aTyr Pharma Inc (ATYR) 2021 Q4 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to aTyr Pharma Fourth Quarter and Full Year 2021 Conference Call. (Operator Instructions)

As a reminder, this conference is being recorded for replay purposes. It is now my pleasure to hand the conference call over to Ashlee Dunston, aTyr's Director of Investor Relations and Corporate Communications. Ms. Dunston, you may begin.

Thank you, and good afternoon, everyone. Thank you for joining us today to discuss aTyr's fourth quarter and full year 2021 operating results and corporate update.

We are joined today by Dr. Sanjay Shukla, our President and CEO; and Ms. Jill Broadfoot, our CFO. On the call, Sanjay will provide an update on our corporate strategy, including our clinical program for efzofitimod and our research and discovery programs in neuropilin-2, including our preclinical program for ATYR2810. Jill will review the financial results and our current financial position before handing it back to Sanjay to open up the call for any questions.

Before we begin, I would like to remind everyone that except for statements of historical facts, the statements made by management and responses to questions on this conference call are forward-looking statements under the safe harbor provision of the Private Securities Litigation Reform Act of 1995.

These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Please see the forward-looking statement disclaimer in the company's press release issued this afternoon as well as the risk factors in the company's SEC filings and included in our most recent annual report on Form 10-K, quarterly reports on Form 10-Q and in other SEC filings. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made, as facts and circumstances underlying these forward-looking statements may change. Except as required by law, aTyr Pharma disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances.

I will now turn the call over to Sanjay.

Thank you, Ashlee. Good afternoon, everyone, and thank you for joining us for our fourth quarter and full year 2021 results conference call. 2021 was a milestone year for aTyr, which culminated in clinical proof of concept for our lead therapeutic candidate efzofitimod, which was formerly known as ATYR1923, and validation for our tRNA synthetase biology platform.

The positive results reported from our Phase Ib/IIa study on efzofitimod in pulmonary sarcoidosis suggests that this novel immunomodulator has the potential to be a transformative disease-modifying therapy for patients with this and other fibrotic lung diseases with high unmet need.

We've carried this momentum into the start of 2022. The receipt of the U.S. Food and Drug Administration or FDA orphan drug designation for efzofitimod for sarcoidosis underscores the significant unmet need for new patient treatments for these patients. And our positive end of Phase II meeting with the FDA has provided a path forward to initiate a planned registrational study of efzofitimod that will incorporate their feedback.

Preparations for this study are underway, and we are on track to initiate this study in the third quarter of this year. We also remain on track with the IND-enabling work for ATYR2810, or 2810, our lead anti-neuropilin-2 or NRP2 antibody. And we expect to initiate a Phase I study in cancer patients in the second half of this year.

Importantly, the strength of the proof-of-concept data for efzofitimod provided the opportunity to generate the necessary capital to carry out the planned registrational trial, which we expect to be the highest value-driving catalyst for aTyr yet.

We ended 2021 with approximately $108 million in cash, and our strong balance sheet positions us well to advance our clinical programs and progress our pipeline in the year ahead. As we begin, I will summarize a few highlights since we last spoke in November.

We will be proceeding with the advancement of efzofitimod in pulmonary sarcoidosis, following a positive end of Phase II meeting with the FDA. We received orphan drug designation from the FDA for efzofitimod for the treatment of sarcoidosis.

We announced an agreement with FUJIFILM Diosynth Biotechnologies, a leading contract development and manufacturing organization for biologics, viral vaccines and viral vectors, for the manufacture of efzofitimod. And we had a poster accepted for presentation at the upcoming American Association for Cancer Research, or AACR, Annual Meeting that details additional preclinical data generated for 2810 in cancer. We're very proud of all that we accomplished in 2021, and we're off to a strong start thus far in 2022 that provides a solid foundation to execute on what we expect to be another highly productive year for aTyr.

Let's begin talking about our clinical program for efzofitimod. Efzofitimod is a potential first-in-class immunomodulator for fibrotic lung disease. Efzofitimod is a novel Fc-fusion protein based on the naturally occurring splice variant of the lung-enriched tRNA synthetase HARS fragment that downregulates aberrant immune responses in inflammatory disease states.

Efzofitimod has been shown preclinically to downregulate inflammatory cytokines and chemokine signaling and reduce inflammation and fibrosis. NRP2 is upregulated on key immune cells known to play a role in inflammation and is enriched in inflamed lung tissue.

