Welcome, everyone. Thanks for joining us. I'm Gavin Clark-Gartner, one of the Senior Biotech Analysts here at Evercore ISI, and really happy to be joined by Sanjay Shukla, who is the CEO of aTyr Pharma. Thanks for joining us, Sanjay.
Thanks for inviting me.
Absolutely. All right, maybe just to kick us off, why don't you give us an overview of the company and a snapshot of where things stand today?
Sure. So at aTyr, we're really focused on advancing a novel biology platform around an ancient group of enzymes called tRNA synthetases, which are really in all of our bodies, help us make proteins within the cells. We are leveraging some discoveries by our founder, Dr. Paul Schimmel, who found that these enzymes break apart into fragments, and those fragments play a role, potentially, in immunomodulation at the local level in different organ systems. So we have advanced a fragment into phase three, a fragment that's enriched in lung tissue that seems to be very selective to modulate lung inflammation and fibrosis, and that's our program, efzofitimod, which is in phase three for pulmonary sarcoidosis.
Awesome. Maybe not to spend too much time here, but just for those who are less familiar, really quick overview of what pulmonary sarcoidosis is and what exactly these granulomas are made of.
Sure, so pulmonary sarcoidosis is a very large subset of interstitial lung disease, and interstitial lung diseases are a group of diseases where there's chronic inflammation leading to eventual progression to fibrosis. These patients have really poor medical options, which we're leveraging, still using steroids for the last 50, 60, 70 years, and sarcoidosis is the most inflammatory form of interstitial lung disease. We don't know the etiologic cause, but sarcoidosis is characterized by clumps of immune cells largely seen in the lungs, and it's those immune cell clumps that form a nidus of inflammation that, unfortunately, does not remit, and these patients then eventually develop this cascade of progression to fibrosis, so though we don't know the etiologic cause, it presents in this very characteristic manner with granulomas largely seen in the lungs that cause a chronic inflammatory state.
Yeah. I think there's two really interesting lines of evidence biologically for support of your MOA and pulm sarc. One of them is the Jo-1 autoantibody, which can cause anti-synthetase syndrome, which some people may be familiar here with in a slightly different context. Maybe you could just lay out what that link is.
Sure. So rheumatologists (I'm not a rheumatologist) but they'll like to focus on diseases where antibody production leads to some sort of clinical morbidity. In anti-synthetase syndrome, there is a very rare autoimmune reaction that sometimes occurs in patients who developed an antibody to actually the full length of one of these tRNA synthetases that we research. That's a full-length autoantibody to full-length histidyl-tRNA synthetase. Now, when patients develop these antibodies, and it's very rare, what do they develop? They develop interstitial lung disease and myositis. So the idea here is this could be a pseudoclinical knockout, if you will, that perturbing the system around histidyl-tRNA synthetase can lead to dysregulation in muscle and lung inflammation. Our lead candidate of efzofitimod is built off a fragment of histidyl-tRNA synthetase. So that fragment, we believe, has the most potent immunomodulatory properties of this enzyme.
We call it the IMOD domain, immunomodulatory domain. But yes, as you point out, there is a natural occurrence of a clinical phenomenon that seems to indicate that this particular enzyme is involved in controlling lung inflammation.
Yeah, great. And the second line of evidence in a specific Amish population, I think in Canada, there's one mutation, the Y454S mutation. What exactly is the link there here?
OK, so that's another interesting, if you like, this sort of aspect of genetic or monophasic type of targets. As you point out, there's a very, very small population in Western Ontario that have this mutation where these children cannot produce really viable histidyl-tRNA synthetase. So they need supplements of this enzyme. What happens to those kids, unfortunately, is they may develop a respiratory infection, may recover from that first hit, if you will, but subsequent viral or bacterial infections cause these kids to develop a very hyperacute interstitial lung disease. So there's another clue that dysregulation of this system around histidyl-tRNA synthetase can contribute, is associated with (I'm not sure of its correlation yet) to interstitial lung disease.
Definitely, what we've learned from both of these phenomena that you've mentioned, the anti-synthetase syndrome and this HARS genetic syndrome, is what it's called. There's an implication that dysregulation of the histidyl-tRNA synthetase extracellular functionality can contribute to an interstitial lung disease phenotype.
All right. Let's move beyond some of the deep biology and go over to the phase 3 design, since that data is coming out pretty soon, very soon, actually. Maybe a good place to start, just remind us why you're using steroid taper or steroid reduction as the primary endpoint and how those conversations with the FDA went.
