Morning, everyone, and thank you for joining our third day at our Piper Sandler Healthcare Conference. Really excited to be featuring the team from aTyr Pharma. We have a great discussion over the next 25 minutes, and just want to say thank you for being part of our conference. Lots to discuss. I figured I'd split the discussion into both of the assets and both of the studies ongoing. Start with EFZO-FIT and then go into EFZO-CONNECT. I guess a good place to start would be, you know, for investors who are new to the story or getting re-familiarized, maybe describe briefly how does efzofitimod MOA and value proposition compare to other immunomodulators that are currently in development? And, and, if you could talk about that, it's the opportunity in sarcoidosis and why it's important.
Sure. You know, the company was really founded around a new, or describe it as an underground area of immunobiology.
Mm-hmm.
I think we are fulfilling the mission of Dr. Schimmel, who discovered these-
Mm-hmm
synthetase fragments and how they can modulate local immune environments.
Mm-hmm.
It's really, right off the bat, very differentiated-
Mm-hmm
... from a small molecule or a monoclonal antibody, and I think we are now harnessing the advantages-
Mm-hmm
... of this new physiology that comes from all of our bodies.
Mm-hmm.
Are finding now ways to retune the immune system.
Mm-hmm.
And I'll be the first to say, I was, you know, very skeptical -- even when I joined aTyr, 'cause this sounded a lot more like-
Yeah
... science fiction. But the clinical data that we've produced is undeniable-
Mm-hmm
... and the experts have said they've waited decades-
Mm-hmm
... to kind of see not only the ability to modulate immune cells-
Mm-hmm
... but do so in a safe fashion-
Mm-hmm
... in a way that does not create more immune suppression-
Mm-hmm
... or infection risk.
Mm-hmm.
I do think that we are a new class of immunobiology.
Mm-hmm.
The drug has direct effects on tuning macrophages.
Mm-hmm.
We can see morphological change.
Mm-hmm
... of these macrophages that shift to much more of a resolution phenotype.
Mm-hmm.
It's really quite exciting days for us at aTyr to be able to finally, I'd say, leverage-
Mm-hmm
... and tap into the science, and retune the immune system at the local level.
Okay, that's wonderful. Would love to kind of dig into the study that, the pivotal study that you have ongoing. As I said, as you know, fully in enrollment year of 85 sites, you guys have continued to say you're on track, for data for enrollment completion in early 2Q 2024. So that's not really that far from now. I guess, where are you with site activation? Could you maybe quantify sort of, the likelihood of really maintaining this timeline? In... You know, we assume that you are quite far along in the process, that you're staying with guidance, but if you could just kind of-
Yeah
... quantify how things are going and the enthusiasm that exists.
Right. So we did wait a bit-
Mm-hmm
... until we had, I would say, a full, gamut of sites up and, you know, 80, 85-
Mm-hmm
... sites, and I'd say the last couple sites now coming online, primarily those sites that we brought on following American Thoracic Society.
Mm-hmm.
We had some interest, in particular with Brazil.
Mm-hmm.
We had a number of countries interested, Turkey, India, Brazil.
Mm-hmm.
We kind of looked at things and said: Where can we get activated within 3-6 months?
Mm-hmm
... with the regulatory environment? And these are probably the last sites-
Mm-hmm
... coming on board. We have locked in on guidance for Q2.
Mm-hmm.
We feel really confident based on the current rate of enrollment-
Mm-hmm
... and then these last couple sites joining, that we'll be able to meet those timelines. I've always wanted to try to get the data out at American Thoracic Society-
Mm-hmm
... in 2025.
Mm-hmm.
That's a main meeting. That would be a spot landing.
Okay.
You know, we're lucky. I know a lot of companies are having 6-9-month delays-
Yeah
... with enrollment. The enthusiasm on our phase II data-
Mm-hmm
... has really helped us.
Mm-hmm.
And then the new insights around mechanism have also brought even more people, more interest. And then just like anything else, once you start to enroll those-
Yeah
... first couple patients and a site sees how they do-
Yeah
... they may be happy with the results-
Yeah
... and then they talk to other patients about getting involved.
Great.
Yeah.
You also noted that there are five or six sites in Brazil that are gonna be added. Given that, what was the rationale for expanding into Brazil, and how many patients do you hope to get into that study?
Lots of inbound interest.
Yeah
... American Thoracic Society. Dan Culver gave a kind of a standing, sitting only-
Mm-hmm
... symposia. There were people sitting on the floor.
Mm-hmm.
