# Episode 162 - November 7, 2025

An episode of [Biotech Hangout](https://invisiblenetwork.ai/podcast/1568911820), 7 Nov 2025, 1 h 00 min.

Audio: https://anchor.fm/s/55bdff38/podcast/play/110860051/https%3A%2F%2Fd3ctxlq1ktw2nl.cloudfront.net%2Fstaging%2F2025-10-7%2F410887689-44100-2-0c0e7bf81846d.m4a

On this week’s episode, Graig Suvannavejh, Paul Matteis, Brian Skorney, Yaron Werber, Chris Garabedian, and guest Adam Feuerstein open with a discussion on George Tidmarsh’s departure from the FDA and the uncertainty it has caused in the markets. Next, the co-hosts discuss the shifting policies of the FDA and Sarepta’s Phase 3 ESSENCE trial of casimersen for DMD with the group debating if the drug actually works. Biohaven’s complete response letter for its new drug application for its spinocerebellar ataxia drug is also mentioned. The co-hosts also overviewed the FDA’s decision deeming Uniqure’s Huntington’s disease therapy data inadequate, and the read through for other companies like Stoke Therapeutics. The conversation shifts to company news where Novo Nordisk and Pfizer’s bidding war for Metsera is noted as a positive for biotech investors. Next the co-hosts discuss Soleno Therapeutic’s stock moves amid questions about its growth trajectory. The episode concludes with a look ahead to ASH 2025 with a preview of Terns Pharmaceuticals CML data. *This episode aired on November 7, 2025.

## Transcript

[0:00] You're listening to Biotech Hangout, a live and unedited
[0:02] weekly discussion of all the latest news in our industry with
[0:05] a group of biotech insiders. I'm Greg Sivanovich and my Co
[0:08] hosts today are Brian Scorney, your own Werber, Paul Matisse,
[0:12] Chris Garabedian and a special guest Adam Forstein.
[0:15] For more information about our hosts and our guest speakers or
[0:19] to listen to the most recent episode, please go to
[0:21] biotechhangout.com. So with that said, it's
[0:24] certainly been a bit of a helter skelter week with earnings,
[0:28] regulatory news, clinical data news, MNA updates, but things in
[0:34] biotech continue to be volatile. I thought they'd be on the up
[0:38] and up. Today seems to be a weekday in
[0:41] the tape, but let's hope things move in a positive direction as
[0:45] we finish out this year. I thought that we'd start with
[0:48] some high level policy and regulatory news, certainly
[0:54] headlines around George Tidmarsh resigning and a lot of theatrics
[1:01] that seem to be in the background.
[1:04] I think. Adam, do you want to comment on
[1:07] this and start off there? Yeah, it was quite the start to
[1:10] the week, right, with George Tidmarsh had a cedar, I guess
[1:15] depending on which kind of side of the story, he either he was
[1:18] put on leave, he resigned, he decided to fight the
[1:21] resignation, but now he's gone. But yeah, this all, you know,
[1:25] kind of give you the little back story.
[1:27] This all had started happening actually a week ago, right when
[1:31] when George Jim March was called into Makari's office.
[1:34] As we reported on last Friday, George thought that he was
[1:38] actually going to get some good news during this meeting with
[1:41] Martin Makari that that Vinay Prasad was going to be fired
[1:46] from the FDA. Instead he heard, he learned
[1:49] that no, in fact it was him who was getting the boot.
[1:54] And this all sent it around as we reported, sent it around a
[1:59] complaint that had been filed by Kevin Tang, healthcare investor.
[2:03] I think probably a lot of people on this call at least know or
[2:06] heard of who had filed A complaint with the F with the
[2:08] FDA about the fact that just that George was using his
[2:12] position as head of Cedar to essentially exact revenge on on
[2:19] Kevin because of some, you know, the, the falling out that the
[2:23] two of them had. Years ago, I think that it's
[2:30] created a lot of uncertainty in the markets clearly.
[2:33] I mean, I think we had come to a place where you know uncertainty
[2:38] with FDA, it seems as if you know, investors had become a bit
[2:44] more comfortable with the uncertainties.
[2:46] But certainly today's or Monday's news clearly kind of
[2:51] sets things in a in a completely different direction.
[2:54] I think we've had some other FDA related news that has impacts on
[3:00] individual companies and particularly with respect to
[3:03] Surrepta. We've got a couple of analysts
[3:05] that cover Surrepta and maybe I'll start off with with Brian,
[3:09] if you want to comment there. Yeah, I'd love to kind of kind
[3:13] of bring that up and think, you know, actually surrept is
[3:17] something we want to talk about a little further down because
[3:20] just kind of going back to Adam's commentary on on the
[3:22] Tidmore resignation. You know, I think one of the
[3:25] things that I've heard a lot from investors and what came
[3:28] really on top of this is not just his resignation, but the
[3:30] the Unicure news. And and you know, I'll try to
[3:32] pass it over to to Paul to kind of to walk through a little bit
[3:35] of that. But one of the big things that I
[3:37] think came about both through the the Tidmarsh news over the
[3:40] weekend and the Unicure decision is this elevation of concern
[3:44] among investors that it is now, you know, more than I Prasad's
[3:49] FDA, then Tid Marsh's FDA certainly or, or sort of the the
[3:55] messaging from, you know, Mccarry that we've had on sort
[3:58] of like the flexibility, like, oh, we're going to prove things
[4:00] for orphan diseases based on, you know, Natural History data
[4:04] or, you know, based on preclinical evidence, stuff like
[4:06] that. Sort of pushing sort of the, you
[4:08] know, the the classical GOP talking points, you know,
[4:10] enormous flexibility around these things.
[4:13] And you know, so I think TID Marsh kind of losing out and
[4:16] what seems to be a little bit of a civil war with with Van I then
[4:21] leading into the unicure decision.
[4:23] And you know, we'll have to discuss thoughts on that.
[4:27] But I think certainly there's a concern that, you know, is that
[4:29] unicure flip tied somewhat to, you know, maybe even I being
[4:34] more of the emerging vector in in in the Civil war period.
[4:37] It's certainly something where I think those those of us who know
[4:40] what I know Adam and I know him from from long ago, you know,
[4:44] it's it's sort of the type of thing that he would really look
[4:46] at and scoff at. So I don't know, maybe I'll
[4:48] maybe maybe we should jump to Paul first to just kind of talk
[4:51] through the the unit care decision.
[4:53] Yeah. Essence kind of ties in down the
[4:56] stream. Yeah.
[4:58] Thanks, Brian. Can everyone hear me OK?
[5:00] Yeah, we can. OK, great.
[5:01] Thanks guys. Yeah, the uni cure thing is, is
[5:04] crazy because I mean, I think at face, you know, even if you're a
[5:10] believer that the efficacy of their Huntington's gene therapy
[5:13] looks promising at three years or really, really promising.
[5:16] I mean it's still I think reasonable no matter how bullish
[5:19] you are that you can debate those data, right?
[5:22] It's not a big sample. We know the study didn't
[5:26] separate from placebo at one year.
[5:28] There's a valid explanation for that, but that's just the
[5:30] reality. So I think like, you know,
[5:33] there, we we all knew, I think people who own unicure, right,
[5:36] that there's, there's valid nitpicks with those data, even
[5:39] if they look really promising. And the three-year data was kind
[5:42] of backed validating the two year breakthrough therapy
[5:46] status. But you know, I think the bigger
[5:48] issue here is that, you know, it just makes the FDA seem super
[5:53] unpredictable in this space. And, you know, none of us were
[5:57] in the meeting, right? Like as an analyst covering
[5:59] Unicare really closely, I haven't seen meeting minutes.
[6:02] So, you know, we've seen companies in the past, right,
[6:05] like misinterpret the FDA or think the FDA's vibe is super
[6:09] positive, but it's a little bit more neutral, right?
[6:11] We understand that there's a subjectivity to this.
