Ep. 350 - Oral SERD Spotlight. Plus: Setbacks at FDA

As targeted protein degradation gains momentum, oral selective estrogen receptor degraders are emerging as one of its most advanced proving grounds. On the latest BioCentury This Week podcast, BioCentury’s Lauren Martz assesses how the oral SERD landscape is evolving.
Washington Editor Steve Usdin then discusses setbacks at FDA for an orphan therapy from Disc Medicine and a vaccine from Moderna, and why he is calling on life sciences industry leaders to publicly demand the dismissal of Vinay Prasad, FDA’s CSO, CMO, and director of CBER.

View full story: https://www.biocentury.com/article/658455

#TargetedProteinDegradation #OralSERDs #OncologyDrugDevelopment #FDASetbacks #CBER

00:00 - Introduction
03:12 - Oral SERD Spotlight
11:40 - Setbacks at FDA
15:12 - Disc Medicine CRL

To submit a question to BioCentury’s editors, email the BioCentury This Week team at podcasts@biocentury.com.

Transcript

0:00

[AI-generated transcript.]

Jeff Cranmer: 0:01

The oral SERD field is expanding as targeted protein degradation gains momentum. Oral selective estrogen receptor degraders are emerging as one of its most advanced proving grounds. We'll discuss the landscape for oral SERDs on this week's BioCentury This Week podcast. And we'll check in on the US regulatory environment in the wake of a refusal to file for a Moderna vaccine by FDA and a setback at FDA for an accelerated approval for an orphan drug from Disc Medicine. I'm Jeff Cranmer, host of the BioCentury's This week podcast and Executive Editor here at BioCentury, today I'm joined by podcast regulars, Steve Usdin, who is our longtime Washington Editor, and Lauren Martz, who heads up all of our product development coverage. But first, we're excited here at BioCentury's to introduce a new exclusive opportunity for our subscribers. It's launching at the BioCentury BayHelix East-West Summit in Seoul. In a matter of a few weeks, you'll be able to step inside the BioCentury Lounge, a dedicated space designed to connect, recharge, and inspire conversation among industry leaders. You can experience unique networking moments, insider insights, and a place to unwind between sessions, don't wait, check out more at BioCenturylounge.com. And if you haven't registered yet, join us in Seoul. It's gonna be, uh, a great chance to check out the Korean biotech ecosystem, and we will have investors from around the globe. We'll have biotechs from China. We'll have investors from Singapore. We'll have a lot of investors from Japan on a panel that I'll be moderating on the Japanese biotech ecosystem. So,

Steve Usdin: 2:18

Jeff, I just have to say that lounge sounds so cool. Are you gonna have lounge music? Are people gonna be re wearing lounge wear, you know.

Jeff Cranmer: 2:25

I, I really hope I'm gonna wear a lounge where I think that sounds really, really awesome, Steve. And I'm also hoping that they're gonna have some, like, you know massage chairs and, and maybe some, uh, some delicious Korean, food, like some mandu or, or perhaps a little, uh, kimchi treats of some sort. I don't know, Steve, uh, why don't you join us this time around?

Steve Usdin: 2:47

I would, I would love to, I, I would go all the way to Korea for a lounge.

Jeff Cranmer: 2:51

it's gonna be good. And, uh, late night, I'm told we'll be doing, uh, some noraebang, which is the Korean answer to, Japan's karaoke craze, and, uh, I'm sure it will be a soju fueled experience. I'm gonna be practicing all my Ringo Star songs. That's, that's kind of my, my wheelhouse there. Alright, let's get to it, next generation estrogen receptor degraders SERDs, aim to differentiate on depth of pathway suppression modality in which treatment settings they can own. Lindsay Martin did a deep dive, one of our new analysis decks that are really cool. And Lauren, you edited the piece. You've been following the space for ages now. What's, what's new?

