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[AI-assisted transcript]

Voice Talent: 0:02

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Jeff Cranmer: 0:45

One of the UK biotech scene's best assets, Patrick Vallance, is out as Minister of State for Science, Research, and Innovation as Andy Burnham becomes UK Prime Minister. We'll discuss what the latest body blow for the UK biotech means on the BioCentury This Week podcast. I'm Jeff Cranmer, executive editor here. Joining me today, editor-in-chief Simone Fishburn, executive editor Selina Koch, and Washington editor Steve Usdin. I'm just back from Bio Asia Taiwan in Taipei, and will share my thoughts on biotech at max heat, humidity, and Xiao Long Bao. Plus, Biogen's Phase III bet on its anti-tau therapy gets complicated, and a psychedelic buy from Eli Lilly. We'll also check in on what's happening at FDA. All right, Simone, your phone has been blowing up this morning as the government begins to take shape, in your motherland. What are you learning?

Simone Fishburn: 1:55

Right. So, I assume you are talking about the new prime minister and not the football team, right? Where I-

Jeff Cranmer: 2:04

but,

Simone Fishburn: 2:05

gotta tell you, there's a lot of people, a lot of people on my phone who seem to think England actually won, and that the other game was just some playoff. So there we go.

Jeff Cranmer: 2:14

Uh, most exciting, uh, consolation match in history

Simone Fishburn: 2:18

It was a great match. Anyway, uh, what's not so great… Well, at least for biotech. So there were, you know, a new Burnham government. Obviously, everybody across the UK is like, "What does this mean?" Blah, blah, blah. And the biotech sector cares about two things, and it got a little bit of a win and quite a loss, but we'll see how it plays out. So the little bit of the win is on the announcement of the chancellor, who will be John Healey, right? And At this point, the main thing we know about John Healey is that he's not Ed Miliband. The point being that when I spoke to people, they were really pretty concerned about Ed Miliband. They… You know, these are business leaders. They felt his policies were a little bit left wing for them. But more than that, that he would be so focused on net zero that it would take away, investment and so on in life sciences. So I think that on that front, people will be reassured. And the reality is actually that the chancellor is, whoever it is, in this case Healey, is going to have a much longer and bigger impact on any sector, including the life sciences sector, than any other appointment. That said, Patrick Vallance, minister for science, announced today that he will be stepping down. And so that is quite a blow because he's really been a big champion. You know, not often that a whole sector really likes somebody, especially not a minister, but he really, uh, was very well appreciated. and also did great things in the pandemic, but even since then for the sector itself. So sort of feels like the, the blows keep coming for UK biotech. We'll see how this one plays out

Steve Usdin: 4:00

So, so one of the things I, my understanding is, is that the, the new government is making a, a big effort to try to, kind of spread the, um, economic development around, uh, and, and not concentrate it in London and the South. I wonder h- uh, what impact do you think that'll have? I- uh, will it actually be successful?

Simone Fishburn: 4:19

That's a good question, Steve. Um, I think that it's gonna have quite an impact, and I think it, you know, people point to the Manchester example. It could be very successful. The devil's in the details, though. when I spoke to investors mainly, but also biotech executives, you know, they're like, "If you're gonna force me to start companies to do company creation all over the place, that's not viable 'cause there just isn't the infrastructure for it." But if what you're talking about is spreading, you know, giving universities more money for translational research, allowing some areas to become, say, very good in manufacturing, you know, tapping into the regional differences, that could be very impactful and, and could absolutely, um, be a good thing for the sector. so I, I think that's absolutely what Burnham said he's going to do. A lot of people look at Manchester as a very good example. I think we all know that being mayor even of a really big place like Greater Manchester is not the same as being prime minister.

Steve Usdin: 5:21

so one, one thing that's interesting, quickly that I was talking to the CMO of one of the largest, um, uh, CROs, uh, in the world, uh, last week, and we were talking about various things. We were talking about the U.K., and he said, "Well, the thing is you have to understand about the U.K. is that there's two economies there, and that, uh, the prices, uh, and the costs of, of doing clinical research in the south there are comparable to what they are in the United States. But in the north, it's much less expensive, Manchester, Leeds, and the capabilities," he was saying, "are just as, strong as they are in the south of England, they're just as strong as they are in the United States."