A lot of countries, as I said, leaders-
Mm-hmm
... came to us. We made the decision in Brazil because we felt like we could get a-
Mm-hmm
... quick, quick regulatory approval. We've done that.
Mm-hmm.
I would expect to see a patient, first patient dose next week.
Mm-hmm.
Brazil is one of those places where we also had good line of sight with our CRO-
Yeah
... and some of the operational-
Mm-hmm
... team there. You know, this can obviously help us-
Mm-hmm
... meet our goals of Q2.
Mm-hmm.
We could see upwards to, you know, 20 patients enrolled there, but it's competitive enrollment.
Yeah.
Everybody's kind of moving. This was a good place for us to allow patients-
Mm-hmm
... there are a lot of steroid-dependent patients in Brazil. It's a good place for us to look at. And I, unfortunately, have to tell, like, folks in India that-
Yeah.
It's just gonna take too long.
Yeah.
To get started. Yeah.
Thank you for sharing that. Given that broad accessibility or sites across the globe, is there any heterogeneity when it comes to steroid tapering when you go from one region to another? What data supports that there shouldn't be any confounding geographical differences in steroid tapering, if that definitely influences the primary endpoint?
Yeah, I would say in Europe in general-
Yeah
-they tend to overdose their patients-
Yeah
less than maybe here in the U.S.
Mm-hmm.
But there's also the fact that you'll have a greater proportion of Black patients here-
Mm-hmm
in the U.S., and the Black community typically has, in particular African American women, more severe-
Mm-hmm
sarcoidosis that requires a bit more.
Yeah
-steroid control.
Mm-hmm.
that also comes with the unfortunate toxicity that-
Mm-hmm
You know, 15 milligrams might be there. But I think what we've observed is Europe tends to be a little bit more-
Mm-hmm
... judicious, but nothing to the degree-
Yeah
—in this cohort of 7.5-25, they're all kind of the same kind of disease.
Mm-hmm.
I don't expect to have really too many people at 25-
Okay
or 20, anyway. Last trial, everyone was kind of in that 11-13 range.
Mm-hmm.
We'll be in that sort of 10-13 range-
Mm-hmm
-10-12 range here, given that we brought in Japan and Europe.
Mm-hmm. That's helpful. The other question that has come up, and it comes up quite a bit, is sort of the reasons for going for steroid tapering as the primary endpoint. So maybe talk about, A, simple one, you know, without going into history, is it signed off by the FDA as the approvable endpoint? And, B, why did you guys want to do that to be a key endpoint in this study?
Right. Right. And just to be clear, I mean, if any biotech CEO says the FDA signed off on it-
Mm-hmm
... like, that's never true.
Mm-hmm.
So they tell you what they don't like-
Yeah
and you have to basically
Yeah
Figure out what you, what they might like. What I can tell you is we went in with FVC as a primary.
Mm-hmm.
There was clear guidance that FVC, while important in this population, unlike IPF, it should-
Yeah
not be a primary endpoint.
Mm-hmm.
Now, the good thing is we had good results with steroid reduction and the PRO instrument in the last trial.
Mm-hmm.
We had a good debate around-
Mm-hmm
what should be the primary there. Steroid reduction was landed upon because we felt as though this is the best feel and function -
Mm-hmm
-type endpoint. It's tied to how you feel-
Yeah
and also how you were doing functionally.
Yeah.
Feel and function is how you get drugs approved.
Mm-hmm.
The feel part of the PRO, even though we had some real substantial benefit-
Mm-hmm
... we also felt like there was a lot of risk to make that the primary.
Mm-hmm.
No drug's been approved just on a PRO, even though that division wants-
Mm-hmm
-a drug approved there. Nonetheless, we have a nice endpoint mix steroid reduction. If you look at ankylosing spondylitis or eosinophilic asthma, there have been-
Mm-hmm
approvals based on steroid reduction. And I think, it's we've landed on that endpoint as a good, solid primary endpoint.
Mm-hmm.
We know from the experts and the patients, they want-
Mm-hmm
a steroid-reducing and maybe even a steroid-sparing
Mm-hmm
type therapy, and we have a shot to produce
Yeah
You know, those kinds of data in our trial.
That's very helpful.
I'll also add one other thing. Not just the FDA, every region-
Mm-hmm
regulator we spoke to, EU, Japan, they all aligned.
Mm-hmm
Very quickly around this. So there was not discordance around steroid reduction. It was viewed as a really nice endpoint.
Mm-hmm. That's helpful. I think, another area that comes up quite a bit is, you know, the steroid tapering period in the phase I and II was eight weeks, now you're going on to 12 weeks. How do you expect that additional four-week time point to really impact the results?