[6:13] But I guess just being close to this Unicare situation, like I
[6:17] thought their regulatory alignment for something flexible
[6:20] like this was, was maybe a lot more thorough and rigorous than
[6:24] average, right? Like they had had a meeting a
[6:26] year ago using this kind of Natural History control for
[6:30] their analysis, right? And you know, that's one thing,
[6:33] right? You could just say the FDA is
[6:34] open to it. But then they had a separate
[6:36] meeting in the spring where they actually essentially like
[6:40] unified on an SAP, right? A statistical analysis plan for
[6:43] this three-year data and incorporated some really
[6:46] specific feedback from the FDA, right?
[6:48] The FDA actually, you know, was kind of aligned with them using
[6:50] a different Natural History database than the two year data,
[6:54] a slightly different analytical methodology with how you compare
[6:58] the patients in their study to a Natural History study.
[7:01] And alongside this meeting Uni cure got breakthrough, right,
[7:04] Which you know, seems like the FDA is kind of saying, hey, this
[7:07] two year data looks promising. We're setting you up with an SAP
[7:12] that if you actually corroborate this again, like you're set up
[7:15] well, right? So for them to have this
[7:17] three-year data that was considerably better than than
[7:20] expected, right? They essentially had disease
[7:21] slowing versus Natural History of 80% of 2 years, 75% of three
[7:24] years for their high dose. And then to have this meeting
[7:27] where essentially we don't actually have the, they don't
[7:29] have the minutes of the outcome, but they're saying that the FDA
[7:32] kind of conveyed to them that this Natural History analysis
[7:35] actually, because it wasn't the goal of the study from the
[7:37] outset, is actually exploratory and not, you know, something
[7:41] that could support a BLA submission.
[7:43] I mean, it's, it's really surprising.
[7:45] And I think there's some investors who again, have come
[7:47] out and said, well, hey, like this data has had issues.
[7:49] We've known that like to me, like that's not the point.
[7:53] Like the point is like they had a meeting around an SAP four
[7:57] months ago. Like are we supposed to believe
[7:59] that that was like a sham meeting, right?
[8:01] Like, for lack of a better word. So like, I just think like for
[8:04] the investor community, if we just kind of take a step back,
[8:06] like obviously we'll see how the UNIC your situation plays out.
[8:09] Like there was a Wall Street Journal op-ed this morning that
[8:12] seems to be applying kind of the same sort of pressure on the FDA
[8:15] that we had seen over the summer with Replimune and and self
[8:18] Biosciences. But then separately, you know,
[8:21] there's this kind of broader flow through to the gene therapy
[8:24] space because you know, there's a number of other companies in
[8:26] this space that are running single arm phase three studies.
[8:30] I think what what a few of those companies have come out and
[8:32] said, and rightfully so, is that we've sort of pre specified this
[8:35] from the beginning. But you know, like as as
[8:38] Scorney's talking about, right, like all these things are
[8:40] changing in real time. Like, you know, if, if Prasad is
[8:43] just kind of won the recent power struggle and like, you
[8:46] know, I think there's investors kind of asking, OK, well, what
[8:48] are the implications for for everybody else?
[8:51] And, and, and I think the other sort of complicating thing here
[8:53] too is that we actually in late September just got FDA traffic
[8:58] guidance for gene therapy and cell therapy that like sort of
[9:03] aligns with Unicure and many of these other companies are doing.
[9:05] And, and again, like late September feels like right now
[9:08] to me emotionally like a year ago, but it was 5 weeks ago.
[9:11] And so I, I mean, I think all of this stuff is, is still really
[9:15] dynamic. It feels like the Tidmar
[9:17] situation to me, even though it's potentially unrelated to
[9:21] what's happening at Sieber, opens the FDA up to maybe more
[9:25] political pressure just because of the broader optics around
[9:28] instability. But you know, guessing what the
[9:30] next move is is hard. And you know when, Adam, I'm not
[9:33] saying this, you're on the call. Some investors have been asking
[9:35] me what's the next catalyst for Unicare.
[9:37] And I'm like, well, let's see the stat news expose and what's
[9:40] happening at the FDA. Well, we're, we're, we're
[9:42] working, we're trying, we're trying to do that, Paul, but I
[9:45] want a question for you that as a follow up, because I think you
[9:47] made a good point about the, you know, that there are, there has
[9:50] been some debate about the data and, and the way it's been
[9:53] analyzed with the Natural History.
[9:55] Do you feel like these kind of issues, though, are review
[9:58] issues, meaning that, you know, maybe in a different time and
[10:02] place within the FDA that these are the kind of things that, you
[10:05] know, they would have filed, that the filing would have been
[10:08] accepted. And these are the kind of things
[10:09] you would see brought up at an ad com.
[10:12] You know, these are the kind of things that you would want to
[10:14] deliberate over during the review process and not just tell
[10:17] a company, no, you can't file. I mean, you would think so.
[10:20] And Adam, I, you know, I, I follow closely what you guys
[10:23] write. I follow what you've been saying
[10:24] about this on, on Twitter. Like, you know, you were saying,
[10:27] Hey, none of us were in the meeting.
[10:29] We don't know if there's something else about this data
[10:32] that we like haven't seen or there's like a nuance with that
[10:34] that's an issue. Like all of that is true.
[10:36] But again, at least as I understand it, like, you know,
[10:40] they're going to have to do if this ever gets filed, like
[10:43] sensitivity analysis around different ways to analyze this,
[10:46] compare the analytical methodology and how you compare
[10:49] first Natural History. I understand it like this enroll
[10:56] HD study that they used versus track HD.
[10:58] And there's one other Natural History cohort that they could
[11:01] be like they're all very, very similar.
[11:03] So you know, to to your point, Adam, like if this actually kind
[11:08] of got rejected under greater scrutiny from the FDA, like it
[11:13] feels like that would have happened during a review.
[11:15] Like I guess what I'm trying to say is like, I don't know what
[11:17] could have happened at this meeting with the data we've seen
[11:21] and my understanding of kind of what the little basic high level
[11:24] sensitivity analysis would be that.
[11:37] Did you all lose Paul? Yeah.
[11:42] Paul, maybe what we can do is, I know we were talking about kind
[11:47] of inconsistencies with FDA and you know, gene therapy has been
[11:52] a space that has had its UPS, it's had its downs.
[11:57] I kind of feel that. You know.
[11:59] Well, there he is, right. Hey, Paul, you're back.
[12:01] Oh, sorry, Paul, we lost you Cut out.
[12:03] Yeah, we cut out. 45 seconds. Yeah, that's awful.
[12:06] OK, I'm sorry guys. I was getting another phone call
[12:10] and I just ignored it and I thought that that was good
[12:13] enough. It's just like the, the platform
[12:15] we're using, I mean, I guess what I was saying and I'll just
[12:18] be very, very brief and then everyone can kind of turn it up
[12:20] is like, you know, what, what Unicurious said about this
[12:22] meeting, which again, what I was trying to say is like just based
[12:25] on the high level disclosures I've seen and then also the high
[12:29] level sensitivity analysis that you would do with this data
[12:31] versus other Natural History databases.
[12:34] It's hard for me to see like what would have come out just at
[12:37] a high level kind of meeting where you're looking at the data
[12:41] like, you know, again, not unlike a super, super detailed
[12:43] patient level. I don't know what would have
[12:44] come out of this meeting that would have like shut the door,
[12:46] right? Like it feels like this should
[12:48] be reviewed to your point, Adam. And then I think the question is
[12:52] just, you know, unit curious said Vinay Prasad was not in
[12:55] this meeting. So is he directing the clinical
[12:58] team, the stats team separately? Is this folks in the clinical
[13:03] team who had been ambivalent but maybe couldn't convey that back
[13:07] when back when others were at at Seaver who've since who've since
[13:12] left like folks that were under Peter Marks.
[13:14] And so just like a lot of uncertainty, but I'm sorry for
[13:18] cutting out and I'll just stop. Talking I would hope, you know,
[13:20] I would hope to see, I mean radical transparency here.
[13:24] And something I wrote this week is, you know, the FDA has talked
[13:27] about radical transparency. I mean, we now get, you know, we
[13:30] now get CRL letters in almost real time, but it can work both
[13:34] ways, right? And so, you know, it seems like
[13:37] it'd be a good if, if Munich feels like it's in the right
[13:40] here and that this is just sort of this unilateral power grab by
[13:44] Vinay to, you know, just sort of to put a stamp on this.