Simone Fishburn: 5:58

100%. 100%. And that, you know, uh, I think it was Kate Bingham actually in a quote was like, "You know, we, we'd love that. You can do clinical trials anywhere." So absolutely, if you can, if you can create… And that's good for those local economies as well, right? So if you can send things to those areas, the issues that Patrick Vallance talked about a lot, as do others, but it was really s- something that, that Vallance, and in fact, Lawrence Tallon as, as CEO of MHRA, the regulator there, have pointed out that very, a really small percentage of eligible patients end up in clinical trials. I have to be honest, I don't know how that compares with other countries, but I know that in the U.K. they feel that is a particularly sore point. So being able to go to those other regions will be, could be very impactful

Steve Usdin: 6:43

Well, and it's, of course it's true in the United States too. Very, very small percentage of patients. And if you look at it particularly in areas where there should be a lot more, for the good of the patients, there should be a lot more clinical trial participation, for example, in cancer. You can argue that anybody who has a cancer that can't be well treated by, uh, an FDA-approved therapy should think seriously about being in a, a clinical trial, and that certainly isn't the case. It doesn't happen anything like that. You know, one o- one other thing is really quick that I want to point out, you mentioned Lawrence Tallon. Uh, you know, it's one of the strengths of MHRA and one of the strengths, I think, of the U.K. that there's no talk of him leaving, right? That, um, he, he's gonna be staying on because it's not like the FDA where there's an expectation that every time you have a change in government, you have a change in, um, leadership of the regulator

Simone Fishburn: 7:30

Right. So two or three things there, Steve. Number one, I've not heard anything like that, and they would be lunatics to do that, okay? Just lunatics. The, the, the Vallance situation is a little bit different for this reason. So I think you pointed out on a previous podcast that the MHRA, sure, it's a government, position, but it's not a political one. And so I- I've not heard anything like that. And, and I think most people really feel strongly that Tallon is doing a good thing, and I don't really think that this is on Andy Burnham's radar. The issue with Patrick Vallance is a little bit different, and I just have to say that there are other people who frankly could fill his shoes. There's Steve Bates at the Office for Life Sciences, who's I think chief executive there. I expect Steve Bates at some point to enter government, in that kind of a role. Actually though, the rumors are that, and these are probably well-founded rumors, is that in fact they're going to fold the, Department for Science, Innovation and Technology, that's DSIT. It was only created in 2023, and that's what Patrick Vallance was the head of. the idea is that they might fold that into the Department for Business and Trade. And there are people who say these things should be closer together. You really should couple science with trade if you want to do what a sector wants you to do. It's, Vallance is great. It's always easier to sort of worry about the loss of something when you don't know what it's gonna look like in its place. So I just have to say, it doesn't have to be a terrible outcome. as with everything, it's really, really the uncertainty that people dislike

Selina Koch: 9:02

So we talked, we talked about these blows that keep coming, but in a positive development, maybe we should mention the second story that you're publishing today, Simone, on the UK, which is about a data resource, a single-- kind of single point of entry for NHS data. Want to just briefly talk about the value in that?

Simone Fishburn: 9:21

Yeah, I think that's an interesting thing. Um, that's called the HDRS. They're not really into very catchy names, I have to say. I mean, UK Biobank was a better name than this. But HDRS stands for the Health Data Research Service. It's annoying 'cause there's a few other HDR things I have to tell you. So anyway, HDRS is a, a, a… And it's sort of like a UK Biobank on steroids almost. It's called a, a single front door they want for the he- UK Health data. And the bottom line is that, you know, they really want people to be able to access NHS data, all patient NA- NHS data. That's 68 million patients, longitudinal records, multimodal records. And at the moment, if you wanna get hold of that data, you have to apply to each region separately because it's very, very fragmented. And so a big initiative was to, create a federated system that would allow you to look across the whole data set. And the reason I bring up the UK Biobank is that, we talk to people, Selina, quite a lot, who tell us they've used UK Biobank in drug development, and that's been quite fruitful, but that's like half a million lives. And here, uh, you know, i- it's… And I think it's sort of from a single point in time. But here this is just much, much bigger. And so there certainly, you know, would be nice to see a continuity of that kind of investment in infrastructure and capabilities. So to point out, that's a slightly rosier story

