Ep. 365 - Thin ice for Makary, redosing AAVs

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<v Jeff Cranmer>Marty Makary's hold on the top job at FDA is slipping.

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<v Jeff Cranmer>We'll take a look at where the FDA Commissioner stands and potential successors.

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<v Jeff Cranmer>Plus, solving AAVs redosing problem could change the economics of rare disease gene therapy, and fire back up industry interest in a modality that has fallen out of favor.

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<v Jeff Cranmer>We'll discuss presentations at this year's American Society of Gene & Cell Therapy that seek to tackle this issue.

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<v Jeff Cranmer>I'm Jeff Cranmer, host of the BioCentury This Week podcast, and joining me to discuss all of this are Editor in Chief, Simone Fishburn and Steve Usdin, our man in Washington, both just back from our European conference, and Lauren Martz, Executive Director of Biopharma Intelligence, and my fellow Executive Editor, Selina Koch.

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<v Jeff Cranmer>Simone, Steve, Prague, is it as cool as they say it is?

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<v Steve Usdin>No, it's cooler.

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<v Jeff Cranmer>Oh.

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<v Steve Usdin>Prague is, Prague is an awesome city in part because it's it's a place that's risen from... I wouldn't say from the ashes, but, you know, if you compare it to Pre-Velvet Revolution to now, you know, there's very few places in the world that have gone from being so grim to being so joyful in, in such a short period of time.

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<v Steve Usdin>So yeah, it's, it's,

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<v Simone Fishburn>So I, I could talk all day about Prague.

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<v Simone Fishburn>I'm now deeply steeped in all these Prague writers from the little Prague bookshops.

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<v Simone Fishburn>And yeah, there is so much history, even you know, even 100 years of history there that, that it really wears, wears it on every corner and everybody.

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<v Simone Fishburn>So it's a great city.

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<v Simone Fishburn>It's a really pretty city.

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<v Simone Fishburn>I will say, I don't know if I'm allowed to say this, but the conference center is not in the prettiest part of town.

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<v Simone Fishburn>So if that's your only experience, go further into the old town,

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<v Steve Usdin>Which, which is probably good because you wouldn't wanna have the old town, you wouldn't wanna have all-- ha- have that there.

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<v Steve Usdin>But no, but it, but it's an awesome city and, and the Bio€quity Europe Conference was awesome.

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<v Steve Usdin>Every single conversation, every single panel was a variation on China, AI, what the hell's going on at FDA?

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<v Simone Fishburn>yeah, my um my, one of my favorite things, this was just before the podcast.

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<v Simone Fishburn>If you listen to our Bio€quity podcast, you will hear this.

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<v Simone Fishburn>somebody said to me, "You know, if I, if I had a dollar for every time somebody said China, I could finance my new funding round, my next funding round." There was a lot of China talk.

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<v Jeff Cranmer>Excellent as,

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<v Simone Fishburn>also a lot of energy.

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<v Simone Fishburn>People, this is not a sleepy conference.

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<v Simone Fishburn>This is a conference that people have like really, really hard to be at,

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<v Steve Usdin>And, you know, and the interesting thing was, and I think this is different from Europe, than the United States, is the talk about China wasn't like it is in the United States that, oh, they're eating our lunch, everything's gloom and doom, or what are we gonna do about it?

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<v Steve Usdin>It was really h-how are we gonna integrate China into global development and how is that gonna-- you know, how could that actually be a force multiplier for European companies that are engaging with China?

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<v Steve Usdin>That, that was really interesting.

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<v Steve Usdin>Yeah.

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<v Jeff Cranmer>that's excellent to hear as we are working on our program for the China Healthcare Summit, which will be in early November in Shanghai, 13th edition of the conference.

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<v Jeff Cranmer>Putting it on once again with BayHelix and McKinsey.

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<v Jeff Cranmer>hopefully uh that whets your whistle to come join us in China.

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<v Jeff Cranmer>And the, the talk with Pazdur went well, Steve?

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<v Jeff Cranmer>I know uh that was a big highlight of the conference.

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<v Steve Usdin>Oh yeah.

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<v Steve Usdin>Yeah, we did the, uh-- we did the fireside chat or the pub chat or whatever you wanna call it with, with Dr. Pazdur and  you know, he was as provocative and interesting a-as ever.

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<v Jeff Cranmer>Excellent.

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<v Jeff Cranmer>Well, as Simone said, we'll have a Bio€quity Europe podcast recorded on stage in Prague with my fellow host, Stephen Hansen.

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<v Jeff Cranmer>That will be out later this week.