We needed to give a little bit more time-
Yeah
-for two reasons. Number one, our basement dose-
Mm-hmm
in last trial was we were trying to taper to five, we're now trying to taper to zero.
Mm-hmm.
We've got to allow a little bit more time for the clinicians and patients to absorb that taper. But the other thing, it's a longer- trial.
Yeah.
So a 12-week taper allows us to perhaps, you know, enroll a little bit-
Yeah
-better in a more stable manner, and we've now got 36 weeks-
Mm-hmm
-on the post-taper period, as opposed to the last trial, which had 16 weeks.
Mm-hmm.
So it was a good trade-off, mainly to allow for a more sort of reasonable schedule of taper-
Mm-hmm
-to get from, like, say, 20 milligrams to zero-
Yeah
in eight weeks can be a little tough on the patient.
Yeah.
Yeah.
That's helpful. The other question is, I think the primary endpoint is powered for 90%, accounts for a 10% dropout. Do you get notified of discontinuation rates or dropouts? How do you feel, as you know, you're at a pretty good state in terms of enrollment? Like, is the numbers sort of aligned with your assumptions? Is it lower, higher? Anything you can-
I mean, all I can say is at this point.
Mm-hmm
... you know, the D.C. rate is better, less than we expected.
Mm-hmm.
You know, we have a lot of safeguards.
Yeah.
And we want patients to-
Yeah
remain in the trial, so you know, they can get more steroids.
Mm-hmm.
If people have truly worsening.
Mm-hmm
... sarcoidosis-
Yeah
It affects another organ system-
Mm
... they may need to then have to get on something like infliximab-
Mm-hmm
-or something more heavy-handed. But thus far, the trends are good. This might even impact our final number in the sense that if we don't have that-
Yeah
that much dropout, we could potentially be done, you know, sooner than-
Okay
... hitting $2.64. But right now, trending, I would say, in the positive direction with some buffer.
Okay.
Yeah.
So assuming you have said, you know, like, let's say enrollment completion, of course, in 2Q 2024, you could have data in 2Q 2025 around ATS. I know there's quite a bit of time between now and then, but I think, what is the data that you're going to have at the top line? And then secondly, which I think a lot of people will ask once enrollment is completed: What do you need to achieve as a bar for success to being eligible for sort of, filing for approvability, for approval?
Well, clearly we have to hit steroid reduction.
Yeah.
We're essentially trying to show, under the assumption that, let's say everyone came in at 10 milligrams-
Mm-hmm.
We're powered to show about a, you know, 3-4 milligram-
Yeah
-difference. One would say: How did you come up with that?
Yeah.
Last trial, we saw a 20-25% reduction in six months. This trial is a longer trial, but we're also forcing people to zero.
Yeah.
We think that's a reasonable number. 50% was bandied about-
Mm-hmm.
but the FDA itself said
Yeah
Well, there's no threshold here. And some experts say even 1 or 2 milligrams.
Mm-hmm
Less a day would be useful. We got to hit steroid reduction. I think the drug also had such substantial improvement with quality of life.
Mm-hmm.
We expect to see that again. FVC is the one variable that-
Mm-hmm
-I think, as long as we maintain FVC-
Mm-hmm
and don't worsen, I think it's an approvable drug. Certainly, if we improve FVC
Yeah
It's, it's a slam dunk.
Could you maybe talk about the hierarchy of the secondaries, which one you need to sort of?
Yeah.
Got it.
Steroid reduction is the primary, and then the next hierarchical analysis-
Mm-hmm
is looking at FVC.
Mm-hmm.
You know, I just talked to an investor where, you know, we get free looks on non-inferiority.
Okay.
But we'll look at superiority in a second.
Mm-hmm.
And then we'll do quality of life. Same thing with the KSQ-Lung, trying to demonstrate superiority there.
Is there a scenario by which you miss on your primary, but you hit all of your key secondaries that could still justify a path forward?
I'm not sure about that.
Okay.
I think steroid reduction, we feel really good about.
Yeah.
I think the way the drug works, it's already been described-
Yeah
as a safer steroid-like
Yeah
-therapy. Patients are going to require some sort of immune-
Mm-hmm
-suppressive agent when you have sarcoidosis-
Mm-hmm
because of risk to other organ damage.
Yeah.
You're going to have to get something to control the immune system.
Yeah.
