Ep. 373 - AbbVie M&A, FDA reversals, a CAR T first

AbbVie's $10.9 billion deal to acquire Apogee will expand its immunology pipeline by delivering assets for atopic dermatitis and asthma. On the latest BioCentury This Week podcast, BioCentury’s analysts discuss the takeout and the assets AbbVie gains.
The analysts then discuss moves by FDA to reverse controversial setbacks that occurred under the agency’s former leadership and assess Acting CDER Director Michael Davis’ memo outlining how his predecessor repeatedly overruled career staff to quash a drug approval. The analysts also discuss continuing signs of political involvement at FDA.
Finally, they discuss China NMPA’s first-ever approval of a CAR T for solid tumors, satricabtagene autoleucel (satri-cel) from Carsgen.

View full story: https://www.biocentury.com/article/659864

#BiotechMA #Immunology #FDA #CART #ChinaBiotech

00:59 - AbbVie Buys Apogee
05:20 - uniQure U-turn
09:02 - FDA Reversals
12:32 - Tzield Memo
20:53 - Solid Tumor CAR T Approval

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

Transcript

0:00

[Auto-generated Transcript]

Jeff Cranmer: 0:02

AbbVie is buying Apogee for $10 billion to bolster its immunology and respiratory portfolio. We'll dig into the deal on this week's BioCentury This Week podcast. Plus, a reversal at FDA for uniQure puts natural history controls back in play for rare neuro. We'll discuss that and other recent reversals of FDA decisions, And we'll also discuss the world's first CAR T cell therapy product approved for solid tumors. I'm Jeff Cranmer, host of the BioCentury This Week podcast, and joining me today, my fellow Executive Editor, Selina Koch, Washington Editor, Steve Usdin, Executive Director of Biopharma Intelligence, Lauren Martz, and our News Editor, Paul Bananos. Paul, let's bring you in right away. Let's hear about this big deal by AbbVie

Paul Bonanos: 1:05

Sure. Yeah, it, it was the big news out of the gate Monday morning, wasn't it? rumored over the weekend, and then the announcement came early today. it's the latest large deal for AbbVie. You, you may remember that the company had two big deals in late 2023. We had Immunogen uh buying Immunogen in cancer and Cerevel in neuroscience. They've done a few smaller deals since then, a couple in the ten-figure range. You may remember Capstan last year. and now here's an eleven-digit takeout, actually even a little bigger than Immunogen or Cerevel. It's ten point nine billion, and it's in immunology, which is AbbVie's biggest therapeutic area in terms of revenue right now. So the company they're buying is Apogee, as you said uh formed in twenty 2022. It's a very quick turnaround. Apogee specializes in optimized biologics. The targets are usually familiar. They're engineered with half line half-life extension technology to enable less frequent dosing and, and some patients will prefer that. Their pipeline has a few programs. The most advanced is in atopic dermatitis. It's called ZUMILOKIBART. AbbVie said that, you know, that's where most of the value is in this deal. Um, ZUMI, we'll stick with that name, had some Phase II data recently suggesting it can be competitive with other drugs in atopic dermatitis. Most directly within the IL-13 class, it would compete with EBGLYSS, that's lebrikizumab from Lilly. There's also the, the big one in this area is Dupixent, different target IL-4 from Sanofi and Regeneron. That's now a blockbuster many times over. And EBGLYSS and Dupixent are generally administered every two to four weeks. Apogee's is more like every three months. So there's a dosing advantage. That usually leads to patient preferences, a-adherence advantages, that sort of thing. And I mentioned uh AbbVie's historical strength in immunology. It's, it's the biggest therapeutic area for that company. People probably know Humira is the, the big one historically. It now has biosimilar competition, but it was one of the best-selling drugs ever. And AbbVie has done a good job, I think, of replacing that drug's lost revenue with two others, Skyrizi and Rinvoq. Rinvoq is approved for atopic dermatitis, so Apogee kind of lines up to be a next-generation drug in that area. and it may expand into other immuno-immunological indications as well. It's clearly a fit

Jeff Cranmer: 3:28

Uh, what else are they getting in this deal, Paul?

