第163期——2025年11月14日

I'm John Maraganore, and my co-hosts today are Yaron Werber and Ami Fadia, with special guests Allison DeAngelis and Drew Armstrong. Don't you like that you guys are special, Drew and Allison? That's nice.

For more information about our hosts and guest speakers or to listen to the most recent episode, please go to biotech hangouts.com.

Now, Ami, I think I was supposed to hand it over to you because you also had some disclaimer language to add to all this.

Oh, thanks for having me here today. I just wanted to mention that any comments that I make about the companies that I cover are not meant to be taken as any type of investment advice. That's all I had. Thank you.

Yeah, great. And Yaron, do you have anything to add like that?

I do not, but that holds true as well. Thank you.

1. Rick Pazdur Takes Over CDER

Great. Okay. Fantastic. We're going to start with some policy topics that emerged during the week. As has been the case for the last 9, 10, 11 months, every week has brought some new piece of news on the policy or FDA side, and this is no exception whatsoever. I think the big news was Rick Pazdur being selected and agreeing to become the director of the Center for Drug Evaluation and Research, or CDER, which of course regulates the vast majority of products that come out of our industry.

Earlier this month, we saw the departure of George Tidmarsh as the CDER director, and that appeared to be related in part to some of his actions involving Kevin Tang and a lawsuit that had been filed. Maybe there were other reasons, but we don't really know. I think the Tidmarsh departure opened up the wound around industry concerns about stability at the FDA, which is obviously an area of enormous focus for our industry. We all need a strong, stable, and consistent FDA to be successful in bringing innovation to patients.

The good news earlier this week was that Rick Pazdur agreed to step in as the new CDER director. I'm sure everybody on the call has heard about Rick before. He's really a legend at the FDA. He's been there for over 25 years, and most importantly, he is the guy when it comes to oncology. A lot of the FDA decisions over the last quarter of a century that have come out of the oncology side really owe a lot of thanks to Rick at the end of the day.

The guy is very well respected. He's a clinician and obviously a very well-known regulatory science professional. So it really is a breath of fresh air for the industry, and I think all of us are eager to see more stability and consistency at the FDA. I think we all hope it goes well. There is some history of disagreement: the CBER chief, Vinay Prasad, has publicly disagreed with Pazdur, including just the other day—just yesterday, I believe. I think we all hope it's a sign of rapprochement that these 3 leaders—Marty Makary, Vinay Prasad, and Rick Pazdur—will work closely together in a collaborative and positive manner to help regulate the science of our industry.

Yeah, maybe I'll chime in, John. It's definitely good news. Pazdur is the one we all wanted as a stabilizing force. We can all hope for 2 things. One, that he's going to have an old-school but progressive—I mean, from a regulatory perspective, progressive and innovative—kind of approach, which will maybe moderate some of the changes and provide an even tone.

At the same time, we just want to make sure that ODAC doesn't suffer any setbacks at all. It would be devastating if, a year from now, Pazdur raised his hand and said, "It's time for me to move on," which I doubt.

Yeah. That would be a big loss not only for CDER but also for ODAC, for sure.

2. The Plausible Mechanism Pathway

Well, let's go on to some other FDA news. I think the other big news from the FDA this week was a New England Journal of Medicine article authored by Marty Makary and Vinay Prasad on the so-called plausible mechanism pathway. This has been hinted at by Commissioner Makary on a few occasions over the last 8 months or so. Part of it was inspired by the remarkable story of Baby KJ, the N-of-1 baby who received a CRISPR therapy for a urea cycle disorder. It's a really remarkable story, and Yaron, I think you wanted to talk a little bit about this pathway first, and then maybe all of us can chime in about what it means. So why don't you take it away?

Perfect. Number 1, this came out in the New England Journal of Medicine literally this week. It's a very short 2-page paper, so I commend them on brevity. It's ambitious. It's a little vague, which is okay at this stage, and it sets more of an intention than an exact policy.

Before we dive into it, because there are some interesting things in there, the one interesting thing is that it is stipulated to apply to bespoke personalized therapies that are gene-therapy- and cell-therapy-focused, but it has the intention of being broadened to antibodies and small molecules. The first thing to keep in mind is that, essentially in parallel, they decided to immediately go a little bit against it in the uniQure situation relating to Huntington's disease. At the end, you can argue that some of these elements would apply to uniQure, and that was set in motion. We talked about this last week in detail, and now they seem to be going against what was already agreed on with the previous team.

