Why two promising heart drugs flopped and what's next

0:05Welcome to this week's episode of The Read Out Loud, a weekly biotech podcast from STAT. I'm Allison DeAngelis.

0:12Ethan Weiss: I'm Adam Forrestine. And I'm Elaine Chen.

0:17We are back from break and we have a lot to talk about. The industry has invested billions of dollars to develop drugs heralded as the next era in the treatment of heart disease. But why did they fail? And what does this mean for the development of medicines moving forward? This is going to pop a hole in the balloon, and it's going to be a long time before somebody wants to do something like this again. I think investors are going to run away from this.

0:40Ethan Weiss: That story and the most recent biotech news coming up next. But first, a word from our sponsor.

1:00Ethan Weiss: biotech moves fast blockbuster clinical trial wins brutal drug blow-ups shifting market tides if you're not paying attention you're already behind that's why i write biotech scorecard every thursday morning i cut through the noise and break down what matters right now data deals and the people and companies making real moves it's unfiltered analysis from someone who's been covering biotech for more than 20 years. If you want to keep up and stay sharp, subscribe to Biotech Scorecard, only for StatPlus subscribers.

1:39Ethan Weiss: Welcome back. God, I feel like we have not, the three of us have not sat down to record a podcast in what it's been like, Allison, like five weeks now? I think so. We took a little summer hiatus. I almost forgot what you guys have sounded like. Elaine, is that you? I know. I think I've aged a bit. Both of you sound wonderful, I have to say. And I'm happy to be conversating with you again. Wow. Thank you. Thank you, Adam. Did anyone do anything exciting while we were gone? I went to Italy. I got out of Dodge. That's very cool. Oh, we know. We've heard a lot about it. A lot about the pasta that you ate.

2:21Elaine, Adam, what did you guys get up to? I've been traveling a lot, too. I've had a lot of weddings as well. A lot more weddings coming up. It's just a very wedding-heavy year for me.

2:30Ethan Weiss: Yeah, I actually, wow. It was a wedding hiatus for all of us because I also went to a family wedding. And, you know, family weddings can be sometimes they can be sort of tense. But I got to say, this family wedding was spectacular. Like, the vibe was just really great. Adam, wait, wait. Family weddings tense? What are you talking about? I know. Who knew, right? What's going on in your family? All right. So let's talk a little bit about, because we have been gone for a little bit, maybe talk about stuff that happened over the last, you know, last month or so that stuck out to us as kind of notable.

3:09Ethan Weiss: Let's start with the FDA, because obviously the FDA is a topic of discussion often on this podcast. And, you know, what I thought was really noteworthy this summer is just how many drugs the FDA approved. So I did a count. And just like in August and so far in September, the FDA has approved eight novel drugs, two cell and gene therapies and one vaccine. Yeah, it's been pretty notable to see so much activity happen in this time period where we're actually we have been in a little bit of a power vacuum and a leadership vacuum. Marty Makari is no longer commissioner. Vinay Prasad, Tracy Beth Hoag have left the agency.

3:50Kyle Diamantis is acting commissioner right now. But regardless of the lack of permanent leadership at this moment in time, it feels like business as usual for the FDA, which is something that hasn't seemed to be the sentiment for the FDA for the last 15 to 18 months. Yeah, I think a notable approval that happened was the FDA granted accelerated approval to Replimune's melanoma drug. This therapy was rejected twice before, so this was the third time that it went up before the FDA. There was a tense advisory meeting before the approval, and a lot of FDA staff had a lot of concerns about the data that Replimune had, but ultimately the agency did grant accelerated approval.

4:40Yeah, and we also saw the approval of a medicine that we've been talking about at length on this podcast, Revolution Medicine's pancreatic cancer therapy. Back in the spring, this drug received a standing ovation at ASCO and is now officially on the market, as is Takeda's drug for narcolepsy, which is kind of a first in its class, really novel therapy for this disorder. And it just goes to show that this agency is kind of revisiting things that it has previously rejected or been critical of, but is continuing the review process despite some of the uncertainty at the top. Yeah.

