Jef Akst: just us today, I guess. ⁓

Heather: Yeah, just us. Anna Lee is having ⁓ weather slash tech issues.

Jef Akst: Yeah, man, this weather all over the country right now, over the continent, I should say, since you guys aren't even in the same country as I am. But yeah, crazy temperature swings. We had, our schools were canceled yesterday due to a risk of tornadoes, although it turned out to be a pretty mild day. The kids definitely should have been in school.

Heather: Yeah, yeah, I think there's a lot of times that kids should definitely be in school that they're not. ⁓ We, yeah, even Tristan, ⁓ who is in the Philippines, our staff writer, ⁓ said that it was like, it was summer a couple of days ago, and now it's December. So it's literally the entire world.

Jef Akst: Yeah. Yeah, these temperature swings from summer to winter, that's what we had to do, was 88 and sunny, I was wearing shorts and a tank top and sweating outside, and then this morning I went for a walk in my full on down coat winter gear, it's been weird.

Heather: Well, poor Anna Lee said that it's, ⁓ I think, I can't even read the number that she wrote on our Teams chat, but I think it's minus seven, but feels like minus 77 billion trillion or something like that. We were just talking the other day that we don't always want to ⁓ revert to the weather ⁓ when we sign in, but I think this time it's appropriate.

Jef Akst: ⁓ cold Yeah, it's pretty bonkers.

Heather: Yeah. Well, ⁓ okay, so intros. I am Heather McKenzie, a senior editor here at Biospace, and I curate the Clinica Space newsletter that hits your boxes every Monday.

Jef Akst: and I'm Jeff Axt, Managing Editor. I'll just give you a quick rundown of some of the other newsletters we have. Don't forget to subscribe to all of Biospaces' newsletters. We've got our daily gene pool for Annalise. She puts out the Biofarm executive email. We also have a career insider and manufacturing brief as well.

Heather: All right, well, let's get to our show. let's start this week with our ⁓ weekly weight loss segment. ⁓ So yeah, so it's the weight loss companies who are making waves this week. Structure Therapeutics on Monday announced that its GLP-1 pill listed just over 16 % placebo-adjusted weight loss at 44 weeks. BMO Capital Markets said that this was a competitive profile with Orphaglipron, that's Lily's candidate that is expecting approval next month, and Novo's oral begovie. So yeah, and also there was some concern about the safety. So there was one discontinuation, which doesn't sound like a lot, but in a separate open label extension study, 2 % of patients stopped treatment due to side effects. So BMO said that there might be some investor concern there regarding these signals, but that structure is working to further optimize these dose titrations.

Jef Akst: You know, we've seen a lot about tolerability being very important as other companies are trying to break into this market that's currently dominated by Eli Lilly and Novo Nordisk. But structure is one we've had our eye on actually. Structure was on our potential, our list of potential ⁓ &A targets late last year. It's something that Annali put together. And it's something industry watchers are once again talking about after this new data drop this week. I saw some buzz about will structure get bought out. So we'll definitely watch for that. And then another company also up and coming in the weight loss space, Rhythm Pharmaceuticals, announced some results this week. So it's got a drug candidate, or excuse me, approved drug. It's already approved for two other types of genetically linked obesity. It's called im-civri. So the new results though were a failure in a basket trial of more of these genetically driven obesity. So Stifle Analyst called this result really disappointing. They thought that at least one of these subpopulations might have been a hit, but unfortunately all four subpopulations that Rhythm was testing failed to show that ⁓ weight loss mark that they would have wanted to hit to move forward. So remains to be seen how that one will play out. Structure is definitely the winner this week.

Heather: Yeah, think in that stifle note, ⁓ the analyst also said that this wasn't a big hit on Rhythm's portfolio, ⁓ but it wasn't one of the key things they were watching. But yeah, too bad that at least one of those basket entries didn't work. Well, turning to those heavyweights, ⁓ Lilly and Novo, let's start with Lilly. ⁓ So Lilly came down hard on compounders last week, ⁓ warning of potential safety risks of taking compounded versions of its blockbuster weight loss and diabetes drug, Terzepatide.