So this is basically: You need to have a biologically defined cause that is pathogenic, with a specific mutation or target characterized by natural history. You need to show that you can successfully engage and target it. Specifically, they're talking about gene-editing or mRNA therapies. You could use animal or non-animal models, if applicable, and you could do invasive or, preferably, noninvasive methods for confirmation. You need to have a clinical outcome that's consistent with improvement when there is progressive deterioration, or a disease-free course if the disease waxes and wanes. The FDA will even consider the patient's natural history as their own control.

The goal is to have single-patient expanded access generate sufficient data to support marketing approvals. This is where it starts getting a little vague and aspirational. They're saying that even if you can start with 1 patient and have several consecutive patients that are successful, that could lead to marketing authorization. Then they talk about using that as a platform technology for personalized products to support similar therapies in other conditions. Exactly what that means is unclear.

It could potentially support accelerated or regular approval. Then, of course, there are postmarketing commitments to look at safety and risk mitigation. Where it's a little confusing is exactly how broad one patient can really lead to approval. What do they mean by a few patients? What do they mean by a platform to then lead to broader approvals?

They even mention a situation where, let's say, you have a disease with 150 mutations—that's the example they're giving—that ultimately have common symptomatic manifestations addressed with this therapy, and that it could lead to approval for all mutations. So, let's see. This is certainly a positive development, but let's see how they implement it.

Yeah, I think that's a great summary. Yaron, I also wonder whether, for the Baby KJ example, it's very narrowly defined. As you know, there are many N-of-1 efforts out there. I'm involved with N-Lorem, which is the effort using antisense oligonucleotides that Stan Crooke has pioneered. There are also a couple of groups out there that are really looking at N-of-1-type tailored therapies.

I think the scope of this plausible-mechanism aspiration remains to be seen. It will probably be really important to see how it gets written into guidelines ultimately, to understand what the breadth and scope of all this is. Obviously, whether it applies to a uniQure-like situation certainly seems at odds with what was written here, in terms of what we all understand, so we'll have to see how that gets defined in the guidance. I don't know if others—Ami, Drew, or Allison—have anything to add.

I think I agree with you that this is really positive in the sense that it encourages innovation, but how it gets implemented is really going to be important. If it's used inappropriately, it could lead to safety or efficacy failures, and maybe that could set back what this is intended to be. I'd also be curious to understand how payers would view this, how much evidence they would need to see, and how pricing gets determined based on that.

Well, I think that's a super important point. Obviously, even with accelerated-approval pathway drugs, there's always been a question around any implications on the payer side of it. That'll have to be watched pretty carefully as this thing gets rolled out. There's no doubt about that. Anything from Drew or Allison on it?

I wanted to echo something and expand on something Yaron said, which is just this idea and this theme that I feel like we've seen over and over again this year: There's a headline policy that people really seem to like and are excited by, and then the actual execution from a regulatory standpoint seems to run counter to that over and over again.

People keep looking for that throughline, looking for some kind of consistent regulatory philosophy or approach, and it keeps being contradicted by the administration's own actions. I think that's starting to really get to people now that we've seen a couple of repeats of it. It's starting to create some meaningful concern that we might not get to a really stable, consistent path forward on some of this stuff, and some doubts when we see these new policies roll out.

Yeah, I mean, it's a super valid point, Drew. There have been some Wall Street Journal editorial board op-eds on this exact topic, and I think we're all looking for some consistency on regulatory guidance and action. It's super important at the end of the day.

3. The MAHA Summit Goes Private

Maybe we can segue to one of the other big events that happened this week, and that's the MAHA Summit. Allison, I think you covered it very nicely, but I'd love to hear what you've learned about that gathering and maybe provide some context for the call.

Sure. We started hearing Tuesday morning that hundreds of people—including members of the regulatory bodies at NIH and FDA, J.D. Vance, RFK Jr., Secretary Kennedy, and members of our biotech community—were going to be meeting in D.C. to have the inaugural MAHA Summit.

There was a schedule that my colleague Daniel Payne and I were able to get our hands on after Politico was kind of the first—I should give a little hat tip to them—to disclose that this summit was happening. Taking a look at the documents—the invitations and the agenda—it was really pitched as an exclusive gathering of people in the know in various sectors, mixing, mingling, and networking.

There was a whole day of events and sessions featuring some of the people we know well in the biotech industry. Over at CRISPR, Samarth Kulkarni took the stage along with Alexis Borisy and George Yancopoulos, where, I understand, Baby KJ was a topic of conversation. Samarth also talked about what CRISPR is able to do to address and really treat sickle cell disease very efficiently. That took center stage.