Efzofitimod binds selectively to NRP2 and, therefore, has the potential to normalize the immune system, serving to resolve inflammation, prevent progressive fibrosis and thereby stabilizing lung function and alleviating morbidity and mortality for patients.

We're developing efzofitimod as a potential treatment for patients with fibrotic lung disease, initially focusing on patients with interstitial lung disease, or ILD, a group of rare immune-mediated disorders that can cause progressive fibrosis.

Our initial ILD indication for efzofitimod is pulmonary sarcoidosis. Sarcoidosis is an inflammatory disease characterized by the formation of granulomas or clumps of immune cells in 1 or more organs of the body. Sarcoidosis that affects the lungs is called pulmonary sarcoidosis, and the lungs are affected in more than 90% of sarcoidosis cases. The formation of these granulomas is driven by persistent aberrant inflammation. And if left untreated, it can lead to irreversible scarring or fibrosis, diminished lung function, which may lead to respiratory failure or the need for a lung transplant.

We estimate there are close to 200,000 patients in the U.S. with pulmonary sarcoidosis, although estimates do vary. About half of all patients will require some form of systemic therapy and, unfortunately, 30% of all patients will have chronic progressive disease despite available treatments.

The current standard of care typically includes treating the inflammation with corticosteroids and other immunosuppressive therapies, which can help manage inflammation and alleviate symptoms such as cough and shortness of breath.

However, they have no demonstrated efficacy on disease regression and can result in serious long-term toxicity. Additionally, many patients do not respond to currently available treatments. There's a substantial need for a safer, more effective treatment that could reduce or replace the requirement for chronic corticosteroid or other immunosuppressive therapy and prevent disease progression.

Considering that pulmonary sarcoidosis is a rare disease with limited treatment options, we filed a request with the FDA to obtain orphan drug designation for efzofitimod. Orphan drug designation is granted to support the development of medicines for patients with unmet needs for disorders affecting fewer than 200,000 people in the U.S. This designation provides certain benefits, including the potential for 7 years of market exclusivity following regulatory approval, exemption from FDA application fees and tax credits for qualified clinical trials.

We were pleased to announce earlier this year that the FDA granted orphan drug designation for efzofitimod for sarcoidosis. This designation emphasizes the need for new treatment options for these patients and will help support our advancing clinical program and future commercial strategy.

The orphan drug designation followed the positive results from our proof-of-concept study for efzofitimod in pulmonary sarcoidosis that we reported in September 2021. Let's briefly recap some of the key findings from that important study. Regarding safety and tolerability, monthly dosing of efzofitimod was safe and well tolerated at all doses. There were no drug-related serious adverse events and no signals of immunogenicity.

Regarding steroid reduction and some of the other exploratory assessments of efficacy, the study demonstrated a consistent dose response and improvements compared to placebo across all key efficacy end points. These included steroid reduction of 58% overall from baseline compared to placebo in steroid usage post taper in the 5-milligram per kilogram treatment group and a 49% overall from baseline of reduction compared to placebo in the 3-milligram per kilogram treatment group.

Complete steroid taper to 0 milligram was achieved and maintained for 33% of patients in the 5-milligram per kilogram treatment group compared to no patients in any other group.

Clinically meaningful improvement in forced vital capacity, or FVC, which is a measure of lung function, at week 24 of 3.3% in the 5-milligram cohort and 2.8% in the 3-milligram cohort, both compared to placebo.

Clinically meaningful improvement over placebo observed for symptoms and sarcoidosis-specific quality of life indices in the 5-milligram and 3-milligram treatment groups.

Finally, dose-dependent trends of improvement in key inflammatory biomarkers compared to placebo with control seen in all efzofitimod-treated groups. To the best of our knowledge, this is the first randomized, placebo-controlled trial of any therapy for pulmonary sarcoidosis that demonstrates effects on physiologic and quality of life measures concurrent with steroid reduction. And these findings confirm the potential of efzofitimod to be a tremendously impactful therapy.

We plan to present some of these findings in more detail in several posters that have been accepted for presentation at the upcoming American Thoracic Society, or ATS, International Conference, which is scheduled to take place May 13 through 18 in San Francisco this year. We've also submitted a manuscript with full results to a major medical journal to be considered for publication in the near future.

Following the proof-of-concept results, we met with the FDA in a Type B end of Phase II meeting to discuss these data and subsequent clinical development and path to registration for efzofitimod for pulmonary sarcoidosis. We're very pleased with the productive feedback we received and, as a result, we intend to initiate a planned registrational study of efzofitimod in the third quarter of this year. Following the FDA's review of the data package, including data from the nonclinical program, early clinical trials and the recently completed Phase Ib/IIa study, we are proceeding with the advancement of efzofitimod.

