Thanks for tuning in. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Next up is Athira Pharmaceuticals. To the left of me is Mark Litton, President, CEO, and to the left of him, Kevin Church, CSO. Welcome, both of you.
Thank you.
Maybe spend a couple minutes briefly talking about Athira, what you're working on, what your lead drug is, and milestone.
Sure. First of all, thank you, Andrew, for inviting us. Thank you for coming this afternoon. It's been a crazy day, but we appreciate you coming to hear our story. For those of you who don't know about Athira, we are all about neurodegeneration. We are a late-stage biotech company taking a completely different approach to neurodegeneration. Usually, when one is developing therapeutics, one looks at how can we identify the cause of the problem and then remove that cause? We're taking a slightly different approach in the fact that what we're doing is we are enhancing a natural repair mechanism, and we believe if we can pre-preserve these nerve cells, we will then improve cognition and function in several diseases. An analogy like we like to use is very similar to immunotherapy.
So when immunotherapy came on board, essentially, there were drugs that were allowing the immune system to attack the cancer cell, and we are doing the exact same thing, but just in neurodegeneration, both Alzheimer's and ALS, with our second molecule. And it's really what. If you think about our biology and you think about nerve cells, nerve cells are one of our oldest cells. They don't replicate, and in fact, they live in healthy individuals as long as the individual lives, for the most part. And so therefore, there are mechanisms that our body uses to keep these cells alive, and we essentially are enhancing what we believe is one of the premier growth factors for nerve cells, and that's the HGF system.
Now, the HGF system has been around for decades, since the eighties, and has really been shown to be vital for nerve cells, vital for development, vital for signaling, vital for repairing, but it's not been so easy to target therapeutically. People have tried to inject it. It has a very short half-life, and it really has not been so conducive to using it as a therapy. So one of the things that we've done at Athira, we've spent many years selecting molecules that both enhance this system and have therapeutic properties that get the molecule to the place in the body that is where it's needed. So in the case of our lead molecule, fosgonimeton, which we call Fosgo, it enhances HGF and also crosses the blood-brain barrier and gets to the brain where it is needed.
Then our next molecule, which is ATH-1105, it also enhances HGF, but it does so in a way that's a little bit more peripheral. We're using that to target for ALS because it will get to the places where the nerves and the muscle cells come together in the neuromuscular junctions. In essence, we've created a pipeline and a pathway-
Hmm
All surrounding HGF. Every molecule is different and unique, and we're getting so excited because we have a late-stage trial called LIFT that's reading out early this year.
Wow
C oming soon. In fact, you know, we're within a few months of having data.
Okay, and we'll spend some time on Fosgo today, naturally. So, you completed enrollment of LIFT January, and so if I added six months, it's a six-month study, plus how many more weeks or months for data cleaning?
Yep. So.
Is that the right estimate?
You're correct. End of December, we finished enrollment. It's a 26-week trial, which is roughly six months. At the end of this month, we will be ending our study.
Hmm.
And then we will be in the process of cleaning up the data, quality, and that's sort of an 8-12-week process, so we're targeting fall-
Got it
T o have our data.
Got it. And, you will be hosting an event, coming up later this month. What is it about?
Yes. So one of the things we wanted to discuss a little bit more is we use, for our Fosgo trial, we use a composite score, which is a composite of both cognition and function, and we've invited a couple thought leaders who, one, Suzanne Hendrix, who is well-known in the industry as a statistician, has been involved in numerous trials and really is a strong believer in using composite scores and GST to assess disease burden, and to evaluate how well drugs are doing in the Alzheimer's space. And then we also asked Dr. Anton Porsteinsson.
Mm
T o also, he's on our SAB, also a PI, and to sort of talk about the need and the thing, and that's gonna happen June eighteenth, so please join us.
Okay. The question would be, why are you confident this upcoming phase III, phase II/III study can succeed?
Why are we confident? There are numerous reasons. One, we have spent a tremendous time surrounding the science, and we truly believe in the science. But the other thing that we've done is we, you know, we did an interim analysis, where we looked at the first. We didn't look at it. An independent group looked at unblinded data of the first 100 patients of our LIFT study, and we asked a question twofold. We asked, the first question, "Is this working?" Meaning, are we having an effect on our composite score, both cognition and function? And the second thing we asked the question was, "If it's working, how many more patients do we need to be successful with our primary endpoint?" And the answer came back, it is working, and we needed less than 150 patients.