[13:48] You know, we, we would be great to see all those meeting minutes
[13:51] from Uniquer, right? All the the past meetings, all
[13:53] the agreements, everything that the FDA told them, you know that
[13:59] I feel like, you know, put that out in the open so that we can
[14:02] all see it. Can I, can, I just want to add
[14:05] just on, on sort of that topic. I mean, I think as much as we
[14:08] can like say, you know, is it Vinay specifically as a result
[14:12] of a power struggle inserting himself here?
[14:15] You know, I think it's going to be like less explicit than that.
[14:17] I think that what you see in the FDA is, you know, review teams
[14:21] feel emboldened one way or another based on sort of the,
[14:25] the, the leadership mentality, right?
[14:26] And like Peter Marks like really pushed for this flexibility.
[14:29] And I think the review teams felt that push from leadership
[14:33] ship for flexibility, right? You know, Wilson Bryan was
[14:36] before him. He was less flexible, but he
[14:38] kind of, you know, he was sort of shown the door by Peter Marks
[14:43] in an effort to be more flexible, right?
[14:45] So I wouldn't be surprised if, you know, this isn't finite.
[14:47] Like very specifically stepping in and saying, Hey, This is why
[14:51] this is like not going to fly and we're not going to review
[14:54] this. I think it's it's more right.
[14:55] He is the de facto leader of Sieber.
[14:57] He has very, very clear views that we know that are well
[15:00] publicized on his YouTube, on his podcast.
[15:05] So, you know, we basically know his take on Natural History
[15:09] studies for slowly progressive diseases.
[15:12] And and you can pretty much pull slides up on that.
[15:14] And I think we'll talk about some other diseases that he's
[15:17] been vocally critical of in a couple of minutes here.
[15:19] But I just wonder if it's if it's less that these are a bunch
[15:23] of applications that are really on the bubble, right?
[15:25] Like I don't think anyone's looking at the uni cure data and
[15:27] saying, Oh my God, this is a Lazarus effect.
[15:30] You're kind of looking at the data and you're hopeful that
[15:33] when you do a comparison to Natural History that you're
[15:35] showing a slowing in the progression of the disease.
[15:37] But I think the level of certainty is certainly not
[15:39] there. And that's a lot of these
[15:41] applications. So I think when you think of
[15:43] these bubble applications, I just wonder is it, is it just
[15:46] the tone from leadership in the FDA that's shifting things one
[15:50] way or the other? Well, we, we for whatever it's
[15:53] worth, we spoke with, I'm just, I guess it's OK for me to say
[15:57] this was public with Ultra Genex this week.
[15:59] We did a session with them and they did mention that the bar
[16:03] and agreement they had with the previous Sieber under, under
[16:07] Peter Marks for the filing in, in MPs 3A, you know, UX 111 was
[16:12] gene therapy. That discussion and that plan
[16:16] then shifted under this new FDA and what they again believe that
[16:21] they will be able to do during the review process and in terms
[16:26] of manufacturing documentation and finished some
[16:28] experimentations. Ultimately the you know the car,
[16:32] the carpet was pulled below them and they had to this, they got a
[16:34] CRL out of nowhere and the FDA wanted all that kind of settled
[16:38] ahead of time. So that was a change
[16:40] unexpectedly. Is anyone else like a little
[16:42] confused though? Like it felt like the obvious
[16:46] backlash that came out when when Peter Marx left and you know,
[16:50] basically we had Vinay Prasad and and Macri was that, you
[16:54] know, they did their listening tour, they did their podcast
[16:58] online and it felt like their commentary around rare disease
[17:02] was very Peter Marxian, right? And then, you know, they put out
[17:07] these guidelines at the end of September on cell and gene
[17:10] therapy and again 5 weeks ago that red pretty pretty bullish
[17:15] for the space. Like why are we seeing at least
[17:18] on my read on their kind of public commentary on this stuff
[17:21] is super flexible. I think we're all reading these
[17:24] recent actions as you know, much more inflexible.
[17:27] Like are we supposed to leave that the public believe that the
[17:30] public commentary is a little bit more like politics?
[17:34] Like how, how do we think this kind of all like I mean.
[17:37] Sort of. Result, I think.
[17:38] I think you hit. You hit the you're exactly
[17:40] right. It's, it's the dissonance,
[17:41] right? It's the, the dissonance between
[17:43] the the commentary and the things that Marty Makari is
[17:46] saying that even in some respect that Vinay is saying when they
[17:49] get together and they do their little podcast or in speeches
[17:54] versus the actions that we're seeing, right?
[17:57] They just don't. They don't line up.
[18:00] Yeah. But let me weigh in here because
[18:02] I, I don't think this is new. I think going back honestly a
[18:06] couple decades and definitely, I mean, we're going to talk about
[18:08] surreptive, but the hierarchy was always signaling
[18:12] flexibility. We don't look at phase one
[18:13] versus phase two. I mean, you can get it approved
[18:16] on. I remember Janet Woodcock saying
[18:18] you can get approved on, you know, a small patient study if
[18:20] you have an effect size. And so there was always this
[18:23] disconnect between what the hierarchy was doing.
[18:26] Rah, rah, we're flexible. Like we're willing to work with
[18:29] you and the divisions who wanted to go old school and, and apply
[18:34] that rigor. And so I, you know, I, I kind of
[18:37] look at, you know, because we all heard this from the
[18:39] hierarchy, but translating that into practice is what has taken
[18:43] time. Some would say it never fully
[18:46] was realized, but we did see this slow creep with accelerated
[18:49] approval rare disease. That pendulum can always swing
[18:52] back. But I'm not that surprised that
[18:54] hierarchy because their their job is almost promotion, right?
[18:58] You know, market. The FDA is willing to be
[19:01] flexible for the sake of patients, you know, not getting
[19:04] in the way of industry. So I'm not too surprised that
[19:07] there's this dissonance because I've seen it too, too many times
[19:10] in the past. I, I don't even know that
[19:13] there's that. I mean, I think that there is
[19:15] definitely some, some element of dissonance, but I think when
[19:17] you, you listen to like the, the words, I think there's a
[19:21] certainly at least a rationalization that it's not
[19:23] just a political leaning in terms of the dynamics.
[19:27] And I think, right, you can just go on to pub Med and, and if you
[19:29] just type in Prasad parachute, you'll pull up a bunch of
[19:32] publications that he has published, you know, where he
[19:34] has this view that, yeah, if you have a parachute, a medical
[19:38] parachute where your effect size is 100%, you don't need
[19:42] controlled trials. You don't need a lot of study,
[19:43] you don't need many patients because it, it is so profound
[19:47] that absolutely you do a Natural History study, absolutely you do
[19:51] a 10 patient approval for a parachute, but his whole career
[19:55] arc is showing how most medical interventions are not actually
[19:58] parachutes. And that kind of, you know, so
[20:00] I'll maybe segue into Surrepta and, and, and the history here
[20:03] because to me, I think to some extent, and, and you know, this
[20:07] was earlier in my career, but certainly not early, early in my
[20:10] career. A lot of us kind of kind of mark
[20:13] the Surrepta decision on Exodus 51, you know, going back 10.
[20:17] Years ago as sort of the first shift and it's and it's the
[20:20] first time I remember the intervention of a cedar director
[20:25] to change what is the normal designated signatory authority's
[20:29] decision and LS hunger's decision to recommend ACRL for a
[20:33] Templar cent and and overturn it led to a bunch of controversy.
[20:35] Bob Kalif reviewed it eventually, you know, supported
[20:39] Janet's decision to overturn it, although not necessarily really
[20:42] giving a lot of the scientific support to it.
[20:44] So you know, and you know, Chris, Chris and I go way back
[20:50] from, you know, basically the early days of Surrepta and
[20:54] Templarsen going through the regulatory approval process.
[20:57] Now what happened earlier this week is Surrepta announced
[20:59] earnings and in the concert with the earnings, they announced the
[21:03] failure of a large phase three study.
[21:06] To my knowledge, the largest longest DMD study that has ever
[21:10] been done, not for a Templarsen, but the the two other Exxon
[21:14] skipping agents that they got subsequently approved by the FDA
[21:18] and Goldersen and and Vidipersen and that study failed.