Jeff Cranmer: 10:52

Sounds good. Well, we'll drop, links in the show notes to Simone's stories. All right. Well, I'm a little jet lagged today, just back from Bio Asia Taiwan in Taipei. reminded me of my Bangkok days, uh, adjusting to the heat and humidity while attempting to wear a suit jacket. Uh, sort of a recipe for disaster, especially when I would walk to my meetings, half a mile, only half a mile, and arrive in a-- in just dripping sweat, and they'd say, "Would you like a coffee or, or water?" And I'm like, "Well, that's kind of clear. I need a glass of water." And they'd serve me a piping hot cup of water. so, uh, it took some adjustment, but I'd like to just say hats off to Wallace Lin and his team at Taiwan Bio. Uh, the event's been in Taipei for-- since twenty nineteen, and, uh, this year attracted more than three thousand attendees, uh, from more than fifty countries. particular focus of Dr. Lin, uh, this year was, uh, regional collaboration in this year's forum, uh, which was sort of a subset of the overall meeting, uh, nearly doubled in size with representatives from across APAC, all the way to the Netherlands.

. Steve Usdin: 12:10

S- so, Jeff, you know, you're just fresh back. what can you say about the Taiwanese innovation ecosystem?

Jeff Cranmer: 12:17

Yeah, it's a good call. I mean, they're very, very good at building companies. TSMC, on the semiconductor side, um, there's a lot of capital from Taiwan's families, uh, going into biotech, also other sectors. There's great government support, for Taiwan's biotech, and, uh, the companies that list on the market there, there's two markets, Taipei and the Taiwan market. Uh, companies can get very strong support from retail investors. Feels a lot like Singapore, Korea. when you're launching, uh, you really need to, look beyond Taiwan's borders from the get-go. Look to the US, as you're building your company. as I said, the biotech isn't as strong as the tech in Taiwan, um, but there are a few companies that I'm watching. Pharmacentia is, uh, the current market darling. It's a 25-year-old biotech formed when its founders were lured back from the US to plant early seeds of the industry here. Uh, Casey Lin is the CEO. He was at Biogen way back when it had, uh, 200 people. the chair, uh, Ching-Lu Tang, also a returnee. and the company is right now waiting on word from FDA on an expanded label for BESREMi. it's Will become, uh, if approved, in the US, the first new therapy in 30 years for essential thrombocythemia. Um, another longstanding company, that's finding its way back to the public markets is lipid-based platform company, uh, TLC Bioscience, which is led by George Ye. Uh, the company delisted, uh, in Taiwan and from Nasdaq, uh, five years ago. They're back on, the Taiwan market, and they're now looking ahead to back-to-back submissions in the US and Japan for, uh, its pain therapies. It's also developing a GLP-1 with reduced dosing frequency for the maintenance se- setting. two other companies I'll quickly mention. Uh, one, uh, Bora, led by Bobby Shang, stole the show in terms of deal-making, uh, when it partnered with Insilico. Uh, the company is rapidly expanding via acquisitions, uh, in the US, uh, where it does niche and rare indications. our colleague Karen Tkach Tuzman will have a story on that coming ahead. And, and another one, uh, the one younger company in the crowd, Hanker Bio, which has, an, FC-based designer biologics platform, and they are, uh, looking to sail through the headwinds that have sunk other, CD47 bets. So, uh, that's another one that we'll be, we'll be watching, uh, there.