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<v Jeff Cranmer>We'll also have on our sister podcast Steve's conversation with... Karen Knudsen of the Parker Institute.

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<v Jeff Cranmer>All right, Steve, Friday afternoons in the Trump administration uh always interesting.

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<v Jeff Cranmer>So we got word   Wall Street Journal breaking the story that Marty Makary is on thin ice.

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<v Jeff Cranmer>Bring us up to speed, Steve

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<v Steve Usdin>So yeah, so uh you know, people listen to this podcast frequently read BioCentury won't be terribly surprised to know that Makary is on thin ice.

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<v Steve Usdin>But I think it's important to say, you know, what is it that we know and what don't we know?

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<v Steve Usdin>So I've spoken with people who are in touch with HHS Secretary Robert F Kennedy Jr., with Chris Klomp, who's essentially running HHS on a day-to-day basis, and other senior HHS officials.

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<v Steve Usdin>They've been looking for ways to push Makary out for months, so that, that's not really new.

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<v Steve Usdin>Makary wasn't Kennedy's choice for the job.

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<v Steve Usdin>Kennedy was never a fan of Vinay Prasad's.

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<v Steve Usdin>And there's a lot of reasons for the HHS displeasure with Makary.

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<v Steve Usdin>It centers on the chaos and leadership churn at FDA.

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<v Steve Usdin>Makary's frequent appearances in the media, including social media, aren't doing him any favors with HHS.

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<v Steve Usdin>What every HHS secretary and every president wants is a set it and forget it FDA commissioner.

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<v Steve Usdin>They don't want the commissioner in the news a lot because it's often bad news and it's almost always a controversy that doesn't win any votes.

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<v Steve Usdin>I don't think there's very many voters that wake up, read about the real-time review program or the plausible mechanism pathway and say, "Well, I want to go out and vote for Republicans in the midterms because of that," you know?

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<v Steve Usdin>So the administration... It may be the administration thinks that they're gonna gain some support by talking about food coloring and food additives, things like that, but Those are things the HHS secretary can do without the FDA commissioner opining on them.

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<v Steve Usdin>The reporting in The New York Times and The Wall Street Journal, and The Wall Street Journal did kind of break this story o- on Friday as I said, it revealed what BioCentury readers and listeners have known for a long time.

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<v Steve Usdin>There's this, this kind of angst about FDA and about Makary.

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<v Steve Usdin>From the perspective of the life sciences, FDA's rejected and dealt setbacks to a a string of therapies, mostly but not entirely for rare diseases.

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<v Steve Usdin>A lot of its decision-making seems to be arbitrary.

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<v Steve Usdin>The policies that have been announced, the commissioner's National Priority Voucher Program, the real-time reviews Were not carefully considered and they're likely to have unintended negative consequences.

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<v Steve Usdin>Some aspects of them may not even be legal.

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<v Steve Usdin>FDA has lost about twenty percent of its staff over the last year.

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<v Steve Usdin>Makary said he has plans to hire three thousand reviewers, but there's no evidence that he's even reversed the continuing attrition.

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<v Steve Usdin>So that's all on one side of the equation.

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<v Steve Usdin>and then on the other side of the equation, there's the reality that this isn't really up to this being Makary's future, isn't up to Kennedy or Klump or the people at HHS who are trying to get him pushed out.

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<v Steve Usdin>It's up to Donald Trump.

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<v Steve Usdin>If you read the, the Wall Street Journal story carefully, it says that Trump had okayed a plan to oust Makary.

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<v Steve Usdin>No one, and I think probably even including Trump, knows exactly what that means.

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<v Steve Usdin>I think what it means is that as I wrote in Friday, it means that Makary's gonna go.

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<v Steve Usdin>That isn't really much of a doubt, but nobody has any idea of when it is gonna happen.

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<v Steve Usdin>I actually think that all of this publicity that's happened over the last few days will delay-- it may delay his departure.

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<v Steve Usdin>I'm not sure.

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<v Steve Usdin>But I think it may delay his departure because I think that the, the plan was to give him a kind of a soft exit.

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<v Steve Usdin>It wasn't for him to leave with a cloud over his head.

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<v Steve Usdin>and this all, all this publicity makes that more difficult to achieve.

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<v Simone Fishburn>Steve.

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<v Simone Fishburn>When I think about this, I, I take your point that it might actually delay it because just that's the quirk of this administration or every administration.

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<v Simone Fishburn>They like to set the tone rather than be seen to be reactive.