Lauren Martz: 3:41

Thanks, Jeff. Yeah, Lindsay did a great job on this very comprehensive deck of what's happening in the oral SERD space. One of the things that triggered this at this time is that it's a very catalyst rich year for oral SERDs. The one that everyone is talking about is the June PDUFA date for Arvinas' vepdegestrant, which is not only a milestone in this SERD you know, estrogen receptor degrader space, but also for PROTACs and, and those sort of rationally designed targeted protein degraders in general. This could be the first approval for this entire, subset of, of modality. In addition to that, there are, I think she has at least five clinical readouts this year with some, um, some really interesting and important ones. So, Roche's giredestrant is up for, potential approval this year. I think they're looking at a fourth quarter timeline that we don't know too much about the regulatory submission. And a few other, uh, clinical milestones. So as you mentioned, we've been following the space for a long time, I think it's getting so much attention because this is such a big and chronic breast cancer indication. So you're talking about patients who have, estrogen receptor positive, in most cases, these are most effective for estrogen receptor mutant. So, you know, uh, mutations that emerge when you've treated this with, with other endocrine therapies. And her two negative, so you're talking about like 70% of all breast cancers, and this is part of a backbone type therapy that could be used for a long time. So it's a huge potential market and the existing options there's room to improve. Fulvestrant been on the market for a long time. It's an intramuscular injection that can be painful, that doesn't address brain metastases because it doesn't cross the blood brain barrier. So there's been a lot of work to, to improve this modality.

Jeff Cranmer: 5:37

Lauren, how does this compare with other ways to target the estrogen receptor?

Lauren Martz: 5:42

Yeah. So compared with Fulvestrant, uh, as I mentioned, crosses the blood brain barrier, and then when you look at the different, strategies. Of targeting estrogen receptor, even within this group that we've talked about, the benefit of a degrader versus something that targets estrogen downstream is that, or, or that just targets the receptor through a different mechanism, is that you're actually blocking, potentially all signaling through this receptor to, you're knocking out the receptor in most cases, not completely. But then a lot of these oral SERDs have sort of a secondary antagonistic activity on the receptor that it remains as well. So the idea is that you're getting a more complete blockade of this pathway. I I think that the main difference between these oral SERDs and the PROTACs, like Arvinas' product that we talked about, are how the degradation happens. So a PROTAC is designed, it's, it's sort of a modular design where you're directly labeling the receptor for degradation by linking it to, an E3 ligase, for example, with the oral SERDs, it's more of an indirect mechanism that destabilizes the receptor. So the result is, um, I think as you mentioned at the beginnings, it may be a different level of knockdown that you're getting, but again, that secondary antagonism maybe makes up for the difference there. In clinical data. We haven't seen a big difference across these slightly different variations of how you degrade the receptor. I don't think there's, necessarily a huge benefit to what you would get from Arvinas' product, for example, in the second line setting where that's up for approval,

Jeff Cranmer: 7:17

And, and of course Arvinas is partnered with Pfizer on that program. Uh, what other strategies are out there? How, how are people kind of rising above the noise? Lauren, given that it's such a crowded space.

Lauren Martz: 7:31

Yeah, so it's a crowded space, but again, it's a really big potential space. But the first approvals that we've seen in this sort of next generation oral SERD landscape are from Lilly and Menarini. In both cases, those are second line approvals, in patients who have mutations in the estrogen receptor. So most of the clinical activity that is happening right now in the pipeline is for this second line indication. In addition to, you know, how fully these different therapies are degrading the receptor or blocking the receptor's function. There's also some differentiation in sort of the where in the treatment, the course of treatment, different companies are taking their programs. As I mentioned most is in the second line, there are a few programs that are looking at first line and even adjuvant settings. And I think that's where you see the, the biggest impact of, of these next generation therapies, uh, sort of appearing at this time. We mentioned Roche's giredestrant program which had positive data in the adjuvant end, um, and first-line setting as well. So that's sort of the, uh, out in front in the earlier lines. AstraZeneca's camizestrant also is expecting data second half this year as a first line therapy. Olema has a a first line therapy program as well. I think sort of trying to find the best place and the least crowded place to use some of these mechanisms will also emerge as differentiation strategy, for the growing number of companies that are working within this space.

Jeff Cranmer: 9:05

Alright. And they're looking to, for starters looking to best the two oral SERDs that are on the market now. Right. We've, uh, and these were years in the making. There's, a product from Menarini Group, got approval in 2023, that's Orserdu. And then Lilly, uh, followed up a couple years later, with its product, approved in 2025. Um, how do you say that one, Lauren? Inluriyo? I think it's, I'm

Lauren Martz: 9:36

Inluriyo, I think how you say it.

Jeff Cranmer: 9:37

Gonna, I'm gonna go, go there. I'm, I'm trying to get better with the pronunciations of these, uh, complicated drug names, but, um, important products, important products. Uh, and so we've got 11 assets in the pipeline. Uh, what, are there anything in particular you're watching out for Lauren as you handicap this space.