There was some conversation about oral GLP-1s hitting the market. Dr. Oz said that could happen as early as March. It's worth noting that Eli Lilly's oral GLP-1 candidate, orforglipron, recently received one of the commissioner's vouchers for expedited review.

Interestingly, I think a notable absence from what we were able to gather from people who were in attendance was that vaccines really weren't much of a topic. It was focused a little bit more on general food and lifestyle, general health trends, and even some brain-computer-interface conversation. Apparently, there was a panel with Neuralink, with the CEO of Neuralink involved, that got some cheers.

It was a full-day summit on Wednesday, where MAHA took a little bit of a victory lap for some of the work they've been doing, talked about their vision for what's to come, and handed out some goodie bags with beef-tallow potato crisps.

Allison, were you actually there, or was there any media coverage or presence at the meeting, or was it closed?

This was interesting. It was a closed media event, invite-only, from what I understand. And I say that not even just in the sense that members of media organizations that the administration might not like weren't invited. No, essentially no media was invited—even Fox News and some organizations that the administration likes.

The one exception was Vice President Vance's fireside chat. He gave it kind of midday, right around lunchtime. CNN had pool coverage that day, which means that it was their turn to have first access to cover what Vance was doing and talking about. So J.D. Vance's session was broadcast. That was the only session.

Everything we were hearing about was from people on the ground. I do have to say that one of my colleagues, Chelsea, was in the venue. It was at the Waldorf Astoria down in D.C., and she was in the lobby, sitting at the bar and trying to scope out what was happening live on the grounds. She said it was a very interesting meeting to observe.

Oh, fascinating. I look forward to my MAHA Summit 2 invitation in the coming years.

So, did you not get invited to it?

No, I didn't, Allison. I wouldn't have gotten invited. I didn't get invited, so it's all good.

Well, good. I can tell you it's been very successful in the sense that now I'm actually looking up what these chips are, and I might even try them. At least they're going to get maybe 1 sale out of this. I'm told that they taste like normal potato chips, to be quite honest.

I love it. Well, fantastic. That's really helpful, Allison. Thanks for that coverage of the event.

4. Alkermes Tests Orexin Agonism

Let's move on to some data and company news. I want to start with Alkermes, and there's also some interesting business-deal news on Alkermes as well. But let's start with their VIBRANCE-2 data for their orexin-2 agonist, ALKS 2680. Ami, do you want to cover that?

Yeah, sure. This week, we received the much-anticipated VIBRANCE-2 data from Alkermes for their orexin-2 agonist in NT2, which is narcolepsy type 2. This was the first robust data set in this population, with data in over 90 patients.

Earlier this month, Centessa had reported data from their orexin program in NT1, too, but it was from a relatively smaller data set. The results now provide strong evidence that orexin agonists can deliver meaningful clinical benefit beyond just NT1 in a heterogeneous population like NT2. This also strengthens the broader thesis around this class and its applicability in other, larger neurologic populations, such as MS and Parkinson's. Certainly, it at least builds toward that.

There was some debate about how this data stacks up, and there were some cross-trial comparisons being done, which, to some people, may have suggested a lower placebo-adjusted improvement in MWT for the Alkermes data relative to what we'd seen from Centessa.

In VIBRANCE-2, ALKS 2680 achieved a placebo-adjusted change in MWT of 9.3, 6.7, and 6.7 minutes for the 3 doses they tested—10 mg, 14 mg, and 18 mg—at week 6. In comparison, the Centessa data had shown over 10 minutes of change at week 2.

While I think it's expected that people are going to compare data across trials, there are 2 caveats worth mentioning. Firstly, sample size: Alkermes enrolled 93 patients, whereas from Centessa we got the data from 10 patients. Given the heterogeneity in the NT2 population, a larger data set is probably critical in fully characterizing the treatment effect.

Secondly, there's treatment duration. The Alkermes data had been reported at week 8 versus week 2 for Centessa, and at this point we don't fully know how much tachyphylaxis emerges or how long it takes to reach steady state. We're going to need to continue to watch how these data emerge over time.

The other key efficacy endpoint was ESS, which better captures the patient's subjective experience of sleepiness and is probably a more relevant regulatory endpoint, especially in the EU. At the 2 higher doses, Alkermes showed roughly a 10-point change, with patients going down to 10 points on the ESS, which is where patients are considered normal. This was comparable to what Centessa had shown at week 2.

