Jef: Hello, and welcome to Biospaces the Weekly. I'm your host, Jeff Axt. This week, all eyes are on the Alzheimer's Association International Conference, or ⁓ AAIC. There, Biogen presented new data from its anti-Tau therapy that industry watchers have lauded as validation for the anti-Tau approach. Meanwhile, psychedelics are back in the news with more positive data from Compass Pathways as well as final guidance from the FDA. And finally, in the ATTR CM space, we got a major shakeup with the late stage failure of AstraZeneca and Ionis' Antisense Therapeutic, which has cast out on Anilem's next gen candidate, but could be good news for Bridge Bio and Intelia therapeutics. Let's get started. Hi guys, how are you doing? We are short one this week with Annalie off visiting family. but glad to have you back, Gabby. Yesterday it was real quiet around here with just me and Heather.

gabby: happy to be I know Mondays are sometimes really hit or miss with news. So how was the news on Monday? Was it busy?

Heather: It was actually quite slow. We were we were grateful for that, although concerned that we might not have enough to talk about today.

Jef: Yes. Luckily AA C I C has come through and then the psychedelics announcement that also r kind of surprised me. That draft is three years old, so I didn't expect that news coming out this week. But anyways, yeah, we did end up with quite the lineup this week. ⁓ we have plenty to talk about.

Heather: Yeah, definitely. I A AAIC has been my world the past week or so. just prepping for it and talking to to companies. And now that it's kinda kinda funny, now all that that data is coming out and I'm like, you know, just kind of watching for the reactions of the analysts. And it's interesting. It's not what I thought it would be.

Jef: you know, some stock movement that maybe we didn't expect even with positive readouts. So yeah, I guess with that, let's go ahead and just dive right in. ⁓ Heather, why don't you start us off with introductions?

Heather: ⁓ sure. I am Heather Mackenzie, senior editor at Biospace, and I together our Clinica Space newsletter, which ⁓ will include ⁓ a lot of AAIC stuff next week.

gabby: And I'm Gabrielle Mason and I curate our manufacturing brief, which goes out weekly on Tuesdays, and then our daily gene pool newsletter.

Jef: And once again, I'm Jeff Axt, managing editor. I'll go ahead and throw out a plug for Annalise Biofarm Executive that goes out on Wednesdays. Again, she's out this week, so I will be putting that together for everyone this week, but she's got us prepped with content. So definitely check out ⁓ Biofarm Executive every Wednesday. All right, so like I said, we're gonna start with AAIC. This is the Alzheimer's Association International Conference. It kicked off in London on Sunday. Heather, as you said, you have been following this closely and you called it when you said Biogen would steal the show with their anti tau readout on Tuesday. So how did that go?

Heather: well the focus has really shifted this week at AAIC from the anti-amyloid therapies ⁓ to anti-Tau therapies such as biogen and ionis ⁓ deer and nursin, which was, like Jeff said, the real hot ticket today at AAIC. despite missing the dose-related ⁓ phase two endpoint, and biogen announced back in May, This anti sense therapy really showed that it slowed clinical decline in patients with Alzheimer's. and s ⁓ that seemingly proved the Tao

Jef: Yeah, it's really exciting to see that we're to tackle so those anti-amyloids you were talking about, Kisune, Lilakembi, those were the first disease modifying therapies on the market for Alzheimer's. But there's real limitations there. And so the fact that we're pursuing a whole new mechanism again with disease modifying therapies this neurodegenerative disease with huge unmet need, it's really quite positive.

Heather: Yeah, because I mean the the way it works is that you have amyloid and then that leads to tau tangles. So once you've cleared the amyloid, there are still tau tangles that are remaining in some cases. And and so you know, as keeps saying to me, all the experts, the Alzheimer's treatment space is going to be a lot like cancer. It's gonna be a combination approach. so we're we're really seeing that come together at this year's AAIC. ⁓ Blackogen, interestingly, also said that Dara Nurson is the first Tau directed therapy to demonstrate robust reductions in two different types of ⁓ of total tau, so CFS, CSF Total Tau, and as well brain tau pathology. so I spoke with Sophia Bulain. she's the the VP of Alzheimer's Disease and Dementia Clinical Development of Biogen last week. And she called the level of tower reduction seen in the Celia trial unprecedented.

Jef: Yeah, again, I'm really excited to see this space, but i evolve, I should say. But I'm curious, how does this particular result fit in and and how does Biogen and Ionas, how do they fit in with the broader tau space?