I think by doing so with a safer steroid alternative or reducing steroids-
Mm-hmm
That's the first step to kind of-
Mm-hmm
I think, really getting an approved therapy. We know it's sitting there in the treatment guidelines, that we're looking for something better. I think we need to show that. Yeah.
Then for investors who are new to the aTyr story and or who are looking at sarcoidosis, they may notice that that there's a very limited number of compounds or none in late-stage development. They may also recognize the history of sarcoidosis has been challenging in terms of development. So maybe just talk to us like, what led you to pick this indication, which has historically been challenging to really move forward with, and really give you strong conviction for a high POS and for into the phase III study readout?
Well, we had a lot of translational data-
Yeah
early on that showed in a number of lung injury models
Mm-hmm.
You know, pick the one you like.
Yeah.
The drug had very consistent anti-inflammatory effects. Secondly, the drug is built around a synthetase fragment-
Mm-hmm
that's enriched in the lungs.
Mm-hmm.
Thirdly, we discovered neuropilin was-
Mm-hmm
the receptor that this drug binds
Mm-hmm
-to. Neuropilin is highly expressed on myeloid cells-
Yeah
in particular in the lung. So all of that gave us confidence to move into sarc.
Mm-hmm.
Yes, sarc is a rare disease where people have not really paid attention to it.
Mm-hmm.
Huge unmet need in our mind.
Mm-hmm.
Talking about 200,000 patients in the U.S. having to rely on-
Mm-hmm
on steroids before they just become fibrotic.
Yeah.
That's not really fair to these patients.
Mm-hmm.
I think, you know, our view was it's a green space opportunity.
Mm-hmm.
You're seeing people now follow us-
Yeah
and join the space. It's not the easiest indication.
Yeah.
But we have really become experts, and this is the first phase III ever in sarcoidosis.
Yeah.
I think it's a real monumental achievement just to even get to this stage.
Thank you for sharing that. You guys have been very prolific in sharing continuous data sets at many medical meetings. Is there any data sets that could be really informative, that could further increase POS of success, that you're hoping to share at other upcoming meetings in the next, in 2024? And if you could just briefly talk about those.
Yeah, I mean-
That'd be helpful.
... we are one of the most published companies-
Mm-hmm
-out there. We continue to give all investors-
Mm-hmm
more and more data.
Mm-hmm
To de-risk things. We had a recent exposure-response data set that we published in Frontiers in Pharmacology.
Mm-hmm.
So all the biotech companies here-
Yeah
-that say they have dose response, ask them: Can you do an exposure response analysis, and can you publish that?
Mm-hmm.
I think we might be the only one in phase III. That's the kind of stuff I learned-
Mm-hmm
working at Roche in Nutley 20 years ago. That is the kind of data-
Mm-hmm
-and that's the kind of data-driven company we are. When you think about what's coming-
Mm-hmm
In the future, we had some great mechanistic data.
Mm-hmm
around macrophage biology.
Mm-hmm.
I might expect to see a publication next year around that ahead of our hopeful-
Yeah
-product launch. The clinicians now really understanding this is how the drug works.
Mm-hmm
because they've had to learn about synthetase biology.
Yeah.
It's not in any textbook.
Mm-hmm.
I think we're filling in gaps of knowledge-
Mm-hmm
that we hope really becomes a new paradigm shift in how you treat inflammatory disease.
Great. Thank you. Maybe in the next six minutes, would love to transition to EFZO-CONNECT. I guess the question is, you recently initiated the study in SSc-ILD, and it's in 25 patients. So at what junction do you feel like you should you could give us an update how enrollment is going, and when you could actually have your first data?
Yeah, I'd like to. I always like to see kind of how the trial-
Yeah
-progresses, how we get the sites up and running. You know, we'll probably have half a dozen sites up here-
Mm-hmm
Pretty soon. And then I'd like to see, you know, what's the enrollment rate?
Mm-hmm.
How are things progressing? It's a smaller trial. It's U.S. only. There's frankly been a lot of excitement to get started on that trial-
Yeah
... because of the sarc data.
Mm-hmm.
A lot of the pulmonologists down the hall wanted to get involved. I also think finding neuropilin expression in the scleroderma plaques has a lot of the rheumatologists-
Mm-hmm
... interested because no therapy has improved quality of life for these patients. So, you know, I hope to probably in the spring, give a little bit of a better update here. This is a phase II trial that I'd like to have some data. I always like to be around medical conferences.
Mm-hmm.
ACR is in November. If you had to pin me down right now, I'd like to have some-
Mm-hmm
... some kind of data there. I don't know if it's going to be a complete data set-
Yeah
... interim.
Yeah.