[21:24] We could like talk about the data and you know, Syrepta
[21:26] certainly tried to make the best argument why even though the the
[21:29] primary analysis failed, the trends were favorable, you know,
[21:33] made they made this argument around if you excluded COVID
[21:36] patients, it it didn't work. And you know, I think I'd love
[21:42] to hear Adam and Chris's take on this because I think we've both
[21:45] been, you know, all three of us have really been in the weeds on
[21:47] this historically. And I think at different points
[21:50] really did believe that this drug or this PMO Exxon skipping
[21:53] method hypothesis would would lead to a benefit.
[21:58] You know, it's kind of like a wake up moment for me.
[22:01] Like I don't think it worked like this.
[22:04] And and Chris will probably remember I really pushed
[22:07] Surrepta to do a two year study because I've always said, look,
[22:09] there's a slowly progressive disease.
[22:11] You might not never pick up a signal in A50 patient one year
[22:14] study, But in in the study of this size to not show an effect
[22:18] size, you know, really calls into question what what are we
[22:23] doing? I mean, I, I, you know, I went
[22:25] full snark on, on Twitter or ex Twitter during the call, the
[22:30] surreptic call, Brian, you probably saw it.
[22:32] You know where I said, you know, Doug Ingram is very, very good
[22:35] at making excuses and you know, speaking, you know, you look, we
[22:40] we all know we you know, we went from the six minute walk test
[22:43] was the most was the best endpoint and then well, that
[22:46] what that endpoint failed. So then we went to the North
[22:49] Star. The North Star is the best
[22:50] endpoint and that failed and then we went to the stair, the
[22:53] stair endpoint that they just used and that failed.
[22:57] So I, I mean, I, I guess I just agree.
[23:00] I, I these drugs just don't, they don't work.
[23:03] And I, and all we're hearing is just excuses for, for why we
[23:08] should do something else. I don't.
[23:10] I just don't understand it. I think there's a, it is a
[23:14] debate amongst investors whether this new regime in FDA is
[23:17] actually good for the industry or not good for the industry.
[23:20] Obviously the uncertainty, the kind of flip flopping or the,
[23:24] you know, just unpredictability is, is not helpful.
[23:29] But I'm wondering what, what you all think about this kind of new
[23:33] regime in terms of like you have to have good clinical data that
[23:38] will support an approval. And for even in these rare
[23:43] diseases where yes, we want something out desperately for
[23:45] patients, we've seen that, you know, we've seen a bending of
[23:49] the rules, so to speak, to get certain drugs across the finish
[23:52] line. And I'm, I'm curious maybe Paul,
[23:54] your thoughts and maybe we'll hand it off to your own on, on
[23:58] your thoughts and kind of is this good for the biotech
[24:01] industry, for companies and then for investors as we look to help
[24:04] them, you know, make good stock? Yeah.
[24:07] Craig, I have. Some thoughts on this too, but
[24:09] I'll let Paul in your own way in as well.
[24:11] OK, I'll be super quick because I know everyone wants to chime
[24:14] in. I mean, I think like I, it can't
[24:17] be good right now unless it's predictable, right?
[24:22] Like the unicure situation, like I said, whatever you think of
[24:25] that data, the outcome of them just approaching a pre BLA
[24:30] meeting after four months earlier agreeing on an SAPI
[24:34] mean, whatever you think of the data like that was not
[24:36] predictable. And by the way, the market's
[24:38] telling you that that was not predictable.
[24:40] You know, and I think when we look ahead at other companies in
[24:43] the space that have certain regulatory agreements that have
[24:47] embedded flexibility in them, even with this current FDA,
[24:51] they're still investors who would be interested in funding
[24:54] these programs and putting capital to work to help bring
[24:57] these treatments to patients. I mean, obviously to get to make
[25:00] money on stocks for at the end game is getting drugs approved
[25:02] for patients. These investors are having
[25:05] trouble because I think people don't know if what is being
[25:08] said. You know, I know Chris, you said
[25:10] this happened before, but people don't know if what's being said
[25:12] publicly on a podcast is really like the truth.
[25:15] And so I think that's difficult. Like, you know, Brian, you and I
[25:19] cover Dine. Like Dine has data coming up in
[25:22] DMD by the end of this year. It's a placebo-controlled study
[25:25] and Phase 2, they make 1515 times as much dystrophin, right?
[25:30] You know, I'm sure Brian, you get the question from people on
[25:32] what is the bar on the functional data for Dine to get
[25:36] approved? I mean, I don't, you don't know
[25:38] and I don't know, right? So like, I do think like, even
[25:41] if we can come to some sort of conclusion that maybe like being
[25:45] more rigorous on the data and the efficacy data could be
[25:48] better, right? Which is like a theoretical
[25:50] argument, but I'm open to it. What I hear right now is I cover
[25:53] a number of companies where investors are asking me like,
[25:58] hey, the company has met with the FDA and the FDA said X or Y.
[26:02] Like they don't even think the company's wrong, but they're
[26:05] worried, like, is that alignment real?
[26:08] And I just think that in itself is not good for the industry.
[26:14] Yeah, let let me comment on just all the whole FDA thing.
[26:16] First of all, I, I wanna, I have mud on my face on I thought Ted
[26:21] Marsh was one of the better picks because of his biotech
[26:23] experience. And man, what a rookie mistake
[26:26] he made because it really hurt, I think, the credibility of the
[26:29] agency by bringing a personal vendetta out in the forefront
[26:33] where people have criticized. Is this how FDA responds?
[26:37] Do they like certain companies and not like other companies?
[26:41] Do they like certain CE OS? And, you know, the idea of
[26:44] having a standard where that should not come into play, it
[26:47] kind of is evidence. Wow, Maybe this does come into
[26:50] play more than people realize. So I think there was some
[26:52] serious damage done, the hierarchy in fighting and just
[26:57] the uncertainty and the chaos that seems to ensue.
[27:00] Again, I don't think this is new.
[27:02] And going back to Brian, I think you mentioned it.
[27:04] And what's interesting, Caliph did Caliph supported a committee
[27:10] that was led by Lou Borio that was called the Scientific
[27:13] Dispute Resolution Board. That Scientific Dispute
[27:17] Resolution Board voted in favor of overriding Ellis Ungers
[27:24] position against approval. Caleb supported the scientific
[27:28] dispute resolution board OK to favor Janet's decision.
[27:33] So this idea that hierarchy gets involved, they, you know, they
[27:37] have a dispute resolution process that was followed, You
[27:40] know, all the debate around, I think they follow the right
[27:43] protocol to ultimately approve a Templar sin.
[27:46] Now, I think you said it with the parachute comment, Brian, A
[27:50] Vexus stands, I believe is the gold standard, right?
[27:53] You've got 12, you know, type 1 SMA patients that were still
[27:57] living after two years. Nobody was disputing.
[28:00] That's a clear signal should get approval, should get full
[28:03] approval. We should always have room for
[28:05] that. And I was always on the record
[28:06] of saying DMD is not that right. You're not going to see that
[28:10] type of effect even with a gene therapy.
[28:12] And so just looking at Essence and by the way, Brian, I, I felt
[28:16] a year was enough. And I, I was against the two
[28:19] year because it just meant we would take longer to get data.
[28:22] And I honestly, I'm, I'm appalled that it's taken this
[28:26] long because they renegotiated the trial design.
[28:29] They didn't start it until much later.
[28:31] I was getting pressure as CEO to start that study sooner rather
[28:34] than later. And, and I was actually the, the
[28:36] one who got the first master protocol approved, which became
[28:40] Essence. But then they renegotiated that,
[28:42] redesigned it and it was delayed.
[28:44] So we shouldn't have to take this long to get a readout when
[28:47] that study was approved and designed originally back in
[28:51] 2014. But but I think that ultimately
[28:55] it was a disappointment. I thought that the drug would
[28:58] show an effect. I think it it hasn't.
[29:01] I'm more concerned with what they haven't shown.
[29:04] Adam, you said it that it was 6 minute walk North Star now
[29:07] forced their climb. What did they, what else did
[29:10] they capture and what did that show if the forced their climb
[29:14] is the best data that they were able to muster over 2 years.