It'll be important to see how these data evolve over time as these companies continue to dose-escalate and pursue higher doses and split dosing. On safety, we saw a very consistent on-target profile. The main adverse events were insomnia and urinary urgency, and importantly, visual disturbances were less frequent than what we saw with Alkermes's data in the NT1 population.

What this means is that perhaps in NT2, it allows these companies to continue to explore higher doses and potentially explore split-dosing strategies. We've seen both companies talk about doing that. Overall, I'd say that this class continues to remain highly compelling.

We continue to expect, I think, multiple companies to reach market, although it’s still a little early to know if there’s any one player that’ll dominate the market. Perhaps the real differentiation could come from other endpoints, like secondary endpoints around cognition or nighttime sleep. Maybe we need to look at how dosing flexibility ends up, and maybe ultimately it’s time to market and payer dynamics as well.

Yeah, that’s great and helpful. Ami, do you want to comment, since we’re on the topic of Alkermes? Do you want to comment on the competitive situation with Lundbeck making a $2.6 billion bid for Avadel, which had previously been announced to be acquired by Alkermes for $2.1 billion? What are your thoughts there?

5. Biotech Deals Turn Competitive

Yeah, I think it’s interesting, and I think we are seeing—this is sort of a second recent case that we’re seeing where there’s bidding. I think overall, it’s good to see M&A heating up.

I think in the case of Avadel, it’s interesting to see how the deals were structured. I think in the Alkermes deal offer, they had an upfront payment of $18.50, with a CVR of $1.50 linked to approval of the idiopathic hypersomnia indication, for which they’re going to have Phase 3 data next year. Whereas the Lundbeck deal structure, out of the $23, includes $2 of CVR, which are linked to sales performance milestones in 2027 and 2030.

So, it’ll be interesting to see how this evolves. Alkermes immediately put out a press release this morning that they’re considering their options. I’d be surprised if they don’t come back with at least a counteroffer, and perhaps there’s an opportunity even within the total deal value of $23 to improve the attractiveness of the deal. So, I think this is an emerging situation, and we’re going to see more come through in the next couple of days, I think.

Yeah, and it’s amazing that this is now the second recent example of an interloper coming in after an announced deal. We’ll talk about Merck and Cidara in just a minute. But, Ami, do you view any potential more limited FTC challenges with Lundbeck versus Alkermes, given the orexin program that Alkermes has? Is that one angle that Lundbeck has articulated?

You know, it’s certainly a possibility, but these are completely different mechanisms. One is a scheduled drug; the other will not be. One is nighttime, one is daytime. And then there’s a broader opportunity with the orexin platform compared to the oxybate, particularly with there being competition in the oxybate market and with additional generic versions of Xyrem that are going to launch in the early part of next year. I don’t know how much pricing power there is in the oxybate market, or with orexin as well.

Yeah. Yeah.

So, I don’t know if there are, aside from—

Yeah.

—they’re both targeting sleep—I don’t know if it truly gives them more pricing power.

Yeah. Okay. Well, let’s move on to the other recent competitive deal. Drew, you just this morning wrote a really fantastic story about the Pfizer–Metsera acquisition. I’m one of the original people who was involved in helping Metsera get started, so I thought Drew’s reporting was great. Drew, do you want to comment on that at all?

Yeah. If you haven’t read the story, it’s on the front page over at Endpoints. It’s worth checking out. I think I’m always interested whenever we get a look inside the boardroom and the high-intensity negotiations that are going on, because a lot of people on this call may have been part of those, but for a lot of folks who work in biotech, this is really a closed-door environment.

I think it told us a couple of key things. We learned a lot about Novo’s motivations, and this was a case where we had 2 big companies that really needed to find out how to get their vibe back, essentially. Pfizer’s been looking for its post-pandemic move for a long time, and they’d had a failure in obesity. Novo had really lost the early obesity lead and the crown there. So, you had 2 companies that really needed this.

I think that’s what’s fascinating: to see how aggressively they were going after this particular asset. It leaves us with a great question about what Novo does next, because nothing about their situation has changed. I think some folks may have seen Pfizer taking a small bit of additional revenge on them this morning. Pfizer’s former head of R&D, Mikael Dolsten, was supposed to join the Novo board and get voted up to that today. At the last second, he pulled his own nomination, and our understanding is that Pfizer raised some objections about that.