Steve Usdin: 15:21

Well, you know, I, I, I think it's really good and really interesting that you're keeping a close eye on Taiwan. I, when I was… I was first there in the late 1970s and early 1980s, and I remember at that time it seemed like a backwater. It seemed like, you know, there were people there who were talking about trying to get into tech. There were people talking about trying to get into, com- in computer technology then and into semiconductors and things, and they were kind of… People thought, you know, this is a backwater. They're never gonna be anything, right? And, uh, and that was a mistake , right? You know, as, as, as you, as you mentioned. You know, they're, they're powerhouses now in, in semiconductors, and I, and I think, it, it'll be really interesting to see if they can kind of follow through with that same playbook, uh, in, in biotech

Jeff Cranmer: 16:02

Yeah. I, I'm certainly impressed that, uh, TLC, PharmAscentia, Bora, these are companies that have been around for more than 20 years. Um, so that staying power, is impressive. Uh, PharmAscentia, uh, the chair told me that, one thing that's really different about Taiwan's markets is that its retail investors, they like their local heroes, and so they'll stick with you even after a setback. Uh, they're very, very loyal, and, uh, that's one key, to success, at least for that company, and, uh, those investors are being rewarded now. all right. Well, we're gonna take a quick break, and then we're gonna get We're gonna take a look at what's happening with Biogen's tau program, with my fellow executive editor, Selina Koch.

Voice Talent: 16:53

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Jeff Cranmer: 18:00

We are back on the BioCentury This Week podcast. Selina, it always gets busy whenever there's a big, uh, Alzheimer conference for you. Uh, in addition to everything else you do around here, you, uh, you like to dig into the data.

Selina Koch: 18:14

Yeah. Thanks, Jeff. well, maybe we should start with, why this particular readout mattered. I mean, obviously, tau's on a new hypothesis. We've seen what feels like failure after failure of tau therapies in phase two. that said, it's become apparent in recent years that, um, y- the pattern-- the level and pattern of tau accumulation in the brain as measured on PET imaging, correlates much more closely with the development and the progression and the types of symptoms people get than amyloid ever did, right? So people have high hopes for tau in general, and this particular, candidate stood out in a couple of ways. So most… So tau is a very complex target. It's one thing that's made it harder than amyloid. Amyloid's basically you know where it is. It's in the extracellular spaces between neurons. That's where you target it. Tau is different. It exists inside cells, it exists outside cells. It is alternatively spliced. It's in various fragments and lots of different kinds of post-translational modifications. So what that's meant is that the therapies that have come before, they've mostly-- they singled out one hypothesis, you know, a particular fragment or modification, et cetera. and they've mostly all been extracellular targeting as well and hope that, you know, they thought had their rationale for why that's the primary disease driver, right? but this therapy, duranersen, goes upstream, and it essentially tries to simplify the hypothesis. So it's an antisense oligo, um, made with Ionis that basically lowers the source material that's essential for creating all of those forms of tau rather than trying to figure out which one is the important pathological species, when in fact many could be important, right? so people were looking forward to the result for that rationale, and because there was an interesting early result where, the therapies that came before either failed to lower the, um, tau PET signal Or what we saw in at least one case was normally the tau aggregation accumulates over time and gets worse, right? And so we saw a slowing of that accumulation. Well, donanemab actually reversed tau PET, so it was lower than at baseline. So that felt like a breakthrough. So here this bigger sort of sledgehammer in a way. And you could say, well, you know, if you just broadly lower tau, can you actually slow cognitive decline or not? unfortunately, as happens often in Alzheimer's disease, the results are kind of murky. Um, you can look at them in a sort of glass half full or glass half empty way as people will, and there will be two camps, of course, as there always is in Alzheimer's. Um, so it missed its endpoint, um, which was trying to establish a dose response on the pre-- um, the, uh, cognitive measure of, um, the standard one, CDR sum of boxes, Clinical Dementia Rating, um, Scale. But yeah, so the, the lowest dose, 60 milligrams every twenty-four weeks performed the best. but then if you look at sort of the absolute changes on that scale and the other cognitive endpoints that they measured in phase two, there was a twenty-six percent slowing on CDR sum of the boxes, slowing of progression, which was h-- and then the other endpoints were actually bigger moves. So forty-two percent slowing on ADAS-Cog thirteen, fifty percent slowing of progression on the Mini-Mental State Exam. So if you just line those up with the approved anti-amyloid antibodies, those results look good, if maybe even a little bit better. and that's kind of the basis on which Biogen's moving forward and, and why the, the study's PIs view this as the long-awaited, proof of principle for tau, right? The complexity come… Yeah, comes from the fact that the biomarkers sort of move the other way. There was a good dose response for the biomarkers, but not so much for the cognitive endpoints

Steve Usdin: 22:16

Ha-haven't we seen this movie before?