Sure. So steroids, as I mentioned, are the mainstay treatment for pulmonary sarcoidosis and many interstitial lung diseases. When we looked at our phase 2 results, which showed really nice trends of efficacy in all of the endpoints we looked at, steroid reduction, lung function improvement measured by forced vital capacity, and also the quality of life instruments, cough, fatigue, shortness of breath, all trended in a very positive direction. We sat down with the agency to think about what should we prioritize as the primary endpoint. And steroids, steroid reduction was viewed as potentially the most clinically relevant of all of those families of endpoints we looked at. So based on some of that feedback, we also know that sarcoidosis patients can present not just with restrictive disease, but sometimes obstructive disease. So forced vital capacity is an important endpoint, but probably better slotted as a secondary endpoint.
Steroid reduction, we've seen recently the agency lean in and look at Tavneos, for example, or Nucala, drugs for vasculitis and also asthma, severe asthma. Steroid reduction is a significant component of their drug label. So I think you're seeing now a shift, even in the agency's mind. They want better therapies, safer therapies, therapies where we can, hopefully, in the next 30, 40 years, we're not talking about steroids anymore in the treatment of interstitial lung disease.
Maybe you could just give us some more details on one, how exactly the steroid taper is mandated in the protocol. Secondly, how you kind of more informally coach sites. And then third, how exactly that endpoint is measured for the primary.
Yeah, I'll start with the second part of that. Patients know going into this trial, they may be made unwell. We are forcing them off a stable dose of steroids. They've been on these steroids for sometimes five, 10, 15 years. So patients have a really strong desire to get off steroids. The steroids are wrecking their lives. They cause a whole host of comorbidities. And the idea here is you're going to actually need to, frankly, be made unwell over the first three months of the trial because we're forcing everybody more or less off steroids. Now, steroids are titrated based on a tool called the PGA. This is a Patient Global Assessment. And we assay the patients every two weeks just to see how they're feeling. Is there any cough, fatigue, shortness of breath? Are they having trouble breathing? So it's a very real-world type of trial.
Typically, these patients might be seen once or twice a year. In a trial, they're being assayed every two weeks. So we can really fine-tune what I would say is the basal steroid dose by using the PGA on a two-to-every two-week period look-back to say, OK, how do we manage your sarcoidosis? Because it is a smoldering disease. So that PGA is really important because it allows us to take some of the bias out of, hey, we're just relying on investigator judgment. So the first part is making sure the patients understand we really need to see them off steroids. And it's this rebound that we're hoping to see by using the PGA. We're going to actually see a real-world number here with regard to the lowest efficacious prednisone dose for most of these patients.
And then every two weeks, we are working with the PIs to say, look, if there's any worsening, you've got to rescue these patients. And it's that rescue that we're, frankly, counting on to occur more in the placebo population compared to the treatment population. You look at the analysis. We're taking the post-taper period from week 12 all the way to the end of week 48. And we're looking at every day how much prednisone are the patients on. We're looking at their patient diary. And then we're just taking that number, adding it all up, and dividing by the number of days between week 12 and week 48. And that will give us the average daily prednisone dose. So we're going to learn quite a bit in this trial about what is that minimally effective dose of prednisone.
It's just that we also then expect there to be a significant difference with EFSO.
Awesome. That makes sense. And on this topic of steroid taper, what endpoints are clinically meaningful? There's been emerging data across the ATS conference, WASOG, and there was also an externally-led patient-focused drug development meeting recently. Maybe you could just summarize what's been coming out of all these different meetings.
So definitely the field is heating up. We're seeing a lot more interest, even from the FDA, with this patient listening session. I think what really came out of that was a real appreciation, first and foremost, is patients want to get off steroids. So maybe we were a little bit ahead of the party here, but six, seven years ago, when we started this program, we were the first company to really try this steroid-sparing reduction type approach. We're now hearing from really all the patients a consistent message. They want to get off steroids. Secondly, they want to feel better. Whatever therapy, they want some disease-modifying effect. They want their cough, fatigue, and shortness of breath addressed acutely. And then over the long term, this progression of fibrosis, it's a lot worse of a disease than people understand.
That fibrotic damage, the inability to work, the loss of functionality, it occurs slowly over time in these patients, but they do progress and become fibrotic. And mortality, we even have some recent data that we're hoping to get published in the spring. Mortality looks like it's a lot higher than 5% in these patients. So better therapies, get me off steroids, and I'm still really scared about fibrosis. I think we have an opportunity here that's addressing all three of those with efzofitimod.
Yeah, great. And for the phase 3 trial itself, how do you handle discontinuations? How is that data imputed? And do you have any expectation, or have you said where any of the discontinuation rates are tracking?
So the beauty of our trial is we should see lower discontinuation rates for the disease because we have this mechanism to rescue patients. I want to see patients, frankly, I want to see a third of the patients, hopefully all of those on placebo, get rescued, and then they remain in the trial. So there's no real incentive here necessarily that if there's any acute worsening of their baseline sarcoidosis, that they should discontinue. Now, if you have real worsening of sarcoidosis, meaning you've got a new organ manifestation or something like that occurring, OK, that's maybe a reason to discontinue. But thus far, discontinuations have been lower than I've expected. I think that's based on our design and how rigorous we are in sort of ensuring the patients remain in the trial.