Paul Bonanos: 3:30

Well, yeah, I said most of the value was in Zumi, but AbbVie ascribed some value to a combo program, APG273. It's a combo that actually includes Zumi along with an anti-TSLP therapy. And AbbVie specifically says they'll move it forward in asthma. Apogee had been developing it in COPD as well. So that's another component, yes

Jeff Cranmer: 3:53

And, and who are the backers of Apogee?

Paul Bonanos: 3:56

Oh, right. So, um, it's worth mentioning, yeah, this is a win certainly for Apogee's team, but also for the founding investors, Fairmount Funds and Venrock, came in at the very beginning in 2022. And Apogee kind of grew up in Fairmount's incubator, which is called Paragon Therapeutics. Uh, you may recognize some other companies that have come out of it. Korsana we've written about fairly recently, Jade, Crescent, Spire, Oruca are their names. Um, the pattern there, interestingly, those five that I just named all went public via reverse mergers, and I think Apogee is the only one that did a traditional IPO. It went first in 2023. Anyway uh Fairmount and Venrock, as of the April proxy statement I saw, are still among the biggest shareholders, um, with more than 20% combined. So on a $10.9 billion takeout, this is a big return for both of them. So good for them

Jeff Cranmer: 4:51

All right, and good for biotech. another $10 billion deal. Uh, earlier this month, we had GSK paying close to $11 billion for Nuvalent. And that was the third and largest M&A deal under GSK's new CEO, Luke Mieils. Well, thanks for that, Paul. Always appreciate your deals report. They come out early every week, and uh look forward to reading this week's. let's turn over to what's happening with FDA. I'll bring in Selina and Steve now. we've seen a few reversals. Uh, Moderna got its advisory committee meeting on Thursday. uniQure got some good news. RegenxBio also some news. Let's start with uniQure, Selina

Selina Koch: 5:42

Sure. Thanks, Jeff. maybe let's start with why the uniQure case was so high profile. I think there are two major reasons. One is just that Huntington's disease is becoming such an interesting and growing area of interest for drug developers that I think there's just a lot of people out there, companies, investors, looking to see what the regulatory path is gonna look like. Second the therapy AMT-130 is almost a poster child for the kind of program where you would hope and expect FDA to consider a flexible, accelerated approach, meaning it checks not, like, one box, but, but many. so some of those are, right, Huntington's is very severe. It's a fatal disease ultimately with no disease modifying therapy. So unmet need, very high. It's also rare, so trial, trial recruitment is already challenging, but then when you layer on top of that the nature of the treatment being a gene therapy that's delivered through a brain surgery, right? So an invasive procedure that's especially hard to, um, placebo control. Um, and it goes on. On top of that, Huntington's is an indication with relatively strong natural history data set to draw from, so that makes that external control strategy sort of more plausible than it might be other places. And finally, well, here we have a company claiming a large effect size compared to that natural history. So it reported, it was last September, a 75% slowing of disease progression on, um, I'll spare you the long acronym but the standard sort of composite scale used in Huntington's trial. So basically, the stakes are pretty high. They go beyond uniQure, and well, I think a lot of people were just looking at it like, well, if FDA doesn't accept a f- a flexible sort of path to submission for this program, what's the confidence that other companies that maybe check fewer boxes, um, will get that kind of flexibility?

Steve Usdin: 7:38

And there's also an element of this that fDA had encouraged the company, right, in the, in the past to pursue a- an approach based on natural history comparator, and that was reversed under, new leadership at FDA, in particular by Vinay Prasad and the, and the staff that he'd put in underneath him at uh CBER

Selina Koch: 7:57

Yeah, there was like momentum building it had seemed. There was, well, there was an RMAT designation, I think in mid-2024, followed by an announcement by the company that they had aligned with FDA on a path that would, allow them to s- not have to go through, you know, Phase III, submit Phase I/II data compared to that natural history. Then September of last year, we got those data, and it was quite a large effect size. But by November, FDA had reversed course. There were more meetings. Then in March of this year, the agency was asking for a sham surgery as a control, so a new trial with a sham surgery control, which raised, you know, ethical issues in the patient community and also some, with some people saying, "Well, I don't know if I want to be in that trial." Like, makes recruitment harder.

Steve Usdin: 8:47

So, so fast-forward, where, where are we now?

