Good afternoon, and welcome to the Jefferies 2023 Global Healthcare Conference. My name is Sydney Varnish from Jefferies, and it is my pleasure to introduce Sanjay Shukla, President and CEO of aTyr Pharma. Just a reminder that this will be a 20-minute presentation with five minutes of Q&A.
Great. Thank you. So thanks for being here. I'm here to talk to you. I'm Sanjay Shukla, the CEO of aTyr. I'm gonna be talking today about how we are probably the only evolutionary intelligence biotech. Everyone knows artificial intelligence and can explain it to me. I'm gonna talk a little bit today about evolutionary intelligence and how we've gotten here over the last couple of years. So aTyr has been working in this area of biology around tRNA synthetases. These are enzymes that are in all of our bodies. They help us conjugate a reaction between a tRNA and a specific amino acid, allowing us to make proteins. But about 15, 16 years ago, our founder, Dr.
Paul Schimmel discovered that tRNAs have a very different functionality when they break apart into fragments and migrate out of the cell, and this was published in Nature and Science. Paul is still on the board. He founded Alnylam RNA, a pioneer company, and at The Scripps, has moved on to tRNA in San Diego. So we are focused on the novel extracellular functionality of these tRNAs, focusing really around inflammation and fibrosis. We really believe that this is a differentiated approach, very atypical, atypical novel immunobiology, that when I joined the company seven years ago, was very much, I would say, science fiction, but we've been focusing on science, because this wasn't something I could necessarily read in Keck Immunology.
So we have been developing literature, better understanding of the functionality of these synthetases, and what we're seeing is they seem to play a role in local inflammation and control of fibrosis, unlike other therapeutic modalities that are out there. Our first-in-class biologic is efzofitimod, and we are the furthest along in an interstitial lung disease program, currently in phase III, in pulmonary sarcoidosis. We are the only company ever to reach phase III in sarcoidosis, and there's many centers here in Europe, about 30 centers that are active here. In the U.K., we've got five-six centers that are enrolling in this trial. This was after demonstrating proof of concept, with some rather outstanding data a few years ago that compelled us to move into sarcoidosis phase III.
We've recently kicked off a smaller proof of concept in an adjacent interstitial lung disease, scleroderma-related ILD, that I'll talk to you about it as well today. Let's talk a little bit about our science. So, why do we, why do we talk about evolutionary intelligence? Well, these enzyme fragments, and you see here about 20 of these here, these are the basic building blocks that I talked about, help us make proteins. What Dr. Schimmel discovered is, for over the last millions and perhaps even longer, billions of years, these synthetases in lower-level species seem to be playing a role in controlling local immune environments. And over time, you can see in all of us that there's added genetic domains to these synthetases. But why were they put there?
The idea was that over time, evolutionary stress in these lower-level species that don't have interleukins and cytokines, use these additional, added domains as almost Swiss Army knife proteins, so that in local stress response or local, fibrotic damage, they are there to police our organs, our local tissues, in controlling those sort of aberrations. We know these domains evolved as we became more advanced. The idea was, why are they actually persisting over, over evolution? When you see these domains released locally, they seem to basically bind to receptors on immune cells. So why is this happening? And we've been able to map over 200 of these proteinaceous fragments now and have found binding partners to, several of them.
Efzofitimod was the one we found early on, bound to a receptor called neuropilin-2, which is highly expressed on myeloid cells, CD4 cells, and it's particularly enriched in the lung. So that gave us a signal that this could play a role in lung inflammation because it seems to actually modulate myeloid cells, in particular macrophages, that could be useful in the lungs. So there's a growing evidence here that these domains function as restorative agents. I, I think of these as rather elegant immunomodulators. It's not a heavy hammer. It comes from our normal physiology. Again, I could assay this fragment that efzofitimod is built on in all of us here in our bodies.
