so proactive about it. A lot of companies would say, “Ah, we've got 10 years of amazing growth in front of us, and we can let it ride and take our time,” instead of being urgent about it. But boy, they're just showing nothing less than incredible urgency around that future build and the future product opportunities that they need to have to be able to bridge the gap of just ginormous amounts of revenue.

That's smart. It's just so smart. The proactivity is just remarkable. Kudos to that team for doing what they're doing.

3. China's Biotech Momentum

Yeah, absolutely. Let's move over to biotech. BioCentury actually had a very nice article yesterday reporting that 40% of new drugs originating from China are now first-in-class, which is actually a departure from last year. I think this year there have been 14 or 15 new drugs. I think it's more or less in line with last year, but, of course, 4 of them—I think it's like 4 out of the 14 or so—it's about 36% to 40%—are now novel. Matt, maybe I know your team is constantly on the hunt for assets. What's changing in China?

Yeah, I mean, I'm on the record in a bunch of different settings as saying I think that China is a bit of a smokescreen or a red herring for other dynamics that are changing pretty quickly on the technology side: around the commodification of antibody development, around certain kinds of even small-molecule chemistry, either with or without AI, getting easier and more reproducible, and about that stuff getting pushed to places that can do it cheaper, places that can do it faster.

Obviously, China is the current leader there, although I think, politically, if we closed off innovation from China, it would just happen somewhere else. Look, I think it's pretty remarkable, the speed with which we can now move things. We collectively, globally, can move things from an idea to an experiment, and I think it's a great thing that more drugs of any kind are coming through the pipeline, ready to be tried.

I'm not particularly biased toward novel targets. Some of the best drugs we have are 6th-generation drugs on the same target, and some of the best drugs we have are the first of their kind. I think they're all great.

I do think we, like everybody else, look to China, among many other places, for new assets. And I'll say, if you compare the surface area of where you find things now to 10 years ago, it is radically different. I think there's been a lot less in-licensing by U.S. companies from Japan, for example, and obviously way, way, way more from China.

The one thing that we still have going for us as an industry in the U.S. is this: What does everyone who invents a new drug anywhere in the world want for that drug? They want it to be studied in late-stage trials in the U.S. and approved for use here. To be honest, a lot of that has to do with our high pricing for drugs. But nonetheless, it means that innovation around the world winds up benefiting us. I think it's a pretty exciting moment.

Yeah. You know, I completely agree with Matt on this issue. As you guys probably know, I think that, for patients and for what our industry really focuses on—which is bringing medicines to patients—having the sparks, or the initial sparks, of that innovation coming out of anywhere in the world is great. Ultimately, we bring it here to this population and this market because it is the greatest place to reward that innovation, and that's what attracts it all here at the end of the day. So the American patient does benefit enormously.

I thought the BioCentury article was interesting. They had called it the Asia-to-West NewCo, and it turns out that they included a couple of Japanese assets out of the 14 or 15 that they studied. So it wasn't only just China per se, but I do think that it probably reflects Matt's comments about the breadth of where things are coming from, and obviously more and more coming from China, which is an opportunity.

Anyway, something to watch in this big China debate, which, of course, is a bit of a polarizing topic for people, but one to continue to reflect on.

Is the data, by and large, completely reliable now from China? 5 to 10 years ago, there was a sentiment that it wasn't reliable. I think now it's a lot more reliable, but we still hear from bigger companies that are very active in that area and are actively in-licensing. They're believers, but they're very much saying that not all data are created equal. Not all data are trustworthy. Any thoughts about that?

I think that's true.

And by the way, there was a big study recently, John, you might know—

The study testing Keytruda, whether you gave Keytruda in the morning or whether you gave it at night.

Yeah, right? It ended up being then—

Debunked.

Debunked. Yep.

Yeah. Yeah. Yeah. Totally. Yeah. No, look, I think there's still gaps in the quality of data from different groups, and I think it is a bit of a Wild West. You have to be super careful about understanding the quality of anything. That's true here too, but because of the volume and the speed aspect of things in China—which is a positive feature in some ways, but also a negative feature when people are cutting corners to try to get things done quickly—you have to take all these things in balance. Buyer beware. People need to be diligent to make sure that they're getting quality at the end of the day.