Selina Koch: 8:50

Right. So now we're in a situation where it looks like the company can submit a BLA, so it intends to submit a BLA this year in the third quarter, for an accelerated approval

Jeff Cranmer: 9:02

So Steve uh Moderna up before what's now become rare in advisory committee, and then we had news out of REGENXBIO today as well. I know you've been tracking, all of this. what else do you wanna highlight as, as being among sort of biggest uh reversals that we've seen at FDA so far?

Steve Usdin: 9:24

the way I look at it, I don't know if reversal is the way I, I look at it. The way I look at it is kind of reversion to the mean. It's, it's

Jeff Cranmer: 9:29

There you

Steve Usdin: 9:30

putting putting things back on the, on the track that they, um, would have been on and that they were on before Marty Makary and, and Vinay Prasad, took over FDA and took it on a very, in a d- very different way. So one of the stories I wrote last week that's interesting also about this kind of reversion to the mean is about a Sanofi drug called TZIELD. The whole story is really… It's too complicated, to explain here. You really have to go and read my story. But here's the short form of it. TZIELD was was already approved, has been approved for other indications. Makary picked an expanded indication to slow the progression of Type One diabetes for the first cohort of the commissioner's National Priority Voucher Program. Makary said many times that selections for the CNPVs were based on recommendations from FDA staff. He also said many times that political appointees never overruled staff on regulatory decisions under him. But I found a memo from acting CDER director Mike Davis. Mike Davis was made acting CDER director after Makary, um, resigned. So uh Mike Davis' memo lays out a very different story. First, he says neither Sanofi nor FDA staff asked for the CNPV designation. So Makary's statement that all of these designations came from staff, at least in this case, weren't true. More importantly, Davis' predecessor, Tracy-Beth Høeg, overruled staff at least three times to either quash or delay approval of this expanded indication for TZIELD. Høeg was a political appointee. She didn't have the medical background or scientific credibility to personally make decisions about a product like TZIELD, and she made unilateral decisions without providing any written justification. That's what Davis' memo, showed. this is really a violation of FDA's rules, and I think even more important, it's a terrible practice. So, you know, when if you have, political staff derailing a medicine that, that FDA officials, that FDA staff believe could help type 1 diabetes patients, who are mostly children and adolescents stay off insulin longer, and not even writing down her reasons, for doing that shows a complete lack of accountability. So anyway, now it's been approved and, um, thanks to Davis's memo we know how close it came to being held up and why.

Jeff Cranmer: 11:52

how about RegenX and Moderna? What can we learn from those reversions to the mean?

Steve Usdin: 11:59

Yeah, yeah. So ReGenx Bio, you know, they have a, a gene therapy for a form of, MPS a terrible progressive neurological disease, very rare. They also had been on track, to get approval. It was derailed under Makary and Prasad. What we've heard today is that, they've reached alignment, with FDA to move forward. Basically, it looks like it's gonna go forward as if Makary and Prasad had never been there, and we're gonna see what would have happened, under a more normal arrangement at FDA

Jeff Cranmer: 12:31

Thanks for that, Steve. You also wrote a story on signs that political influence at FDA are continuing. Um, didn't go away with change in leadership necessarily. Uh, what have you found there?

Steve Usdin: 12:45

So look, there's a lot of enthusiasm among patient advocates in the biopharma industry over FDA getting drugs that were derailed under Makary and Prasad back on track. We just talked about some of them, right? I think that there should be some concern over how this is being accomplished. In some cases, there's an appearance of political involvement, indications that the walls between FDA review staff and political appointees and the White House that were breached under Makary haven't really been patched up. So one example is Replimune's melanoma therapy. It received two complete response letters, rejections under Makary. FDA was sharply criticized by the Wall Street Journal editorial page. there's a lot of other criticism. Now it's back on track. and I'm not really expressing it, I'm not expressing a view about whether the drug should be approved or not. That's a completely different issue. But what I want to flag is that I found that on May twenty-seven, Replimune's CEO, Sushil Patel, met with FDA's acting chief of staff and chief counsel. Those are both political appointees. Josh Hoyt, associate counsel in the Executive Office of the President, also attended the meeting. That's really unusual, maybe unprecedented. I've never seen it before that a, a White House lawyer attends a, a meeting about a product approval with two political appointees. Prior to Makary, this would have been completely extraordinary, even leaving aside the White House involvement. You wouldn't have CEOs meeting with staff of the office of, in the office of commissioner or the, chief counsel about a live controversy that's at FDA that's going to be decided by FDA reviewers. So two days after this meeting, Patel announced in a press release that Replimune and FDA had aligned on a path forward for resubmission and reconsideration of the company's BLA. again, I'm not commenting on the merits of the BLA or what decision FDA should make about it, but this really has the appearance of a political process rather than a scientific decision, and it's not by itself.

