421: The future of heart drug research in the wake of study setbacks

0:07Welcome to The Read Out Loud, a weekly biotech podcast from STAT. I'm Adam Feuerstein. And I'm Elaine Chen. Today, we look at what's happening in cardiovascular research and what the recent failures of two major drug trials mean to the future of the industry. We'll also dive into the latest biotech news. Drug safety issues are a problem for both Vertex and Novartis, while L-Nylam's stock price tumbles on growth concerns. But first, a word from our sponsor.

0:45Hey, Read Out Loud listeners, Bob Herman here, stats, business of healthcare reporter, and the writer behind the newsletter, Healthcare Inc. Healthcare Inc. is a weekly newsletter devoted to unpacking the business and secret inner workings of the U.S. healthcare industry. If you're someone who has ever received a medical bill or craves in-depth policy explainers or loves a playful meme now and again, I highly recommend you check this newsletter out. Learn more at the link in this episode's description. And now, back to our regularly scheduled programming. Thanks.

1:16Welcome back, Adam. Thanks. I have to say, Elaine, I have a confession to make. I think your football team is better than my football team. Wow. Okay, I was going to wait until the end of the season to bring this back up. I mean, things can change. Let's not get too excited. But I have to say, at this point, the Bears, they look pretty good. It's not looking great. for the pats. Like I said, we'll see what happens at the end of the season. Okay, so we've got a lot of biotech news to catch up on. First, let's talk about Vertex. It has one of the more important FDA approval decisions coming. This drug is called POV-Tachacept, or POV for short, and it's being developed to treat a chronic autoimmune disease that affects kidney function called IgA nephropathy.

2:05This disease affects roughly 200 ,000 people in the U.S. Billions of dollars in sales are at stake here. So the FDA is expected to announce its decision on POV by November 30th. Adam, you've been following the story, including a recent twist that's added some controversy. Tell us more. Yeah, let me start by saying that the FDA is almost certainly going to approve this vertex drug, like you said, POV. And so if disapproval happens, POVI is going to be the third drug in this class of IgA nathropathy treatments to reach the market. Vertex will launch its drug behind Japan's Atsuka and Vera Therapeutics.

2:47Both those companies have drugs already on the market. But, you know, this treatment market is worth about $20 billion in the U.S. alone. So, you know, that's a really big pie for the three companies to slice up. Competition between these three drugs is going to be intense. The controversy pertains to a potential safety issue that's tied to POV and the risk of serious infections that has emerged of late. And that could make it a less attractive option compared to the competitors. And what has Vertex said about these safety concerns? So Vertex executives have been adamant that POV does not place patients at an increased risk of serious infections.

3:32The company points to safety data from its pivotal clinical trial. This is the trial that the FDA is using to review and approve the drug that show infection rates are comparable between POV and placebo. Yet despite that, that has not silenced the debate. Yeah, it really hasn't because there's been some revelations about Vertex's clinical trial that emerged in a citizen's petition that was filed recently with the FDA. This position was filed by an anonymous source. It asked the FDA to require monthly immune monitoring of patients who might be prescribed, Hovi, as a precautionary measure to reduce the risk of serious infections.

4:15Vertex has been asked about this, obviously, and they insist that it doesn't expect that patient monitoring is going to be required. However, no one knows what the FDA will or won't do until the drug is approved. And then we all get a chance to look at the prescription label. Yeah. So I guess we'll see on November 30th. Yeah, indeed, we will. Moving on, but sticking with this broader topic of drug safety. Elaine, last week, Novartis disclosed, or maybe I should say reluctantly disclosed, seven previously unknown instances of tumors found in children treated with its spinal muscular atrophy therapy.

4:55What's going on here? Yeah, so this is in relation to Novartis' gene therapy, Zolgensma. These tumor cases were initially publicized by a European advocacy group, and then only after that did Novartis issue its own statement confirming that there actually have been nine total reports of tumors in patients treated with a gene therapy. Of those nine cases, two to date have showed evidence that the tumors may be linked to the treatment itself. So spinal muscular atrophy, or SMA, to progressive neuromuscular disease, without treatment, babies with the most serious type of SMA are likely to die. Zolgensma has helped children who would have likely died, but there have been these concerns that gene therapies of this type could cause tumors in some patients.

5:44Right. So this risk is already included in the Zolgensma prescription label. So far, more than 6 ,000 children worldwide have been treated with the gene therapy. So from that perspective, the number of tumor cases is relatively small, but still it's a significant safety concern and one that the FDA is investigating. This is also important because there are a lot of other gene therapies designed similarly. And so this tumor risk does raise questions about the safety of other gene therapies. And just zooming out, it's been a difficult period of time for Novartis. they've faced several safety concerns and setbacks recently.