But I do think there will, in life, be trade-offs between regulatory speed, clinical trial speed, manufacturing speed, cost, quality, and hope. The thing you hope is that you can advance along that curve such that what was possible in 6 months at low quality before is now possible in 6 months at high quality, and whatever. Those trade-offs are going to exist, and some of the very same things that make China faster are probably also things that would contribute toward just a little bit more variability. If you run a big study, you’re going to get less variability than if you run a small study, at some level.

I think all that’s going to obtain, but my personal view is, look, I think the proof’s in the pudding. There are lots of great drugs invented in China and studied in China that are now being studied in large studies here. First of all, in many cases, the data has panned out. Second of all, it doesn’t really matter because the phase 3 study is going to be the answer that goes on the label.

Maybe let’s tuck in—we have a regulatory and policy section later on—but I think this would be a good tuck-in here. Maybe we could be brief about it, just given how much we got. There’s a company out of China that was advised by the FDA not to file because the drug is manufactured in China. Any thoughts about that?

Yeah, I’ll pitch in on that, because that’s what I heard. Obviously, I can’t tell you who the company was, but I double-checked the fact, and that’s exactly what it was. I don’t know how new this is. This is not about data—the data is being generated in the U.S. It’s not even that some of the trial patients are in the U.S.; it’s a U.S. trial being conducted.

So the question ends up being: Why would manufactured product in China not be acceptable? Is this a completely new thing? Have you guys heard this before, or how does this fit with what you know and what you think?

Well, Sam, I wondered. I don’t know any of the details here whatsoever, but it’s not unusual that a given site in a given country or state, or whatever, as a manufacturer, does not meet FDA standards. That could lead to an RTF if the FDA is aware of it in advance of a filing, or it could lead to a CRL. That happens all the time. But I don’t know the specifics in this case.

Dozens of approved drugs in the U.S. are manufactured in part in China. So it’s certainly not the case that the current view of U.S. regulators is that drugs manufactured in China are not eligible for sale in the U.S.

Beyond that, I think it’s really hard to interpret without more detail. This could be as extreme as a strong political commentary by political appointees at HHS that could have drastic implications, or it could be that simply a specific manufacturing site wasn’t up to snuff and, for various reasons, people were choosing to describe that as an anti-China stance in order to achieve some objective. So, something to watch.

Yeah, but I agree with Matt. I don’t think there’s any reason to think there’s a broader theme here, given the much larger number of drug products that are manufactured out of China.

Okay. All right, perfect. Matt, let me put you on the spot, and then, John, I’d love for you to comment as well, just given your extensive experience launching drugs.

Roivant’s brepocitinib is expected to get approved for dermatomyositis. For the audience, many of you know the drug. It’s a JAK1/TYK2 oral inhibitor that showed very nice positive VALOR phase 3 data. Our consultants and all our work suggest this is going to be one of the best launches in the sector. The PDUFA date is coming up. The guidance is to launch in September, so in the next 1.5 to 2.5 months.

We’re modeling several billion dollars. I think we’ve been consistently saying we think this is between a $6 billion and $12 billion product because it’s got 4 different indications now in pivotal testing. The next one, we’re expecting noninfectious uveitis phase 3 data by the end of this year, which should be positive on the heels of the positive phase 2 data. So this is going to be probably the next big launch in biotech.

What’s interesting is that about 20% to 40% of patients are taking JAK inhibitors off-label. There are physicians already warehousing patients who want to switch, and there’s obviously a high unmet need because currently the standard of care is IVIG, which is extremely inconvenient.

The question is, this is not the first drug that Roivant is going to launch, right? You’ve launched another drug in the past, but I think this is certainly going to be the biggest. One question is: How do you price against IVIG? IVIG is one barometer at $225,000. The next drug that’s going to have data is Vyvgart. Vyvgart, on a gross basis with weekly dosing, is $870,000 before gross-to-net. So how do you position Roivant to launch? How do you think about pricing with the first launch, first indication, and 3 more to come?

Yeah, thanks, Yaron. We’ve said lots of times we’re not going to give much in the way of specific launch guidance because y’all are mean to companies that do.

Look, I think you gave 2 bookends on pricing. I think we’ve basically said those are our bookends as well and that we’ll be somewhere in that range—probably framed the way you just framed it, closer to the lower end of that range than the top end. That still leaves a pretty broad range. When we’ve talked about Vyvgart pricing in the past, it’s been more of a $500,000–$600,000 number. I think we’ll fall between those bookends.