So we talk about if the next 200 patients behave the same way the first 100 patients, we will be successful in this trial.
Mm.
That really is what gives us confidence that we're on the right track.
Is there any way you've ensured that the next batch of 200 patients will show a similar result?
So-
In terms of-
F rom a baseline characteristics, there's no difference between the first 100 and the next 200. So we've done everything we possibly can from an execution, and from a baseline perspective, so they're mild to moderate patients, and we're hopeful that they behave the same way.
I see. And from that interim on the 100 patients, what can we rule out in terms of the efficacy that the DSMB saw?
Rule out?
As in, you know, can we rule out futility, rule out, the, you know. Basically, how strong of a signal did.
Yes. So clearly, it had to be working, right, in both the composite score of ADAS-Cog11 and ADL. So we can rule out, at least in those first 100, it was working. And then the question was, okay, well, if you run a larger trial, how many would you need? And it was roughly greater than 250. So, and the reason we can rule that out is it, there has to, it has to be working, and the magnitude of effect has to be strong enough so that you can see that in roughly 300 patients. Because at the time, we didn't wanna run a 3,000 patient trial to see the effect.
Got it. And one of the learnings from the prior phase II was Fosgo works better as a monotherapy. That is what is going on in the space, in the LIFT trial. Maybe talk to us about the real-world applicability of a monotherapy.
Sure
... trial.
So first and foremost, you know, our goal is, and it's not easy in Alzheimer's, is to understand how best to test and evaluate Fosgo. First and foremost, we wanna understand our dose. Second, we wanna understand what are the clinical endpoints that we're using to assess its, its efficacy, and then there's safety, of course. So one of the things that we found in our phase II trial, which was 77 patients, is when we looked at the efficacy of Fosgo on top of donepezil, it wasn't clear. And in fact, when we looked at Fosgo by itself, we then saw that it had a benefit on cognition, roughly about three points for ADAS-Cog. We had an improvement in several biomarkers, including statistically with NfL, and in fact, the P300 by itself had an improvement.
We decided to investigate, in the LIFT trial, just Fosgo by itself. Now, keep in mind, this is a marketplace we're in mild to moderate patients, and it's completely different than most of the antibody trials, which have been doing a much earlier stage of the disease. Because when one becomes moderate, that is the time when you lose your independence. You need a caregiver. A lot of times you go into assisted living, and if you look at the lifespan of a moderate Alzheimer's patient, it's roughly within four years. These are a much more advanced patients that we're looking at, and the need for these patients is very significant.
There's really not a lot out for them, and what we found in, as we were recruiting for our trial, is that most people have already gone through all of the standard of care, whether it's donepezil, whether it's memantine. By the time they become moderate, they're looking for something. So from a market standpoint, we don't believe there's any lessening of the need-
Mm
G iving Fosgo by itself.
Right.
And-
Let me just-
Yeah
... add that we were getting 40% of patients coming in to the study that were not on background therapy. They were either naive or had been through the standard of care at that point. So there was a sizable number just that we recruited, even without excluding, you know-
Mm
W hich we later changed to exclude background therapy. So there's a, you know, significant need for another option.
Makes sense. This is given as a daily sub-Q.
Mm-hmm.
So maybe talk about the feasibility of that, and what were the compliance rates?
Yeah
... like phase II?
Yeah. So the other thing that we learned was we had two doses, right? We had the 70-milligram dose and the 40-milligram dose in our phase II study. And in the 77-patient phase II study, what we saw was there was a much higher dropout rate on the 70-milligram dose. And then the other thing that we've done is everybody had the choice, whether you were on ACT or LIFT, to go on open-label extension. So we roughly have about 360 people today on open-label extension, and what we found was they were having, on 70-milligram dose, they were having tolerability issues, and they were dropping down to the 40, and then the 40 resolved those tolerability issues. So we decided to drop the 70-milligram dose and just look at, for LIFT, 40 versus placebo.
And just the tolerability was due to injection site reactions?
Mm.
That was the primary complaint.
Yeah.
But with 40, it's significantly fewer.
I see. And what's been interesting is we have roughly a little over 50 individuals that they're going on their fourth year in open-label extension, giving themselves a daily injection.