[29:17] And I don't know, maybe they've shared more or maybe they'll
[29:19] share it at a a future conference.
[29:21] But you know, I wouldn't want to see the full data set to make
[29:25] any decision. And the only difference here
[29:27] between the way I see it for gene therapy versus oligo RNA
[29:33] chronic administered drugs is that one you've got safety.
[29:37] That is more clear, right, than the gene therapy safety data
[29:41] sets that are coming out. So that's number one.
[29:43] The risk benefit is definitely different.
[29:46] And then #2 you know, there was always this talk of if you
[29:49] approve drugs that are not great, that might, you know,
[29:53] quell other drugs from getting to market.
[29:55] We have not seen that. So over the 10 years, we've only
[29:58] seen more and more and more technologies being moved into
[30:03] the clinic for development because the FDA used a pretty
[30:06] low standard to approve those drugs.
[30:09] But on gene therapy, I think the the issue still stands because
[30:12] you may have to factor out patients who will not be able to
[30:16] get a better gene therapy down the road without taking
[30:19] significant risk with immunogenicity etcetera.
[30:22] So I think these are complicated.
[30:23] And the other thing is this raises the question of is
[30:26] accelerated approval even good for the industry?
[30:29] Does it work when you've got over 10 years, right?
[30:33] You know, thousands of patients that have been on these drugs.
[30:36] I am sure there are parents and Adam, you guys have showcased
[30:40] DMD out of the gene therapy of hey, they're benefiting, they're
[30:43] seeing benefits. So you know, what is the FDA's
[30:46] position to go and say we're going to pull those drugs from
[30:48] the market? And maybe what's driving the
[30:50] bullishness from Doug and surrept is saying, hey, I don't
[30:53] think there's any way these drugs are going to get pulled.
[30:56] And I'm not saying that's necessarily good for the
[30:57] industry, but when you look at the risk benefit, you can
[31:00] understand where they may allow something.
[31:03] And then it comes back to the reimbursement is, are the
[31:05] insurers having more of a position to say we're not going
[31:08] to reimburse because the evidence isn't there and then
[31:11] these poor families are going to have to pay out of pocket.
[31:14] So it's very complex. We do three shows on this, as
[31:17] we've joked about, but I just wanted to highlight kind of
[31:20] those those themes. And then Brian, you've had Bio
[31:23] Haven, which got ACRL, you want to talk about that?
[31:25] Yeah. So I think, I think this is also
[31:28] super interesting in the context of everything that we are
[31:30] talking about as well as uniquer, right?
[31:33] Because in many ways there, there's a lot of similarities
[31:35] here. So by Haven received the CRL
[31:38] this week for their drug Triliazole, which was under
[31:42] review not by Sieber, but by Cedar.
[31:44] So Tid Marsha, you know, last weekend it was Tid Marsha's
[31:48] center. As of today, we have no center
[31:50] director, which is also interesting because I mean,
[31:53] people are reporting that pastor has turned it down as has the
[31:56] OND director. So we'll see who wants to
[31:58] actually take that spot. But Bio Haven sterile was from
[32:01] Cedar. And you know, the, the story
[32:03] here was they, they ran a, a phase three study that was a
[32:08] short follow up and, and it failed on the primary analysis
[32:11] had a very, very high T value. I think it was like above .9 on
[32:14] the primary analysis. But they found a subgroup that
[32:17] they thought there there was some effect size in, you know,
[32:21] eventually they were, they were trying to get approval for that,
[32:24] but said they wound up having a discussion with the FDA to
[32:28] discuss using the open label extension data that they've had
[32:33] to compare to a match Natural History cohort.
[32:36] They've gone through a lot of meetings with the FDA and by
[32:39] Havens press release kind of goes through the, the history of
[32:41] meeting with the FDA to discuss a statistical analysis plan and,
[32:45] and the the way to look at the data sets for this Natural
[32:48] History to then file for a natural, you know, a comparison
[32:51] between this three-year open label data and Natural History.
[32:54] And, you know, there the statistical analysis that they
[32:57] did, you know, hit on primary endpoint, hit on all secondary
[33:00] endpoints. And, you know, it was really
[33:03] kind of marketed as, hey, you know, for, for a Natural History
[33:06] statistically significant data set, this may be the gold
[33:11] standard. And they filed for approval.
[33:12] And there's a lot of skepticism. You know, I think a lot of this
[33:15] kind of look at these Natural History data sets and, and a lot
[33:18] of the comments that, you know, FDA reviewers and, and the bio
[33:22] stats groups within various centers have have talked about
[33:26] just the problems with Natural History and, and, you know, the
[33:29] biases that can be introduced. And it goes back to what I was
[33:32] talking about with like Venice publications on what parachutes
[33:35] are in in medical intervention and they got ACRF.
[33:39] So, you know, it wasn't a total surprise because of its Natural
[33:42] History basis. You know, I think it was a
[33:44] little bit of a surprise in the context that, you know, the bio
[33:47] haven management team kind of position this as a discussion
[33:51] over a long time with the FDA going through rigorous kind of
[33:55] statistical analysis plans for looking at this comparison.
[34:01] And CRL was issued and, you know, the they made an effort
[34:04] within their press release to kind of criticize the FDA and
[34:06] the history and say, hey, you know, this was a big surprise to
[34:08] us. And you know, we really feel
[34:11] like that are not given the proper due course in the review
[34:16] and the CRL is up. And, you know, looking at the
[34:19] CRL, I think it came up yesterday.
[34:20] It's unsurprising they bring up the, you know, the FDA just
[34:23] brings up, hey, you know, when you you make these selections
[34:26] for studies, there's a lot of biases on a Natural History
[34:29] cohort that, you know, you're not accounting for.
[34:32] And you know, they kind of, you know, they don't have a full
[34:35] review out, it's just a CRL, but they do have a couple of
[34:37] paragraphs and sort of the statistical analysis and tipping
[34:40] point analysis to say, you know, when, when you do certain
[34:42] tipping point analysis around the assumptions, they they, they
[34:45] wind up failing statistically. And, and that seems the
[34:48] derivation for for that CRL. So here's kind of an example
[34:51] where, you know, we don't, we were, we were a little blind on
[34:55] what the unicure discussion is. We're less blind on what the
[35:00] biohave and back and forth was because now we have the CRL and
[35:02] we can see actually, you know, this was a review where the
[35:06] statistics of it were were really hammered in the CRL to
[35:11] say, you know, they they just can't look at this three-year
[35:13] open label Natural History comparison data set and have
[35:16] real confidence that the effect size is real.
[35:19] And that's and that's the driver of the CRL.
[35:23] Well, the stock got hammered. And Speaking of stocks that have
[35:27] been reeling, your own you you cover Stoke Therapeutics, which
[35:33] sold off on the heels of the Unicure News.
[35:37] I would love for you to spend a minute or two just on that
[35:39] situation as they try to get a drug approved for a Gervais.
[35:42] Yeah. So, so it's a, it's a great
[35:44] point. And these, these are all, this
[35:45] is a chain and they're all interlinked, all these events
[35:48] and, and, and maybe just to zoom out and and piggyback, Kristen,
[35:52] what you said, is this positive or negative?
[35:54] The the one concern is recall what it was only about 3 months
[35:59] ago that FDA came out with a new draft guidance on behalf of
[36:02] Cedar and CIBAR about using Natural History using for
[36:06] clinical modeling predictive analysis set on on areas where
[36:12] you can have targeted therapy slash genetic medicine based on
[36:16] biomarkers and then using real world data.
[36:20] And all of that can support an approval for orphan indications
[36:23] without controlled studies. Since then it's been a little
[36:27] bit of a train wreck. So you know, this kind of seesaw
[36:31] situation obviously is is sort of not not a positive for the
[36:34] industry. And this leads to Stoke.
[36:36] So Stoke has a drug it just called Zora.
[36:41] It's a Zorvan Orson, it's an ASO for NAV 11, which causes drove a
[36:45] disorder. The Phase 1 two data, the the
[36:49] NAF 11 channel is both excitatory and inhibitory and,
[36:53] and neurons. And that's a channel that's on
[36:56] that is completely affected unquestionably in Dravae's order
[36:59] and it's knocked down. What they're doing is
[37:01] essentially knocking up expression.