The FDA discussed endpoints that we detailed in our proposed registrational study and prioritization of outcome measurements that would best support the evaluation of efzofitimod's efficacy, including a combination of both objective and subjective clinically meaningful outcomes, as the assessment of these outcomes is what is most meaningful to providers and patients.

The FDA advised the continued evaluation of multiple doses of efzofitimod in a longer duration study to establish a controlled safety database that supports the determination of the optimal dose for chronic use. While we saw the strongest efficacy effects in the 5-milligram per kilogram treatment group in the Phase Ib/IIa study, signals of efficacy demonstrated in the 3-milligram per kilogram treatment group also warrant further exploration in order to assess the safest, most effective dose rather than only a maximum effective dose.

In addition, the FDA determined that the completed, ongoing and planned nonclinical studies were considered supportive of clinical development, and a waiver of carcinogenicity studies was -- requirement was granted, a waiver of that was granted.

Based on the weight of evidence from the nonclinical studies, no additional animal safety studies are required for this novel biologic. We were fortunate to be joined in this meeting by some very strong supporters. This includes Dr. Robert Baughman, Professor of Medicine and Pulmonologist at the University of Cincinnati Medical Center. Dr. Baughman is the world-leading authority on sarcoidosis, and he came away from the meeting impressed that the FDA appreciated the need for a therapeutic that demonstrates a steroid-sparing effect in these patients. We were also joined by Mary McGowan, CEO of the Foundation for Sarcoidosis Research, or FSR, who is our partner for the Phase Ib/IIa study.

The FSR is a strong advocate regarding the need for safer, effective treatments, including those that focus on patient-centered outcomes and serve as a critical and much-needed voice on the behalf of the sarcoidosis community. This positive end of Phase II meeting is an important milestone for aTyr, and we now have a path forward to initiate a planned registrational study of efzofitimod that will incorporate the feedback we received from the FDA.

As the most advanced clinical development program for pulmonary sarcoidosis, we have an opportunity to establish efficacy endpoints that demonstrate clinically meaningful treatment effect, which will serve as the basis for future FDA review of other therapies in this significantly underserved disease. Preparations for the study are underway, and we are on track to initiate this study in the third quarter of this year.

We're working to finalize the protocol, incorporating feedback from the FDA for an IND submission. We're planning for this study to be a large worldwide trial, spanning multiple centers throughout the U.S. and other countries. In response to our proof-of-concept data, we've received excellent interest from physicians who may want to serve as investigators. And we intend to implement a robust clinical operations plan that will permit us to open numerous clinical trial sites to support timely completion of this next study.

KYORIN Pharmaceuticals, our partner for efzofitimod for ILD in Japan, will be an important part of the study, having successfully completed a required Phase I safety study of efzofitimod in healthy Japanese volunteers, which permits KYORIN to join this late-stage study in pulmonary sarcoidosis patients. KYORIN will manage all operations and enrollment in Japan and may intend to use this data to support their own filing of efzofitimod in Japan. As we've mentioned before, we plan to be active at the upcoming ATS conference in mid-May and anticipate being able to provide additional updates on this program at that time.

Now let's take a few minutes to discuss our preclinical programs. Through a broad receptor screen for efzofitimod, which is derived from the tRNA synthetase, HARS, we discovered its binding partner, NRP2, as a target. NRP2 is a cell surface receptor that plays a key role in lymphatic development and in regulating inflammatory responses. NRP2 binds to multiple ligands and co-receptors to influence various cellular functions, and we believe it's a compelling therapeutic target, not only in inflammation and fibrosis, but also cancer.

To approach this target in a manner distinct from efzofitimod, we developed a panel of blocking antibodies to selectively target distinct domains of this untapped target, including those interacting with semaphorins, VEGF and certain chemokines, such as CCL21.

One of the blocking antibodies we developed, 2810, is a fully humanized monoclonal antibody that selectively and functionally blocks the interaction between NRP2 and VEGF. This novel antibody is our lead candidate to advance the clinical development for cancer, including aggressive solid tumors with increased NRP2 expression, which is linked to worsened patient outcomes and promotion of resistance to certain current therapies in cancer.

We've generated a body of compelling preclinical data in multiple aggressive solid tumor models, including triple-negative breast and non-small cell lung cancers, demonstrating significant effects on tumor growth with the treatment of 2810. One administers in combination with widely used anticancer therapeutics, including chemotherapeutic agents such as cisplatin or targeted VEGF antibody bevacizumab.