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<v Simone Fishburn>But all that aside, when I think about Makary, when I read the things you've written and other people, in a way, there's a curious upside to this, in that what I think seems to have brought him down is that he's only ever acted politically.

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<v Simone Fishburn>And he's been, you know, subject to being pulled in this direction politically, in that direction politically.

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<v Simone Fishburn>He's gone with the wind.

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<v Simone Fishburn>He's gone with his gut.

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<v Simone Fishburn>But all the way along, this just seems to have been clouded by political considerations rather than the science.

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<v Simone Fishburn>And, you know, when I say there's an upside, I mean, it's actually good that that's not working out, is what I'm trying to say.

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<v Simone Fishburn>I think that you talked about a previous commissioner who very early on was faced with a political kind of interference and said, "I have to clamp down on this now, otherwise it's going to plague my entire tenure."

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<v Steve Usdin>Yeah.

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<v Steve Usdin>So, so, so what I've heard from...

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<v Steve Usdin>Yeah, so, so what I've heard from other commissioners, and I don't know Makary, but I've known every other commissioner going back to Mark McClellan, and they all say a variation of the same thing, which is that if you let the White House, if you let politicals in the administration think that they can push you around on one thing, there's never gonna be an end to it.

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<v Steve Usdin>They're gonna push you around on everything.

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<v Simone Fishburn>And that's the story of this.

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<v Steve Usdin>the sort of this, and it's not, and it's not so much the of FDA commissioner preserving their power or their perquisites or something like that.

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<v Steve Usdin>It's really about um the effect on public health of having political appointees who aren't public health experts making decisions and influencing decisions in ways that may be well-meaning, may be intended to satisfy political constituencies, but aren't likely to result in decision-making that's the best for the American people.

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<v Simone Fishburn>All right, very quickly, you're gonna tell everybody who's next uh in line, who's, who the candidates are?

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<v Steve Usdin>I have no idea.

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<v Steve Usdin>I don't think... I, I, I've heard various rumors, but you know, they, they, they're only rumors about who might be the next commissioner.

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<v Steve Usdin>But what is fairly certain is who's going to be the acting commissioner.

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<v Steve Usdin>So there's, there's likely to be an acting commissioner It could be for some time depending on what happens with the composition of the Senate after Makary leaves, whenever he goes.

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<v Steve Usdin>And again, we don't know when he's gonna go.

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<v Steve Usdin>But after he goes, there's gonna be an acting commissioner.

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<v Steve Usdin>There's actually pretty tight legal criteria for who can be the acting commissioner, and there's also a strong incentive for the Trump administration to adhere to those criteria because if they don't, if they  name somebody to be acting commissioner who doesn't comply with the parameters of the law, then any decisions that that commissioner makes could be determined to be null and void.

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<v Steve Usdin>So I don't think they're gonna do that.

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<v Steve Usdin>The most likely uh course of action is to promote somebody from within as the acting commissioner.

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<v Steve Usdin>There's three people who would be qualified and who who seem to be in the running.

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<v Steve Usdin>Grace Graham, who's the Deputy Commissioner for Policy, Legislation, and International Affairs.

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<v Steve Usdin>Lowell Zeta, the Deputy Commissioner for Strategic Initiatives, and Kyle Diamantas, who's the Deputy Commissioner for Human Foods.

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<v Steve Usdin>I've heard that the most likely interim or acting commissioner would be Kyle Diamantas, but any one of those three could get it.

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<v Steve Usdin>It's also possible there's a, there's a list of people who are outside of of FDA who are appointees, senior appointees at other parts of HHS who could get the job.

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<v Steve Usdin>In the past, twice, NCI directors have gotten that job as uh on an acting basis, and one, Andrew von Eschenbach, was converted to get it on a permanent basis.

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<v Jeff Cranmer>And if you're curious about who some of the other candidates are Tracy Beth, Høeg, Sean Keveney and others Steve has a tidy table in his story listing everyone that has a shot and could be the next acting FDA commissioner should all this come to pass.

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<v Steve Usdin>And, and I'm sorry, just one, one, one final point, which is that there is a history, there's a tradition at FDA of having FDA commissioners who have served in that job for quite a long time and have been very important in policymaking.

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<v Jeff Cranmer>All right, we're going to take a quick break, and we'll be back to talk AAVs and the American Society of Gene and Cell Therapy annual meeting.

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<v Voice Talent>This episode of BioCentury This Week is brought to you by the 3rd BioCentury Grand Rounds in Seattle.

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<v Jeff Cranmer>All right.

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<v Jeff Cranmer>Well, you heard it there uh BioCentury Grand Rounds right around the corner but not too late to register.