Look, I think it’s a privilege to launch a drug with great data. It’s a privilege to launch a drug that doctors care about and that we think patients will care about. Obviously, I made a comment earlier about how sometimes the best drugs available are late in class or not the first in class. JAK inhibitors have been around in different forms for different purposes for a while, and I think brepocitinib is a phenomenal example of a current- or next-generation JAK inhibitor. I’m really excited.

The last drug we launched was a topical in psoriasis. I think our experience there, among other things, convinced us that we want to launch a lot more drugs like brepocitinib. The other thing I’ll say is we’re coming at a moment where we get to watch—or have gotten the privilege of watching—a number of other companies, including Alnylam, launch drugs extremely successfully, especially in this kind of orphan zone. I think we’re trying to soak that all up, learn every lesson that we possibly can, and stand on the shoulders of giants, so to speak.

Yeah, no, super interesting. Of course, as you think about launching a drug these days—in terms of getting formulary placement and getting on guidelines—how are things different now than they were 10 years ago? John, chime in as well.

Look, first of all, to all of the payers listening, I’ll remind you, as I said, this is not a large patient population. This is not going to be a huge budget impact. This is an orphan disease, a relatively small number of patients in the grand scheme of things. These are patients with high unmet need and high medical burden, and I think access—as with every one of these launches, what every company in our position says, and what I think the industry is largely delivering on at this moment in time—is that every patient who needs this drug should have access to it.

We are committed to that, and our job is to get the drug to patients and then work with them to navigate the U.S. health care system to get it paid for. The honest answer is, in these markets—in orphan and orphanish indications with high morbidity—in general, that seems to work.

It’s not—look, I think payers have a job to do, and that job is to make sure that these patients need the drug. I think we have to work with them to make sure they’re doing that job effectively. But in general, I think what the world will find is that these patients need this drug and they’re going to be able to get access to it.

I think a lot of techniques have arisen in the past half-decade to make this work. These are not generally—I mean, they’re not, by definition, highly competitive markets. It’s not like there are 4 big pharma companies competing with rebates in this dermatomyositis space. So I think these are generally not rebate-intensive markets, and what you wind up doing is having good bridge programs and great patient support people, and working with the payers to get it done.

You know, the one thing that I think we experienced in launching many of our drugs—all of our drugs—was working very proactively with payers and even setting up proactive value-based agreements at the beginning. That turned out to be really positive in terms of reducing what ordinarily could have been headwinds.

One of the reasons we were able to do that is we had outstanding data, like Matt does as well, which is really important. On top of it, we had a way that we could engage with the payer in a setting where the budget impact was not going to be enormous for them.

Right. And that helps as well. It’s one of the benefits of the rare-disease space in some ways. I’m sure Matt and his team are doing those types of things. But those are changes in the system that are, I think, positive and do enable smaller companies to be very successful in doing launches, which is great.

All right. Well, fantastic. All right, John, let’s stay with you. Can you talk about BIO’s response to the OMB proposal regarding political influence on federal grants, and what’s the latest there?

Yeah, look, I was really happy to see BIO come out with a statement on the issue. I think we’ve all heard about the proposal to have political operatives make decisions about either continuing grant funding or authorizing a new grant to be funded. I think all of us have been hoping the industry associations would make some statement around this because nobody finds it to be good policy.

BIO’s response was a pretty sharp rebuke of the OMB proposal, stating, among other things, that it would destabilize the research ecosystem, weaken merit-based funding decisions, weaken U.S. competitiveness, and undermine U.S. health security, among other concerns. It’s just great to see our industry association making comments in defense of our academic research enterprise, which, again, is the top of the funnel for biomedical innovation, as well as the top of the funnel for training our future scientists.

It is important that this gets done in a merit-based manner, as it traditionally has, and that political influence is not part of that picture. It is also a reminder that we all need to be vocal on some of the administration’s policies—for any administration, not just this one, but previous ones—that can weaken innovation. We must all be part of the process of making sure that we defend our industry and defend what’s important for getting medicines to patients.

Thanks. Let’s move next into a very juicy topic, and, Sam, I’m going to call on you first. Kalshi has recently announced, literally in the last 2 days, that they’re going to be opening a new venue to bet on clinical trial outcomes and regulatory approvals. They’re going to put guardrails in place to preclude insider trading and prevent anybody with nonpublic information from participating. Teleprompter, teleprompter people.