I've got some more levers with that trial, looking at skin and lung.
Mm-hmm.
Skin is an earlier look.
Yeah.
It's a three-month biopsy.
Mm-hmm.
We may see some skin changes. I'd say stay tuned to see. Let's see how things go, and then I'll be able to guide a little-
Yeah
... bit more tightly.
Is there—Let's say you do provide an interim look in the second half of 2024. Obviously, that would be maybe two quarters ahead of sarcoidosis. Is there any translation that one could infer from going from SSc-ILD to the sarcoidosis population?
Let's understand, scleroderma will be much more fibrotic-
Mm-hmm
... tougher, harder disease-
Mm-hmm
... in some ways, but a more validated FVC endpoint there.
Mm-hmm.
In my mind, I think our drug is a lung-
Mm-hmm
... you know, immunomodulator. So I'd like to see some improvement with FVC there.
Mm-hmm.
We're going to get some more information on how much this could be useful in a more fibrotic phenotype.
Yeah.
You know, this is definitely an experiment to look at some things there.
Mm-hmm.
Why I like this and it's de-risked, is we see a lot of neuropilin expression-
Yeah
... right there at the skin level.
Mm-hmm.
So that gives us some upside there. I'd like, I mean, I'd like to see some encouraging signals-
Mm-hmm
... with the skin, with the lung. If we see improvement with skin-
Yeah
... we would be the first therapy to ever show that. And then I think it opens up the systemic, just the non-ILD-
Mm-hmm
... side of the fence, and a lot of the rheumatologists are really curious to try the drug even in that population.
You alluded to seeing some positive signals in FVC and even in the skin fibrosis. Given the small size of the study, like, could you maybe help us fine-tune? Like, what would be a magnitude that you would consider sort of, "Yes, this is the treatment effect we're seeing, we will move forward into a larger pivotal study?
Tocilizumab was, for example-
Mm-hmm
... approved with about a 5%-6%-
Mm-hmm
... improvement over the course of a year in FVC. So it's a six-month trial.
Mm-hmm.
Like, I want to be at least half of that, 2.5%-3%.
Mm-hmm.
What I like in the sarc data, we showed about a 3.3% improvement-
Yeah
... with the high dose in just six months. We can replicate that-
Mm-hmm
... in the scleroderma population.
Yeah.
That's a really good-
Okay
... kind of bar.
Okay.
Yeah.
How soon could you, I guess, could you engage with the FDA with the interim data next, or would you want to, I guess, wait for the, for the full results?
I'd say right now, let's track to the full results.
Mm-hmm.
I mean, there's ability to maybe make this-
Mm-hmm
... adaptive at that point.
Yeah.
You know, I think it's a bad disease with drugs that we need-
Mm-hmm
B etter drugs than tocilizumab and etanercept.
Yeah.
I think they were approved kind of a little bit-
Yeah
... sort of as a throw-in.
Mm-hmm.
I mean, Toci, they weren't going to approve it-
Yeah
... and then the FDA asked Roche-
Yeah
... to submit on that. I think we could have a good dialogue.
Mm-hmm.
We have a Fast Track designation for EFZO for both indications.
Mm-hmm.
We continue to keep in touch with the agency. They want to know our plans for other ILDs.
Mm-hmm. Perfect. That's great. I think we, I guess the... Are you thinking at this junction, the focus of the company is really execution across these studies, or given the mechanism, there's a lot of other pipeline expansion opportunities, and-
We-
... is that a strategy moving forward in 2024, or?
We're doing that in the background.
Yeah.
I have some big shareholders in the audience. They want me focused on sarcoidosis-
Yeah
... and get the readouts there.
Yeah.
That's where I'm keeping focus.
Yeah.
But I'm really encouraged with our pipeline.
Yeah.
We're seeing other synthetase fragments binding things-
Mm-hmm
... like TGF-beta family-
Mm-hmm
... LTBP1, we see FGFR4 with another. Why are these fragments binding these other-
Yeah
... cell surface proteins on other?
Yeah.
That just tells us that we're validating-
Mm
... that this is a real underground system.
Yeah.
We don't play that up a whole lot-
Yeah
... publicly, but, I do think that this is a, you know, we are a platform-
Mm-hmm
... company, a truly platform biology company, but we're keeping our eyes on the ball-
Mm-hmm
... with regards to the phase III trial. That's really where investors really are paying attention.
Well, that's great. I think we had a really wonderful and productive discussion over the last 25 minutes. Just want to say thank you so much for being part of our conference, and really excited for 2024. Let's say thanks to the team.
Thank you.