5:17Ethan Weiss: And then the last bit of big FDA news was the nomination of Heidi Overton to take over as the next FDA commissioner. She will replace the current acting FDA commissioner, Kyle Diamantis. She was handpicked by HHS Secretary Robert F. Kennedy Jr. Overton has spent a good number of years in the Trump orbit. She was an official in the first Trump administration and then also went to work for a conservative health policy think tank before returning to work for Trump. Her Senate confirmation hearing has not yet been scheduled. So while there's been a lot of positive activity at the FDA, there's been a lot for the agency to keep tabs on with regards to patient safety.

6:05And in particular, I want to zoom in on some of the instances we've seen of patient deaths in clinical trials. Elaine, can you kick us off with that? Yeah, so I think another theme that's happened is we have learned about instances of patients who have died after taking new treatments. And the companies have not been forthcoming or transparent about these deaths. So most recently, we learned last week that Novartis paused trials of its CAR-T therapy for autoimmune conditions. This is a novel area of research. Traditionally, CAR-T therapies have been used in oncology, but increasingly companies are researching them for autoimmune conditions.

6:49So it's a pretty promising area. That's why people were really surprised to learn that there were safety concerns. And the way that we learned about it was also kind of convoluted. So a group of analysts had reached out to Novartis to ask why they halted these trials. And Novartis said there were some instances of serious immune responses, but they did not say that there were any deaths. It was only later on after a reporter reached out to Novartis did the company reveal that there were actually three deaths. So the company was not proactively disclosing this information. And we still don't have many critical details like when did the deaths occur?

7:25What types of autoimmune conditions the patients had? So a lot of questions still. We also learned that there were a few cases of patient deaths in trials of gene and cell therapies in China. Similar to what happened with Novartis, the larger public learned about these deaths not through any proactive disclosures by the companies or the researchers, but after reporters reached out and asked around. Notably in China, these studies were all what's called investigator-initiated trials, which is the type of study that allows Chinese doctors and companies to test new medicines without sign-off from central regulators.

8:05Yeah, Elaine, I want to underline that last point because there's been a lot of conversation around investigator-initiated trials in the biotech industry at large, even here in the United States, because there have been many investors and many companies that see this form of clinical trial that you can do in China as a way to speed up the testing process and get some early clinical data. You can't use this data to get a drug approved in the United States, but it allows the investors and the startups to get some early signals about whether the drug is working, whether the drug might not be working, to give them assurance that they're making a good investment.

8:45We've seen a lot of interest in investigator-initiated trials. And when these trial deaths were getting reported, it started to give people some pause about that framework that they've been operating under and, you know, whether that is a good way of doing drug development, a safe and ethical way of doing drug development. Right. There has been, in the wake of these deaths, there has been a lot of discussion about these types of trials in China that are loosely regulated. But as I was thinking about all of these instances that we're discussing right now, this issue of transparency with clinical trials is not limited to just Chinese companies.

9:23Like I just talked about what happened with Novartis. You know, when the Novartis instances happened, people pointed out we had a lot of concern about what happened in China, but are we also holding other companies outside of China to the same standards of transparency? On this note, there was one last instance surrounding patient safety that I wanted to discuss. It's related to the reporting you've done, Adam, about Prader-Willi.

9:51Ethan Weiss: Yeah, and this is not involving clinical trials. This is actually involving a drug for Prader-Willi syndrome that was developed by Seleno Therapeutics. Ultimately, they were acquired by Neurocrin Biosciences. And, you know, the drug is on the market. And what we've seen here is that now that the drug is out there in the real world and is being used by larger and larger numbers of patients, we're starting to see side effects, toxicity, and unfortunately, deaths that have occurred in patients that are prescribed this drug. It's called Vicat XR. And, you know, that underscores an issue with the development of a lot of drugs for rare diseases where you test these drugs in a relatively small number of patients because, you know, again, these are rare diseases.