Heather: Yeah, so bifogen seems to be the furthest ahead, although there's another quieter one in in development by ⁓ by Asi, Biogen's longtime partner. so ASI is working on a drug called E. tilanotuc, which targets the microtubial binding region or MTBR tau 243. so it's a specific type of tau, and and this drug is tested in a phase two, three trial, in combination with ⁓ their lecembi. in patients with dominantly inherited Alzheimer's. and it's also being tested for sporadic early Alzheimer's. and then there was Jeffries who who seemed to think pretty highly of an early ⁓ candidate from Dennelli ⁓ so it's also an ASO ⁓ and it is in ⁓ a phase one B trial. ⁓ the thought is that the delivery mechanism of this drug, which ⁓ leverages Denali's platform, the same one that its drug earlier that was approved this spring was based on, could lead to more efficacy because it is able to more effectively cross blood brain barrier.

Jef: Definitely one to watch. We've been following this anti-tos space for a while, but it's all been earlier stage. So to see some of these getting to the later stages is exciting. Denali, even in the earlier stages, with that mechanism that could get a higher efficacy. Let's keep watching it. ⁓ for now though, Biogen, very exciting to hear that that was positive. We were anticipating that and hoping for the best. but they actually, interestingly, yesterday on Monday, surprised us with more good news. It was another approval for the subcutaneous formulation of Lakembi.

gabby: Yeah, so that was kind of a a a surprise a little bit. So Biogen and alongside their partner ISI, they just secured an FDA approval for an under the skin version of Liquembi to be administered at home. so that decision it was surprising in the sense of it came much before its PADUFA date, which is August twenty fourth. but that Padofa an extension after the agency requested more information. So Now it looks like, you know, they have enough information, they like what they see, and the data that underpinned the approval is being shared today at AAIC in London. So the market overall, the green light differentiates Lequembi from Lily's Kissunla, which the only other anti-amyloid Alzheimer's disease therapy that has received an approval.

Jef: so Lakembi was already approved subcutaneously for maintenance, right? So this is just the initiation. And so with the combination now of being able to get Lakembi subcutaneously for both initiation and maintenance, it's now entirely can be done this way without the ⁓ need for infusions, which is the only way Keisunla is delivered.

gabby: Yes, it can all be done at home now.

Jef: Yeah, that's a pretty big differentiator for sure.

gabby: Yeah.

Heather: It might actually ⁓ also help to overtake some of the advantage that Kazunla has because of its regimen. so Kazunla is delivered for a certain amount of time, ⁓ until it clears the the plaques and then you can stop treatment. Whereas Lakembi is ⁓ indefinitely. this is you know, analysts are saying that this this actually might help to improve the uptake for Lakembi.

Jef: Yeah, I remember that as well because, you know, at this point, Keisuna kinda has a quite a lead, I think as something like 80% of the market right now, despite, you know, being not having first-to-market advantage. And I think that's largely because patients could ⁓ this is my presumption that I one reason that analysts have pointed to, I don't know if it's the main reason, is the fact that, yeah, there's an end in sight. You have the treatment, you clear your plaques, and then you're done. But interestingly, we did report a few months back that biogenesi were ready to kind of scoop up those. Alzheimer's patients after they finish Kisoon Law, we might as well keep maintenance, might as well switch over to Lakin because there isn't that end. So that that's a really good point, Heather, in terms of understanding what patients value. The at-home treatment is certainly one, but being able to be done with the treatment. But there's also, I think, the point that Biogen and SI were making in terms of being ready to catch those Kisunla patients when they came off treatment was that maybe there's a patient segment out there that wants to be better safe than sorry and maintain these anti-amyloid antibodies to prevent it from coming back.

Heather: Yeah, that's that 80 per percent number ⁓ that you were saying. I think that was from from three different neurologists that ⁓ that that they were that Jeffries was I think it was Jeffries that Jeffries was citing. and it was in the early treatment space. so no no wonder that that Cozumla would have more of the market at that at that point. But yeah, like like like everyone keeps saying, it's a combination treatment space.

Jef: Okay. Right. So in that light, let's get back to AAIC. about Lily? I mean, we don't have a weight loss segment on our podcast today. They've taken a short pause from deal making. We haven't covered any Lily deals this week, so they're we need to get them on the show somehow. Do they have a readout coming out maybe on Kisunla at AAIC?

Heather: ⁓ they do. Yeah, we we can't forget about Lily. I mean, no, the they they are tackling ⁓ what is another hot topic in AI AAIC this week, which is, as we were just saying, early Alzheimer's treatment. so Lily has a presentation on Wednesday on Kisunla in early symptomatic Alzheimer's. and I can't say anything about this presentation yet as it's embargoed, ⁓ so you'll have to come to Biospace and and check out Full Story tomorrow.