So, this is a deeply nasty and, at times, almost personal fight between these companies. I think the other piece of this that’s really interesting—and Ami alluded to some of this—is that we’ve all been waiting for a really long time to see if we were going to get a good first look at how the Trump administration is going to approach antitrust in biopharma. I think we caught a glimpse of that here, but in some ways it’s tainted by—I’m going to speculate here—maybe tainted a little bit by Pfizer and Bourla’s close relationship with this administration. They were really talking about it, and I don’t know how heavily they were actually able to lean on this.

If you look in the proxy documents, the FTC called Metsera on the final day of this—November 7th—and basically said, “If you try to do this deal, we’re going to sue.” So, I think we got close to getting a real glimpse on this, but they were more focused, I think, on the structure of the offer and the kind of unusual way of putting this transaction in place, rather than actually the anticompetitive aspect. So, I was hopeful there. I think we still don’t know, but I do think it’s something that’s going to be interesting to watch closely if we start to see more M&A happen around the space.

I’ll also just highlight our cousins over at the Financial Times. They had some reporting last night, I believe, about the Merck–Cidara deal, suggesting that there was another bidder up until the very last minute in that transaction as well. I don’t know if we’ll see something go public, but it seems like all of a sudden we’re moving away from single bidders and CVRs to get things across the line, into competitive—and at times nastily competitive—situations. So, I think the last 2 months of the year, the last month and a half of the year, are going to be fascinating from an M&A standpoint.

Yeah. Well, it just highlights the intense interest from pharma in biotech assets and probably recognition that this is the time to either buy them or lose them, at the end of the day. Yaron, do you want to talk about Merck–Cidara? That just happened this morning. That was another big piece of news—yet another $10 billion acquisition, which is fantastic.

Yep. So, Merck is continuing its recent playbook. What they’re doing is continuing to build up their cardio—in this case, really pulmonary—capabilities with a late-stage asset. It’s got breakthrough status, with a strong Phase 2b, to help with the Keytruda LOE, which we all know is 2028.

So, Cidara is getting bought for $9.2 billion. It’s 3× its recent market cap. And again, remember, Merck is increasingly going into pulmonary with a recent Verona deal. Obviously, the previous Acceleron deal closing is expected in the first quarter of next year.

What are they buying? They’re buying a drug called CD388. It’s a long-acting, strain-agnostic antiviral. It’s a neuraminidase inhibitor, but it’s tagged to a proprietary Fc fragment. So, it’s essentially creating a long-acting, low-molecular-weight biologic with an antiviral for a once-a-season preventative for influenza A and B—seasonal and pandemic.

The Phase 2 looked really good. It showed 60% to 76% protection against lab-confirmed flu with a single shot. Recall, typical seasonal vaccines are around 40% to 50%. Phase 3 is ongoing, and the data is expected in the first quarter of next year. This is the ANCHOR study in high-risk adults and adolescents.

So, I mean, the Phase 2 looked really, really good, and it’s nice that Merck continues to be fairly aggressive and active.

Yeah, absolutely.

I’ll just add on—

Go ahead.

Sorry, John.

No, go ahead, Allison.

I was just going to add on to expand a little bit on that. We had Dean Li, one of the executives at Merck and its head of research, on our podcast, STAT’s The Readout Loud, this week, and we were asking him about this precise issue: How is Merck looking to the future, post-Keytruda and that patent cliff that they’re facing? We were talking in particular about their work in heart disease with their PCSK9 oral medicine.

Dean was indicating that Merck’s strategy is not going to be searching for 1 big product. They’re looking to do an assortment of deals and have an assortment of products that they’ll bring into the company over the next couple of years to help backfill some of that patent cliff and then even grow on that.

Yeah, it’s fascinating. It’s good to see these transactions. We had another very interesting deal this week: the acquisition of Mersana by Day One. What’s unusual is that it’s a relatively small-sized, midsize—barely midsize—biotech, Day One, with about a $1 billion market cap, buying Mersana, which had been challenged, I think, in its story, but was certainly one of the pioneers on the ADC side.

They went ahead and put in an offer to acquire Mersana, which was agreed upon, largely for its B7-H4 ADC. For Day One, it’s obviously an effort to build on its first commercial product, Ojemda, which is an oral, brain-penetrant RAF kinase inhibitor that showed stunning data in pediatric low-grade glioma—a really terrible indication, but a relatively small market, of course. In addition to that product, they have their own ADC efforts, so they grabbed Mersana and are obviously consolidating that effort within Day One. It’s not usual for us to see smaller biotech acquisitions taking place, so that was a bit notable in this one. I don’t know if anybody had any other observations or thoughts on that deal to follow up on.