[37:03] And in the Phase 1 two data, the data overall looked really,
[37:07] really good. There are four years of data now
[37:08] showing a profound seizure reduction in patients who had 6
[37:11] pretty previous drugs and there's no cognitive benefits as
[37:14] well. It really looks like a disease
[37:16] modifying therapy, but there are some questions and the questions
[37:21] were because they are back up regulating NAV one.
[37:26] One in preclinical models, there was actually some untoward
[37:29] affecting dogs admittedly in very high doses because of that
[37:33] FDA captor dosing. They subsequently in the US had
[37:37] a slightly different trial design than in the UK.
[37:39] They actually had a partial clinical hold in the US also
[37:42] because of an NHP finding which was never seen in patients.
[37:47] And the data overall looked really, really good.
[37:49] But it's not perfect because it's against Natural History.
[37:52] The seizure reduction of you talking about 6080% is
[37:55] unquestionable. So they're in the meantime are
[37:57] now enrolling really quickly. Biogen is their partner.
[38:00] A phase three, it's going to be global looking at one year.
[38:04] I'm sorry. A 24 week seizure reduction is a
[38:08] primary and then secondary endpoints which are important
[38:10] for neurocognition to really get a disease modifying label.
[38:14] In the meantime, because they've breakthrough under a new CEO who
[38:18] maybe is a little bit more kind of savvy or or willing to maybe
[38:23] engage more with the agency under a breakthrough designation
[38:26] maybe than previous management to see if they could file based
[38:29] on phase 1-2. That's the the biggest bottom
[38:31] line and that's why the stock essentially doubled as of two
[38:35] weeks ago and then the unique your decision happened.
[38:38] So now we know Kusto reported they'll meet with FDA in
[38:41] December. There's some challenges though.
[38:44] We've talked to other companies who are developing AS OS for DE
[38:48] ES and they're saying filing based on phase one of phase two
[38:51] data is very complicated and we shall see.
[38:56] It's a little. Unquestionably the drug works,
[38:59] but there's some questions about if you really want to get a
[39:02] broad label with neurocognition, you're going to be looking
[39:04] against Natural History. The dosing in the US study
[39:08] versus the European. The UK study was different, and
[39:11] that's actually even different than what they're doing in the
[39:13] phase three. So which dose do you even
[39:15] suggest to put on the label? There's some structural issues
[39:18] as to what's going to happen with this.
[39:20] Hey, Hey, your own question, just as a follow up, do you
[39:23] think, you know, the stock really started moving up, you
[39:26] know, over the summer, right when when Ian Smith, their new
[39:29] CEO, you know, started kind of talking about this possibility
[39:34] of the early filing because you know, one of the bear theses are
[39:37] or, you know, one of the criticisms was Page 3, it's
[39:39] going to take a long time, right?
[39:40] So like, why be in the stock? It's going to take a long time.
[39:42] So this was, you know, a faster, potentially faster way to get to
[39:46] approval and the company started talking about that and that
[39:49] really resonated with investors. Do you think that that was like,
[39:54] I think people just read too much into that?
[39:56] I mean, you know, obviously it was always going to be sort of a
[39:59] high risk. Thing, right.
[40:01] I mean, it's it's like you like you mentioned it was going to be
[40:03] it's always difficult to to file on on early data like that.
[40:07] Did people didn't? Do you think that people just
[40:09] got too ahead of themselves? On that.
[40:12] Yeah. I mean as you know, Adam, and
[40:13] then it gets into a situation where they have a certain amount
[40:15] of cash and this is going to be a sizable product, right.
[40:18] If and, and all our consultant checks are unbelievably
[40:21] encouraged with the status set that they they think this is the
[40:24] best looking product in development probably ever for
[40:26] Dwivet. But we're not going to have data
[40:28] to your point until second-half 27.
[40:30] So it's a question of what's the chance that they can potentially
[40:33] be on the market a year or two earlier essentially, let's say
[40:37] you know, second-half next year as opposed to second-half, you
[40:39] know 28 in a drug that's going to be you know at 500,000 per
[40:45] year. It's going to be a sizable
[40:46] product and that's got its own inherent value.
[40:49] And so even when the stock was at 38, you know, a week or two
[40:53] ago, people were thinking, OK, it's a 1 1/2 billion market cap,
[40:55] 400 in cash. And if it's going to sell 2
[40:58] billion peak, you can kind of figure out what you think the
[41:00] stock is going to go. And it's not a bad risk reward.
[41:04] And the stock was setting up for an update on the earnings call.
[41:07] People thought, and we all thought the updates going to be
[41:09] whether they met with FDA already or not.
[41:12] And I think there was some hope that they've already met with
[41:15] FDA and had the green light. Look, there's also a question of
[41:18] what FDA says and we all know and then what the company
[41:22] communicates, right? And there's probably 3
[41:24] scenarios. One thumbs up, go ahead and
[41:26] file. And you know, we're very
[41:28] encouraged by the date. I'm very supportive.
[41:30] AK, you're getting approved. 2 is you can file if you really
[41:34] want to. We'll see if we even accept it.
[41:36] And you didn't meet any of your endpoints and things like that.
[41:39] That's probably not going to go out.
[41:40] And then there's always that graze on.
[41:42] It's going to be a review question or review decision.
[41:47] And what exactly that means for Wall Street that's completely
[41:50] opaque because it could be a review decision and they're just
[41:53] kind of, you know, saying, saying it to keep their options
[41:56] open, but they're going to approve it.
[41:57] And they're actually very supportive versus yeah, go ahead
[42:00] and file it to review decision and just say FY how you're not
[42:02] getting approved. We we don't know which one it
[42:05] isn't. That's usually the challenge.
[42:07] And the question is, does the company?
[42:08] Yeah. These are all go ahead I.
[42:12] Was just going to say I, I think like one of the ironies about
[42:15] the Stokes situation and I don't know if there's any, you know,
[42:17] I'm not saying there's tea leaves to read about it, but
[42:19] just to bring things full circle, is the outgoing CEO who
[42:22] left before sort of the concept of filing on this data was
[42:26] actually the CEO who was at Surrepta when a Templarsson got
[42:30] approved? Yeah.
[42:33] That kept a lot of us know. Small world, yeah.
[42:37] In in other industry news, we've got a bidding war going on for
[42:43] Med Sarah, which is a saga in its own right.
[42:47] I can't believe the back and forth.
[42:50] You know, Chris, I think you might want to provide a
[42:53] perspective on what's happening here.
[42:56] Yeah, sure. And it's just a final comment on
[42:59] this whole FDA thing. I honestly, I think it was maybe
[43:02] necessary when the old guard left the FDA.
[43:06] But I long for, I mean, many of us long for the days when you
[43:09] had Janet Woodcock, the Bob Temples, the steady decades
[43:13] long. You've got a whole new regime
[43:16] who has not worked together. And and I think there was even
[43:20] battles and infighting with the old guard.
[43:22] But I think and and Adam, you had a good kind of sober minded
[43:25] view, like let's not blame everything on the FDA.
[43:28] Sometimes you got to look at the data.
[43:30] And I'll just add that industry really looks at these decisions
[43:33] less so than guidance, right? What is the FDA calls on all of
[43:37] these then that's guiding all of us.
[43:39] So moving to Metsera, I mean, this is overall as a investor
[43:43] now this is a good thing. You know, we've been five years
[43:48] in, you know, what was ultimately a by siders market
[43:52] for investment, meaning that like the investors, you know,
[43:56] would dictate the terms for a startup.
[43:59] And this is a clear signal that if you have a good drug and you
[44:03] are in demand and there's scarcity value for a battle,
[44:09] that this is what you ultimately want to see as a biotech
[44:13] investor is that pharma is tripping over themselves to get
[44:17] good assets, right or to not lose out.
[44:20] And so this when we see these types of bidding wars, I think
[44:24] it's good. I mean, at the end of the day,
[44:25] the market caps and the currency value that Pfizer and Novo have,
[44:29] I mean, these become rounding errors and the beneficiary is
[44:33] the mid Sarah shareholders and and and team.
[44:36] And so and it's just nice to see even this kind of a mudslinging
[44:41] right of Novo calling Pfizer right?