Lauren Martz: 9:56

So I'm watching for, uh, as, uh, data continue to emerge, I'm watching for efficacy against brain metastases, which again, is something that I think there's a potential to differentiate there. And it's a really important, um, application for breast cancer. So I know that we'll see some data. I think it's in the fourth quarter for Orserdu from Menarini, as you mentioned. and finding out those little places where we may see benefits from, uh, different programs and how this all lays out, will be interesting.

Jeff Cranmer: 10:26

Mm-hmm. Sounds good. And, um, yep. 2026. Uh, as I believe Lauren said we could get that first PROTAC, to gain approval in any disease. and that's the, uh, Arvinas, Pfizer product. well Lauren, uh, thanks much for the update. We will take a quick break and we'll go to Washington to get an update from Steve.

Alanna Farro: 10:52

BioCentury This Week is brought to you by The 5th East-West Biopharma Summit in South Korea. An arc of innovation is emerging across Asia, and Western biopharma leaders are taking note-from cross-border deals to newcos. In March, 2026, The 5th BioCentury-BayHelix East-West BioPharma Summit visits South Korea for the first time. Meet the biopharma leaders putting Korea innovation on the global map. Learn why Korea has become a clinical trial in manufacturing hub. Discover if Korea is the next hotspot for NewCo formation. Plus, meet biopharma innovators from India to Singapore, to China and Japan. Register now at BioCenturyEastWest.com.

Jeff Cranmer: 11:40

All right. We're back. I'm actually on the road today, Steve. and, uh, as we record this, like my screen is lighting up with flash flood warnings and I believe we got snow in the mountains around LA which, which is always a little trippy for me. Just, uh. You know, all those songs about it never raining in Southern California. But, uh, maybe this, uh, helps set the stage for, uh, what you wanna talk about. Steve. We had the, the Moderna, refusal to file, obviously that is pretty big news it comes against this, this backdrop of, HHS Secretary, RFK Junior's, assault on vaccines. I don't know what to call it really, but, um, he, he is dramatically shaking things up and then we had this Disc setback, Steve, uh, what's happening at FDA?

Steve Usdin: 12:32

Yeah, so last week you, as you mentioned, you know, FDA, refused to accept Moderna's application for a flu vaccine. It was an extraordinary decision. It was taken by CBER Director Vinay Prasad. We can get into the details, but basically he came up with an excuse for not accepting the application and for overriding the recommendations of CBER staff. It's clear that FDA Commissioner Marty Makary, and especially HHS Secretary Kennedy, are determined to sharply reduce access to vaccines, eliminate mRNA based vaccines if they can, and stop forward progress in developing new vaccines. you know, there, there are could be question reasons to question whether Moderna used the best comparator in its trial. But that's the kind of thing that's typically adjudicated in a review, and preferably with input from an advisory committee. It's difficult to give FDA the benefit of the doubt here, given HHS Secretary Kennedy's false assertions that mRNA vaccines are inherently dangerous. And, and his remark last week that he isn't afraid of germs because he snorted cocaine off of a toilet seat.

Jeff Cranmer: 13:40

Who among us, Steve, who

Steve Usdin: 13:42

what?

Jeff Cranmer: 13:43

I said who among us hasn't, anyway, um, yes, and, uh, that jives with his comments about if all the skeletons in his, closet could, uh, could vote, he'd be, uh, king of the universe. But, uh, yes, it's, uh, I.

Steve Usdin: 13:57

So, so, but the thing this, it's one thing to have skeletons in your closet and it's another thing to boast of them. And to make statements as the Health Secretary, that suggests that, germs aren't something to be afraid of. And that cocaine snorting is something be proud of. Look, the, the action against Moderna makes the US vulnerable, not just a seasonal influenza, which this vaccine is intended to protect against. But also to pandemic influenza because when, and it's when not. If there's an influenza pandemic, the world will need mRNA vaccines to avoid catastrophic loss of life. This is especially true if there's an avian influenza pandemic because traditional egg-based manufacturing won't be able to meet demand. Chickens may be cold, reducing egg supplies. It may not be possible to produce AAV influenza virus at scale in chicken eggs, and it certainly won't be able to do it as fast as you can do, do it in mRNA, uh, based vaccines. So creating this tremendous disincentive for forward motion in mRNA vaccine development, particularly for influenza, is really inviting a public health, disaster.