It’s going to be later-stage clinical studies, and it’s going to be restricted to companies with a market cap of about $500 million. This led to a lot of questions, both frankly supporting it and also on the negative side. Some of the supporters said that this is a free market, that these are going to be a great way to play clinical studies and not play stocks. Maybe it’s going to lead to less volatility in stocks.

Some people even thought that, potentially, based on this, patients will be able to look at which clinical studies are given a high chance of success and, on a personal basis, might want to enroll in those studies as opposed to the other ones that are less likely to work. Of course, the drawback to all of this is, how do you enroll in the other clinical studies if that becomes the norm? There are concerns about the integrity of data, more volatility in the stock market, and obvious ethical and regulatory issues.

Sam, one of the companies that is a partner is AppliedXL, which, obviously, at Bloomberg you guys have had a relationship with. What are your thoughts about all of this?

Just for disclosure, we do have a partnership with AppliedXL. They are an excellent team with whom we’re doing some exciting stuff. All the things that you’ve just listed are, I would say, fair—the criticisms and the positives.

I think it’s something that this market needs to figure out as it happens because, unless the regulators get in the way by stopping it from happening, it’s going to be something that becomes part of our lives. We have to see how big a driver it becomes. For it to become a way for physicians or patients to decide which trials to go to, this is going to have to become a very major source of information flow with regard to the number of bets that are put on, if you want to call it that, or the number of positions that are taken for or against the trial.

A lot of times, I say to my team—and I think we all believe in this—let’s have those problems when they occur. Of course, you have to be in front of them and be prepared for them. I think the company, Kalshi, has put quite a lot of restrictions on the types of people who can participate. In the list that I saw, I don’t think I saw patients necessarily in there.

What I’m looking forward to is being able to get some kind of prediction over time and statistical analysis of whether they actually do predict the outcome of the trials. That could be an interesting way of bringing another new probability of success into our calculations.

I’m sorry I’m being very academic about it here, but all I can tell you is that the group we work with is sound, solid, and very ethical. How this pans out, I think time will tell. I can’t judge it more than that, to be honest.

I agree with you, Sam. I think the concerns should be discussed, and they are being discussed. I think that’s good—that they’re out there. It’s interesting to me that they’re selecting larger companies, where ordinarily one can’t really generate a bet.

If you wanted to look at buying stock in Sanofi or Gilead, for example—which are 2 of the companies that apparently have phase 3 trials being considered—you can’t necessarily enjoy the benefits of a prediction based on just the size of those market caps and so forth. This does allow you to parse out the specific trial being investigated for that purpose. That does have an interesting flavor to how they’re doing it.

We’ll have to see, but I do tend to agree that, instead of worrying about something and not allowing it to happen or permitting it, it might be worth seeing how it goes first.

I mean, honestly, we do have much bigger problems potentially brewing with regard to AI, jobs, security, and all that. Nobody seems to be putting a block on that, and we’re worried about one thing here. Of course, that’s our job, right? But let’s see how it pans out. I might give you a new probability.

One fun thing is that you can bet on the approval of brepocitinib now. It’s one of the contracts. Yaron Werber

There’s about $3,000. Yeah, it is. According to Kalshi, we have an 81% chance of getting approved by the end of this year.

Oh, well, that’s good, right? I like the 1% in there.

The bid-offer is 81 to 26, I think. Yes. It looks like 81 at 74 is really where the order book is, and it looks like there’s about $3,000 staked on each side. We had a brief debate inside the company yesterday about whether our insider-trading policy forbade employees from participating in this market.

I think it forbids it.

We haven’t issued a formal decree yet, but I would not be happy to find out that my employees were spending time trading.

I agree.

As for Kalshi, the honest answer to that question is that I have no insight. The truth is, I have no inside information as to whether brepocitinib will be approved, and really, it’s the FDA that should be making these rules. To me, it’s mostly an entertaining curiosity.

I will say this, in response to Sam’s comment about probabilities of success: My prediction is that it will be a long time before anyone does a proper statistical analysis of whether this is a good or bad predictor. Frankly, it would take a lot of whatever the thing you’re betting on is—it would take a lot of n—to actually answer that question.