Simone Fishburn: 22:19

So I gotta do that as well. So Selina, why is this field so difficult? And why… Okay, why is it so difficult is one question, but what I'm really asking is that just when Steve says this movie, before I was thinking the same thing, it seems to be that in this field in particular, there's this sort of, "Well, I like this bit of data, but I don't like that bit of data, but I can explain

Steve Usdin: 22:41

The, low dose didn't work, but I mean, the low dose worked better than the high dose, and it missed its endpoint. But,

Simone Fishburn: 22:48

but it's still really good and I'm still gonna go forward with it," you know? So we're not asking you to defend them, but, um, can you unravel it a little bit for us?

Selina Koch: 22:57

Well, so like I said, they lined up these results with the approved anti-amyloid therapies and said, "Look, it's at least-- it appears to be that could change in Phase III. But for what we have today, it appears to be at least as good as them and they're on the market." And eventually everybody thinks this is probably a combination play,

Steve Usdin: 23:13

Yeah, that, that's what I was gonna ask too. Is there, is there any reason to think that it'll be a cumulative effect if you have-- if, if you combine them? and would you get, if, if the results are about the same, you know, would you then, if you combine them, get a doubling of efficacy?

Selina Koch: 23:27

It's unclear yet if it'd be quantitative like that. And the amyloid hypothesis, you know, posits that the amyloid reduction is like a little bit before the tau reduction. But there's a, there's-- this is a-- we're talking about very lengthy disease, and there's a lot of overlap in these pathologies in their development. So, yeah, I think probably if they're safe enough to combine, you would in principle expect greater efficacy from combining. And you could think about… say, "Oh, it's always the same in Alzheimer's disease," but they would say, " Yes, but that's also true in cancer." Incremental benefit really matters, and you have to start somewhere, and you have to build on each result, right? So that's the other side of the coin.

Steve Usdin: 24:04

when do we find out what happens next? What, you know, what's the next shoe to

Selina Koch: 24:07

company has decided that it's enough of a single to-- a signal to move to phase three. Investors weren't so happy about that. I think company's market cap fell over two billion that day. But that might be also a function of, you know, um, Wieback coming in and saying he's going to diversify the company away from some of these high-risk bets, and, and he has done quite a lot of that. But here they are making another, you know, embarking on a very expensive, long, large phase three, um, in a high-risk situation. Anyway, for s- the sake of science, it will be interesting to see the result. There's no doubt. Um, it's, a little complex because when you have-- It's a little hard to interpret the disconnect, the fact that the biomarkers showed a dose response and the cognitive endpoints didn't. So how you design your phase three? it may be that, well, that's just a side effect of the small noisiness of phase two and the fact that, you know, Alzheimer's is such a heterogeneous disease, and we d-don't have-- like, we're only at the beginning of narrowing that with biomarkers. but there's another possibility which would have bigger implications for the whole field of tau, right? which is that if you're taking this kind of a broader approach to lowering tau of all, all of its forms, there are other siRNA therapies doing this. There's targeted protein degraders, et cetera. there could be a therapeutic window above which getting rid of more tau isn't better. Tau is an important protein in neurons. It could, in theory, have harms if you get rid of too much of it. so, you know, I guess we'll see, um, how they design the phase three in terms of what doses they include. But certainly from an efficacy perspective, that, that low dose is looking like the most promising bet right now

Jeff Cranmer: 25:53

It sounds good. While staying with Neuro, uh, well, Eli Lilly, uh, not to be denied, uh, yet another company that it wants to acquire. paying 2.8 billion up front, to enter into psychedelics, buying Eteplirsen. Uh, what did you make of the deal, Selina?