I think I could add that it was interesting how the deal was structured. I think it’s giving midsized, or smaller, biotechs the ability to acquire and build their pipelines with a low upfront payment, while the majority of the deal value is linked to development and regulatory milestones. It allows Day One to get access to this drug without paying a huge amount upfront.

The other thing that was interesting is that I think it’s a differentiated asset. There are a lot of companies pursuing B7-H4, but many of them are really going after ovarian and endometrial cancer. That’s probably where Mersana is also expanding the cohorts, but the main anchor of the deal for Day One is really the ACC indication, which is a rare cancer in the salivary gland where expression of B7-H4 is actually quite high, around 94%. The data there was quite compelling, with about a 55.6% response rate in that subset.

I think it gives Day One a unique way to go after a rare disease, even though the B7-H4 market is pretty crowded, with a lot of large pharma companies pursuing other indications. So I thought that was interesting.

Yeah, that’s super interesting. Let’s move back to some data readouts from the field. Ami, if you could maybe comment on Neurocrine’s unfortunate news about its MDD program, that would be a helpful place to start.

6. Clinical Data Challenge New Mechanisms

Sure. On Monday, Neurocrine announced its Phase 2 data from its signal-seeking study of NBI-770, which is a negative allosteric modulator of the NR2B subunit of the NMDA receptor. It was a 73-patient study in MDD and did not reach its primary endpoint. The company did note in its press release that there are some aspects of the data set that warrant further analysis before determining next steps.

The broader NMDA pathway has long been pursued in depression, especially with the strong and rapid activity we’ve seen with ketamine and esketamine, but the mechanisms are different. With ketamine, it involves a broad blockade of the NMDA receptor, whereas this particular drug is targeting a subset of it. The goal is to spare PV-positive interneurons, which cause the dissociative effect we see with ketamine.

It seems that maybe this is failing to trigger the full circuit-level changes that are required for the robust antidepressant activity we would have liked to see. We’ve seen a long history of failures in this space, so the question is whether that’s why we’re not seeing the broad activity that is needed around AMPA, mTOR, and BDNF for antidepressant activity, or whether this was just a small, multi-arm study that was underpowered to see the rapid effect at day 5 that it was designed to detect. I think we’re going to need to see what the company reveals after further analysis, but for the time being, the outlook for this mechanism is probably less attractive.

Such a tough space and an enormous unmet need. I hope we can catch a break one of these days. No doubt about it.

Let’s turn to some news from the American Heart Association meeting, which happened this past week and over the weekend as well. It was actually a pretty action- and data-filled meeting by AHA comparisons. One of the readouts that was really quite interesting was the CRISPR program with ANGPTL3. Do you want to comment on that a little bit?

Yeah, absolutely. Maybe just to throw in there, I’ll touch quickly on the other data. Ionis had really good olezarsen sHTG data, and of course Novartis had the VICTORION-1 PREVENT primary-prevention data. So, to your point, let’s start with CRISPR.

CRISPR showed data with CTX310, its Cas9 in vivo gene-editing therapy, in 15 patients with high cholesterol, high lipids, and mixed dyslipidemia on maximal background therapy after a single IV infusion. The data looked really, really good, and it’s really encouraging. Again, this is relevant to what Ionis is doing: ANGPTL3 is trying to reduce dyslipidemia by having muscle and other tissues outside the liver do the metabolism, which is different from what Ionis and Arrowhead are doing.

It showed a 73% dose-dependent reduction in ANGPTL3. It was nice to see a 55% reduction in triglycerides, almost a 50% reduction in LDL, and a 33% reduction in ApoB. Participants who came in with triglyceride levels above 150 showed a 60% reduction. Overall, the results were really good.

If you look at people who actually had a PCSK9 inhibitor, they got upwards of more than an 80% reduction in LDL. The big thing—and I think, John, you’re going to want to talk about this later when we discuss Intellia—is the patient issue and the death that occurred there.

The safety looked okay. There were no treatment-related serious adverse events and no grade 3 liver enzyme elevations. Twenty percent had grade 2 reversible infusion reactions. One participant had grade 2 transaminitis that resolved by day 14, but there was one death that was reported as not judged to be related to treatment.

They’re planning now to move into a phase 1b. The data were published in the New England Journal of Medicine, and the FDA is calling for 15 years of in vivo genome-editing surveillance. Again, the data look really good, but you have to put this in context. You can take an antibody from Regeneron, or you can take other antisense oligonucleotides or siRNAs, which require continuous or frequent dosing—not one and done.