In healthy folks, I think it's playing a role in the background of controlling things, but in folks who have, you know, aberrant signaling or maybe a chronic inflammatory state, maybe they don't tolerize as well, could this protein, could these proteins be useful to basically supplement and restore that balance? That's our, our working hypothesis. We have been published. This is all publications over the last couple of years, talking about efzofitimod as a novel anti-inflammatory agent. Our data was published in Chest. I think it's very important. I find it very important that as we're embarking in a new area of biology, we wanna be well-published, put our data out there so that experts in the field can really digest, understand our data, understand our biology, as we advance into phase II, phase III, and even eventually, hopefully, approval.
Just last week, we had an exposure-response analysis. All the companies here that claim that they say they have dose response, everyone here should ask them: "Can you please do an exposure-response analysis? Because then you can't lie to me from a clin pharm perspective." This is actually FDA guidance, and when I was at Roche 20 years ago, we only advanced therapies if they actually showed exposure response. We also made the cover of Science Translational Medicine about six months ago. That's an immune cell stained looking at neuropilin, and neuropilin now is a really intriguing receptor. It should probably be called immunopilin, 'cause it has more to do with immunology than actually the neural development.
This is our pipeline, heavily focused efzofitimod, sarcoidosis, SSc-ILD, but we are finding other fragments that now are binding receptors like LTBP1 and fibroblast growth factor receptor. Why are these proteinaceous fragments binding these receptors? We're seeing functional effects on other immune cells, fibroblasts, and we expect to move into other conditions in the future. We also have some legacy programs, a monoclonal program, where neuropilin-2, to activate it, we've seen some ability to actually modulate tumors. But this is something that about a year and a half ago, we said we're not gonna be focusing on. We're looking at some strategic partnerships. We really are focused on lung and inflammation and fibrosis right now. So let's talk about efzofitimod.
Efzofitimod takes a small 59 amino acid component of histidyl-tRNA synthetase, one of these synthetases, and this little guy, this helix, turn helix here, is that actual protein that we can see enriched in lung tissue. We fused it to a human IgG because this, this little guy only has a half-life of about 4-5 minutes. By doing this, by engineering this biologic, we now have a half-life 8-9 days, so it can be administered for a chronic therapy in a chronic therapy setting like sarcoidosis. That Fc fusion protein, the active domain, as I mentioned, is enriched in the lungs. It down regulates myeloid cells. So about five years ago, we ran a receptor screen, got a very selective hit on neuropilin-2.
We've learned a lot about neuropilin, but neuropilin is seen mostly on macrophages, and in fact, when we assayed the granulomas of sarcoidosis patients, both in IHC and on ISH, we saw neuropilin light up. Recently, we've looked at scleroderma plaques, and we've seen neuropilin also light up there. So the target, the receptor target, is enriched in the very tissue that's causing a lot of pathology for these patients. It's a once-a-month IV, 60-minute infusion. We'll think about life cycle improvements after the drug gets approved, but right now, this is the way we're administering it. We've ran over a half a dozen different types of animal models, different types of lung injury. You probably heard of bleomycin, but we've looked at P. acnes, which causes a granulomatous reaction in rodents. We've looked at a scleroderma mouse model, a GVHD type model, an RA-SKG mouse.
This was presented just on Monday at ACR. A basic chronic arthritis model. In all of these models, we see the same consistent anti-inflammatory and anti-fibrotic effects. We're knocking down things downstream like IL-6, TNF, MCP-1. This gave us confidence that, look, this is an active therapy, but where do we move it into? We picked pulmonary sarcoidosis about four years ago. We were about a $10 million market cap company. You know, if I'd still worked at a place like Novartis, I could run seven phase II trials, but we had to pick the right one to establish POC, and we did that a couple of years ago. So the basic hypothesis is this: In a number of conditions in interstitial lung disease, there can be a number of immune triggers.