Selina Koch: 26:14

so yeah, the Tai Beckley, uh, molecule is, um, a psychedelic that is a form of DMT. So, it would-- it's just behind in the clinic, I guess. Um, another psychedelic, a syl-- a synthetic form of psilocybin from Compass Pathways. so they're kind of positioned against each other in treatment-resistant depression. Ahead of both of them on the market is a psychedelic-adjacent compound, Spravato. It's a, the S enantiomer of ketamine from Johnson & Johnson. Spravato has kind of paved the commercial path for psychedelic-type, therapies, which are delivered with a very different sort of care model than your standard antidepressant, right? what's different b-um, between Spravato and these, these other two, the Compass and the Tai Beckl-Beckley programs, is that Spravato is given fairly frequently, whereas these are-- the hope is that they're given not, you know, once, twice, maybe three times with large gaps in between those doses, and, and then that would be it, right? So that would be the primary differentiator from s-- the way depression is treated today. Tai Beckley has said that it thinks it has a best-in-class therapy. So our colleagues, Stephen Hansen and, and Tierney Baum, looked into the data to, you know, see what they could find about that. Um, if you compare just the Phase IIb results from each, they look broadly similar really, in terms of the, um, point reduction on the primary endpoint. They weren't that different from each other. And given the, you know, the small differences between the trials, the way they're designed, you know, you can't-- the differences between them, you know, you can't make, um, conclusions about them being meaningful. They seem relatively similar. Now, Compass, it-- and when it went on to Phase III, it has read out multiple Phase III studies, and the point reductions on the primary endpoint reduced considerably from what they saw in Phase II. Still looks effective, still gonna probably be a good addition to the treatment, you know, toolbox. but looking more like your standard antidepressant in terms of magnitude of the benefit. We'll see what happens with, with the now Lilly program, you know, when it has-- when it's at that stage

. Jeff Cranmer: 28:26

Okay. It's the, uh, twelfth acquisition so far this year for Lilly. that brings its total outlay on M&A alone to around twenty-three billion in upfront payments. Uh, notably, it's one of Lilly's most clinically advanced acquisitions of the year. Uh, mostly it's been, uh, buying earlier stage assets and companies.. It's Lilly's second major takeout in neurology. as we discussed a couple of months ago, Lilly bought Sentessa for six point three billion upfront, along with a one point five billion dollar CVR. and that brought it into narcolepsy and hypersomnia. all righty. Let's head over to Washington Steve. Uh, you had a couple of stories last week. Uh, where do you wanna begin?