Jeff Cranmer: 15:10

It is. It is. It's, uh hmm.

Steve Usdin: 15:12

so you mentioned also, Disc Medicine. Right. So last week, FDA issued a complete response letter to Disc Medicine for a therapy to treat a very rare disease that has no effective treatment. It looked like the company was on track for approval before it got the CRL and even received a Commissioner National Priority Voucher from Commissioner Makary. The CRL was based on skepticism about the clinical relevance of a biomarker, and this is one of a string of setbacks based on FDA's refusal to accept a biomarker for accelerated approval most of them in rare diseases. Vinay Prasad, was heavily involved in this decision, even though it was a CDER decision, not a CBER decision. Remember, he is also the Chief Science Officer and the Chief Medical Officer for FDA. So FDA staff told me that, um, Prasad was involved with this decision also, it may come out okay in the end for Disc. Disc will have clinical data later this year. So its drug may be approved on that clinical data, but the CRL is increasing concerns that FDA is upending the paradigm for orphan drug development, which is really based around, getting accelerated approval, on the basis of biomarkers.

Jeff Cranmer: 16:32

And it sort of seems to kind of go at odds with, some of the things we're hearing out of FDA leadership that they wanna speed development of drugs that, you know, help orphan diseases. Isn't that the case, Steve?

Steve Usdin: 16:46

Well, they certainly are saying that, um, Vinay Prasad has said it. Marty Makary has said it. They've talked about it in the context of N-of-1 therapies, but they've said it more broadly as well. Look, there's just a discordance between their words and their actions, when it comes to accelerated approval for, drugs to treat orphan diseases. And, and, you know, and that's a good segue to, a commentary that I wrote, last week, which, seems to have resonated with people. I, I've gotten a lot of, comments back about it. And in the commentary, I, I say basically that it, it is past time. For the leadership of the life sciences industry, particularly for the CEOs of the largest multinational pharmaceutical companies to demand that Vinay Prasad exit FDA expeditiously.

Jeff Cranmer: 17:36

Hmm. well, Steve, we've worked together 20 years. You've been following FDA for at least 30 years now, and I, I don't recall you ever, uh, making such a dramatic call. Uh, what are your reasons?

Steve Usdin: 17:50

What, what we just talked about, what's happened, um, with Moderna and more broadly, with vaccine policy is one thing. Another is, Prasad's, management style. He is, um, had one, at least one that I know of, sexual harassment complaint filed against him from an FDA staffer and another who's filed another, complaint against him for, you know, for abusive language, in the way that he deals with the staff there. You know, he put out this memo that we reported on, a few months ago where he said that, uh, basically anybody that FDA doesn't, who doesn't agree with him, should just resign, and there were no consequences to him for that. There are people who think, oh, well this is just about vaccines. First of all, of course, there's nothing just about vaccines. They're, they're, the most important public health protection that, uh, that we have. But it's not going to limit, it's not gonna be limited to vaccines. It's not gonna be limited to, um, Disc Medicine. You can look at what happened to uniQure. It's a, a small biotech company that is developing a, a gene therapy for Huntington's disease. Another terrible, terrible disease that has no, um, effective therapies. FDA, Prasad, moved the goalpost for approval of that gene therapy, uh, which was, uh, you know, a gut punch to patients with that disease and to their families. And, you know, I, I, I could go on and on, but the, yeah.

Jeff Cranmer: 19:12

So I importantly, you also said that he is, uh, overriding staff scientists as well. Like, is it common for someone of his level to get down into the weeds of decision making by, uh, his staff?

Steve Usdin: 19:27

Well, it's not common, okay, but it's not unprecedented. You know, um, CBER directors, CDER directors, Peter Marks when he was at CBER, Janet Woodcock, when she was running CDER, occasionally in very rare instances. Did do that. It was highly controversial, they did it. And they laid out their, their reasoning for it publicly. They discussed it publicly. Now it's become, almost routine. You know what people at FDA tell me is that Prasad is involving himself in basically all of CBERs approval decisions, and he is involving himself in CDER decision making. He's conducting his own analyses, and in many cases, the analyses that he's conducting are at odds with the analyses that experienced FDA staff, have made. So it's not unprecedented, but the scope of it, um, it is unprecedented and it's having detrimental effects on, uh, morale at FDA and it's making FDA regulatory decisions far more unpredictable.