We've gained key mechanistic insights regarding the ways in which 2810 may mediate its antitumor effects. And as we continue to generate valuable data for 2810 to determine tumor types, an exact treatment setting, which is novel antibody, may demonstrate the most beneficial treatment effects.

We plan to present some of these new findings in a poster at the upcoming AACR Annual Meeting on Monday, April 11, in New Orleans. The presentation will further characterize the shared elements that render certain solid tumor types responsive to the 2810 treatment.

We're in the process of completing the required work for 2810 to support its planned clinical development in oncology. We're currently finishing up some remaining IND-enabling activities and honing in on selection of an indication. Manufacturing activities with our partner, Lonza, remain on track, and we expect to initiate a Phase I study of 2810 in cancer patients in the second half of this year.

Finally, we continue to mine our tRNA synthetase biology platform, which is the foundation for aTyr's science and approach to drug development, to discover new targets and signaling pathways affected by these extracellular fragments in order to yield new pipeline candidates.

There are 20 tRNA synthetase gene families, and our intellectual property portfolio covers protein derivatives from all of these with over 300 protein compositions patented.

I'll now turn it over to our Chief Financial Officer, Jill Broadfoot, to review our financial results.

Thank you, Sanjay. I'm happy to report that we ended 2021 with $107.9 million in cash, cash equivalents and investments. This includes net proceeds of approximately $80.6 million raised through a public offering in September 2021, a milestone payment received from our partner KYORIN and use of our equity vehicles.

On the expense side, research and development expenses were $23.3 million for the year ended 2021, which consisted primarily of product development costs for the efzofitimod and 2810 programs. Program costs for efzofitimod included preparation for the upcoming planned registrational trial in pulmonary sarcoidosis, which included manufacturing of clinical trial material and initiation of technology transfer activities with FUJIFILM Diosynth Biotechnologies. Program costs for 2810 included costs related to IND-enabling activities and the initiation of manufacturing activities with Lonza.

General and administrative expenses were $10.8 million for the year-end 2021. This included an increase in the number of employees as we prepare for the efzofitimod planned registrational trial in pulmonary sarcoidosis and the Phase I clinical trial of 2810 in cancer.

Common shares outstanding were 27.8 million and fully diluted shares were 29.2 million as of December 31, 2021. For 2022, we expect an increase in expenses as we prepare to initiate 2 clinical trials. In addition to the clinical trial costs, we will continue to incur manufacturing expenses for the tech transfer to FUJIFILM and additional clinical trial material manufacturing costs for both efzofitimod and 2810.

We expect some of those expenses to be offset by a potential double-digit milestone payment from KYORIN, which is based on certain clinical development goals that we expect to achieve this year. With our current and projected year-end cash position, along with a clean balance sheet, we feel like we're in a strong position to carry out our key catalysts for this year.

Now I'd like to turn the call back over to Sanjay before we open it up to Q&A.

Thanks, Jill. Overall, we're delighted with all that we achieved in the past year, generating clinical proof of concept for our lead therapeutic candidate, efzofitimod, which also validated our tRNA synthetase platform and NRP2 as a target.

We progressed IND-enabling activities for 2810 and continued to use our tRNA synthetase engine to generate new targets and signaling pathways that warrant further exploration as potential pipeline candidates.

We invested in manufacturing for both efzofitimod and 2810 to assure the necessary clinical trial material to support future studies. And we raised valuable capital that shored up our balance sheet and puts us in good position to continue to advance our programs.

With the receipt of the orphan drug designation for efzofitimod for sarcoidosis and the positive end of Phase II meeting with the FDA, we're intending to initiate a planned registrational study in the third quarter of this year.

Our partner KYORIN in Japan will join this study, and we expect upcoming clinical development activities for efzofitimod this year to yield a milestone payment, adding to the $10 million received thus far under this licensing agreement.

We're also on track to initiate our Phase I study for 2810 in cancer in the second half of this year, which will put us with 2 newly initiated clinical trials for this year, which we expect to serve as key value drivers for aTyr in the years ahead. We appreciate your interest and continued support.

At this time, Jill and I will be happy to take your questions.

(Operator Instructions) Your first question comes from the line of Kennen MacKay with RBC Capital Markets.

Congrats on the progress. First question is on 2810. As you're moving that into the clinic, are there any indications or sort of broad classes of oncologic indications that stand out as potentially the most amenable to treatment, whether solid or liquid tumors? Or are there any biomarkers that could potentially be indicative of a higher likelihood of response based on your preclinical data?