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<v Jeff Cranmer>it is in,  as you heard the awesome  city of Seattle, which has become something of a biotech innovation hotspot.

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<v Jeff Cranmer>And, well podcast listeners, you're in luck.

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<v Jeff Cranmer>you can email conferences@biocentury.com or hit me up on LinkedIn.

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<v Jeff Cranmer>and we'll share a discount code with you And that's good for delegates uh presenting companies.

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<v Jeff Cranmer>still a few spots left for presenting companies, and we also have posters.

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<v Jeff Cranmer>Uh, Simone, word on the posters?

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<v Simone Fishburn>First of all, I have to say, this conference is shaping up to be extremely interesting.

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<v Simone Fishburn>Very hot conference, so we've got all these cutting-edge topics that we're gonna be discussing.

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<v Simone Fishburn>Also David Baker is going to give a keynote, and Mary Brunkow is gonna give a Horizon Session, and I'm gonna be interviewing Chris Arendt, the CSO of Takeda.

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<v Simone Fishburn>So we have a lot of headliners there.

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<v Simone Fishburn>But what I wanted actually to do with this podcast is I know that we have entrepreneurs and academic entrepreneurs who listen to us.

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<v Simone Fishburn>And if they don't, go find one and tell them they should.

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<v Simone Fishburn>But I do get people telling me that.

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<v Simone Fishburn>Anyway um we would really love to see them.

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<v Simone Fishburn>This is a conference for them.

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<v Simone Fishburn>This is a conference where they can come and really present their work.

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<v Simone Fishburn>We have poster presentations, which is just a great way to get your information and get your discoveries, even if they're really early stage, in front of VCs and pharmas and people that we think of will be the people who one day partner with you or invest in you.

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<v Simone Fishburn>And these posters have been really successful in the past.

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<v Simone Fishburn>Very much encourage academic entrepreneurs or would-be entrepreneurs or wanna-be entrepreneurs to come to the conference, and if they've got some cool work, send us a poster

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<v Jeff Cranmer>Yep.

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<v Jeff Cranmer>it's gonna be a good time for sure.

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<v Jeff Cranmer>Well over in Boston, other side of the country, the American Society of Gene and Cell Therapy is holding its annual meeting this week.

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<v Jeff Cranmer>The meeting is featuring  multiple preclinical presentations that describe strategies to enable repeat dosing or overcome preexisting immunity to AAV vectors.

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<v Jeff Cranmer>Lauren has been digging into this for a story that is out now on BioCentury.

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<v Jeff Cranmer>Lauren, what have you found?

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<v Lauren Martz>Thanks, Jeff.

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<v Lauren Martz>so this is the second year in a row that we've looked into this issue of immunity against AAV vectors as a theme from the ASGCT meeting.

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<v Lauren Martz>And I think it's, it's just because it's so important and because there really have been some big steps forward over the past year.

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<v Lauren Martz>Taking a step back, immunity against AAV vectors causes several different problems.

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<v Lauren Martz>It's obviously, you know, a, a major contributor to the toxicity issues that we always, are on the lookout for with all of these different AAV therapies.

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<v Lauren Martz>It's also, as you mentioned, behind two really big limiting factors for the applications of these gene therapies.

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<v Lauren Martz>The first is between thirty and sixty percent of people, you know, any people, have preexisting immunity to AAV vectors, which means they can't get an AAV gene therapy at this time at all.

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<v Lauren Martz>You know, even if you have a terrible rare disease and a gene therapy is developed for it, you're not eligible for it.

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<v Lauren Martz>And then there's also the issue of only being able to dose an AAV gene therapy one time.

00:18:18.630 --> 00:18:38.951
<v Lauren Martz>And if you think about the impact that that has on just anyone trying to develop a gene therapy for a rare disease, it's, it's really limiting because once you have a gene therapy approved or a gene therapy in a late-stage development for any indication, especially a rare disease That's going to be used to treat many of the patients with the disease.

00:18:38.951 --> 00:18:41.086
<v Lauren Martz>So the market then begins to shrink.

00:18:41.385 --> 00:18:44.923
<v Lauren Martz>And if the gene therapy isn't durable, you can't dose it again.

00:18:44.923 --> 00:18:46.258
<v Lauren Martz>You can't help patients in the future.

00:18:46.258 --> 00:18:49.728
<v Lauren Martz>So we don't know how long some of these gene therapies are even going to last for patients.

00:18:50.095 --> 00:18:55.433
<v Lauren Martz>So it's a huge problem, and if it's solved, you know, these are two slightly different issues that need to be solved.