In sarcoidosis, even though we don't know the etiology, it causes a clump of immune cells called a granuloma, which is largely seen in the lungs. But if you have autoimmune disease like scleroderma or Sjögren's, and it attacks your lungs, you also have this chronic loop of active inflammation. You can have forms of pneumonitis, burn pit or pigeon breeders, chronic hypersensitivity pneumonitis. In all of these conditions, you see aberrant inflammation and fibrosis, and this adaptive and immune loop that patients can't get out of. Unfortunately, they don't have a lot of options, and what happens is, many of these patients, that chronic inflammation progresses to fibrosis. We intervene early. We intervene, and we directly act on these myeloid cells to retune them because they're all expressing neuropilin.
By binding neuropilin-2, our view is we're gonna tamp down the inflammation, we're gonna restore the balance, and then basically you know, hopefully tip those patients over so they don't become fibrotic, they basically start to resolve. So efzofitimod's goal is to really improve lung function, improve quality of life, because right now there's also a lot of bad drugs out there, but resolve those symptoms and really prevent that progression of fibrosis. We all know from the IPF data, the PANTHER trial 10 years ago said that steroids make fibrosis worse. We need a better therapy for for these patients. Steroids are what is primarily being used here. So this is really our focus here right now, sarcoidosis. We've now moved into SSc-ILD. Could there be other areas where we could move into pneumonitis, other connective tissue disease, ILDs?
These are all diseases characterized by a lot of immune pathology that's more inflammatory. Once you become fibrotic, you know, IPF, there are a couple drugs out there that do an okay job of extending mortality, but our view is, can we basically play on this side of the fence, the inflammation side? ILDs, there are about 200 of these. A lot of morbidity, a lot of mortality, incidence keeps rising, about 200,000 patients that have sarcoidosis in the U.S., about the same amount in Europe. This is a large market opportunity, and we are the leader. We're the biggest company right now, the furthest along of anybody out there in the interstitial lung disease space. A little bit about the market opportunity. I've highlighted this, 200,000 patients in the U.S. The predominant phenotype is pulmonary.
We still see a number of these patients become fibrotic, so that's where the need is. Steroids are really the mainstay here, but we gotta do better than steroids. In 50 years, we'll be talking about steroids in the medical texts and saying, "Why did we administer this poison?" We've seen steroid-sparing and replacement therapies in other areas like RA, lupus, myasthenia. Why not ILD as the sort of next frontier where we get rid of steroids? The problem with some of these other heavy-handed immunosuppressants, a lot of toxicity also associated with those. We think our drug could be a first-line therapy, a steroid-sparing type agent. That's what we're trying to demonstrate in our trial. Here's some of the data from the last trial, and this was published in Chest.
We're the first therapy that has checked all three boxes. So if you talk to Professor Wells here at the Brompton, he's been waiting basically his whole career to have a therapy that not only showed improvement in lung function and quality of life, but also doing both of those things while removing steroids. So we were the first therapy to basically try a steroid-sparing, you know, taper design here in the trial. We were happy with the dose response. We saw the ability to actually reduce steroids. It was a small trial, 37 patients, but all of the signals lined up. And as we advanced from sort of our lower dose to our higher dose, we see better lung function improvement. Symptom control, this was the big thing. This is what I like to see as a clinician.
We're improving the quality of life of these patients beyond the MCID, 2, 3, sometimes 4 factor higher beyond the MCID. So fatigue, dyspnea, KSQ-Lung, that's the King's Sarcoidosis Questionnaire. Shout out to King's College right here across the river. They developed this validated instrument. We are seeing, in some cases, you know, as I said, threefold higher MCID improvement, very encouraging dose response. I'm not showing you here. Also, the inflammatory biomarkers also show a dose response. So subjective, objective measures, we're showing a dose response, and this was all written up also in an exposure response paper that was just published, where we looked at the PK of each individual patient. So a lot of consistency there and a lot of trends. Now we wanna see it in a well-powered trial.