And then second question is on efzofitimod, and just wondering what the final steps are towards getting the Phase III design finalized and implemented as we get a little bit closer to Q3. And congrats again.

Great. Thanks, Kennen, for the question. So your first question about 2810, we are very much anchored to solid tumors. And there was quite a bit of literature early on, which is why we targeted neuropilin here that neuropilin-2 was basically associated with some really poor prognosis in some pretty aggressive forms of cancer. Triple-negative breast cancer, lung cancer, also renal cell, neuroendocrine phenotypes.

So we really focused on solid tumors, first and foremost, and we are now looking at those particular tumors where we've seen 2810 most effective in our preclinical animal models. So what I've said here is we're focusing on those neuropilin-enriched tumors. It appears as though when resistance starts to develop for many of these cancers to current agents, we may be able to look at how neuropilin is further expressed, perhaps as a resistance mechanism. And this is the sort of work that we're currently going to be highlighting at AACR coming up here next month.

So I would say, stay tuned here as we get closer to an indication. But just based on, historically, what you've seen here, we see some really nice effects of 2810 in solid tumors, expect this next indication to be a solid tumor that is enriched with a neuropilin signature. We continue to look at other biomarkers right now to hone in on which tumor types are most responsive. And we're doing so in a very sort of systematic, data-driven manner so that once we launch the Phase I trial, we expect 2810 to demonstrate hopefully good objective response in whatever subclass of solid tumors we go after. So stay tuned there. I think that's a work that's nearly -- we progressed quite a bit here in the last couple of years and nearly complete.

To your second question around efzofitimod, really, at this point, Kennen, we've taken the feedback from the FDA, there was a significant amount of feedback. One of the most productive meetings I've ever had in my career as a drug developer, very collegiate, very collaborative. And I think we are going to now be able to -- we have a clear understanding on how to prioritize the endpoints, the design of this trial, the statistical modeling and the assumptions.

And this will now be submitted as part of an IND package. Once we actually receive approval, that's the time for us to sort of then really get into all of the details. I want to allow the FDA the ability to approve what they told us to go after. No reason, I think sometimes biotech companies can jump the gun here, and we don't want to annoy our partners at the FDA. We feel pretty good about following the path that they've sort of mapped out for us around -- with their guidance, and I expect a successful IND here in the short future.

Your next question comes from the line of Ted Tenthoff with Piper Sandler.

Appreciating what you were just saying and that there's still a little bit of follow-up to have with the FDA for the Phase III trial design, I'm wondering if you can give us a sense for what the doses or how many doses might be included in the registrational study. Would this go back to doses that were evaluated in the Phase Ib/IIa? Or could this even look at potentially higher doses?

Ted, good question there. So we are thrilled with the efficacy that we observed certainly with 5 milligrams but also with our 3-milligram cohort. And this was something that we discussed with the FDA. I think there was very much a viewpoint from the agency that we saw robust clinical efficacy in 3 milligrams as well.

So I think the guidance was perhaps, I'm paraphrasing here, but don't give up too soon on 3 milligrams. So this will allow us to look at 3 and 5. I think one thing to remember with the biologic, there's always that concern that if you keep pushing the dose higher, will you find some kind of off-target effects?

We've been fortunate, preclinically, nonhuman primates, healthy volunteers, this study to have good very good, consistent tolerability and no issues. But as you can imagine, when you get into a larger trial, there's always that potential. We think by adding perhaps a 3-milligram arm into the next trial in addition to 5 milligrams, we'll be able to derisk the program even further because it effectively gives us another shot on goal. In the event that we do see anything develop in 5 milligrams, 3 may be a very effective dose. And this happens quite a bit with biologics.

So we like both of those 2 doses. To your question about going higher, we have done some post-hoc modeling with a very, very well-known clinical pharmacology group. We are very, very confident that we've achieved Emax at this point. And as we pointed out, the 5-milligram effects we see here are still above and beyond the threshold of what is clinically important, we really think we have a winner certainly at that dose. If you look at our 3-milligram data, too, we also are beyond the clinical thresholds of improvement, meaningful improvement there as well.

So both of those -- we took that feedback to heart. And I think it's a smart way of approaching the next trial.

Yes, really helpful. I appreciate that color. And maybe just a quick follow-up. So how big of a safety database is the FDA looking for? Or how many patients do you think you might need to enroll per arm with the control?

Yes. So that's another great question. I mean my general view is the safety database, the FDA, for most indications, they like around 200 patients that have had long-term exposure. It's what I've always been trained in drug development team for that number. Within rare disease, it can be sometimes hard to get to that number.