00:18:55.433 --> 00:19:02.007
<v Lauren Martz>But if they are solved you solve a lot of the financial disincentive that exists for developing  AAV gene therapies.

00:19:02.406 --> 00:19:11.916
<v Selina Koch>And if I could jump in and just say, yeah, I mean, changing the economics for rare diseases is, is huge because of course in aggregate they're not rare at all, even if any one of them is rare.

00:19:12.351 --> 00:19:19.857
<v Selina Koch>but it-- the conversation I think was something that drops out of it often or that gets ignored is the promise in prevalent diseases, right?

00:19:19.857 --> 00:19:27.900
<v Selina Koch>There's this whole concept of vectorized biologics where you can encode an antibody or protein therapy as DNA sequence, give it as a gene therapy.

00:19:28.166 --> 00:19:33.704
<v Selina Koch>So much open, wide open territory that could be traversed there if there was a way to do this.

00:19:33.939 --> 00:19:51.522
<v Selina Koch>And then just, what was it, last week or recently on one of these podcasts, we were discussing how, in vivo CAR T therapies whether they were gonna be successful was completely gonna hinge on the durability of that first treatment, because these are what is an in vivo CAR T, but a gene therapy, right?

00:19:51.856 --> 00:19:55.493
<v Selina Koch>They're delivered with a lentiviral vector, which can't be redosed.

00:19:55.560 --> 00:19:56.461
<v Selina Koch>But what if it could?

00:19:56.929 --> 00:19:57.762
<v Selina Koch>Back to you, Lauren.

00:19:58.529 --> 00:19:59.230
<v Lauren Martz>Exactly.

00:19:59.230 --> 00:20:03.935
<v Lauren Martz>And so again, if we can solve these problems, I think it just burst this field wide open.

00:20:04.368 --> 00:20:31.563
<v Lauren Martz>The biggest advance that we saw over the last year was maybe not even at this meeting, but uh we did hear about an ESGCT in the fall, a patient with a high enough level of neutralizing antibody titers against the AAV vector for a gene therapy in a Genethon trial for a disease called Crigler-Najjar syndrome was treated with this gene therapy.

00:20:31.863 --> 00:20:38.903
<v Lauren Martz>So what Genethon did was they treated the patient with an IgG depleting enzyme imlifidase.

00:20:39.203 --> 00:20:42.106
<v Lauren Martz>Uh, this is approved for um other indications.

00:20:42.106 --> 00:21:00.025
<v Lauren Martz>It's used in other settings, but uh there's been a lot of speculation that maybe if we bring down the  IgG antibodies that preexist in, in these patients, for long enough, you can treat them with an AAV gene therapy, and it will be successful and  reach its target, express the gene that you need it to express.

00:21:00.424 --> 00:21:07.231
<v Lauren Martz>And we will hear an update at ASGCT from Genethon on clinical data from that trial.

00:21:07.499 --> 00:21:19.711
<v Lauren Martz>Hopefully we'll see some additional information about how that's been working in that particular patient and what the next steps are you know, introducing this gene therapy for more patients who have preexisting antibodies, maybe taking it to other indications.

00:21:20.244 --> 00:21:23.281
<v Lauren Martz>So that was sort of the big thing that happened.

00:21:23.382 --> 00:21:31.923
<v Lauren Martz>And then when you look at this meeting versus last year,  there is a diverse set of strategies that are proposed to tackle this problem.

00:21:32.356 --> 00:21:41.465
<v Lauren Martz>So the IgG-depleting enzymes are sort of the focus of this preexisting antibody issue, preexisting immunity.

00:21:42.000 --> 00:21:50.107
<v Lauren Martz>When you think about the problem of redosing, it's a little bit more complicated because you have a little bit... There are more entry points for therapeutic intervention.

00:21:50.107 --> 00:22:01.019
<v Lauren Martz>So you want to prevent this immune response when you're giving the first dose, and then you want to deplete whatever immune response still does result.

00:22:01.019 --> 00:22:11.663
<v Lauren Martz>So you still probably have that need for depleting the IgG antibodies, but there's also a lot of work around how do we prevent those antibodies from being produced in the first place.

00:22:12.029 --> 00:22:19.171
<v Lauren Martz>Many different groups are proposing different strategies to deplete the B cell activation or, you know, take out the B cells in general.

00:22:19.538 --> 00:22:27.645
<v Lauren Martz>There are some really extreme proposals like CAR Ts, which you, you have to kind of weigh the safety and benefits of, of using something like that.