Jef Akst: Yeah, that's right. So specifically, Lily was warning about remixed formulations that these compounders make and specifically combining trisepatide marketed as Zep-Bound for weight loss or mandrar for diabetes, combining that drug with vitamin B12. Lily said that this can react with the active ingredient in a way that can yield an impurity that might alter the way trisepatide interacts with target receptors or affect something about the drug's toxicity or immunogenicity or somehow change how trisepatide is absorbed into or distributed. through or cleared from the body. So in some way change how this drug works and potentially cause a safety risk. ⁓ We have heard from Lilly and Novo a lot over the past year or two about compounders. For a while they were supplying these drugs when the branded drugs were in short supply. But since those branded drugs have regained full supply and been taken off of FDA shortage lists, The compounders are continuing to produce the drugs and Lillian over continuing to kind of slap them on the wrist saying, no, you can't do this for various reasons. this concern about potential impurities is the latest on that saga, but certainly we will not the end that we're going to hear from compounders and both Novo and Lily fighting them.

Heather: Right. Well, in the other corner, we have NOVO, which found itself on the other end of an FDA warning this week.

Jef Akst: Right. Yeah. So NOVO is usually the one we're talking about in the context of compounders and usually the one issuing those warnings. This week, NOVO itself is getting a warning and not from compounders, course, but from the FDA. This was pretty interesting news that broke last week that the FDA had early last year, early 2025, sent NOVO this warning letter specifically for failing to investigate reports of adverse events potentially linked to Ozempic. Ozempic being the first GLP-1, first semaglutide product on the market from NOVO. And these adverse events that are potentially linked to Azempik included two deaths and one case of completed suicide. So not minor side effects here. So Novo had submitted a written response back to the FDA in January, but apparently the agency is still displeased. ⁓ say that the response from Novo lacks specific, sufficient detail to determine whether the issues have been resolved or whether we might see similar issues in the future. Not great news on, you know, already a hard year for NOVO.

Heather: you Yeah, you can say that again. It's been a very tough year for NOVO so far. ⁓ They've been on quite a losing streak. So their up and coming combo drug, Kaepersoma, ⁓ fell to Lilly in a head-to-head trial. And then Orphaglipron ⁓ beat Semiglutide in another trial ⁓ in weight loss again on the oral weight loss front. ⁓ And then, of course, there was the whole thing with NOVO Holdings last week.

Jef Akst: Yeah, so all the trouble that Novo Nordisk is facing is of course not, you know, just limited to the pharma because it's part of this very, I think it's complex, maybe just because I'm American. Apparently this is not so weird for a Danish company to be structured this way. But as a reminder, Novo Nordisk, the pharma company is controlled by Novo Holdings, which ⁓ holds a majority share of the pharma company. And all of these fall under the Novo Nordisk Foundation. So we got earnings from Novo Holdings recently. And like I said, all of the struggles that Novo Nordis, the pharma companies were facing definitely hit Novo Holdings bottom line. it's a little bit different. It's not, you we're not reporting revenue numbers here, but total assets under management for the Holdings and investment company fell by 34 % for 2025. So a big hit there down to, you know, this translates to about 107 billion. in assets for Nova Holdings at this point compared to what used to be about $164 billion.

Heather: Yeah, that's quite a hit. ⁓ I'm a perpetual fan of the underdogs. So I just want to see them turn it around. Not that they're suffering or anything, but yeah, be good.

Jef Akst: It's just when we compare against Lilly, right? Annalise always telling us we shouldn't compare, but it's hard not to. These two juggernauts in the weight loss space. And yeah, when you compare the two, Novo is not the winner.

Heather: One's a big juggernaut, one's a little juggernaut. ⁓ Well, speaking of complexity, let's get back to that RFK Junior News that I teased at the beginning of the show. ⁓ So yesterday, after hours, ⁓ Judge Brian Murphy of the District Court of Massachusetts found that Kennedy's efforts to overhaul US vaccine policy were likely unlawful.