[44:43] Like, you know, BS on on their call that it's antitrust.
[44:47] So anyway, it's fun to watch, but I think overall this is good
[44:51] when pharma's stepping and they realize that biotech has
[44:54] important assets and it's nice to see when there's a bidding
[44:58] war that is. For pharma than it's several
[45:04] years other whether we've been huge billions of dollars of
[45:14] revenues that are potentially going away and and big balance
[45:17] sheets by pharma. I missed a little bit of that,
[45:24] Craig. I don't know who was, but
[45:25] basically I think the patent clips are real.
[45:28] I think we had. This is why we've seen some
[45:30] robust M and AI think it will continue for assets that have
[45:34] clear clinical proof of concept that everybody believes is
[45:37] headed to approval. Obviously Avidity is a good
[45:40] example of that recently. And so, you know, this is all a
[45:43] good thing. And along with the XBI, along
[45:46] with the follow ONS, along with, you know, IPO window, I know
[45:49] billion to 1 is not necessarily, you know, drug biotech, but I
[45:52] think there's really good signs that, you know, momentum is, is
[45:56] hopefully going to be sustained. We do have some other company
[46:01] specific news, but before we go there, Adam, you wrote a really
[46:04] fascinating article on Arena Bioworks.
[46:08] Could you share with us kind of with that shutdown kind of what
[46:11] you reported on? Yeah, Yeah.
[46:14] That was my colleagues Jason Mast and Allison Deangelis.
[46:18] Allison actually had gotten a tip a week or so ago, maybe even
[46:22] longer, just that that arena fireworks was was having some
[46:27] difficulties. And for those who aren't
[46:29] familiar, it's kind of, this was a very buzzy sort of, I don't
[46:33] know, I don't know, maybe Chris, you can kind of maybe describe a
[46:35] little bit better than I can, but kind of a hybrid between
[46:37] like a, it's like a Research Institute that, you know, they,
[46:40] they raised like $500 million where it had had $500 million in
[46:44] committed capital to this new venture, which was going to kind
[46:47] of be a bridge between academia and industry.
[46:50] And you were going to get all of these very, you know, a list
[46:54] type scientists to come in and tackle big, big, big scientific
[46:58] challenges and then spin off companies.
[47:01] And then the company by arena, you know, very suddenly and
[47:05] surprisingly shut down this week.
[47:08] There was an all hands meeting where they shut down and
[47:10] essentially over, you know, basically over financing and
[47:13] then the inability to kind of, you know, because of the
[47:16] difficult financing market these days, particularly for private
[47:19] companies, they didn't see a way forward and are shutting down.
[47:24] Yeah, yeah. I'll just add to that briefly.
[47:26] So first shout out to Allison Deangelis because she was first
[47:29] on the on the trail when Arena was being formed.
[47:32] I remember getting calls and I didn't know, but it was
[47:35] basically taking like the the best science out of, you know,
[47:38] the broad and the Whitehead Institute and the Koch
[47:40] Institute. But privatizing that, turning it
[47:43] into an investment profitable model, which many of us felt
[47:47] that was a dubious goal because drug discovery is not easy to
[47:52] drive money. And if if you're gonna pay
[47:55] people top dollar to do bench work and lab research, you might
[47:59] come up with some potential investment ideas.
[48:02] But 50 million a year over 10 years was the idea to turn out
[48:06] all of these new biotechs. And many of us are like, wow,
[48:10] how are you going to really create value when you're
[48:12] basically just coming up with a new drug with maybe a novel
[48:15] target? And the other thing is I think
[48:18] they're dealing with the headwinds of this year alone.
[48:22] When you look at seed and Series A investments, it's been
[48:25] essentially at a 10 year low. So most of the money has been
[48:29] going into de risk, later stage, clinical data-driven biotech
[48:33] series BS, CS and DS. And, and I think they were
[48:36] probably feeling the effects of that.
[48:38] But it's already a hard model even in a, in a healthy market
[48:42] unless everything's going IPO. So not too surprised, but I
[48:46] think the investors were probably saying how we're going
[48:47] to get our money back and make a return after two years and $100
[48:52] million investment. Maybe the writing was on the
[48:54] wall there. What's the pulse from what you
[48:57] you guys are all hearing from private companies have have
[49:00] things maybe gotten a little bit better or they still really,
[49:03] really challenging? I'll just jump in from the
[49:07] venture side. It's a trickle down South.
[49:10] Venture is always a lagging indicator.
[49:13] So when the the public markets downturn, we kind of like say,
[49:17] well, let's wait and see, maybe it'll rebound.
[49:19] And when the market start to turn up, it's also wait and see
[49:22] like is it real? Like can we expect more IP OS?
[49:25] Are the valuations going to be, you know higher and sustained?
[49:28] And so I think right now is probably the most optimistic
[49:32] that venture has been and we're starting to see more check
[49:35] writing, but I'd say we're not all in at this point.
[49:39] We're kind of waiting and seeing, but I think another
[49:41] quarter or two of some IPO's, you know, valuations, you know
[49:45] keeping steady obviously XBI over 100 and seeing some, some
[49:49] growth there. All of those signs are going to
[49:52] really, I think, bode well for venture private companies
[49:56] receiving money in 2020. 6 And my guess, Chris, is that it's as
[50:01] you might have mentioned before, more of the D risk later stage
[50:05] companies may be further in the clinic may be close to, you
[50:08] know, phase two, phase three versus some of the earlier stage
[50:13] stories unless you're a Unicorn of some sort.
[50:15] Is that is that fair as an assessment?
[50:17] Well, yeah, I mean, if you look at the IPO, Q, there's a there's
[50:20] several flagship companies and those were, you know, the the
[50:23] bubble IP OS for a while there. So I think we're going to be
[50:26] watching that closely. I think if if the IPO comes back
[50:29] to supporting an early stage program that maybe is de risked
[50:33] with some you know in vivo PK that shows differentiation or
[50:36] something like that, then you could see you know more money
[50:40] flowing. I think you see a chasing and a
[50:42] following and crowding around certain targets.
[50:44] So best in class I think has a better chance of getting early
[50:48] money than a new unvalidated novel target.
[50:52] You know that is that is in preclinical testing.
[50:54] I think that will take a while for the checks to really start
[50:57] flowing to those types of OK. Great.
[50:59] Let's switch to some of these more company specific items.
[51:02] And Brian, you cover Salino Therapeutics, which was a hot
[51:07] stock and certainly one that people were watching and I guess
[51:11] they reported and and comments on Seleno.
[51:15] Yeah, So, so, you know, you could say I wasn't only blown up
[51:19] on regulatory stocks this week, also commercial.
[51:22] So Seleno announced their quarter and yes, this was, this
[51:25] is a, a, a drug that was approved back in March, you
[51:30] know, not controversial, but a debated approval decision is
[51:33] because they, you know, who originally did an RCT that
[51:37] failed. And you know, they had a similar
[51:40] explanation like Surrepta that, you know, COVID had a role in
[51:43] that failure, but they didn't, they didn't really file for
[51:46] approval based on the RCT. What they did is they did a
[51:48] randomized withdrawal study and the randomized withdrawal study
[51:52] looked very positive. Now there's obviously debates
[51:55] about, you know, how much confidence one can have in a
[52:00] randomized withdrawal study. There's there's more potential
[52:02] bias at play there than in a treatment initiation RCT.
[52:07] But the data looked really good. The FDA approved, I don't think
[52:08] it was a really controversial decision And it's on the market
[52:13] for for Creator Willy, which is, you know, really horrific
[52:16] disease. If if anyone has familiarity
[52:19] with the patients are really need like 24/7 7 care for sort
[52:23] of this, you know, really compulsive desire to eat and the
[52:28] drug treats the this primary symptom which is this compulsive
[52:31] desire called hyperfagia. And that you know, this was the
[52:35] second quarter of sales and it, you know, it doubled the first
[52:39] quarter of sales. It beat consensus.
[52:41] We were street high at 58,000,000.
[52:43] They came in at 66 million. So you know, I think if if you
[52:47] look back in March or April and thought they were going to do 66
[52:50] million in the second quarter, you would think this is a home
[52:53] run of of a stock. If you just kind of looked at
[52:56] the headline without knowing much about it and and knowing
[52:58] sort of where consensus was versus where the sales came in,
[53:01] you think the stock would be up a substantial amount.