Jeff Cranmer: 20:29

Now, when RFK Junior was, uh, up for approval, it, it, it seemed as though, uh, CEOs of biopharmas kind of look the other way. They've now gone on to, or, or at least held their nose. I, I don't know what the right term is, but you know, and now they've gone on to strike MFN deals with the Trump administration. Where do things stand for those companies Are they likely to, you know, you wrote that these CEOs are, are privately furious and yet, crickets, I, I haven't heard anyone speak out.

Steve Usdin: 21:06

Well, there, there has been some, um, there have been some comments about, uh, vaccine policy. Albert Borla, the CEO of Pfizer has said that, he's, uh, disagreed strongly with the decisions that FDA, um, has made about vaccines. The trade associations have also, spoken out about vaccines, but they haven't spoken out, you know, nearly as, as strongly as I believe that, um, that they should have. I think that they're, they're sitting back and hoping that things kind of sort themselves out, without them.

Jeff Cranmer: 21:38

Hmm. And, and you got into some of this in, your conversation with Peter Kolchinsky of RA Capital on our sister podcast, which we're actually releasing early, earlier than we normally would given how quickly things are moving. Uh, do you wanna touch on some of Peter's comments?

Steve Usdin: 21:55

So, yeah, so that was a really interesting interview, I think anybody that listens to, it's gonna be kind of on the edge of their seat. He's far more passionate and interesting than I am on the, on these topics. Um, he talked about a lot of things. He talked about why he's advising, companies in RA's portfolio to conduct early stage trials outside of the United States if they can. He talked about, his concerns about, the effect of public policy in the United States on innovation, the most favored nation discussions are bargains that have been made between companies and the administration, the, um, IRA's, pill penalty and other things. And then he also talked in very personal terms about why he is such a strong advocate on some issues that some people in the industry think are not, central, not core to what, um, a life sciences leader should be talking about, particularly talked about immigration. He said he's an immigrant, and the whole industry is fueled by the brains and, uh, motivation of, of immigrants. And that's one of the things that's led him to speak out very strongly to oppose anti-immigration policies and actions, of, of the current administration.

Jeff Cranmer: 23:10

Alright. well, you'll be able to check out Steve's conversation with Peter on our YouTube channel, or of course wherever you get your podcast, Steve will be, you know, writing a story about it as well, And Steve's story on Disc and his commentary. Uh, also available at, BioCentury.com BioCenturypodcast.com. Steve, final, final word, what, what are you expecting in the near term? Hm.

Steve Usdin: 23:38

More, more, chaos, uh, more change. You know, there's been some movement of some senior staffers, from FDA, who are also have been given, um, joint appointments, at HHS last week. I think that that's intended to try to, to quell some of the turbulence, at FDA. I'm not sure how well that's going to work, and I think that we're gonna see, a shift in FDA and the administrations. Messaging about some of these issues in the runup to the midterm elections. I wrote a story last week about, a memo that one of the leaders of the Maha movement sent to congressional Republicans telling them that, that it doesn't really pull well to come out overtly against vaccines as a whole. And then basically suggesting what I consider to be somewhat insidious strategy. Instead saying that they should promote, medical freedom, which is a way to try to erode the childhood vaccine schedule and also to try to remove liability protections from vaccine manufacturers, which would make it difficult, if not impossible, for companies to continue to market certain vaccines in the United States. So I think you're gonna see that, and you're also gonna see a shift in a lot more energy put into messaging around food issues, because those seem to pull even, you know, much higher than, um, the vaccine issues with the Maha supporters.

Jeff Cranmer: 25:10

Yeah, and this is as measles, uh, outbreaks are, are mounting in the U.S. So, um, you've gotta believe that the pendulum will, will, will swing back at some point. But, um, Steve is something that you had said last week was, you know, that aside, it's, it's also about the vaccines, the programs that aren't going to get done in this environment.

Steve Usdin: 25:34

Yeah, that's right. That's why I think that it's really important to push for science-based independent regulatory system in United States to basically to regain that credibility and um, and the ability to incentivize the development of medicines that are gonna benefit patients in the United States and around the world.

Jeff Cranmer: 25:55

All right, we'll leave it there. if you like what you're hearing, uh, subscribe to, uh, our podcast. leave us a comment. We'd love to hear from you. Kendall Square Orchestra provides the music for BioCentury This Week and the BioCentury Show. Thanks for tuning in. We will catch you next week.