So let’s discuss Intellia. Intellia, this week—and 2 weeks ago—had the unfortunate situation in its phase 3 program for ATTR cardiomyopathy, something very close to John’s heart. This is a CRISPR-based therapy. They had over 650 patients across the MAGNITUDE-1 and MAGNITUDE-2 studies. Before this, less than 1% had grade 4 liver enzyme elevations. In MAGNITUDE-2, which enrolled only about 47 patients, they didn’t have any.

What happened? In late September, sadly, an elderly male in his 80s in the first MAGNITUDE study was hospitalized with grade 4 transaminitis and increased bilirubin—clearly markers of liver injury. A few days later, this was announced on October 27. The program went on clinical hold on October 29, and they announced that the patient had sadly passed away around November 5.

This program is now on clinical hold. Recall Amvuttra, which John developed: It’s an incredible product with quarterly dosing, approved based on the HELIOS study. Of course, Ionis and AstraZeneca are behind eplontersen, and they’re going to read out their CARDIO-TTRansform study probably in the third quarter of next year. That’s an outpatient, monthly autoinjector, so it really begs the question: Do you really need a CRISPR-Cas9 therapy, and what’s the avenue by which this comes back at this point?

A big overhang.

Yeah, it is. It is a challenge, and obviously the CRISPR and ANGPTL3 data and the death—while graded as unrelated—it’s odd that that would be happening in a population like the initial population they aimed to study. I think we’re going to have to learn more to understand more.

At the end of the day, I do want to talk about a sort of related, but not totally related, topic: the work that Korro reported this week on its alpha-1 antitrypsin deficiency program. Its effort is focused on RNA editing, which is a reversible approach. It harnesses the ADAR enzyme in cells to achieve base editing.

In 2024, there was some very promising data from Wave Life Sciences on alpha-1 antitrypsin RNA editing, which they updated a little bit recently. That looked a little more confusing, but Korro chose an LNP-based approach and had very promising preclinical data. However, it did not meet the thresholds in its REWRITE phase 1/2 study, and the company chose, I think smartly, to discontinue the program in light of both the data it generated and the competitive landscape.

That includes Wave and other players out there, a company called AIRNA, as well as what Beam is doing with base editing at the DNA level. I think they made the right decision—the tough decision.

They got penalized as a stock, but we're going to see if they can pull it all together, which I hope they do with their program in urea cycle disorder. That was also some other news. And then maybe, Ami, you can quickly cover the Cogent news in GIST with those programs.

Sure. This fall, it seems like we're seeing several companies double their market cap on the back of positive data readouts. Earlier last month, we saw Praxis in my coverage universe do that, and this week it was Cogent, where they delivered a standout data set in GIST.

The first-line therapy in GIST is Gleevec, which has a PFS of almost 19 months, but the response rate quickly goes down significantly once you hit second line. The standard of care in second line is Sutent, and it has a PFS of a little over 8 months.

What Cogent did was combine bezuclastinib with sunitinib, and what bezuclastinib does is offer complementary mutational coverage. It targets exons 17 and 18, whereas sunitinib targets exons 13 and 14. In the phase 3 PEAK study that they announced, they reported a median PFS of 16.5 months, which is pretty impressive relative to about 9 months shown by sunitinib, and an overall response rate of 45.6% versus 25% for sunitinib.

The enthusiasm is warranted, particularly given the history of GIST. It's sort of been a graveyard for targeted oncology programs, where several drugs that had promising data in phase 1/2 ended up failing in larger trials. One that obviously seems recent is Deciphera's Qinlock, a drug that failed in its phase 3 INTRIGUE study. There are a couple of others in the past.

From a commercial standpoint, this is a $4 billion-plus market opportunity, given about 3,000 patients in second line. Following the data, it was good to see Cogent's market cap increase by about 2.5 times. They were also able to raise capital on the back of that with a $200 million equity offering and a $200 million convertible offering. I think it's just good to see positive data and companies being able to capitalize themselves to continue to develop the programs in the future.

Well, it's certainly a sign of the markets coming back, which we're also seeing more generally with the XBI, when companies can get rewarded for good data and robustly raise capital as a result of it.

There are a couple of other topics we want to cover, and then we'll do a wrap-up. We did see this past week—actually, I believe it was Friday last week, but perhaps after the last Hangout was recorded—the passing of James Watson. He obviously lived a very long life, reaching the age of 97. He was the co-discoverer of the structure of DNA, along with Francis Crick, and he's really the last of the key scientists involved in the discovery of the structure of DNA to have survived.