00:22:27.846 --> 00:22:32.683
<v Lauren Martz>But different combinations of B cell-depleting antibodies or B cell-targeting antibodies are also proposed.

00:22:33.050 --> 00:22:43.561
<v Lauren Martz>And then there's another set of, you know, this isn't a new idea, but as we're designing new AAV vectors, trying to design them in a way that evades the immune response has been a longstanding goal.

00:22:43.662 --> 00:22:44.762
<v Lauren Martz>There's some work around that.

00:22:45.196 --> 00:22:55.307
<v Lauren Martz>And then some more  innovative ideas like cloaking the vector in extracellular vesicles, for example, that help it evade immune response from the start.

00:22:56.474 --> 00:23:10.255
<v Simone Fishburn>Lauren, I suppose my question is this,  your lead up to this when you describe the problems that are being addressed at the ASGCT conference, as you pointed out, those are longstanding questions, right?

00:23:10.255 --> 00:23:13.325
<v Simone Fishburn>We've known about redosing being an issue.

00:23:13.325 --> 00:23:20.265
<v Simone Fishburn>We've, we've known about that for a while  and the various limitations, and Selina, your sort of what if is obviously a really tantalizing one.

00:23:20.265 --> 00:23:21.599
<v Simone Fishburn>What if you could solve this?

00:23:22.000 --> 00:23:34.445
<v Simone Fishburn>And so what I want to ask you is whether, you described now just several different strategies that companies and innovators, I guess they're not all companies, right, are taking to address it.

00:23:34.846 --> 00:23:37.816
<v Simone Fishburn>Do you think that there's a sort of critical mass now?

00:23:37.816 --> 00:23:42.453
<v Simone Fishburn>Do you think it's... You know, what I like to think about, is this ultimately an engineering problem?

00:23:42.686 --> 00:23:50.494
<v Simone Fishburn>Is it something that you keep hammering away at it, you try different, different ways, and the field is sort of incrementally getting to solve this?

00:23:50.494 --> 00:24:04.308
<v Simone Fishburn>And I ask this because gene therapies, I don't know if it's more than any other, but it feels like it, has just got this history of waves where they try it and then it, there's a disaster and it goes away, and sometimes it's a commercial reason and whatever.

00:24:04.675 --> 00:24:07.179
<v Simone Fishburn>We're still knocking on the door really with gene therapies.

00:24:07.546 --> 00:24:19.758
<v Simone Fishburn>But I think what I'm really asking is whether there's reason to believe that this massive activity that you're talking about can actually change the trajectory, start to solve some of these longstanding questions

00:24:20.826 --> 00:24:21.893
<v Selina Koch>Are we at a tipping point?

00:24:22.827 --> 00:24:23.761
<v Simone Fishburn>Are we at a tipping point.

00:24:23.795 --> 00:24:24.296
<v Simone Fishburn>There we go.

00:24:24.596 --> 00:24:25.396
<v Simone Fishburn>Thanks, Selina.

00:24:25.830 --> 00:24:29.300
<v Lauren Martz>We have a history of identifying things maybe before we get to the tipping point.

00:24:29.366 --> 00:24:31.702
<v Lauren Martz>So um we may be

00:24:31.702 --> 00:24:34.271
<v Simone Fishburn>That's what we pay you the big bucks for, Lauren, you know.

00:24:34.338 --> 00:24:36.775
<v Lauren Martz>We may be almost getting to a tipping point.

00:24:36.842 --> 00:24:41.313
<v Lauren Martz>I will say, I don't think there's a massive amount of research around this, this topic.

00:24:41.480 --> 00:24:43.647
<v Lauren Martz>I think that it's something that people are working on.

00:24:44.148 --> 00:24:47.818
<v Lauren Martz>I think, that companies and academic groups are chipping away at the problem.

00:24:47.919 --> 00:24:56.461
<v Lauren Martz>I think that what we've seen, we have a patient with preexisting immunity who was dosed with an AAV gene therapy, and, and we'll see how durable that effect was.

00:24:56.694 --> 00:24:58.630
<v Lauren Martz>I, I think that's, that's a big step

00:24:59.096 --> 00:25:02.200
<v Simone Fishburn>And that...Sorry, that patient would've been screened out of earlier

00:25:02.666 --> 00:25:05.503
<v Lauren Martz>Oh, that patient would have absolutely been screened out of earlier trials.

00:25:05.737 --> 00:25:16.047
<v Lauren Martz>I think there's still this challenge of preclinical models not translating to humans when you're talking about the immune system.