So we sat down with regulators in the U.S., in Europe, in Japan, and designed this phase III trial. And here, what we're doing is we took forward our five- and 3-mg-per-kg populations, and this is a trial that's now powered over 90%. So our view is either 5 or 3 will beat placebo, primarily around steroid burden. Why did we pick steroid burden? Well, we went to the actually regulators, and we said, "Which of the three endpoints do you like best? Which should be the primary?" FVC has traditionally been used in most, in ILD trials, but it was viewed as not the most sensitive endpoint for sarcoidosis. So we... Steroid burden was moved as a primary endpoint. We are seeing the agencies with regards to ANCA vasculitis and some of the more severe asthma drugs.
Steroid replacement is actually becoming a more in vogue primary endpoint. But we're still gonna look at lung function with FVC, and we're gonna follow quality of life here with King's Sarcoidosis Questionnaire. Trying to get patients that are stably managed, but yet still morbid, still having symptoms, anywhere from seven-25 mg. We have a forced steroid taper over the first 12 weeks. The last trial, we were able to show actually a few patients, about a third of the patients in the high-dose group could be weaned off steroids completely. Now, we're getting a little bit more aggressive. We're gonna try to push everyone to 0, and then I'm gonna follow the steroid area under the curve. Our expectation is the placebo patients will start to exacerbate or flare. They'll move back up.
We think three and/or five can keep people at a low or no dose, and at the end of the day, we expect to see a delta of about, I would say, 3.5-4 mg. That's significant for these patients. That's every day, three-4 mg less of prednisone. That steroid burden that builds up over time leads to all the debilitating effects we know about steroids. So if we peel off, say, 30% here, I think that's a big win for patients, especially if we're also showing good quality of life, and we maintain, at least maintain the lung function. We are excluding some fibrotic patients. The drug works better when there's more inflammatory substrate.
We learned in the last trial, a couple patients that were a little bit more fibrotic didn't move as much, so that's a key exclusion criteria. As I mentioned, we've just moved into and, you know, before I get into SSc, that's a trial that has about 80 centers around the world right now, about 40, 40 centers in the U.S., another 10 or 15 in Japan, and then here in Europe, we're in about 7 or 8 countries, where we have another 25-30 centers. Scleroderma represents the expansion of efzofitimod, another condition that has quite a bit of inflammation. Obviously, the etiology is different.
It's an autoimmune disease, but now when the autoimmune disease, the systemic disease attacks the lungs, this is really where bad things happen for these patients, and they fall off a cliff. 60,000 in the US, mycophenolate is standard of care, but mycophenolate doesn't touch ILD. So you've seen approvals for nintedanib and tocilizumab, where the label was expanded, but this was based on no improvement in quality of life. They showed some less reduction of decline, and in fact, Roche was asked to submit their toci data. It wasn't even a primary endpoint. I think it was a secondary or tertiary endpoint, but it showed about a 5% FVC improvement.
Talking to some of the experts who helped us design this trial, even those who are on that NEJM paper, they don't even like using tocilizumab, but I think there's a real opportunity here for a disease-modifying agent. Why do I like our therapy? I think we can win with regards to lung function, but I've also seen quite a bit of neuropilin in the plaques of these patients. UT Houston, experts in Japan said, "We see a lot of neuropilin." We took a look ourselves. We got some samples up, and we've seen neuropilin light up. That was presented at ERS in Milan about two, about two months ago. So we've enrolled our first patient here. We, again, are testing more or less the same doses.
We've gone to a fixed dose because I can get a little bit more robustness statistically, with a continuous variable here for a PK, for an exposure response, but 450 and 270 approximate 5 mg and 3 mg per kg. This is a trial. We're trying to get a signal. We should have readouts here, hopefully in about a year, next year at ACR. But this is an opportunity for us to hopefully get a signal. The big upside here is skin. No drug has shown any improvement from a systemic point of view. I think we have some hope here for, for efzofitimod to also, hopefully improve quality of life for these patients. So basic value proposition here is, this is a new area of biology, and we actually are finding new targets.