That includes Watson and Crick, of course, but also Franklin and Wilkins and even Linus Pauling. It is the end of a generation of scientists that served as the foundation for most of everything we do. His remarkable scientific career was unfortunately clouded by a history of unacceptable comments that were both bigoted and prejudiced, and he was ultimately shunned by the scientific community because of his behavior, which I think, appropriately, people found unacceptable.

It's sad to see him go, as with any human being. Unfortunately, his history was a little bit checkered, I would say. I actually had the chance to meet him once, and he knew about Alnylam. He knew about our efforts to advance RNAi, and the one thing he said to me was, “John, just go fast.” It was good advice, I guess. Anyway, RIP, Jim. I hope you find peace in your next chapter.

7. Biotech Finds Its Public Voice

The last thing I want to cover is something fascinating this week, which is a podcast with Dave Ricks on Cheeky Pint, which I'd never heard of before. This was brought to my attention. It's a podcast done by John Collison, and I haven't listened to the full 2 hours of the podcast, but I listened to a good chunk of it. It's actually a really remarkable interview that covers a far-reaching set of subjects, from R&D to GLP-1s to drug pricing.

I was really struck by how amazingly well and authentically Dave Ricks explains our industry in this podcast. I hope there's more of this because podcasting is such an important way to speak to the public these days. I was also really proud of Dave and how well he did this. I don't know if any of the other speakers on the Hangout listened to this as well, but I'd love your thoughts if you did.

We were definitely chatting about it on the STAT Slack this week, particularly about the line he had about, “If Taylor Swift can sell out X number of arenas, we can certainly enroll X trials.”

Yeah.

As someone who has had Dave Ricks on the podcast at STAT, I can say that he is a very good public speaker. He has clearly tapped into the fact that he needs to be speaking to consumers, not just to his peers and people in health care, but to consumers.

I found it really interesting also because I had a conversation recently with Catherine Friedman over at GV, and she was talking about her view of what's happening. She said, “This is an era where health care is becoming more and more consumerized.”

I think the type of stance that Dave took in going on a podcast that isn't for you, me, Drew, Yaron, and Ami, but for the average person who may not know how our ecosystem works—and to speak so candidly—was really a smart move.

Well, I'll tell you, I would love to see more of it because we need to connect with the broader public in better ways. We all know that, as an industry, we've done a horrible job communicating what we do, why it matters, and why it's good. I thought that was a really terrific start from Dave.

We've only got a few minutes left, and I want to leave some time for people to make some final comments. Let me go around the horn here. It looks like Yaron has stepped off, so let me go to Drew next. Drew, do you want to—

Yeah. When you guys were talking about all this, something I've been thinking about a lot, looking at the data coming out of AHA, is how fascinating it is to see this explosion of new potential treatment modalities in cholesterol.

We've gone from statins to having a long-acting injectable PCSK9 biologic, to now potentially having these gene therapies, and now, from Merck, potentially a small-molecule PCSK9. If you're treating high cholesterol or are a patient, I think it's pretty extraordinary. I think it's going to be fascinating to watch the commercial and scientific battle to see where these things find their place in the world.

Absolutely, it's fascinating to watch what that suggests about other diseases, where we may see a lot of different approaches. Efficacy doesn't always have to come with more complexity. Sometimes it will. It's really cool to see, and I can't wait to see that battle between modalities and mechanisms start to unfold.

Yeah. I think that's right. Ami, anything to add?

I heard about half of the interview with Dave Ricks, and I would recommend that everybody on this podcast listen to it as well. Some of his comments about how to drive transparency in pricing while also not adversely impacting the amount of effort that goes into research to develop new medicines, and how you solve for that, were particularly interesting. He laid out a couple of ideas that he had.

I thought that was really interesting, and it gets to the core of what's happening at the Hill and what I think a lot of us think about day in and day out.

Yeah, I agree. Ami, Allison, any last comments before we wrap up here?

I can't think of too much other than that we're looking to see who the next players in a bidding war are going to be.

Yes, because we're seeing more M&A.

Yeah, you bet. Well, let's see if this Merck deal has a bidder that comes in, given what the FT was reporting. That would be super exciting, for sure.

Well, listen, everybody, thanks for taking the time. Have an amazing weekend, and we look forward to being back next Friday and chatting with all of you about our amazing industry.