00:25:16.047 --> 00:25:17.382
<v Lauren Martz>Huge, issue.

00:25:17.548 --> 00:25:18.650
<v Simone Fishburn>Shocked, shocked to hear this.

00:25:18.650 --> 00:25:21.586
<v Lauren Martz>Shocking problem, but um, so,

00:25:21.685 --> 00:25:28.759
<v Selina Koch>Lauren, how much of the data would you say at this year's meeting is maybe in non-human primates, say, instead of mice or whatever?

00:25:28.759 --> 00:25:30.895
<v Selina Koch>Are we seeing an advancement in that way?

00:25:30.895 --> 00:25:30.961
<v Selina Koch>So,

00:25:31.663 --> 00:25:36.268
<v Lauren Martz>There are some studies in non-human primates, which is of course a better model than a mouse model for this.

00:25:36.634 --> 00:25:44.643
<v Lauren Martz>But it, it... There's still, you know, even with the clinical trials with gene therapies that we've seen, there are always unpredictable things that happen.

00:25:44.643 --> 00:25:55.653
<v Lauren Martz>So I think, what we're expecting to happen is if you dose someone with preexisting immunity with an AAV vector, and maybe the strategy that you've chosen doesn't work, hopefully that it just...

00:25:55.686 --> 00:25:56.688
<v Lauren Martz>it won't be effective.

00:25:56.721 --> 00:25:59.691
<v Lauren Martz>But we don't know what the risks are.

00:25:59.691 --> 00:26:07.699
<v Lauren Martz>We don't know how ethical it is to bring like a redosing strategy into humans, and I, I think it's just gonna be a relatively slow process.

00:26:07.699 --> 00:26:23.949
<v Lauren Martz>But hopefully the first step is that you can treat patients with preexisting immunity, and then you can use some of these B cell depleting therapies that are becoming safer and more standard in inflammatory diseases and cancers as a way to sort of bridge this immunity problem.

00:26:23.981 --> 00:26:28.452
<v Lauren Martz>And maybe in the future we'll have vectors that, that evade the immune system completely, you know.

00:26:28.686 --> 00:26:31.021
<v Lauren Martz>the... I think we're, we're moving in the right direction.

00:26:31.690 --> 00:26:46.538
<v Selina Koch>so you list a bunch of targets in this story that people are, are trying, you know, for the various-- either to prevent new B cell responses, address existing ones, address the T cell component of it, so on and so forth.

00:26:46.538 --> 00:26:51.076
<v Selina Koch>And you all-- whoever's listening to this can go read the story and see these various targets.

00:26:51.509 --> 00:27:09.560
<v Selina Koch>But because it's still, there's lots of things being proposed and it's still early does that mean right now would be a good time for the field to get together and think about how do we create standardized assays so we know how to use these things effectively in individual patients?

00:27:10.494 --> 00:27:12.096
<v Lauren Martz>This would be a great time to do that.

00:27:12.130 --> 00:27:16.334
<v Lauren Martz>It's something that we talk about for a lot of different targets, a lot of different drug classes.

00:27:16.734 --> 00:27:22.574
<v Lauren Martz>Assays to measure neutralizing antibodies are not standard.

00:27:22.574 --> 00:27:25.143
<v Lauren Martz>They're all measuring different things from what I hear.

00:27:25.175 --> 00:27:26.678
<v Lauren Martz>You can read about it in the story.

00:27:27.077 --> 00:27:39.423
<v Lauren Martz>Um, so it's hard to tell,  which of these approaches is working better at bringing down the antibodies, which is going to address the T cell component, which is gonna be a, a... probably going to be an issue when you come to redosing.

00:27:39.423 --> 00:27:42.961
<v Lauren Martz>So you sort of need to inhibit both of those processes.

00:27:43.394 --> 00:27:46.163
<v Lauren Martz>Yes, it would be wonderful if people came together to

00:27:46.297 --> 00:27:49.500
<v Simone Fishburn>count me skeptical here.

00:27:49.634 --> 00:27:56.374
<v Simone Fishburn>How many times have we said if the industry would get together and solve this thing, they'd all do better from it?

00:27:56.607 --> 00:27:57.342
<v Selina Koch>Oh my gosh.

00:27:57.342 --> 00:28:00.045
<v Selina Koch>Um, I don't know, PD-1 might come to mind.

00:28:00.111 --> 00:28:00.244
<v Simone Fishburn>Yeah.

00:28:00.979 --> 00:28:03.213
<v Simone Fishburn>It's just, what about a single assay?