Remember, we thus far have experience human data north of 30, 40 patients, if you even go back to our healthy volunteer trial. So in this next trial, for example, if we were to have these 2 doses going forward, you might actually have, say, closer to 150 patients exposed in a trial that might be out to a year. You add that to the 30 or 40 patients that we previously have exposed to efzofitimod. We're getting closer to that safety database.

This is another reason why it's good to also look at another dose in the next study. It adds to the body of evidence that your drug is safe and well tolerated. And then you can basically say, well, what does the efficacy look like between 3 and 5? Because both of them performed outstandingly in our last trial.

Your next question comes from the line of Zegbeh Jallah with ROTH Capital.

Just had a couple of ones here for you. I think the first is just about whether or not for efzofitimod, you will need to go lower than 3 milligrams just because you mentioned needing to determine whether 3-milligram was the minimum efficacious dose. So could you maybe have to explore 2 milligram, for example?

No, I think, at this point, having tested 3 and 5, both observed as safe and both showing really nice activity in our previous trial. We're going to go with what works. And I think that's primarily what the discussion was with the FDA. I think those are the 2 doses to anchor on as we think about the next trial.

Thanks, Sanjay. And we've asked this one before, but I was just wondering if there was any change to the strategy around the patient population being enrolled into the study, meaning, disease severity because, I think, one of the key things that you wanted to do with the last study was make sure the patients weren't too far gone, meaning, too fibrotic. So is that the same intent here to go after that same patient population and [have] using very similar enrollment criteria for the next study?

Yes. Yes. That's a great question. And again, we want to stick to what's working, right, not tinker too much with the outstanding results we had last time. But you're right, from a rationale perspective, trying to get the patients that have a bit more inflammation a bit less fibrosis. We're able to actually disease-modify these patients a little bit easier. So we will be putting criteria similar to what we had in our last trial.

You might see a few more patients come in. One of the things we're discussing is potentially lowering the threshold of entry. When you go to Japan, other parts of the world, a heavier dose of prednisone might be 7.5. So this could also be something that we're thinking about in certain sort of areas of the world where practice might be a little bit different.

The other thing to remember is we had the signal of patients getting to 0. So that's really, really gotten a lot of patients interested to get involved in our trial. If you're sitting there at, say, 8 milligrams a day and you've been taking that for the last decade, why shouldn't you maybe have the opportunity to try to get off steroids. That's the kind of patient population that I need to listen to, to potentially get involved in our trial.

But on the whole, we will be looking for a phenotype that is highly inflamed, not yet very, very much scarred, having that sort of end-stage sarcoidosis. And I think in a worldwide trial, we also have to think about how treatment is slightly different in different parts of the world, depending on practice patterns there. So stay tuned for that. I'm really excited to get the details out as soon as we get the green light post an IND approval.

And I'll just double my last 2 questions here. I think the next one is for Jill. So you have a really strong cash balance. But I was just kind of wondering, in terms of the milestones from KYORIN, do you expect to receive another milestone payment, say, when you start the Phase III study? And apologies if you've already mentioned this. And then the subsequent part about that is whether or not KYORIN [will just be covering] expenses associated with Japan or will they be helping with additional expenses (inaudible) leveraging some of the data in the U.S. and perhaps elsewhere as well?

And then the last one is for 2810. I just wanted to clarify what's needed to kind of pin down the timing of the IND. So you generally said second half of 2021. I was just wondering what are some factors driving that? Is it difficult to determine the indication? Is it the manufacturing component? What's driving that fluidity in the timing of the IND? And congrats on the progress.

Zegbeh, I'll take the KYORIN questions. With regards to the milestone, so we've received $10 million so far. We aren't allowed really to talk about the specific milestone triggers per se, but it will be related to the initiation of the Phase III trial in their territory. So that, we are looking forward to. Hopefully, they'll be joining the trial soon after we initiate in the third quarter. And then when they do initiate, their trial costs, like you said, they're paying for all of their trial costs. And they aren't paying for anything in the U.S. So that's completely separate.

And we're able to structure the clinical trial so that we have kind of a good distinction between those 2. But what they are also paying for is the clinical trial material that they'll be using in Japan, and that's the cost plus basis. It's just a small markup. But that will be another way where we'll be able to generate a little bit of income in that third or fourth quarter of this year.