6:26We've talked about how Novartis is studying a CAR-T therapy in autoimmune conditions, a promising area of research, but they did disclose that there were a few deaths that occurred in their CAR-T trials. They also had a really big high-profile failure of a cardiovascular drug that we're going to discuss very soon. And they also had a failure of a neuromuscular drug in a trial. So there's just been a lot of setbacks for Novartis recently. So finally, let's end with a discussion of the troubles engulfing L-nylam pharmaceuticals. Yes. So Adam, in a column last year, you said L-nylam was on its way toward becoming an$100 billion biotech.

7:11We know that your track record is a little spotty. How did that take turn out for you? Yeah, that take was about as hot as my take, the Patriots are better than the Bears. So we're not doing all that great. Considering that Al Nilem was about a$60 billion company when I wrote those words, Elaine, today Al Nilem is a $20 billion company. So yeah, that hot take looked actually pretty cool in retrospect. It's okay. We can't get it all right, Elaine. Right. We can't be me. So a lot of the stock movement is due to disappointing sales of L. Nylem's drug Amvutra, which treats the progressive heart condition called ATTR-CM or ATTR cardiomyopathy.

7:54And this drug, which investors did expect to be a blockbuster, it's an injectable therapy given once every three months. The problem for L. Nylem is that it's competing against Pfizer and BridgeBio, which both have pills. And it seems like L. Nylem is struggling with getting more prescriptions. Yeah, that's true. Amputra is a blockbuster drug. It's kind of just not blockbustering enough in line with expectations. But Al Nilem acknowledged that there was lower demand. And they also said that Medicare reimbursement cuts that are set to start in January have clouded its ability to forecast future sales.

8:33Yeah, and we know investors hate uncertainty. Yeah, and the company's inability to forecast Amutra sales moving forward, I think that's been mostly responsible for the stock's collapse. And, you know, the consensus view is that the company is not going to turn around until it can string together two or three quarters of sales performance that meet or exceed investor expectations.

9:15The annual meeting of the American Heart Association is one that cardiologists will not soon forget, and for reasons that have left the entire field of cardiovascular medicine scratching their collective heads. Yeah, for years, it was widely believed that a deeper understanding of genetics was going to speed the development of newer and better medicines for patients with heart disease. But then came this year's AHA meeting, which was dominated by presentations of clinical trials that showed no benefit whatsoever for two drugs long thought to be genetically validated. Joining us to help sort out this cardiovascular conundrum and what it might pretend for the future of drug research is our colleague, Stats senior medical writer, Matt Herper.

9:59Matt, welcome to the podcast. Thanks, Elaine. It's great to be here. So, Matt, let's just start with what happened. Tell us briefly about these two negative studies. So there are two studies. There's a Novartis study to lower something called LP little a, and there was a Novo study related to IL-6. They were super neutral. One researcher said to me, this is kind of what you'd expect if you gave people water. There's genetic data showing that the targets of these drugs are involved in causing heart attacks and strokes. And these are the largest killers in the developed world. And so it's a bit of a puzzle, not just why the drugs failed, but why there's really no signal there at all for benefit.

10:44That's really the puzzle here. Right. So this Novartis drug targeted something called LP little a Novo Nordisk drug targeted an inflammatory marker called IL-6. And what seemed to flummox cardiologists is that these drugs seem to work as expected in terms of targeting what they were supposed to target. Yet in the end, it did not result in cardiovascular or survival benefit for patients in their studies. What does that mean, Matt? So it's really fascinating. You can make a bunch of arguments. You can make with the inflammatory marker, what did it hit? With LP little a, this is a genetic risk factor that does seem to increase people's risk of heart attacks.

11:28And if it's low for your whole life, it seems to benefit you. But having those genetic data don't tell you that giving somebody a drug and lowering it is going to make them better. And that's what we saw with these studies. We saw that however they were hitting the targets, they weren't good enough. But it also raises this question because for the past decade, people in drug development have been saying, well, if we have genetic validation for targets, if we know the genetics, we can be pretty sure the drug will work. And it certainly helps. It's really important to know the genetics of why a mechanism works when you're developing a drug, but you can still be wrong.