Jef: All right, we'll definitely keep an eye on that. now moving on though to one of my favorite topics, as you all know, psychedelics. We've been talking about this space a few times recently. Well, it's back in the news again. This time we have more data, which is always good to see and positive data. ⁓ we also have that new final guidance that I mentioned from the FDA that was in draft form three years ago, but they now have released the final. So the news in terms of the clinical readout comes from Compass Pathways and its psilocybin-based comp 360. Heatherick, what can you tell us?

Heather: in a second ⁓ late-stage trial, ⁓ Comp360 ⁓ gave the company more ammo for its FDA approval run. ⁓ almost 40% ⁓ patients with treatment-resistant depression who received two fixed doses of the drug saw a clinically meaningful reduction in depression severity after six weeks of treatment. analysts are really bullish on COM360. They they kind of ⁓ have been all year. ⁓ but this just gave them more, I guess, ammo. so the new readout quote paints a consistent picture of Com three sixty's durability. ⁓ that's according to Stiefle. And Jeffries seventy five to eighty five percent confident in ⁓ the drugs approval.

Jef: And they've got an ongoing rolling submission with the FDA, right, right now. So when when can we expect that possible approval?

Heather: Yeah, well the the approval could happen later this year and ⁓ Encompass anticipates a launch in the first half of 2027. So right on the cusp of it.

Jef: Okay. I keep I keep waiting for that first one since that Lycos fail a couple of years ago. I think everybody's really waiting for, you know, somebody to break that glass ceiling. So definitely exciting to hear, especially since that readout came not long, you know, a week or two after we had that positive late stage efficacy data from Definian therapeutics for its LSD based treatment for major depressive disorders. So those two readouts combined kinda seem to have given a little more momentum back to the space.

Heather: And then

gabby: Yeah, and the the data together, like you said, you know, it didn't just help the companies individually. They really bolstered the entire drug class. And so between Compass and Definium, the findings have helped analysts and investors alike really move their focus from just, do psychedelics work to ⁓ actually differentiators between the candidates like durability. Gregory Malzberg, a psychiatrist who analyst Jeffries hosted an event with, he even said that, the drug class has the potential to quote, wipe out the SSRIs, end quote, ⁓ if safety durability hold up.

Jef: That's a really interesting comment in light of this week's news that Robert F. Kennedy Jr. is going to is moving forward with his initiative to get Americans off SSRIs. These selective serotonin reuptake inhibitors, they've been, you know, kind of the mainstay in psychiatric medicine for a while now. But they're chronic treatments. And I think RFAK kind of sees them as contributing to the over-medicalization in this country that he's talked about. It's one of his platforms that he's run on, you know, push towards diet and and healthy lifestyle and get off of chronic treatments. So I think SSRIs are targeted in part for that reason. it's one of the reasons I've always been so excited about psychedelics. It's potentially a one-and-done or of at least a very less frequent resermin that has shown real efficacy in some of these really hard-to-treat depression and other mental health disorders. And we know, again, the SSRIs being one push by the administration, but specific to psychedelics, we know the administration has been very supportive of these drugs. Trump issued that executive order back in April. That led to Compass specifically getting a commissioner's national priority voucher for CONT 360. There are two other psychedelics makers that also got vouchers at that time. And then again, coming back to this FDA guidance, issuing final guidance this week after it's been in draft for three years, Jeffrey's analyst said that the document, quote, suggests the agency remains receptive to helping sponsors succeed. So it's kind of a step. I don't know, there were no kind of surprises or breakthroughs in that ⁓ guidance that that changes how we're moving forward, but it just shows that the FDA is thinking about this and is supporting a a regulatory path for these very new ⁓ this very new drug class.

Heather: Yeah, the the guidance from from my understanding, it really does kind of ⁓ hit on some fine tuning areas. you know, like ⁓ the difference between an effect from the therapy and an effect from the drug itself. so it clarified some things around there. but the FDA apparently was ⁓ the FDA was still very clear that it wants ⁓ you know, placebo controlled trials that it it favors those. So so that was

Jef: Yeah, that is a tricky one because that's that's one of the things we've talked about. Is placebo is hard when the drugs have such an obvious effect, you're gonna know if you're getting it or not. And then that other component you just mentioned, had the fact that most, if not all of these require ⁓ you know, talk therapy in conjunction with the psychedelic, it is hard to kind of differentiate those sometimes. So it's a really complicated drug to study, certainly in our traditional clinical, you know, models. So ⁓ I I it's good to see the flexibility, s still hurdles to overcome and the big the big test will be that actual review and a potential approval from the FDA. All right, well, moving on again to ATTRCM. This is Transyridin amyloid cardiomyopathy. This has been a space, again, we've been following for a while. we've had recent approvals ⁓ from Al Nylum and others over the last year or two. And it's definitely not a space that's even close to done. So Ionis ⁓ was moving forward with a drug in partnership with AstraZeneca in this space, but they have had Not such a great week, or as you noted here, the no good, very bad, terrible week. There's been a lot of ups and downs for Ionis this week. But it all started last Thursday with this ⁓ readout from Ionis and AstraZeneca for their antisense therapeutic, I think it's called Wainua. ⁓ this is actually already on the market. it was approved in December twenty twenty three for the treatment of polyone neuropathy, polyneuropathy, associated with a hereditary form of ATTR. ⁓ Astrogenica bought into the drug a couple years prior, ⁓ giving Ionis 200 million up front and then another almost half a million upon the approval and promising up to almost 300 or sorry, up to 3 billion in milestones the line. So it's a pretty big deal, this partnership. And Ionis AstraZeneca were moving Wainua into ATTRCM ⁓ with a big phase three study. but things don't seem to be going so well for right now.