So I’m not that optimistic that we’re going to know for a while whether this is a good tool or a bad tool from that perspective. Matt, I intend to be doing analysis for another 20 years. Hopefully, we can get some answer by then.

In 20 years, it’s going to be all Claude betting against Anthropic, or ChatGPT betting against OpenAI on these things, right? We’re not even going to have to do it. We’re just going to watch the robots talk to each other about it.

That’s a scary thought.

They’re going to write the analysis reports, too.

Exactly. We’re still waiting for that to happen. Look, I think conceptually this is absolutely a need, so why not have this tool? It’s just a question. I’m more concerned about the regulatory side, to be honest. This would not be good if you’re having physicians or even nurses in big, open-label studies participating in this. The regulatory element, I think, is the stickler for me.

All right, let’s move to another exciting topic. John, I’m going to call on you for this one.

This is so close to your heart. Merck’s enlicitide, the oral PCSK9 drug, was just approved. It’s the first one. That one does have good data—almost kind of antibody-like PCSK9 reduction.

I might butcher this one, but this one does have a food effect, and AstraZeneca, I believe, does not, coming right behind it. Thoughts about whether this is going to be a revolutionary drug? They have great data, but they don’t have outcomes yet. Are outcomes important, or at this point do we know that the lower, the better on LDL is no longer questionable, and do you really need outcomes? And then I’d love it if you could comment about the exciting work that Corsera is doing, too.

Yeah. No, absolutely. Look, I think it’s fantastic. It’s great to see this approval. PCSK9 was one of the poster-child undruggable targets for a long time, and Merck succeeded. AstraZeneca is following with a macrocyclic peptide that binds to PCSK9 and inhibits its interaction with the LDL receptors. So it’s an exciting piece of science to start with.

It is going to enter a market with PCSK9 inhibitors that is now a multibillion-dollar market, with Amgen and Repatha leading on that side of it. Second in the mix is Novartis and Alnylam’s drug, Leqvio, which was fun to bring to market along with The Medicines Company.

I think it’s going to be wonderful to have another option for patients out there. It’s interestingly priced under the price of the antibodies: $3,800 per year, compared to roughly $5,000 to $6,000 per year for the antibodies and the mRNA products that are currently on the market. Now, of course, with all the rebates, I don’t really know what that means on a net basis, but it’s interesting that that’s where they landed on the pricing.

It’s also interesting that this was a drug approved under Marty’s CNPV program that he brought forward. So I’m excited to see how it launches. I’m going to predict that it will do well, but let’s see if Kalshi agrees with my prediction ultimately.

On a personal note, it’s obviously an area of interest because we’re developing at Corsera—one of the companies I’m building—a PCSK9 and angiotensinogen siRNA given once a year for prevention, which is a different market and a different population from where this drug is approved.

I still think that in the setting of prevention, especially primordial prevention, lowering the disutility of these types of therapies with once-a-year administration, compared to a daily pill, is going to be important because the adherence issues are really prominent and problematic with statin-based drugs. So anyway, it’ll be great to see it and follow it. I’m really excited to see it come to market.

So, John, a quick question for you. The question with Corsera is the path to market, and I know this is something that you and Clive are obviously very much pioneering with the team. Any updates there? I’m not sure if that’s suitable for here.

Yeah. No, it’s fine. I mean, I can tell you what we tell everybody, which is we expect to run 2 studies for approval: 1 biomarker-based and the other outcomes-based. So there will be an outcomes study.

I don’t think the outcomes data will be an impediment for enlicitide’s initial launch. Obviously, it’ll be supportive when the data are mature enough to be made available. The same will apply with what we’re doing. Our outcomes study will have to be much larger because it is a primordial population, with the event rate being lower, but there are ways of enriching populations to make that more tractable and doing clinical studies with reduced cost, which is what we aim to do.

At what point are outcomes studies not going to be required? I mean, we know, right, that the lower, the better. Even 20 mg per deciliter confers benefits. This is back to when babies are born, right?

Confers benefits. Well, they’re not required for approval. I mean, they haven’t been required for approval for a while, which is good. I think everybody believes that they are helpful in supporting the business case, and I think that’s why they continue to get done at some level, especially in unique populations.

Our population has not actually really been studied because we’re talking about primordial prevention, which is much earlier, and people who are predicted to have a high lifetime risk of developing ASCVD, heart attacks, and strokes. So it’s a bit of a unique population. But we do think approval can still be done with biomarkers at the end.