10:36Ethan Weiss: And the drug looks promising. The benefit-risk profile is favorable and the drug is approved. And it's only after the drug reaches the market that we start to see some of these safety issues crop up. And I think that's something that we are seeing here with this drug for predobility syndrome, which is a really devastating disease. It's an inherited disease where a person basically has this insatiable demand to eat. Their brain is just basically telling them that they are constantly hungry. They're basically starving to death, and so they overeat. But again, here's a drug that may have a lot more toxicity and may be causing deaths that were not initially picked up in the clinical trial.

11:20All right. So we just had a little bit of a heavy conversation about some of the safety side effects we're seeing from new medicines. Let's talk about something that was exciting, that really grabbed the industry's attention, which was Merck and Moderna's kind of surprise success in a way. Merck and Moderna have been working on a personalized mRNA cancer vaccine, and they announced a couple of weeks ago that it actually slowed the return of melanoma and it spread to other parts of the body in a late stage clinical trial. Now, that all came from a press release. That's about all the information that we have.

11:55There's no data yet. But these results sent Moderna stock through the roof and have renewed the hope and optimism, I would say, around mRNA, which is a type of treatment that we all became familiar with during COVID. but there has since been a bit of backlash around. This new cancer vaccine data from Merck and Moderna turned the tide a little bit and brought back some of that excitement.

12:22Ethan Weiss: And so Elaine, Alison, while we all had nice summers or at least nice end of summers, I think it's fair to say that Novartis, the Swiss pharma giant, really did not have a very nice end of summer. We had some big clinical trial setbacks starting with a cardiovascular heart disease drug that targets something called LP little a, and we're going to get into that in a lot more detail coming up. But then rapidly on the heels of that large phase three failure, they also had the failure of a drug for a neuromuscular disorder called DM1. That was one of three drugs that they had acquired from a small biotech company called divinity that they had bought last year for about$12 billion.

13:11Ethan Weiss: So yeah, not a great time over there in Basel for Novartis. Yeah. And not to forget what we just discussed about having to pause their autoimmune CAR-T trials as well. So they have a lot to work through right now. But zooming out, let's focus a little bit more on the LP little a trial failure. It's been a tough week for Novartis, it's been a tough week for the cardiovascular field in general. We know that despite dozens of treatments that we've had in the market for decades, heart disease is still the number one killer in the U.S. And so that's why the drug industry has really been trying to find new types of therapies, new mechanisms to see if we can continue to lower the risk of heart disease.

13:57And we've gotten a lot of big setbacks this week. This Novartis study in particular, I think was so notable because one, it is a new type of approach. Lipoprotein little a is something that is a hereditary measure of heart health. About one in five people worldwide are estimated to have elevated levels of lipoprotein little a, which places them at higher risk for heart disease, a heart attack, stroke, and so on. And it's something that is probably under-assessed right now, but there's been growing interest in this. And as a way of tackling heart disease, the thought process has been, if you can lower lipoprotein little a, you can help people not have cardiac events.

14:44And Novartis has actually invested quite a lot of money, billions of dollars, and a lot of time in running an outcome study, which is something that has not happened much, where you run a years-long trial, which is incredibly expensive, to see if it actually prevents health effects down the line. And ultimately, this trial failed. And this was a trial that had been very highly watched. Novartis was banking a lot on this, and there are a couple of other companies following behind it that are also developing lipoprotein little a therapies that have also been watching this trial. So it really was a huge upset.

15:22Ethan Weiss: Yeah, and Elaine, you mentioned how this was a bad week or bad time for the entire cardiovascular field because while we had the setback with LP little a, we've also had some disappointing study results and some trial discontinuations around a Novo Nordis drug, which targets something called IL-6. It's essentially a protein that is involved in inflammation. Like with LP little a, there's been a lot of science that suggests that increases or elevated levels of inflammation are tied to a higher risk of cardiovascular adverse events like heart attacks and strokes. And here again, we have what seemed to have been a genetically validated target, just not showing the kind of benefit for patients that a lot of people thought they would.