Mm.
Giving a daily injection has not been an impediment. It may, you know-
Right
... we're heartened by that.
In the prior study, what were the discontinuation rates like? And you expect the same for the 40 mg.
Yeah. So I believe it was roughly 11% was the dropout rate for the 40. I think it was close to 30% for the 70.
I see. And you expect around 10%.
Mm
... 11% in the-
Yeah, yeah, I think we'll see the same with,
Okay
... with LIFT.
Okay.
Yeah.
And so you spoke to the FDA, I believe, after the interim data, back in 2023, maybe. What did you discuss, and what did you get clarity on-
Yeah, yeah
... in relation to?
So we met with the FDA last July, I believe. Last July, I think we met with the FDA. We essentially got alignment on LIFT. We walked them through all the changes, and they were fine with how we set up LIFT.
Mm.
They again, they're very supportive of looking at both ADAS-Cog11 and looking at activities of daily living, two validated scales, in addition to the biomarkers that we're gonna look at. We're looking at inflammation with GFAP. We're looking at protein pathologies in p-tau and A-beta, and lastly, cell death with NfL. So they were all aligned with that strategy.
I see. And so, again, the primary endpoint is GST, which is a composite of ADAS-Cog and ADL. So if you are successful, stat sig on all three, GST, ADAS-Cog, ADL, what do you do next?
Yeah, so it's a really good question. So let me just set the stage 'cause we get asked this question all the time about accelerated approval. What's the pathway? And I just wanna remind everybody, here's what has happened in the past. So if you look at Biogen and Eisai, they ran an 800-patient dose-ranging study, followed by another 1,800 patients, so 2,600 patients, and then they filed for accelerated approval, and they got that, and it's approved. Lilly started out with a 237 dose-ranging study, followed by a 1,700-patient study, and they tried to get accelerated approval, and the agency denied that, based on the fact that they didn't have enough 12-month exposure data.
Mm.
We have 77 patients on ACT. We will have roughly 550 patients per LIFT if you include all of the arms, and we have 360 folks on OLEX. So we're well on our way, but it's quite likely that we're gonna need another study.
I see.
If you put it in context of everybody else, I think this is sort of our first step. We will go meet with the agency, but it's highly likely that we need another trial.
Mm.
Hopefully, just one.
Right. Right. Okay, and, for GST to be stat sig, what do the individual components need to show?
Yes, so we're gonna highlight this on our webinar, right? 'Cause we truly believe that GST is a measurement of disease burden, and so you're gonna get a score when, if you can improve cognition, and you can improve function, you will be impacting the disease. Now, it's quite possible that both of those could be trending, but what we really wanna learn. First and foremost, we wanna hit GST. That's the first hurdle, which is a high bar in itself. And then the second is, we really wanna understand the magnitude of effect, of how much are we improving cognition, how much are we improving ADL? Now, to put a number, 'cause a lot of people want to understand, well, what does that mean? How do we measure that?
Meaning if they're trending, right, so you're not stat sig on both of them, but you see the magnitude of effect. If you look at these patients over six months, historically, they would decline roughly two points for each. So that our goal is to preserve those two points, and that should be roughly what we're shooting for in terms of magnitude effect.
Hmm, okay. And what are the scenarios in which you do not run another trial?
We don't need to hit GST, we're done. Like, that's sort of the bar that we're set. Hitting GST is a huge win, and it will allow us to understand how many patients do we need for the next, for the next study.
Right.
We will also understand the biomarker and how we're modifying the disease, and that will impact, is there anything we can learn by looking at tau or A-beta, or inflammation? So we're gonna learn a lot from this study, and we will absolutely assess it and understand how best to go forward.
Mm-hmm. And then maybe one more question on it is, for this study to be conservatively considered one of two traditional pivotal studies, what would you need to show?
Yeah, I mean, to go back, let's just go back for a moment. If you look at what Biogen and Eisai did in their 800 patient study, and they used a composite score, too.
Mm-hmm.
That they were trending as well, right? And so they clearly showed that by blocking A-beta, there was an improvement. and they spent 800 patients to understand their dose, and then Lilly did the same thing. They used another composite score to use that. So I think we're on track to use our composite score to understand how our molecule is helping these patients. but we're, we'll see. We're gonna know shortly.