Jeff Cranmer: 14:48

What else, Steve?

Steve Usdin: 14:50

so on, May twenty nine, the day that Replimune announced that it aligned on a path forward, with FDA, FDA's acting chiefs of staff and chief counsel met with Amgen's executive vice president for R&D, Jay Bradner, about Tavneos. Tavneos is at the center of a complicated controversy. Short form, FDA wants it pulled off the market, Amgen is resisting. In my story, I outlined the arguments, both sides of the story. but the point I wanna make today is that this is the kind of dispute that in the past, again, would've been handled entirely by non-political staff, and now we're seeing meetings between the company and two political appointees. I don't know, nobody knows how this is gonna work out. We don't know, what they discussed, but it adds to this sense that, FDA kind of, breached this wall between being a nonpartisan and non-political agency that made decisions that were made by career staff based on science and medicine. And people could argue with the decisions, people argued with many of the decisions, but they couldn't, they couldn't lean on them through the political process or through political appointees to change their decisions. That's definitely what was happening under Makary, and it appears to be, at least there's an appearance that it's still happening, under Acting Commissioner Diamantis. I think that the real issue is going to be w-what happens with the next commissioner when, when they appoint and uh and, and the Senate confirms an acting… uh, I'm sorry, a permanent commissioner. One of the real things to look for will be whether we see this continuing involvement of political appointees, in regulatory decisions about, issues that are pending before the agency

Jeff Cranmer: 16:37

why do you think we're seeing it now? Is it, is, is it something inherent in the Trump, the way the Trump administration operates? Is it sort of this disruption of normal chain of command at FDA that's occurred over the past, you know, 18 months, 12 months?

Steve Usdin: 16:54

I, I think that there has been… I, I think it's a couple of things. One, I think that there's a recognition by the new acting leadership at FDA that, um, there were a lot of things that were done under Makary that were bad for patients, and that were bad for the biopharma industry, so there's a desire to clean up that mess as quickly as possible to show that there's high level interest among the political, appointees at FDA in cleaning up the mess. So that may be one of the things that's motivating these meetings. There's also, I think, an issue that a lot of the staff who had been there for years and years, for decades in some case, were swept out by the DOGE and by the things that happened in the aftermath of the DOGE. So the, the institutional memory about the importance of maintaining a firewall between regulatory decisions and political appointees and the political process may have walked out the door, with experienced people who left, and there's this kind of precedent that was set under Makary

Selina Koch: 18:00

So that's interesting because I-- when I was listening to you, I was wondering, okay, is this need to show right now that they're doing things to clean up the mess, does that indicate that this might be a temporary situation, or is it longer lasting?'Cause earlier you had talked about FDA undergoing a reversion to the mean, like a process underway. Certainly doesn't sound like we're all the way back to normal yet. Do you think it's gonna resolve itself, or what, like, what needs to be the path?

Steve Usdin: 18:27

Well, so we're not back to normal yet. Nobody knows, what's gonna happen. Look, we still have, Robert F. Kennedy as the HHS secretary. Um, we still have, Donald Trump who's got ideas about, running government that are different from, um, from his predecessors, and they involve m- much more direct, assertion of executive power over decisions that in the past, were left to the experts and, and, and career staff. I think it's, it's too early to say. I think it's possible that a, a new commissioner will come in and have the, the will and the authority to re-erect these walls between, the political appointees and the political process and, regulatory decisions. You know, what, um, former commissioners have told me, they viewed their job as being a heat shield, you know, between, um, the political process and the, um, and, and regulators. So it's not out of the question that that could happen, but it's also not a certainty

Jeff Cranmer: 19:24

All right thanks for that, Steve. Good question, Selina. We're gonna take a quick break, and then we're gonna come back. Lauren Martz is here to talk about a first in the world of CAR T cells.