[53:04] And, you know, the stock is, is down, you know, more than 30%
[53:08] on, on, on the report. And you know, there's a lot of
[53:12] reasons for this. So, you know, over the summer,
[53:14] the, the Scorpion Capital issued a short report on, on, on this
[53:18] company, you know, basically claiming that you were seeing
[53:22] adverse events stack up, in particular hyperglycemia and,
[53:26] and peripheral edema and pulmonary edema, leading to
[53:28] hospitalizations that, you know, the patients were not wanting to
[53:33] go on the drug or they were stopped taking the drug.
[53:36] Physicians are being more and more hesitant to put patients on
[53:38] the drug. And this is really sort of
[53:42] clouded a lot of the Selenos story.
[53:45] And, you know, interestingly, like talking to investors, it
[53:49] doesn't seem to get a lot of traction that that call is right
[53:52] that, you know, patients are going to stop taking the drug,
[53:55] that physicians are not going to prescribe the drug.
[53:57] And a lot of the data even in the quarter kind of indicates
[54:00] that that isn't the case. That the 397 new start forms,
[54:03] which is certainly down from like the initial bolus.
[54:05] But I still think, you know, weekly rate of about 30 is, is a
[54:08] decent number. The 8 the drug discontinuation
[54:11] rates look that I was sort of what one would expect for a drug
[54:14] and disease of this profile. So, you know, it's not really
[54:17] showing that things are falling off of a Cliff, But, you know,
[54:20] certainly people are, are, are now concerned that, you know, is
[54:23] this a a drug that has a couple of good quarters and then kind
[54:26] of runs into a plateau. And, you know, when I try to
[54:30] have tried to pitch it in in, in the fall off in the stock price
[54:34] this week, you know, a lot of people come back to me and they
[54:36] say, you know, look at like a sky Clara.
[54:38] So look at a debut which had, you know, 2-3 great quarters and
[54:42] then just kind of ran into a wall and like this, you know,
[54:44] call it 80 to $100 million range.
[54:48] And, and those drugs have kind of just been clicking away
[54:50] getting, you know, maybe a little patient growth, but but
[54:52] nothing, you know, like what investors have been looking for.
[54:56] So that's sort of where the, the controversy on on Salino falls
[54:59] right now. Investors are, are a little
[55:02] worried that it's going to take time to really show that like
[55:05] the the plateau isn't going to occur in another quarter or two.
[55:10] And I think with sort of the, the short report criticism that
[55:14] sort of hammered on the ability for people to kind of take more
[55:18] risk on the name. But you know, Adam, Adam had a
[55:21] commentary on, on, on Twitter listening to the call.
[55:23] And, you know, part of the feedback is Selena's sort of a
[55:25] management team that I would argue is very.
[55:29] Opposite. In terms of like Surrepta, you
[55:32] know, and I actually like their management style.
[55:34] They're very non promotional. You know, they kind of talk down
[55:38] their dialogue with FDA throughout the whole review
[55:41] process. They were never like, Oh yeah,
[55:42] like we are, you know, we're personal friends with this
[55:44] reviewer. And you know, the data is just
[55:46] so crystal clear and you know, there's there's no problem.
[55:49] They just kind of characterize it and said, you know, here,
[55:50] here's the data, here are the issues with it here what we
[55:52] think. And you know, to me, they've
[55:55] sort of been a great example of under promising and and over
[56:01] delivering on things, you know, push back now is kind of in this
[56:04] commercial launch cycle of, you know, investors are kind of
[56:07] calling for more energy and more enthusiasm.
[56:09] And one of the things I think really turned people off is they
[56:12] they sort of cited the short report in the call.
[56:15] And you know, I think a lot of us will say management one O 1
[56:20] recommendation would be do not publicly call out the shorts.
[56:25] You can criticize them. You could leave the sell side to
[56:27] kind of try to counter detail of it.
[56:29] But when you when you give them sort of the air, you know, it
[56:33] takes on a whole connotation and people worry, you know, are you
[56:37] worried? And that's why you're doing.
[56:39] Right. I think, you know, I've had
[56:41] experience with Scorpion Capital and my own coverage universe
[56:45] cover a company called Harmony Biosciences, which is in the
[56:48] narcolepsy phase. We have had some narcolepsy
[56:54] marketplace updates and Paul Santessa had some erection data.
[56:59] You want to come on on that? Yeah, very briefly.
[57:02] You know, this erection space has continued to be super hot
[57:05] and interesting. We think these could be a big
[57:08] class of drugs across an array of sleep disorders.
[57:12] You know, we've seen data from Takeda and narcolepsy type 1,
[57:15] Alchemy, some narcolepsy type 1. There's been some historical
[57:18] mixed data and narcolepsy type 2.
[57:20] So going into this Entessa readout, I think there were
[57:22] really like 2 questions. 1 is just as their drug going to be
[57:25] differentiated and two, are we going to see efficacy outside of
[57:29] narcolepsy type 1 because the biological rationale and type 1
[57:32] is uniquely great and then type 2 and other indications like
[57:35] idiopathic hypersomnia, it's it's less clear cut.
[57:38] You know the cintesta data are positive and that the drug
[57:40] clearly works in narcolepsy type 1.
[57:42] There's a big effect size, there's an effect that's clearly
[57:45] clinically significant in narcolepsy type 2.
[57:47] You know, maybe the data didn't meet the bulk case for Syntessa
[57:50] because I think at face it looks more similar to some of the
[57:53] other products. And you know, in the sleep
[57:55] disservice space, we've seen data sets that are in kind of
[57:58] these smaller phase one type studies regress a little bit to
[58:01] the mean in phase two and phase 3.
[58:03] And so, you know, maybe the story there is not over as it
[58:06] relates to Syntessa because they will be kind of tweaking their
[58:08] dosing and potentially going higher.
[58:10] But as I kind of think about it, I mean, this is sort of
[58:11] validating for the whole class in that you can have success in
[58:15] type 2 when you push the exposures higher than type 1
[58:19] because it's a less sensitive population.
[58:22] And you know, and, and the next kind of data set here is we're
[58:24] going to get a bigger, longer phase two narcolepsy type 2 data
[58:28] set from Alkermes. And I think that's, that's going
[58:31] to be a big catalyst for, I think how investors even just
[58:33] kind of view this Contessa data, right?
[58:35] Because their type 2 data set was small and a shorter duration
[58:39] and also the size of the class, because if the Alkermes type 2
[58:42] data is clear cut, you can start to dream the dream around other
[58:46] sleep disorders that are more heterogeneous.
[58:48] So continues to be an exciting space.
[58:52] Yeah, Harmony does have also their own Aurex and it's
[58:55] preclinical, they're going to put it into the clinic.
[58:58] But yes, it's a Rex and this is really and fascinating one that
[59:00] we'll be watching. You know, maybe the last thing
[59:03] that I'll wrap up with is I wanted to make a comment on
[59:06] Turns Pharmaceuticals, especially as we head into the
[59:09] ASH cancer meeting in December down in Orlando.
[59:13] Turns has an allosteric site acting tyrosine kinase inhibitor
[59:20] for CML. Lots of debates amongst
[59:23] investors with another company called Enliven Pharmaceuticals
[59:27] which are therapeutics that has a very intriguing compound
[59:30] that's a little further ahead than Turns.
[59:32] But Turns had some ASH abstract data where six month MMR data of
[59:37] 64% basically like blew the doors out when looking at
[59:43] benchmarks that are for the current other competitor
[59:48] allosteric drug, which had a 25% six month MMR, we had benchmarks
[59:53] of 32% for a six month MMR for the enliven compound.
[59:57] And so if it turns to show 64% was really, you know, a home
[1:00:02] run, the stock is more than doubled since the the beginning
[1:00:05] of the week. So with that said, it is a small
[1:00:07] data set. They're going to have an update
[1:00:09] in ASH. I'll be down there down in
[1:00:12] Orlando later or in early December, but certainly a lot of
[1:00:16] fireworks happening and lots of therapeutic areas.

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