Jef Akst: Right, there you go. Yeah, so let's unpack some of this. There were a number of issues of concern here, things that Biospace has been covering from the beginning of RFK's ⁓ tenure as HHS secretary. So one of the things that industry and others were concerned about was Kennedy's unilateral decision to remove COVID-19 vaccine recommendations for healthy children and healthy pregnant women. This is an announcement he made last year, announced it via video on social media. And so bypass not only the advisory committee, they called ACIP for short, but also the CDC staff themselves. So that was of concern. And then he followed that move up by entirely revamping the ACIP committee. So getting rid of all of the previous ACIP members and stacking the committee with additional ⁓ new members, many of whom shared these anti-vaccine sentiments of Kennedy. And then in response to that, the American Academy of Pediatrics sued the HHS. The group alleged that Kennedy had violated the law in reforming ACIP in addition to putting Americans in harm's way and eroding public trust in vaccines. So the ACIP, even after that, that'll happen around last summer. Since then, the ACIP has overseen substantial changes to the CDC's recommended vaccine schedules, especially with regard to kids. So this is all in front of Judge Murphy and he basically took issue with all of this. It's unclear to me how long this legal battle could go on. Current ACIP Vice Chair Robert Malone as well as HHS both spoke about an appeal to this ruling and potentially overturning the ruling. Andrew Nixon, HHS spokesperson, had strong words to Stat News saying that the department, quote, looks forward to this judge's decision being overturned just like his other attempts to keep the Trump administration from governing. basically accusing the judge of ⁓ blocking normal government procedures. And he's specifically referring to the appellate court suspension of Murphy's prior ruling regarding the Department of Homeland Security's deportation policies. The appellate court had overturned a ruling that Murphy had declared those activities unlawful. So yeah, it remains to be seen whether this one will be overturned. don't imagine this is the end. This is not the end of the story. There was supposed to be an ACIP meeting this week and still on the CDC website as of this morning, it was listed for starting tomorrow, March 18th. But according to HHS and a comment to Politico, it has been postponed in the midst of all of this.

Heather: Right, well, they were supposed to talk about some pretty spicy stuff as well. Vaccine, potential vaccine injuries or responses to those injuries. So if that meeting were to go ahead, you just think it would compound all of this. It is interesting that you mentioned Judge Brian Murphy. I feel like he's been involved with another one of ⁓ RFK's decisions. Has he not? Or was that maybe the Homeland Security?

Jef Akst: Yeah. That could have been it. I've had trouble keeping track of all of this, to be honest. There are a lot of different legal battles going on with regard to not just within the biopharma space, but some of the policies that are unfolding. yeah, the deportation is one of the other big ones, but of course outside of biospaces purview. But yeah, it's very possible it was Murphy on more than one of these.

Heather: Well. ⁓ Murphy's ruling also comes on the heels of ⁓ some of a White House crackdown ⁓ on Kennedy's vaccine policies. So according to the Wall Street Journal, ⁓ the White House wants ⁓ RFK to tone down his vaccine skepticism. This is an election year, of course, and officials are apparently frustrated with what they consider to be a series of, quote, policy missteps. ⁓ However, the secretary still on solid ground with President Trump according to WSJ's sources.

Jef Akst: Yeah, I mean, I think with the midterm elections coming up, there is a lot more discussion of this. But to this point, there hasn't been a lot of change. There's not been a lot to stop RFK from revamping the vaccine schedules as he has to this point. So I'm curious. We did have that ⁓ investigation underway by Ron Johnson into the FDA. I know we're to talk about that in a minute. So I wonder if some Congress people will step up with regard to the... what's going on in the vaccine sector as well. But to this point, we haven't seen substantive movement in a way that would stop some of the changes that are going on.

Heather: Yeah, definitely. Well, on the rare disease side, Senator Ron Johnson has always been quite an advocate for rare disease therapies in patients. And he launched an investigation into the recent FDA denials of rare disease drugs.

Jef Akst: Yeah, so I was curious, I know you covered this a bit, did he name names? Like we've seen so many of these, Replumoon, Capricor, Biohaven, Ultragenics, was he targeting any of specific decisions or just saying across the board, there's been a trend here?

Heather: Yeah, it was more across the board. ⁓ He did call the FDA's request for a phase three sham controlled trial of Unicure's Huntington's therapy, quote, bureaucratic idiocy. So bureaucratic idiocy. ⁓ But yeah, was ⁓ more broadly, he was saying that, ⁓ quote, these stories are so outrageous. ⁓ It just appears that they're looking for excuses to say no. That was already to Bloomberg.