I'll take your 2810 questions, Zegbeh. I mean, really -- we want to get the efzofitimod trial launched and on the track really nicely and launched that really first. We're prioritizing that. And then with regard to 2810, I think what you're going to see is a start to that trial shortly thereafter. Right now we're coalescing on indication selection. I think some of the academic work we have coming out there is going to give you a better indication around the types of solid tumors we're targeting there.

So I would just say that right now, we're excited to have 2 clinical trials really launched this year. And I think it provides a real view for investors to start thinking about these are the programs that are going to drive future value here for us at aTyr.

Thanks, Sanjay. And looking forward to the data at AACR?

Me, too. Thanks for the questions.

Your next question comes from the line of Yale Jen with Laidlaw & Company.

And my congrats to you guys as well. Just got 2 here. The first one is for Sanjay that you did mention about the functional endpoint during your prepared remarks. Are you suggesting potentially that will be the primary endpoint to be considered for the Phase III study? Or are we reading into too much of that and still to be determined?

No. We know the -- following feedback from the FDA, what I can tell you is steroid reduction was a big discussion that we had. And I think you read some of the comments from Dr. Baughman that there was a real appreciation that this, in many ways, may be the most meaningful endpoint for patients and providers.

We also know FVC has been used for the IPF drugs to get approved. But there's an understanding that IPF may not -- FVC may not be the best endpoint primary -- from a primary perspective, in sarcoidosis patients because it's a bit more variable compared to the [fibrotics] and more fibrotic lung diseases.

So I think there's -- there was an appreciation that all of our endpoints moved in a really nice direction, steroid reduction, FVC improvement, symptom improvement. So I think we had a sort of a bevy of opportunity here for the FDA to guide us. We've taken that guidance. We have now written a protocol. And as I said, stay tuned here. But what I can maybe highlight here is how impressed everyone has been around the ability to reduce and potentially even get off steroids.

That could really change treatment paradigm for really millions of patients worldwide who suffer from fibrotic lung disease. We're really the first, as I said, therapy, to show physiologic and QoL effects while also reducing steroids. And I think that is something that has the experts worldwide wildly excited about this as a therapy in the future.

Okay. Great. That's very helpful. Maybe one more follow-up here, which is that during earlier year -- early part of this year, you guys had suggested that you guys also want to explore in other ILDs. Just curious what's your thought at this moment in terms of potential time line on that. And it seems there's 2 types of ILDs that will be maybe most relevant to you guys at this moment. And any preference or any color on that front?

Appreciate the question. Yes, we've demonstrated really nice animal efficacy data in scleroderma ILD and also pneumonitis models. So as you're aware, we believe the therapy can be useful in those indications as well, and patients do actually suffer from scleroderma-related interstitial lung disease and chronic hypersensitivity pneumonitis.

As a small company, we're prioritizing efzofitimod right now for pulmonary sarcoidosis. Those are indications we can consider potentially in the future. But as of now, for this year, we're really focusing on the phase -- this next phase trial for efzofitimod and launching 2810 in cancer. That's what our plan is for this year.

Your next question comes from the line of Joe Pantginis with H.C. Wainwright.

A couple of questions. So Sanjay, you've gotten this question already in, I guess, 3 iterations so far and -- about the design of the pivotal study. So I guess I would ask it this way. I certainly agree with you that a lot of biotechs in the past have jumped the gun regarding discussions or talks with the FDA. But based on your experience, I would certainly think that you wouldn't have put out that press release unless you already had the minutes in hand. So I guess I would talk to the minutes that have been published, if you will and, I guess, ask are there any open discussion about the end points about what might be the primary?

It was a major part of our discussion. We received great guidance, and we know how to basically set up the hierarchy now. So it's pretty definitive. Again, I'm going to let the FDA give us the green light on everything that we discussed. But you've got to be careful about putting this all out kind of in a press release.

As I said, we know the end points which are prioritized. We understand the duration of the study. We have modeled the study now. You're going to see a study that statistically we're not going to cut any corners here. We're going to power it adequately so that when we hit that P value once the study reads out, we will have, obviously, then a productive discussion around efzofitimod's ability to move to the patients.

So what I can tell you is endpoints have been prioritized, length of the trial. I've mentioned the 3-milligram and the 5-milligram [lean] to move with those 2 forward. It will be placebo-controlled, worldwide. And I think just from an I/E criteria, we want to stick to what worked in the previous trial and try to replicate those findings.

I understand. And then just one question, sticking with pulmonary sarcoidosis and then a quick one on 2810. Is KYORIN doing anything in -- or what, if anything, is KYORIN doing in the background while they're now -- other than, say, like manufacturing ramp-up or their own clinical trial preparedness ahead of the pivotal study?