Voice Talent: 19:36

This episode of BioCentury This Week is brought to you by the 13th China Healthcare Summit, taking place November 2nd to 4th in Shanghai Everyone has an opinion about China biotech, but there's a difference between reading about cross-border deals and seeing it for yourself. The 13th China Healthcare Summit brings you to Shanghai November 2nd to 4th for a firsthand look at China's innovation moment. Join BioCentury, BayHelix, and insights partner McKinsey & Company for a deep dive into China's biopharma ecosystem and meet the biotech leaders who are driving all the newsflow. Sourcing innovation. Building NewCos. Generating faster clinical data. Reimagining your R&D strategy. For a dozen years, the China Healthcare Summit has gathered the right people to network and build business. Now it's your chance to be in the room. Join us in Shanghai this November. Opt into the tour of Suzhou and a visit to Shanghai clinical trial centers. See it for yourself. Register at biocenturychinasummit.com.

Jeff Cranmer: 20:43

All right, we're back on the BioCentury This Week podcast. I'm Jeff Cranmer host of the podcast and executive editor here at BioCentury. news out of China. CARsgen announced the approval of Satri-cel the world's first CAR T cell therapy for solid tumors. Here to talk about it is Lauren Martz. Lauren

Lauren Martz: 21:08

Thanks, Jeff. yeah, so I, I think this is noteworthy because it's the first approval for solid tumors. Um, so this is just a big milestone that companies have been working toward for a long time. CARsgen's Satri-cel was approved as third line therapy for gastric and GEJA cancers in China, as you mentioned, and this is targeting Claudin 18.2. So this is a hot target that we've seen emerge for gastric and related cancers, in China, in Asia particularly, where these are pretty prevalent. Overall an important milestone. I think it also tells us a few things about at least what this first generation of solid tumor CAR Ts is going to look like, and it's different from the heme CAR Ts that we already have on the market. This is not necessarily positioned as a cure, you know, as something that's creating really long-term remissions for a huge percentage of, of patients with this disease. In the registrational trial in China, there it did almost double progression-free survival, but you're talking about gains from, you know, less than two months to less than four months, in this group of patients, and response rates that are, you know, a, a-- twenty-two percent, I think, in that trial. So it's sort of a different bar, but a very important advance still for the modality and for this really difficult to treat cancer

Steve Usdin: 22:40

think they uh do you think that we're gonna see them applying it in the United States? And, and if they do since this is a, an indication that's much more prevalent, in Asia, do you think that there's a chance that the FDA would accept, China-only data? Or are we gonna have to see-- Are they gonna have to do trials outside of China, in the United States and other countries to be able to even file in the United States?

Lauren Martz: 23:06

I think those are great questions. I think this would be a great example of where FDA could accept China-only data because of the prevalence in China versus in the US. I, I don't know the answer to that question. The company hasn't said too much specifically about development in or for the US. They did say that the plan is to expand for other regions. but the trials that I've seen ongoing are within China. There are a couple of IITs for earlier lines of treatment where you may see better efficacy, be- uh, better durability, and there's also a Phase I study in pancreatic cancer

Steve Usdin: 23:40

And I- IITs, investigator-initiated trials, right?

Lauren Martz: 23:43

Yes

Selina Koch: 23:44

Let's think through the risk-benefit a little bit. So if this is doubling the survival from less than two months to less than four that's just a very different situation than what we've seen with prior CAR. So if this is autologous, we all know about the manufacturing being very difficult COGS are very high. The adverse events with CAR therapies are also, formidable. They have to be managed. They can be severe. How do you, you know, in that context, how do you think about the applicability? Of a therapy, CAR therapy like this?

Lauren Martz: 24:17

A good question. Um, and I think the fact that-- For, so first of all, we're talking about progression-free survival on the two to three and a half month range. Um, overall survival in the intent-to-treat population was almost eight months for the Satri-cel arm and five and a half months for the physician's choice. So longer than those timelines, but still very short. So I think it's, it's an unmet need situation. But yes so complicating the risk-benefit sort of equation is the fact that this therapy was also dosed up to three times in these patients, which also hasn't been typical of a, a heme autologous CAR T. And each time that it's dosed, it's given with the preconditioning regimen, which is something that adds toxicity. Cytokine release syndrome was seen in almost all of the patients. A high percentage of patients had grade three adverse events more broadly. So yeah, logistics, toxicity, those are really big factors in how and when this would be used. But again, very short survivals in the third line setting. And we don't know how this will look in the earlier lines of treatment, where we've seen with heme cancers much, you know, much better, results when patients are treated earlier and their T cells are healthier and things like that.