16:21so we want to delve into what happened with these failed Novartis and Novo Nordis trials and what this may all mean for the industry and for patients with heart disease Allison and Adam recently spoke with Ethan Weiss he's a cardiologist at UCSF he's also the co-founder and Chief Scientific Officer at Mireya Therapeutics, a biotech company developing drugs for cardiometabolic and endocrine diseases.

16:51Ethan, thank you for joining us again. Thank you for having me. So we've obviously had different therapies out there for cardiovascular risk and heart attack, heart disease, for many years, going all the way back to statins, which really set things alight. And we have seen a lot of activity of late against these targets like IL-6, LP little a. Why has the industry been investing so heavily in this field and in these types of targets? And what's the problem that these approaches are trying to solve when it comes to heart disease? The high-level answer to that is a term that we call residual risk.

17:29And that means that if you take somebody who's had a heart attack and they come out of the hospital and they're on all the medicines that you think you'd be on. So they'd be on statin, aspirin, plus or minus a PCSK9 inhibitor, let's say some diabetes medicine. If you look at these people, there still are people who continue to have events. They continue to have more heart attacks, despite what we would consider optimal, maximal medical therapy. And so I think the world has thought, well, there must be some other pathway that you could attack that would reduce the risk, that would be independent from the really well-validated ones that we know about, like LDL, cholesterol, or blood pressure.

18:07We all know that LPLLA is not affected by statins. It's modestly affected by PCSK9 inhibitors. So it really felt like it sort of checked all the boxes. The only thing that was missing was the actual experiment to show that if you could lower it with a drug, that it would reduce the risk. So there are two options here, or three, I guess. One is that this was just a crappy drug. Two was we designed the wrong experiment. You need to treat people longer, or you need to pick a different population of people. And three was the hypothesis is wrong. We just did, you know, we got it wrong here. The genetics were wrong.

18:39Epidemiology was wrong. Everything was wrong. These two drugs were aimed at addressing heart disease through different means. Novo Nordis' drug was addressing overall inflammation, and Novartis' drug was being very widely watched for its approach at targeting something called lipoprotein little a. And it's a type of treatment that there's a lot of interest in and a lot of potential followers of. What did you think of these trial failures? It's so hard to know what I actually really thought versus what I thought I thought. But I think there was surprise, maybe borderline shock among people who really believed in this inflammation hypothesis.

19:15I think I can say honestly that I probably was surprised that there wasn't an impact on event reduction. I think I sort of believed that you could probably see an event reduction. But I think I had little things in my head that bothered me. And I think the thing that really bothered me was, you know, the genetics can tell you what happens with lifelong loss of function in a whole population of people. It doesn't tell you what happens in a short-term trial in people who are on a lot of other really powerful medicines. And I think the powerful medicines part of this, to me, feels like the smoking gun.

19:51The fact that going back 35 years that in people who are really well treated, the risk of LpA as a biomarker seems to go away or at least get significantly diminished. So I think going into this, I wasn't jaw on the ground surprised. And the reason that these two got as far as they did was because they were both quote unquote genetically validated. And I think people thought, well, genetics is really good. And, you know, I think the world sort of said, look, genetic validation is the only way you can get comfortable going forward with these billion dollar programs that are going to take forever to read out.

20:23And the fact that these two, quote unquote, genetically validated targets both seem to fail is going to make the bar very high for somebody to want to do this again.

20:34Ethan Weiss: So to step back a second, Ethan, so with IL-6, obviously it's a marker of inflammation. And I guess you felt like there was enough evidence to show a causative effect that if you reduce inflammation, you will also improve cardiovascular outcome. Was the field generally aligned with that view? Yeah, of course. And now in retrospect, everyone's pouring over it and saying, well, really, probably it was never going to work. So I think, you know, we have all these multiple lines of evidence we always look at in these games. One of them is going to be the epidemiology, which we've had, you know, now for 30 plus years, actually longer at showing that there was this relationship between systemic markers of inflammation and risk of coronary events.