00:28:03.248 --> 00:28:08.219
<v Simone Fishburn>As I said, they did it in COVID 'cause they had to, so we know that they've got that muscle in there somewhere.

00:28:08.720 --> 00:28:10.855
<v Simone Fishburn>Not holding my breath on that one, I'm afraid.

00:28:11.623 --> 00:28:13.692
<v Selina Koch>Just making an appeal yet again.

00:28:15.292 --> 00:28:19.364
<v Simone Fishburn>Well, if they do, then we'll definitely point it back to your comment on this podcast, Selina.

00:28:19.364 --> 00:28:21.432
<v Simone Fishburn>We'll be like, "Maybe we, we can influence." Yeah

00:28:22.500 --> 00:28:27.105
<v Jeff Cranmer>Lauren, I'm curious, are there any uh other things you're watching at the conference?

00:28:28.205 --> 00:28:28.873
<v Lauren Martz>Always.

00:28:28.873 --> 00:28:32.911
<v Lauren Martz>Yes, there's a lot of interesting stuff within the abstracts that will be presented this week.

00:28:33.243 --> 00:28:39.150
<v Lauren Martz>So a few disease areas that stood-- or there are indications that stood out as hot to me this year.

00:28:39.451 --> 00:28:42.453
<v Lauren Martz>muscular dystrophies, including but beyond DMD.

00:28:42.453 --> 00:28:47.125
<v Lauren Martz>There's a, there's a lot of research on limb-girdle muscular dystrophy, for example.

00:28:47.157 --> 00:28:48.593
<v Lauren Martz>I'm gonna be looking into those.

00:28:49.126 --> 00:28:52.396
<v Lauren Martz>Gene therapies for the eye, of course, always a big topic.

00:28:52.396 --> 00:28:57.167
<v Lauren Martz>There's a lot of research into retinitis pigmentosa and the different genetic forms of that disease.

00:28:57.535 --> 00:28:59.136
<v Lauren Martz>those are two things that stood out to me.

00:28:59.537 --> 00:29:07.578
<v Lauren Martz>going back to Selina's comment on the encoded antibodies, one thing that I saw quite a bit of was strategies...

00:29:07.578 --> 00:29:13.718
<v Lauren Martz>Well, first of all, DNA-encoded antibodies, the, you know, vectors to create drug factories in the body.

00:29:13.751 --> 00:29:15.452
<v Lauren Martz>There, there's quite a lot of that.

00:29:15.787 --> 00:29:36.141
<v Lauren Martz>There are also different strategies to tune expression of the-- and levels of the transgene and the protein that's produced from gene therapies, which I think will be increasingly important as you're talking about long-term production of therapeutic proteins, not just replacing a lost gene, for example.

00:29:36.607 --> 00:29:39.611
<v Lauren Martz>There's a lot of activity on in vivo CAR Ts as always.

00:29:39.611 --> 00:29:46.951
<v Lauren Martz>There are a few new companies that are new to BioCentury in, in this list and a few different strategies to um create the in vivo CAR Ts.

00:29:47.417 --> 00:29:50.654
<v Lauren Martz>Yeah, just a lot of, a lot of interesting topics within the abstracts

00:29:51.623 --> 00:29:52.056
<v Jeff Cranmer>Excellent.

00:29:52.123 --> 00:30:03.968
<v Jeff Cranmer>Well I'll drop a link in the show notes to Lauren's story as well as Steve's story on Marty Makary's tenuous grip on the FDA job.

00:30:04.067 --> 00:30:05.403
<v Jeff Cranmer>We'll see what happens there.

00:30:05.403 --> 00:30:11.108
<v Jeff Cranmer>Steve, of course, always working the phones, and Lauren always digging into the abstracts.

00:30:11.108 --> 00:30:13.577
<v Jeff Cranmer>Uh, that's how we roll here at BioCentury.

00:30:14.011 --> 00:30:15.413
<v Jeff Cranmer>Thanks for tuning in.

00:30:15.680 --> 00:30:27.392
<v Jeff Cranmer>Look out for our special Bio€quity Europe episode this week, as well as The BioCentury Show's interview with Karen Knudsen of the Parker Institute.

00:30:27.724 --> 00:30:33.397
<v Jeff Cranmer>And a thank you to Kendall Square Orchestra, which provides the music to BioCentury's podcasts.

00:30:34.665 --> 00:30:43.974
<v Voice Talent>BioCentury would like to thank Jeito Capital for its continued support of our BioCentury This Week podcast and our 26th annual Bio€quity Europe conference this May in Prague, Czech Republic.