Steve Usdin: 29:21

Well, maybe we can start with, acting FDA Commissioner, Carl Diamantis, vowing to abandon, uh, Marty Makary's policy by podcast approach and returning to conventional methods for communicating about agency guidance. Interestingly, he talked… He did-- He actually didn't make that as an official announcement. Diamantis sent a private letter to a member of Congress, Representative Diana DeGette, affirming FDA's commitment to follow its own rules on communicating policy. He did that in July, on July the 2nd, in response to a letter that she sent to Makary back in March. And then at a hearing on July the 15th, DeGette disclosed the existence of this letter. The letter hasn't been officially released, by anybody yet, though any reporter who's, um, cares about it has, has gotten a copy of it one way or another, including me. Um, and, and so it raises a lot of questions. You've got, on the one hand, I think a lot of people think, well, this is great. FDA's disavowed these informal, uh, means of communicating things through podcasts, through journal articles, through, um, social media, um, statements, uh, which caused a great deal of confusion. On the other hand, they haven't done this in an official way, and they haven't officially walked back all the controversial policies or exactly said, which policies are gonna be, w- you know, what, what companies can, r- rely on One example. So DeGette asked about three specific sets of policies. One of the ones that she asked about was CAR T therapy. So, uh, Vinay Prasad, when he was CBER director, was one of the authors on a, a journal article that said that FDA basically has moved-- had moved the goalposts for CAR T, and that going forward it would require, demonstrations of superiority over existing, treatments, and that it wouldn't allow single arm, trials to support new CAR T therapies, approvals. There's a lot of concern about that for a variety of reasons. One of them being that a lot of the CAR Ts are being used, um, to treat very, very rare, uh, conditions for which it's really not, um, uh, not feasible to conduct your convent-conventional, um, superiority randomized controlled trials for that. So in his response to, to DeGette, Amicis said, you know, that article didn't represent, FDA policy, that FDA policy, has been spelled out in, in guidance documents in the past. but if you're a CAR T, uh, developer, for example now, what are you to do? Because there's this article that was, uh, that was published in a peer review journal that the then CBER director and the then FDA commissioner said,"This is the new policy. This is what FDA is doing, and this is what you're gonna have to-- this is what you're gonna h- the standard going forward." And then you've got news articles, you've got articles in BioCentury, you've got articles in other publications saying, well, de Amicis said that that article's, uh, that journal article's actually not policy you know, the policy hadn't changed from what it was prior to that, but there hasn't been an official statement of this, from FDA. So you can see it still raises a, a, a lot of confusion. There's a lot of It's, it's very muddy. Uh, and there, there are other examples. There are two other examples that DeGette asked DeAmicis about, and the responses were, were similar, saying that, you know, these, the what, um, Makary had said, for example, to, Megyn Kelly about the agency's plausible mechanism framework, didn't reflect policy and that developers should rely on, the draft guidance that FDA has published. But on the other hand, CEOs have told me, I've written stories about it, that, FDA doesn't seem to be complying with that guidance, at least, in the opinion of, some of the CEOs who are trying to develop therapies and, and say that they've been knocked back when they get to FDA. They think that they qualify for the, um, plausible mechanism framework, and FDA said, "No, you, you, you don't." The framework is, according to these CEOs, they say the framework is really just for N of one therapies or N of a very few therapies, and, their, applications didn't meet that standard, even though the framework, that's been published, the draft guidance on it, and statements from FDA officials very explicitly said it's not, limited to N of one or N of a very few

Jeff Cranmer: 33:44

All right, Stephen, another way that FDA has, been signaling that things are getting back to normal, Ad Comps. what's happening there?

Steve Usdin: 33:52

yeah, so, you know, so under, um, former Commissioner Makary, the agency, really, really dialed back on its use of ad comms and at the same time, it made a lot of controversial decisions without a lot of accountability or transparency about them. And many of those decisions were either complete response letters or set regulatory setbacks to, companies that believed that they had aligned with FDA on, development programs, and then FDA's, new leadership came in and said no, that those, understandings were no longer in effect and that, the companies would have to do quite different things if they wanted to get their products approved. So FDA, under acting Commissioner, uh, Diamantis, Diamantis has said that they're going to be holding advisory committees, more advisory committees. FDA staff have told me that that's gonna be the kind of the default pathway going forward to resolve, the regulatory controversies that occurred, Makary and Prasad. And I think that there's a lot of, uh, kind of relief among the companies and the patient groups, that there's going to be a-another look at these things, that there's gonna be accountability, and that hopefully FDA will be getting, independent scientific judgments on, uh, on these controversies. The signals that FDA has sent about this so far are a little bit mixed, right? Because one of the first advisory committees that's gonna come up is going to be looking at whether FDA should allow bulk compounding of unproven peptides and that, that's, you know, we've talked about that on the podcast before. I've written about it. we've written some commentaries about it. It's a really concerning thing to, to a lot of people in the public health community, a lot of people in the, biopharma world. So good news, right? They're gonna have an advisory committee about it. Concerning news, that advisory committee has been packed. They've got, um, new members that have been added to it. Many of the new members who have been added to it have financial stakes in the peptide industry. They're people who, work at, uh, who own, clinics that administer peptides. They're people who have made, their, uh, living, prescribing peptides. They've, commented favorably about these untested peptides on social media. On the other hand, we do have a change from what was happening under Makary because FDA staff have been allowed, maybe even encouraged, to present their views on, on this. And, um, the briefing memos that, or review memos that FDA staff have written and that have been, uh, released publicly reinforce, um, the agency's prior position that these peptides haven't been tested, there isn't enough known, about their efficacy and safety to allow them to be, compounded in bulk. And, um, and in fact, uh, for some of them, they're concerning safety signals. So it's gonna be really interesting to see how that plays out. The other thing that's gonna be really interesting to see how it plays out is an advisory committee meeting that's gonna be coming up about Replimune's RP1

Jeff Cranmer: 36:57

Yeah, see, there's been a lot of noise around this. Uh, what are you expecting?