I get investors always ask me, "You know, I don't know much about neuropilin." I look at it this way: It's a real novel biology. If we were just hitting the same targets that everyone else knew about, how important could it be? So it doesn't really bother me that much. I think it's an asymmetric opportunity that in diseases where other drugs have failed, we can test this new system and perhaps you know pioneer a new you know class of immune therapeutics here. We're not repurposed. We really are trying to be data-driven. When we look at the receptor binding, we also look at functional effects, and then we slowly move into the clinic. I'm not a pulmonologist, so this isn't as though I'm romantic about interstitial lung disease.
It just made sense for us to move there, given, you know, some of the signals we saw. I think some of the efficacy that we saw first in animals and now in patients, improving lung function, resolving symptoms, and reducing OCS burden, yeah, I think that's the trifecta that... You know, Dr. Baughman, who's probably the most preeminent sarcoidosis expert in the world, just retired from the University of Cincinnati, 50 years has been waiting for a drug to kinda get to this point. Right now, no known safety issues, too. We just had a major DSMB update, and I put that out publicly. Things are tracking well. Just a few minutes here on the preclinical pipeline. I think it's...
You know, when people ask about platform companies, yeah, I think we have a very unique platform, and it is generating data and new opportunities, as I said, mostly in inflammation and fibrosis. And we are trying to basically leverage this sort of intelligence that over, you know, millions of years or billions of years, evolution has sort of added these appended domains. What are they doing when they break apart, and they migrate out? We see them binding to immune cells. Why is that happening? It's there for a reason. Let's try to unlock that and actually try to get therapies from there. We validated our approach with efzofitimod. I think there are some people in the audience here who are really waiting for us to have that data.
I think the skeptics look at that data and say, "Okay, it's a small data set." Nonetheless, to show that dose response in every single endpoint we looked at, I think gives us a lot of confidence. We are generating a pipeline of candidates now. We think there's a lot of areas where we're focusing on those sort of high-value opportunities. I don't wanna just make a therapy that, you know, is an additive sort of therapeutic. We really wanna have disease-modifying opportunities. So we'll look at things like kidney and lung fibrosis next. Big research team. We also have a unique partnership here with a group in Zurich. They're the group that actually has unlocked the ability to find a lot of these receptors. That was a spin-out of University of Zurich.
My expectation is we will develop more targets with other synthetase fragments, and this could be something that we would advance, or we would potentially partner with bigger pharma. So to summarize, aTyr is translating tRNA synthetase biology into new therapies for inflammation and fibrosis. Here's a summary sheet. Lots of IP that aTyr basically has under its umbrella. Two shots on goal right now, a phase III and a phase II. We expect to have enrollment complete with the EFZO-FIT trial in early Q2, and then that data will be out about a year after that. So you have some time here to do your homework before we really start to get into these catalysts. Growing pipeline of tRNA synthetase candidates, we'll continue to do that work in the background with our research team.
As of just a couple days ago, we put out our earnings, about $105 million in cash. This gets us through those catalysts, also allows us to file a BLA, so we feel pretty good about our runway. Last thing I'll say, we have partnered in Japan, so we have a number of regulatory and commercial milestones upwards to about, I'd say, about $150 million that could be coming our way should we, you know, reach success with the phase III trial. With that, I'll take any questions if there are any.
Start off with one. For the SSc study, maybe talk a little bit more about how enrollment's going there and what the line of sight is for enrollment milestones.
Yeah. So SSc, just as I mentioned, we just enrolled our first patient. My view is, let's see how things go over the next three to six months with enrollment. More crowded space. You know, we're sort of far along in SARC, and we have the space to ourselves. But with Prometheus and Horizon doing phase III work, we actually are slotted in, obviously, behind those companies. But I would anticipate that we would, at a minimum, have some data towards the end of next year.
I don't know if it'll be the full data set or if it'll be interim, but ACR would be a nice target for us next November to have some data where we look at some of the early signals. Lung is a six-month readout, but skin is a three-month readout. I think some of the skin findings with regards to gene expression, protein expression, we may have the ability to put out a late-breaking, you know, abstract or poster at ACR next year.