21:13But then the genetics came around, the genetics sort of got everybody really excited. But if you really look at the genetics, the signal's not that strong. So I think there was hesitant belief in the inflammation hypothesis. Most people, including myself, if I'm being honest, thought it would work, at least in terms of reducing events. I just thought that it wasn't going to work as a drug that I would ever want to take. I guess today, I would say anyone who thought this was going to be the next blockbuster is probably wrong. And maybe I could include myself in that. I don't think it's going to be that.

21:41Are we ever going to see a positive trial? Maybe. Yeah. I mean, I think I'd give that one a decent chance.

21:49Ethan Weiss: We don't know basically anything about this Novartis, Pellicarson LPA study, just because all we have is a press release that said they didn't separate from a placebo. So ultimately, there'll be a medical meeting where we'll get all the data. But I guess it sounds like from what I'm hearing from you is that you're not ready to dismiss LPA as kind of a target that could ultimately show benefit for people? I guess I'll dismiss it as something super important. I mean, already we were limited by the number of people who have LP little A at the levels that you need to have to actually have the risk.

22:26Only 20 % of people have elevated LP little A. And then it's really only the people at the tail, at the extreme tail, with the very high elevations in LP little A that seem to have the risk. And then the other strange thing is you have to reduce it substantially. I think in the Novartis trial, based on the phase two data, that it reduces LpA by about 80%, which I think is thought to be the bare minimum in terms of what would be predicted to see an event reduction.

22:51Ethan Weiss: Ethan, some of the cardiologist groups have recommended LpA testing, right? Was that premature? I mean, did people sort of get on this LpA bandwagon too soon? I don't think so. I mean, I think it is still a risk marker. I think there are plenty of things that are risk markers. You know, we don't have drugs to necessarily deal with. I think, you know, look, the way we dealt with LBLA, it's been around as a risk factor that we paid attention to for 10 plus years. And the way we dealt with it, you know, patients are really educated now and they would often come to the office and they'd say, look, doc, I've got this marker.

23:25It's like sky high. It scares the crap out of me. And like, it's gonna make me have a heart attack. What should I do? and what we told them was, well, just like, let's really control your LDL cholesterol. Let's put you on maximum statin and, you know, maybe even a P6K9 inhibitor. We said that because that's all we had and it made us feel better and it made them feel better because there were no other options. But the reality is that might have been, even though we didn't necessarily know it, that might've been the right answer. That's my guess here is that that was the right answer that on the background of all those other drugs that the risk of Lp-l-A is actually pretty modest.

23:58I want to dig a little bit further into that kind of sentiment, Ethan, because, I mean, you are working in the startup world in cardiovascular drug development. This has been a space that, you know, 10 years ago, a lot of players had moved away from. A lot of the big pharma companies were not tackling big, big disease areas. And we've seen this resurgence of companies and of investors that are willing to put quite a lot of money into years-long trials, as we've seen here with this Novartis example. Does this put a damper on that? Of course, yeah. I mean, I'm still relatively new at this game, but I think I've sort of learned now how investors think.

24:42And my guess is that these two trials coming on the heels of each other. And again, obviously, there could be some subtle differences with the other drugs that are coming. But my guess is this is going to pop a hole in the balloon, and it's going to be a long time before somebody wants to do something like this again. I think if you're a big company and you are trying to think about where to deploy your capital, I would guess they're not going to be excited about doing these big trials for a little while. And I think for investors in small companies, I think it's going to be almost impossible.

25:10I think investors are going to run away from this, especially because they have so many other places they can put their money.

25:15Ethan Weiss: So, Ethan, as the chief scientific officer at Marea, co-founder of the company, what does that mean for you? Do you think about drug development in this area differently? Are there things internally that you guys are discussing coming out of these setbacks? Yeah, for sure. You can't possibly be in this space and not think about it. And I think about it not just as an executive at a small biotech company, but I think about it in the context of being a physician taking care of these patients. And obviously what we're trying to do is to make new therapies available for people to reduce the risk of still what's the number one killer of people in the world.