Yeah. And so the natural question is, do you have a target LDL level? You can go—it depends on the patient’s risk and, obviously, on characteristics and family history. Do you go to 70? Do you go to 40? Do you just go below 100? Yeah.

Yeah. I mean, again, we’re going to target primordial prevention, so it doesn’t even have to be over the guideline limits of what is currently indicated for treatment of hypercholesterolemia, and also in a younger population. But that’s based on the belief that we can predict lifetime risk using an AI-enabled tool. That’s the key to our approach at the end of the day.

Yeah. Yeah. Okay. Terrific.

Yaron, just one last thing to add here: AstraZeneca’s ambition is to do a combination with their oral obesity drug. That’s what they’ve talked about. Whether that’s a fixed-dose combination or not, I don’t know, but that’s one of their ambitions.

And what are your thoughts about that? I mean, there’s so much going on these days in longevity, and then people are—

I don’t know if you need that. If John’s successful with an annual drug, which is priced more affordably, then why do you need that, right?

Yeah.

Okay, John, let’s stay—and we do want to talk about M&A—but we also have a data section to talk about. Biogen, along with Ionis, just unveiled, 2 days ago, their phase 2 study of BIIB080, or IONIS-MAPTRx. This was an injectable tau ASO that goes intrathecally. It’s an ASO targeting tau.

This was a randomized study with 3 different arms: placebo versus a low dose versus a high dose, with dosing either every 12 weeks or every 24 weeks. The primary endpoint was at 76 weeks. They were looking at whether the higher dose versus placebo was significant. They didn’t compare the low dose versus placebo on ADAS-Cog, essentially, and CDR-SB for Alzheimer’s.

Technically, the study failed because the primary endpoint—the high dose—did not do as well against the lower dose. By the way, in the 76-week study, the lower dose looked better, which is actually consistent with the phase 1b data.

Based on all of that, which included a reduction in phosphorylated tau and a reduction in tau imaging, there was also a slowdown of deterioration on ADAS-Cog and CDR-SB scores—0.54 points—which is considered clinically meaningful by the FDA. The bogey was 0.5.

Based on that, Biogen is going to go into phase 3, but this is fairly controversial. Biogen stock was down. From an Ionis perspective, people were looking at that and thinking, it’s intrathecal. Arrowhead’s ASO is IV or subcutaneous, so that’s going to be easier. That’s behind it.

So maybe thoughts about this data and the overall technology?

Yeah, I mean, look, I think obviously it’s a bit of a confusing data set. I’m overall net encouraged by this as it relates to tau as a target in Alzheimer’s, and I think we all have to be mindful that this is a super-tough disease.

But the Wall Street reaction was mixed, and part of it was the inverted dose response. There was also the view that the level of efficacy that was achieved was really no better than current anti-amyloid drugs like Leqembi and Kisunla. So I think that’s the real nature, the real crux, of the response.

What has got to be considered here is that the nature of this inverted dose response is due, once again, to the poor tolerability that one sees with ASOs versus other technologies. That’s why, with what Arrowhead is doing, and with Alnylam’s program targeting tau, which is intrathecal—Arrowhead’s program is a transferrin receptor shuttle—I’m excited to see where those programs will go.

The ASO story in the CNS has been complicated. Just to that point, last week we saw Roche terminate tominersen and another ASO program in Huntington’s, and we also notably saw eplontersen fail in CARDIO-TTRansform last week. That’s a reminder that ASOs have tolerability issues, and they could be contributing to mixed interpretations of overall results.

So I’m net encouraged by this as it relates to tau. I think a lot of the complexity around the results could be mostly tolerability- and ASO-related, just like we’ve seen time and time again. We’ll see how it plays out longer term with other approaches that target tau, but I don’t think we should damn the target just because of the ASO.

Yeah, I mean, to your point, the higher dose did have more AEs and lower dose density than the lower dose.

Yes. Exactly.

Can I just ask quickly about this? These are not targeting an offending form of tau necessarily. They're targeting tau production, right? What do you think is the risk if you're actually reducing tau levels? The protein has a function in general, so what do you think about the fact that you're reducing tau levels? Is it a balance between the two? That was one of the conversations I heard being played out.

Mhm. What do you think?