Okay. Okay, the study is looking at biomarkers, like you said. What- so what biomarkers are you looking at specifically?
Kevin, you-
Yeah. So we're looking at plasma, as Mark mentioned. Plasma NfL, we're very interested in that. We saw encouraging signs of decrease in plasma NfL in our small phase II study. That's a really good biomarker for us because it's a neuroprotective mechanism primarily. And so NfL is, although it's nonspecific for AD, it is specific for neurodegeneration. And so if our mechanism is preventing neurodegeneration, we should move NfL, and that's exactly what we've seen. And what's really nice about that is, we saw that preclinically, we saw that in small numbers, but we saw that in the clinic, in our phase II, and now we hope to see it again in our larger phase II/III LIFT study. We're also looking at p-tau, plasma p-tau217 and p-tau181.
We're very interested in that as well. We just published some preclinical work earlier this year in Alzheimer's models, and we saw impacts of Fosgo on tau levels, phospho-tau levels, and we highlight the mechanisms for that, which we've elucidated and published that. It's through prevention of phosphorylation of tau. And so we, and again, we saw that move in the right direction in our small phase II study, so we'll look at that. GFAP, as Mark mentioned, it's a marker of neuroinflammation. Done a lot of work there to support that, and we'll look at A-beta 42-
Mm-hmm
... you know, to, to characterize A-beta in these... 42/40, excuse me, characterize, that in these patients as well.
Great. Is there anything you're doing in terms of the inclusion criteria to maximize the chances that the drug shows a benefit in these patients?
Well, I think, if I could jump in.
Please do.
Yeah, I mean, I think one of the things we've done, as part of our inclusion, as Mark mentioned, this is mild to moderate, and it is only a 6-month study, which is a little bit shorter than a lot of studies in the space. But usually they, you know, the antibody trials were in MCI or mild, so you need a long time period to see any kind of decline. In mild to moderate, decline is actually pretty rapid, so in our inclusion criteria, we really went for a cognitive score, so a baseline cognitive score around MMSE 19. And in that area, you would expect pretty rapid decline in a short amount of time. And so, if we do see rapid decline of placebo over...
We're able to prevent that, we should be able to see that separate in six months. That was a key feature of our inclusion criteria, to-
Yeah
... to try to give ourselves a better chance of success here.
Mm-hmm. And, okay, so we're just gonna wait for the data. You're hosting an event later this month. So then you're starting up an oral HGF program for ALS. So what exactly are the next steps?
Yeah. So we got the green light from the FDA, and it's in process now. We're doing our single ascending dose in healthy volunteers. That will be followed by a multiple ascending dose, and the goal is to have that done by the end of the year and then to go into patients early next year.
Mm-hmm.
Maybe, Kevin just published on this-
Yeah, so this is...
Yeah.
Yeah, this is for ALS. So this program's called ATH-1105. So Fosgo is our first compound. It's formulated for sub-Q injection. This is our next generation. It's formulated for oral delivery. It has really good brain to plasma ratio, BBB penetration, and we have a robust preclinical data package in ALS models, and we published some of that earlier this year. And, we're very excited about this program as well, and getting it into the clinic. So.
Yeah, I mean-
Yeah, because-
'C ause some of the data was pretty astounding in this preclinical model, where we showed an improvement in overall survival, improvement in weight loss, improvement in nerve function, and overall, motor function.
Yeah, and importantly, NfL again. So we saw a significant reduction in NfL in our animal models of ALS, and we know NfL is essentially a validated biomarker of neurodegeneration in ALS, given the Tofersen precedent for using that for approval. So we think that's a translatable biomarker. It works, it fits very nicely with our mechanism, and we're excited to get into patients hopefully next year.
Yeah
A nd, and look at that.
Okay, and then maybe last question, cash, cash runway. Where are you, where are you at?
Yeah, we're trading above cash. We're below cash, unfortunately. We ended the quarter, I believe, with $120 million. I believe that was correct. We have cash to get through our data. So we're doing okay on the cash front.
Okay.
Yeah.
Anything else you wanted to point out, otherwise?
We're just so excited, and I can't wait for the next Fireside Chat-
Mm-hmm
To have discussions about our data.
That's right.
Yeah!
And, um-
Yeah
... really showing that enhancing HGF is improving these patients.
Right. Right.
Yeah.
Best of luck.