25:52It never changes as people continue to die of heart attacks. The question is, are they dying from heart attacks because they're just not being treated adequately with the drugs that already exist? Or is there really something we're missing? Are there other potential pathways or targets that could impact risk that would be independent from existing pathways and drugs that we already have? That's the question. And of course, if that's the case, we want to go find of because it's important. But I think it's going to be a lot harder to convince people to make those investments for at least a little while.

26:26I think there's going to be some dark days ahead in the space. I mean, that's just my honest assessment. I think it's going to be hard. And honestly, I don't blame investors necessarily. These are huge risks. They're huge investments. And there are other places that they can put their money to work that maybe don't have the same degree of risk and don't have the same degree of investment. So I would be nervous if I were trying to develop. And frankly, there was a time when we were developing our lead program towards a cardiovascular endpoint. We were going to run a big cardiovascular outcome study.

27:00We changed our strategy about a year ago. And wow, I guess I could say I'm happy about that now, because I think it would be really hard today. Ethan, do you think this is somewhat of an instance where people are over-reliant on genetic data in heart disease? Like, are we reading too much? I mean, Adam, we used to use the line when we were raising money for Morea. We would use the line, and it's obnoxious not even say it after the fact, but we would say genetics is undefeated, that it always, you know, in the experiments that we could look at, it always predicted which drugs were going to work in outcome studies.

27:41We cannot say that anymore. So I think, you know, as we sit back and actually really think hard about what we can learn from these experiences, and obviously we've got so much learned because we haven't even seen the trial results yet, and then there are all these other trials coming. I think it's going to be really important for us to be honest about what did we get right and what did we get wrong. And I think, you know, just to make this really simple, I think for the inflammation hypothesis, the risk reduction predicted by the genetics was really modest. So that one, I think, is a little easier to swallow because it was it wasn't so robust to begin with.

28:12For Lp little a, the prediction was you were going to get a 30 percent risk reduction in an outcome study. So somewhere we've missed because we're not getting that. So somewhere had something happened, and was that because people are just treated so well with these other background therapies? Was it that we were missing how high you needed that marker to be or how much you needed to reduce it or other things? I don't know, but we're going to spend a lot of the next couple of years figuring this out.

28:39Ethan Weiss: Putting back on your cardiologist hat, you know, as someone who sees patients, I mean, is one of the lessons here that, you know, maybe we just need to do a better job of treating patients with the existing medicines that are available? Or do you think there's just a limit to that? Like we're sort of running into a limit where like those medicines only go so far. I think both. I mean, look, like I said, I think we're clearly not treating everybody optimally. And so there's a huge amount of effort that we should, you know, we should all be aware that we have great tools in the toolbox. Let's use them.

29:14Let's use them as much as we can. But I think despite that, we know from the clinical trial evidence so far that that doesn't treat everybody. There are still people out there that still are going to have recurrent events, significant heart attacks, despite being on all these great drugs. There are going to be people out there, and I'd like to be one of them, who are going to continue to think about this and continue to try and find novel ways to reduce the risk of having another heart attack, because that is still the number one killer of people in the world.

29:37Ethan Weiss: Ethan, you're a great chat. Thanks for joining us. Thank you for having me. It's always fun.

29:49Ethan Weiss: That does it for another episode of The Read Out Loud. Our podcast is produced by Rachel Gottbaum. Our senior producer is Alyssa Ambrose. Our executive producer is Rick Burke. And our theme music is by Brian Joel. And we'd love to hear from you. Tell us what you like about this week's episode, what you didn't like, and whether or not you're going to get tested for LP little a. You can do all that by sending us an email at readoutloud at statnews.com. And if you like what we do, leave a review or rating on Apple Podcasts or whichever platform you use to get your podcasts. See you next week.