Well, I think that's always the issue: the on-target, rather than off-target, pharmacology being problematic at higher doses. I don't know if there's enough support for that based on the biomarker data that have been published from the study, which wouldn't support that.

That's true. That's true, because when you look at that tau-level dose response, unfortunately, I'm not looking at that chart with the reductions in tau and saying, “Oh, look, there's a dose response here: the high dose isn't reducing tau as much as the low dose.” All those error bars were overlapping.

But there is a point here: this is a difficult subject, and Biogen pays the price for trying something at the edge of our understanding of biology here. I find that a bit tough to swallow. I'm not supporting—I’m not saying the share-price reaction was wrong or not—but somebody has to do this and figure it out as time passes.

So, absolutely, have the courage to do it.

As well—absolutely.

Yeah, absolutely. Look, I have a mother who's got Alzheimer's, so I've been following this very closely, and I obviously follow Ionis. The challenge with the antibodies is that they were always putting a little bit of a cork into a huge kind of fire hydrant. They were too late, so you need to go early. We were always very interested in the modality of actually going and preventing the propagation.

Some of the challenges, again, having a family member, are that you've got to decide: do you treat someone or not? The complexity of the therapy, the issue with ARIA and the antibodies, is that monitoring was extremely difficult, even if you live in New York City and have good access to care.

The benefits were modest, and the benefits are maybe a little bit better here. But it really is preventing deterioration, with very little or some modest cognitive benefit. That's always the challenge, but the lack of an ARIA signal so far is encouraging news.

It's a big deal because the big challenge with the anti-amyloid antibodies, of course, is that risk that factors into it. Not that any drug is without its toxicity and tolerability issues, but if there's only potential upside, then it changes the equation a little bit, doesn't it?

Yep. And you have to remember, when you have this disorder, a lot of times you don't want to be reminded of it over and over again.

Yeah.

And going in to get monitored over and over again is not exactly easy, even in terms of convincing the patient themselves to do this.

Yeah.

Okay. Sam, we have about 2½ minutes left, and we have 3 topics. I think we're going to cut it down to 2 on M&A. Let's start with the more interesting one: the AstraZeneca–Dizal deal for EGFR exon 20.

AstraZeneca is marketing Tagrisso, the EGFR inhibitor. They're the 800-pound gorilla; sales are over $7 billion or so. They're now licensing another one in, and EGFR exon 20 has been a well-known class with mixed results in many ways. What do you think of this deal?

Yeah. Remember, Astra has an investment in Dizal, actually. What was interesting is that we were wondering why it took them so long. There’s $600 million upfront, up to $900 million in development milestones, and so on.

The data that we've been looking at all along suggest that sunvozertinib, which is the drug that's not approved anywhere outside of China, does stack up. I'm looking at our charts, comparing it to Cullinan's data, to Takeda's data, to Hansoh's data, and also, of course, you've got Rybrevant out there, which is Johnson & Johnson's EGFR/MET bispecific antibody. The data stacks up, and the side-effect profile looks easier to manage.

I think Astra is the ideal partner here to sell this, given that they have the broader EGFR space. This is a small indication, but it's one that needs their drugs. We're positive on the Dizal product, and we'll see. It's marketed in China, and it's doing relatively well over there.

Okay. And maybe in the last 30 seconds, Erasca had data relating to RAS, and then they did a $500 million raise. Thoughts about the data?

Yeah. There are a lot of people who are skeptical about Erasca in terms of where the drug came from, and I think Revolution Medicines helps fan that conversation. There are some legal discussions. I don't want to say—I don't think they've actually taken them to court yet—but there are questions about whether the drug infringes Revolution's IP.

The $500 million raise, which was upsized to about $600 million, is quite a tick in the box in a market that was looking a bit dodgy in the past week, as we just talked about at the beginning of the conversation. To me, that sounds like a sign that somebody believes in this.

The data improved relative to the previous readout, with the addition of 4 more patients and a month more of follow-up, which is always a nice thing to see because we're used to the opposite most of the time, where the data deteriorates. The ORR is beginning to get very meaningfully into the range that you see from Revolution, and the side-effect profile looks a bit better.

That does make me wonder sometimes about drugs that show a lower AE rate: you think, “Well, how do you manage that?” Of course, they have explanations for it. So, it looks decent for now, and we have a whole bunch more catalysts coming in the next few months. It's going to be fun watching this in pancreatic cancer.