Steve Usdin: 37:02

So I, I don't know what's going to happen. but one of the things that's interesting is that the, uh, the RP1, BLA is not going to be going to the ODAC, to the Oncologic Drugs Advisory Committee, which is what y- you would have expected. Uh, it's going to the Cell Therapy, Advisory Committee. It is a cell therapy, but, in the past, cell therapies, gene therapies, products, uh, CAR Ts, things like that, that involve cancer have gone to ODAC, not to the Cell Therapy Committee. So that's, that's unusual. I think that what's gonna be really critical is gonna be to see who, who exactly is on that, um, committee. The, the committee rosters are depleted for all the advisory committees because, they, they hadn't been holding very many committee meetings under Makary. membership, uh, lapsed, and there weren't, new permanent members appointed for a lot of those, um, committees. So there are a lot of open positions. I think the key thing that everybody's gonna have to look at, are, are two things for that Replemune advisory committee meeting. One, what kind of expertise is put on as, temporary voting members, to the committee, and then what are the FDA, presentations like?

Selina Koch: 38:14

Steve. cause one thing I've been curious about is, um, talk about as a return to normalcy, um, but some ways we'll never revert to an FDA that's led by Richard Pazdur, Peter Marks, you know, so on and so forth. So if you look ahead though, how much change for the better or just change in general might you expect before there's more like permanent leadership?

Steve Usdin: 38:34

Well, so look, y-y-you can't step into the same river twice, right? FDA's, is not going to return to where it was before, January twenty twenty five. Too many people have left, too many things have happened for that to be the case. I think what's gonna be really critical is to see who the next commissioner is, who the permanent center directors are, who's gonna be made permanent, um, center director at CDER, who's gonna be made permanent center director at CBER, and w-what do they do to try, if anything, to try to restore, FDA's, scientific integrity, its independence from political and ideological, influence, and then what do they do to, to bulk up or to bolster, if anything, the, uh, the whole process, for, for advisory committees. Because it's not like the advisory committee process was perfect before, January twenty twenty five. There were a lot of problems with it. I've written a great deal about, some of those problems and recommendations for how to fix it. But, you know, the, the issues with the, with Reptimmune and, and, also with the peptides point out one of the, I think one of the fundamental flaws about the advisory committee, which is that you can look at it as, as kind of an adversarial process. It's, maybe it's too simplistic, but it's a bit like a trial, right? And you've got FDA presenting one point of view, you've got the sponsor presenting another point of view, and you've got the advisory committee looking at it basically as if they're a jury, right? But in this case, the prosecution, FDA, gets to pick the jury. And I've spoken with, um, senior officials at, at FDA, um, some of them still there, some of them who have left, and they openly acknowledge that they pick people for advisory committees who, would give them the results that they thought that they, that, that were the right results. You know, they had their, their finger on the scale when they were picking people for the committees. And then there's a great deal of concern, and there has been concern expressed again by, um, former senior FDA officials, Janet Woodcock and others, that, um, the rules around conflict of interest have made it impossible, in many cases, to appoint members of advisory committees who have the requisite or the necessary, uh, expertise. And that's particularly, acute when it comes to, rare diseases because there are, rare diseases and very rare diseases where the only people who would be, who are really experts, who would really be qualified to serve on advisory committees are precluded under the current, uh, rules unless there's a waiver, which FDA's, um, reluctant to give because they've all conducted clinical trials that were sponsored by companies that are developing drugs for those conditions

Jeff Cranmer: 41:17

All right. Thanks for that, Steve. Uh, we'll drop links in the show notes, to your stories along with Selina's Biogen story. thank you for tuning in. if you're hungry for more BioCentury's podcasts, tune in later this week. we'll have, VC Jessica Owens in conversation with our very own Lindsay Martin on The BioCentury Show. we'll be back next Monday with the next edition of The BioCentury This Week podcast

Voice Talent: 41:50

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