We have powered the trial over 90% power, 92%, that as long as 240 patients finish the trial, we had 268 with the final number. So we've got a 10% buffer there for any DC reason. But thus far, as I've said, those rates have been lower, much lower than I expected. And I think we have a mechanism to keep patients in the trial because we want as many valuable patients as possible.
Great. And looking ahead, what should we expect you guys to publish or lay out before we see the full phase 3 data? Have you thought about presenting the baseline characteristics or anything like that for the trial? You kind of alluded to maybe some updated epidemiological analyses that might be coming out. What should we expect?
I think those are two things that we'd like to perhaps get organized for the spring conferences. American Thoracic Society is typically in May. We're hopeful to get some posters in there, both on perhaps the baseline demographics, as you mentioned. I know you've asked me for that a few times. That'd be nice to see. I agree. I think it'd be nice to kind of get that baseline data out there. Can't promise that until we submit and get approved with that poster, and then the EPI data is, I think, really striking because it is showing signals of a much larger proportion of patients, especially here in the U.S., who are steroid dependent. Originally, we thought about 50% of the patients are on steroids. It may be closer to 75%. That significantly impacts our modeling when we think about how EFSO could be used as a frontline therapy.
Then I mentioned mortality, seeing that the disease is a lot worse, looking at claims databases. These are things that we'd like to also get published. Let's see if we can get that organized and out there in the spring.
Awesome. Worth touching on a piece of news from this morning, which is the namilumab program being discontinued. Maybe just kind of frame, what are the differences in patient population, trial design? Why do you believe this doesn't have any read-through to the EFSO program?
First of all, I think the premise that Kinevant took forward was interesting looking at GM-CSF. Now, GM-CSF has been a target. Unfortunately, it has not worked out in about a dozen indications. But it had some interesting theoretical biology that it could prevent granuloma formation. So I think it was, in that sense, there was some rationale to test it. When you think about the design of the trial, I know there were some changes within the protocol. Endpoints were changed midstream. But steroid reduction is something that I think they leaned into after, frankly, probably seeing some of our engagements with the agency, things of that nature. I did notice at ERS that their data showed that they only had about 40% of the patients, 40% of the patients were not on steroids.
So I think it makes it very difficult to evaluate if you're looking for steroid reduction if you've already enrolled four or 10 patients who aren't on steroids. So how are you going to show that? I think that was also going to be difficult there. So as far as read-through, look, I think it was a single-target anti-inflammatory cytokine they were going after. EFSO we see as multinodal, works upstream. We already have demonstrated anti-granulomatous effects in an experimental model with Ohio State, Elliott Crouser's lab. That was something that I think that therapy, I believe, didn't check that box, if you will. Our program, of course, there's no real changes with our protocol design. We've always looked at steroid reduction from the top of the ticket here. And I think the other component here is beyond just new granuloma formation. Can the drug impact quality of life?
That was something that we saw with our drug in phase 2. I think if you remove steroids and do so in a robust manner, patients are going to feel better. I think these are some of the differences why I think EFSO, frankly, maybe should be looked at in a different lens compared to that therapy.
Yeah, that's helpful framing. Looking ahead to 2025, you'll be showing some systemic sclerosis-related ILD data prior to the pulmonary sarcoidosis data. We just kind of frame. How does this read through or not read across to that indication?
It is something we want to look at in a small interim subset of patients in Q2. SSc-ILD is the next frontier, if you will, for EFSO. It's a more fibrotic indication. Still a lot of inflammation, but it's another form of interstitial lung disease that has quite a bit of inflammation. That trial has an interesting skin readout at three months. Why do I like skin? We saw neuropilin, our receptor, highly upregulated in SSc patients with their skin plaques. So there's an opportunity to perhaps move skin fibrosis and inflammation. No drug has done that before. There are also some lung endpoints there. FVC is the primary. We'll look at that as well. From a read-through perspective, I think the way to think about it is it's a more fibrotic disease. Let's see if the drug can work in a different population.
But it's really a different disease if you think about it. The etiology is different. We understand the etiology. It's a systemic disease. And frankly, I think there's a lot of upside here. If EFSO shows, in particular, the impact on the skin, rheumatologists have said, I might want to use this in a systemic population. So a lot of upside there. But I'm not sure there's as much read-through because there isn't a steroid reduction element also to look at there. These patients are not on steroids in that population.
Yeah, that makes sense. And that actually puts us right at time. So very exciting 2025 coming up. I'm sure we'll be speaking again soon. And thanks, everyone, for joining.
Thank you. Thanks.