Selina Koch: 25:35

So one of the difficulties, right, of applying CAR T therapies to solid tumors is that you can have multiple drivers within a solid tumor. There's heterogeneity in the tumor, and I think this has a one target, right? So is-- are these GI tumors with Claudin 18 a little bit more homogeneous than other tumors?

Lauren Martz: 25:53

It's a-- I, I'm not sure what the answer is. It's a, a widely expressed target, and I think the fact that this target is pretty selective for the tumor tissue is one of the reasons that this worked out. Um, so something else that's interesting about this approval is the fact that a lot of the CAR T development activity that we're seeing in solid tumors has sort of fancy add-ons versus what we've seen in heme cancer. So they're armored, they're logic-gated, they, you know, it only works if you're hitting both targets, things like that, to sort of bring down the immunosuppressive tumor microenvironment barriers to these cells and make it more selective for the solid tumor cells, um, or potentially address heterogeneity with multiple targets. This is more simplified than those. Therefore is not necessarily a reflection of how well those will work when they're applied to solid tumors as well. But, you know, there was definitely an efficacy signal. It's, it's a, a clinical benefit for these patients, and, again,

Selina Koch: 26:54

Baby step. An important baby step. Yeah.

Lauren Martz: 26:56

it's a step, it's a milestone

Steve Usdin: 26:57

and,

Lauren Martz: 26:58

for sure.

Steve Usdin: 26:58

And is uh is it important because I think people are gonna call attention to it that this ba- this step, baby step or not, was taken in China, right? Not in the United States. Is it indicative, do you think, of China being a- ahead of the United States, if you wanna call it that way, if you wanna look at it as a competition in CAR T?

Lauren Martz: 27:17

I think so. So a lot of the solid tumor CAR T-cell studies that we've seen have been early-stage trials in China, taking advantage of the IIT pathway. It's where a lot of the innovation is happening. I don't really have a response about, you know, the fact that it was approved in China. But again, this is-- it's hard to find a solid tumor target where you could just target it simply without any kind of, um, as we talked about, the logic gating, things like that, to make it more selective for the tumor. So this has been a hot target, and it's one that happens to be for China-prevalent cancer. So that has contributed as well. But I think it's the fact that you can do this testing of high-risk, innovative new technologies and mechanisms, cell therapies in China, and the fact that we happen to have a target that's proving very interesting for cancers that are, are prevalent in the region as well

Selina Koch: 28:12

We did quantify in one of our analyses, like I think last fall, the level of clinical activity and deal activity across different modalities in cancer and the bulk of the cell therapy work, of which most was CAR T-cell therapy work, was happening in China in that analysis

Lauren Martz: 28:31

Yeah, that's not surprising. And, um, also one more note about this program is that it was approved with a modified preconditioning regimen. So I said there are no fancy elements to, to this particular CAR T-cell therapy. That's not entirely true. They approved it with the standard preconditioning plus a low dose of paclitaxel, which is not generally used. So that helps sort of penetrate the tumor stroma more than the traditional preconditioning and, maybe help the, the cells access the solid tumors better

Jeff Cranmer: 29:05

Okay, and uh I'll drop a link to Lauren's story on this approval in the show notes, as well as uh Steve and Selina's coverage of the revisions to the mean. Steve, I'm gonna go with that. It's a little longer than reversal, but, you know, we're all about getting it right. And of course, Paul's story on the big AbbVie deal. I'll be away next week. Stephen Hansen will be here to guide you through the latest in biotech. Thanks for tuning in. If you like what you're hearing, drop us a comment give us a like, subscribe, and stay tuned later this week. I have the pleasure of speaking with Franck Jiang of Hengrui the biggest deal maker in China right now China's leading biotech. It's, done a lot of NewCo deals, um, a lot of big partnerships with BMS, GSK, and it'll be a fun conversation, so that will be out on Thursday. Thanks for tuning in