gabby: So analysts were pretty surprised when the approved drug, failed to show significant cardiovascular benefit in the phase three. they kind of thought, you know, they they know TTR silencers are effective, that it would have been a slam dunk. So the companies, didn't share the data behind the fail. We don't have those specifics, though, they did say they'd present those, the full findings at an upcoming medical conference. So we're keeping our eyes out for that. But Since the announcement last week, Ionis's stock has fallen about thirty five percent as of Tuesday.

Heather: Yeah, the no good, very bad, terrible week for Ionis. yeah, so ⁓ I have been kind of obsessed with this. I mean, we we were just mentioning earlier it was like there's more notes even today. but think part of the reason for that is that this is one that has ripple effects across a lot of different companies in this space. so the outcome is quote, complicated for El Nylum. that was from Stiefle analysts ⁓ last week. ⁓ Because they have two programs, one marketed and one investigational that work similarly to Wimiwa silencing TTR. however, AstraZeneca the AstraZeneca Iona setback is also a competitive win for Al Nylam because it looks like their Mvutra, is going to be the only TTR silencer on the market for ATTRCM, at least for now. a more clear winner was Bridge Bio, who has Trubi, which was approved a couple of years ago for E ATTRCM and it has a completely different mechanism. so so they got a real boost in the market. Their shares popped fifteen percent on on Thursday.

Jef: Yeah, definitely a mixed bag across the space. It's it's kind of interesting to see what Al Nylam is dealing with because it potentially means that their next gen candidate is not gonna be as effective as maybe analysts were hoping.

gabby: unfortunately that ⁓ wasn't all the news for Ionis. The hits kept coming. Roche, their ⁓ a pharma partner, actually dropped two Ionis studies for Huntington's disease. So the discontinued studies are for two separate assets, both of which Roche is ending its investment in. and the pharma told us that in an statement. Basically, both both were investigational antisense therapies, and Roche made the decision based on the totality of data. asset failed to meet the main efficacy point in a phase two trial, while the other clinical trial was stopped based on data from a parallel animal study that was, you know, running. so a a really, really tough week for Ionis

Jef: Yeah, that's gotta be contributing to their stock tumble this week.

Heather: Yeah. Hopefully they get a little bit of a boost off of the dinersin ⁓ data in Alzheimer's, but that's kind of one win against a lot of losses. that ⁓ the phase two asset you mentioned, ⁓ Gabby, one is called Thominerson, and it has been in development for Huntington's disease for several years. they Roche had canceled a or

Jef: Right.

Heather: dropped the asset after it failed in one population and then they were trying it in an earlier patient population of Huntington's but so i that was just the final death nail for this treatment unfortunately in a space that's really had a lot of momentum lately. But according to analysts at at Rodman and Renshaw, Roche's failure Indicates that wave life sciences might be on the right path with their more selective antisense therapy. So both Roche and Ionis's Thomanearson and WAVE's WVE003 ⁓ are But Thomanirson's mechanism action lowers both mutant and wild-type Huntington protein, WAVES drug is allele-specific, targeting only mutant Huntington while preserving wild type. And this is important because wild type Huntington is understood to be neuroprotective. So WAVE is awaiting a partner in order to embark on a phase three trial. So we'll have to wait to see how that hypothesis plays out.

Jef: Thanks for those updates. Yet another one to watch. And Huntington's yet area that we have been following very closely, a lot of movement of late. So hopefully those patients can actually see some more, some actual therapies, good therapies at their disposal. Well, it for our show today. I will close by just letting you know that Biospace's Q2 job market update is now out ⁓ from our colleague Angela There's a lot of good stuff in there. And she and I sat down just yesterday to chat about. ⁓ it on a special episode of the weekly. So if you missed that, check it out as well. And then you will get the full update on our website in the actual job market report, which you can find there. So again, subscribe to all the newsletters that we mentioned at the top of the show and hit subscribe to this podcast as well. Thanks for listening. We'll see you next week.