12:10And that was really the chastening simple message here that just because you have a whole bunch of genetic data showing that people with lower LP little a have lower risk of heart attacks, it doesn't mean giving somebody a drug that lowers LP little a is going to have that same effect. It is really a surprise how little benefit that had in this trial. So we should note that these studies that we're talking about are really big. Thousands of patients enrolled. It takes years to run these studies, hundreds and hundreds of millions of dollars, and yet they came out just totally negative. You spoke to several cardiologists about these studies.

12:52How are they feeling these days? There's generally a lot of just puzzlement of why when you do everything right, things don't work. I do want to say we have had some wins in cardiovascular disease where some of the best drugs that have come out were things nobody thought would work for cardiovascular disease. Over the past decade or so, they're diabetes drugs. They're the GLP-1s. There are other medicines that have shown a surprise cardiovascular benefit. So this is a system, this is supposed to be sort of like plumbing. We're supposed to understand the genetics here pretty well, and we're really struggling.

13:33And one of the biggest problems is that if you want to study cardiovascular disease, you have to count heart attacks and strokes, and they take a long time to happen. And they take even longer to happen with all the great drugs we have, the statins and the blood pressure medicines and the blood thinners. And so these studies take a long time and they're super expensive, and it's much faster to develop drugs for things like cancer, where you can see, do you shrink the tumor at the beginning of the disease? So that's a real problem for a disease that is the thing that we're most likely to die of.

14:05Do you think the setbacks reported at this year's AHA meeting are going to cause biotech and pharma companies to cut back on the development of new heart medicines? Well, I don't think they're going to cause them to reaccelerate them, and they already have cut back. I mean, Adam, you know this. We used to cover a lot of new drugs coming through in cardiovascular, in broad cardiovascular, preventing most people's heart attacks, preventing sudden cardiac death. Now, when we write about cardiovascular drugs, they're often more of a niche medicine. If you're a drug company, it's been very frustrating.

14:43You need a lot of capital to play in this game. And that's not great in the sense that what often gets biotech innovation going is when if you can raise a lot of money to us, you know, $20 million and do something that gets you to the next leg of something that a large pharmaceutical company will want to buy, that's always been a hard place for cardiovascular and it only seems to get harder. And so my worry is really just that we don't get that innovation engine that we get in other parts of biotech. But there's a lot of good interest in genetics, which isn't worthless. It's just more complicated than we thought.

15:22And there's this huge, huge need. And how do you think these results might affect how drug companies think about the role of genetics in figuring out biological targets to hit with new drugs? Look, no one's going to just stop using genetics to find drug targets. It's one of the main ways you find drug targets. It's one of the main ways you validate drug targets. And I'm sure there are people whose genetics told them not to do this and think they're very smart now. The thing I would say is what this reminds us, and I also think this extends to artificial intelligence, is that there's often this idea in the drug business that somebody decides they figured it out.

16:04They figured out how to know where they are and what's going on and not to live their entire life in a fog of pea soup. And my observation, having covered drug development for a long time, is that usually that gets you in trouble. It's going to be more complicated than you think. That's just how everything in the history of biology has always gone. Biology is maddeningly complex. It doesn't make sense. And maybe someday we'll have some set of tools that will involve genetics and AI and all sorts of other things where we won't have one out of every 10 drugs fail. But that success rate hasn't meaningfully changed.

16:46And the question is really whether drug companies and researchers overestimated the power of genetics for validating drug targets. Because it seems like in this case, if we didn't get it wrong, where we've made ourselves think it was going to be way easier than it was. We do have several other drugs in development that target LP little a and also several drugs targeting inflammation. And so those studies are ongoing. Is there any hope that those might be more positive? Absolutely. I would expect everyone to have taken their probability of success on everything down. But there are absolutely reasons to believe that maybe you need to get LP little a all the way down in order to have an effect.

17:34There are also reasons to believe that maybe you need to be in a different population, like people who have high risk but don't have their first heart attack. And with inflammation, it's even more complicated because there's every reason to believe that inflammation plays a role in heart disease. And if you find the right target, you're going to have a huge drug. And remember that the previous drugs to be of the scale of like the GLP-1s financially were the cholesterol medicines. Lipitor is still one of, if not the most prescribed medicines in the country. So there's a huge market here and companies will chase it.

18:13This is just discouraging.

18:20Matt, thank you so much Thank you guys It's always great to hang out with you That does it for another episode of The Read Out Loud Our podcasts are produced by Rachel Gopbaum Our senior producer is Alyssa Ambrose Our executive producer is Rick Burke And our theme music is by Brian Joel We'd love to hear from you Tell us what you like about this week's episode What you didn't like And whether you think the Patriots Will end up being a better team than the Bears 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 wherever you get your podcasts.

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