Jef Akst: Yeah. Yeah. OK. Well, we'll see what comes of that.

Heather: Yeah, so he's CRLs. He's also considering having Commissioner McCary appear before the Senate's permanent subcommittee on investigations, which he chairs. Yeah, I hope it is, because I want to cover that.

Jef Akst: Ooh, I'd tune into that. I wonder if that'll be broadcast. Yeah.

Heather: Also on the FDA front, we've written a lot about transparency issues within the agency in the past year. And now outgoing CBER director Vinay Prasad's request to remain anonymous a couple of weeks ago during a press briefing on Unicure's Huntington therapy is just the latest example. And I put out an editorial on this on Friday. It also looked into the FDA's failure to discuss close Prasad's apparent one year leave of absence from UCSF prior to, you know, just basically two months before he's supposed to leave at the end of April.

Jef Akst: Yeah, questionable order of information coming out there. We talked about it little bit last week, but yeah, still more to learn there.

Heather: Yeah, and you know, there's also it's interesting There's a like a response that that's really common for the FDA these days that I just haven't seen in the past ⁓ You know, they they'll choose to respond to some of our requests and not others And then they'll actually reach out with with more context that they'd like us to add to our articles. And there's also a lot of deep background ⁓ references on the responses that I get, which kind of reminds me of just like deep behind a, I don't know.

Jef Akst: Yeah. I wonder how much of this comes down to just cuts too, right? Because they eliminated the entire FDA comms team. So all of our communications, all media relations are going through HHS more broadly. And I don't know how many people are actually manning that team that responds to journalists like us.

Heather: I've seen, you know, I've had conversations or a little mini email conversations with two or three of them, maybe three, I would say. And it's got to be tough for them to manage all of the onslaught of questions and comments they probably get. Yeah. So I'm actually surprised with how well they do, but it would be nice to have a little more transparency there. And this is just, you know, this is

Jef Akst: Yeah, for the entire HHS, again, this is not just FDA.

Heather: really just the tip of the iceberg. mean, there have been questions over recent guidances, not being clear enough, ⁓ lack of internal transparency with CDC leaders on vaccine changes last year, and then confusion around unexpected reversals of guidance, as we just talked about. ⁓ For several biotechs, I think the count is maybe nine at this point. ⁓ But yeah, so we'll have to see what happens as we get closer to the election ⁓ with Kennedy and all of those leaders that still remain.

Jef Akst: All right, and also what happens after Prasad exits the FDA, who will replace him. There's still a lot of open questions for how these agencies are being run.

Heather: Yes. Yeah, we've got to, that's another announcement that we've got to keep our eyes out for probably Friday at five o'clock when they do a saver director. ⁓ Well, Jeff, do you want to do want to tell us a little bit about what's coming out in BioFarm exec this week?

Jef Akst: Right. That's right. Yeah, I'll do my best. Annali always gives better rundowns, but she's got a couple of really great stories, including the biggest pharma deals of all time. This is super helpful for me to always look back at the industry and kind of remember where it's been and place where we are now in that context. And then the other story that I'm excited about, I actually added to this one, was top pharmas by revenue. So of course, we're always talking about Lilly and its amazing growth in terms of its valuation, hit that one trillion mark for the first pharma ever to do that. But it is not the biggest earner, at least not yet. So you'll have to read BioFarm Executive to figure out who that is.

Heather: All right, thanks, Steph. We'll definitely do that. Well, ⁓ it is only Tuesday as we record here, so that is it for us for this week, but I'm sure we will be back with much, much more from the rest of this week next week. Thanks for listening. Welcome to Biospaces the Weekly. We'll start out this week with our weekly weight loss segment. We got a peek at new data from a couple of up and comers in the space, structure therapeutics and rhythm pharmaceuticals. While heavy weights, Eli Lilly and Novo Nordisk made headlines with a couple of non-clinical updates. ⁓ We'll also come back to another big theme here on the weekly, leadership drama at HHS. This week, the biggest update revolves around the top dog himself, Health Secretary Robert F. Kennedy Jr. federal judge issued scathing ruling on Monday about the changes he's made to the CDC's Vaccine Recommendations and Advisory Committee. Let's get started.