Got it. And for the two different doses for both studies, what are your expectations there? Do you think you'd see better efficacy with 5.5 mg? How are you thinking about that?
You know, five showed some really, obviously, outstanding benefit, but three, the FDA actually was a group that compelled us to say, "You may wanna actually include that." Why? Because three actually demonstrated some nice effects, and in some ways, it's a backup dose that should you see any safety in a larger trial. This occurred to me once in my drug development career, where having that backup dose allowed us to basically, we had some, you know, tox in the higher dose. We're not seeing that, but, you know, just from the standpoint of having two real shots on goal, the, you know, trial's powered 92% for three or five to show efficacy over placebo.
So, the trial was originally, I think when we spoke last, gonna be closer to 200, 220 patients, but by adding that arm, we wanted to make sure that we actually had retained that statistical power over 90%. So, you know, I think 5 will perform better than three, and, you know, in a bigger trial, if we see anything spooky about five, we've got three to potentially commercialize.
Got it. And maybe last question for the EFZO-FIT study. You said delta of 3.5, 4 mg reduction in steroid. So that's basically mean across the board versus the control arm?
Yeah, that's an assumption that if everyone came in at 10, you know, I think the drug label, if we were able to reduce, you know, down to about seven and saw that kind of a difference, that's what that modeling is built on. Obviously, you'd have to normalize how, you know, what the entry dose is, but, you know, our goal right now is to not get too aggressive and, you know, get into 50% reductions. There was no set threshold by the FDA, so we looked to basically mimic some of the data we saw in phase II, maybe go a little bit further. So the idea here is in a model where if everyone came in with 10, we could get them down to, say, 6.5 or seven.
Could you weigh in on a responder analysis? I don't remember if that was, like, a scenario endpoint where-
We're looking at a responder criteria, but again, not validated.
Got it.
So, we have done post-hoc responder analysis that was published in Milan as well in a poster, and we showed in that responder analysis, about 2/3 of the patients in 3 or 5 in the last study were responsive based on steroid X amount of steroid reduction, I think it was 60% there, KSQ lung improvement, and FVC improvement of more than 2.5. So that's not validated, but some of the experts said, "Let's look at those three," and I think we saw more than 2/3 of the patients respond, but I'm not putting that as a classic endpoint. We'll look at that as an exploratory endpoint.
Got it.
Yeah.
Okay.
How many, how many sites do you have in your SSc study now?
Right now, we're targeting about 12 to 15 centers in the U.S. only.
Just the U.S.?
Yeah.
Yeah. And do you have the same pulmonary fibrosis exclusion criteria to have more than what you're saying?
You know, with SSc, we have a little bit more leeway, so we wanna actually perhaps see a, you know, a few more fibrotic patients. They tend to be more fibrotic, so not putting that cap per se, but that's something that we'll talk with the medical monitors. Obviously, if someone is tipping to 25%, you might question, "Hey, should they be on nintedanib at this point?" That study showed that in patients actually more than 20%, it worked rather well, but BI's data under 20% really didn't show, you know, that much of a difference. So I'd like to still stay under 20, but it's not a hard cap in that trial.
Do you understand the downstream mechanism following binding to neuropilin? I mean, you talked about, you get modulation of immune parameters, the usual suspects, but what's actually happening at a cellular level?
So-
Are you changing cell behavior or trafficking or a mixture?
I think it's a mixture. I think we are actually inducing some cell cycle changes that actually push things—break through some things. We also are seeing some things like acidification change, which causes chemical release, which also changes signaling. So those are two things we're seeing. But neuropilin works through VEGF, plexins, and semaphorins, so that's upstream of, say, PI3K and Akt, but I could probably draw a map to kinda get to IL-6 there. But it is rather upstream, and in some ways, the drug being a little bit upstream and maybe a little dirty is actually helpful in a multinodal disease like sarcoidosis. Great. Thank you.