Yes. So KYORIN is going to, obviously, have their discussion with the Japanese PMDA, and that will follow very quickly here prior to them launching in Japan. So drug product, we control that. We have drug supply. Unlike many biotechs, we invested quite a bit in manufacturing during the pandemic. We're glad we did that because right now, CDMOs are pushing most biotechs out 6, 12, 18 months. So I'm glad I'm not reporting that kind of delay between starting the next trial. They, in fact, purchase material from us at a small premium. So really for them, it's about getting that regulatory green light similar to us, and then in a staggered manner, they would start the trial, opening up centers in Japan and enrolling patients there.

Got it. Got it. And then just on 2810, I just -- I want to make sure I heard correctly or if I misheard you. When you said about completing the IND for 2810, I think I heard you say about selecting an indication for the Phase I. Is that correct? Or is this more of a all-comers in solids that might have the target expression?

Yes, I think that's the key question, Joe, there that when we submit that protocol for that IND, what is that -- what does the design of that trial look like? And right now, we're honing in on which -- if it is a basket trial, which exact solid tumors enriched with neuropilin that we want to include in that trial or do we want to get a little bit more aggressive in focusing on 1 or 2 tumor types. So that's the discussions we're having currently right now with our scientific advisers in the company and some of our Board members who, obviously, have a lot of oncology experience.

But that's a program that, as we start to put out more data here at AACR, you're going to start to see which indications we're sort of bucketing. And then the data is going to tell us which -- where we should go. As you know, we're a data-driven company. We follow the data to the outstanding results we had with efzofitimod. We are running the same playbook here with 2810.

Your next question comes from the line of Hartaj Singh with Oppenheimer & Company.

Great. Sanjay, Jill, everyone, really, really nice update. I've just got a few questions, just go through them quickly. Sanjay, I know you're going to wince when I ask the 18th question on the primary endpoint. It's not the primary endpoint question, but let me put it another way on the pivotal study. If you were -- could it be possible, for example, to have an endpoint analogous to a primary where you have steroid reduction, let's say, over 24 weeks and then FVC for the full readout? So meaning that you could show steroid reduction over 24 weeks for over the placebo arm or the control arm, get approval in the interim on that and then read out the full study for a full approval. Is something like that even possible in pulmonary sarcoidosis? And then I've just got a couple of questions to follow.

Well, I like your question, Hartaj. It's a very -- you should come to our clinical development strategy meetings. I like that. Our statisticians would love some of these ideas. One thing about doing interim readouts. You give up some of your alpha when you do things like that. I'm not sure necessarily if I would agree with that element of it. However, if you think about our trial, having 3 people getting off steroids, DSMB could certainly look at the risk/benefit. And certainly, if on next trial we have a number of patients getting off steroids, that might be a better way for us to perhaps look at things in the interim.

But again, I don't want to get into that yet until we've actually put out the design. But I like the way you're thinking about things here with regards to an objective and a subjective endpoint. So steroid reduction, FVC, those 2 endpoints are going to play key roles here in the hierarchy as we start to actually design our next trial because I think those 2 start to represent a pathway, in my mind, for a drug label that's really meaningful here.

Patients really want to reduce their steroids. Providers want to get people off steroids. FVC is another way for them to also look at that objectively to look at lung function. We are fortunate in our trial that we saw the kinds of reductions, 58%, 49%, with our 2 top doses; an FVC improvement, more than 2.5%, we had 2.8% and 3.3%. That kind of improvement has not been observed in this area of lung disease really ever, maybe for 15 years here. And as I mentioned, none of this has ever been observed in a trial where we also are reducing steroids. So I think we have something really profound here with efzofitimod. Bear with me with the primary endpoint. As I said, once we launch that protocol, you'll start to get a view on that hierarchy.

Yes. No, no, that's great, Sanjay. And like you say, I mean, just a great, great data set you had last year and continue to do so. Just a quick question on commercial. I know like kind of maybe getting ahead of ourselves, but you've been doing a lot of work, you and the team, educating investors and, I think, reaching out to the patient and physician community on steroid reduction on pulmonary sarcoidosis in a variety of venues. Can we expect that -- those sort of activities to ramp up over the next 12 to 24 months as you get ready to start the pivotal in Phase III? And then I have one last question after that.

Absolutely. We've always thought this market is a $2 billion to $3 billion of global market opportunity for efzofitimod. We -- our numbers are rather conservative when you compare them to what others think, especially some of the numbers when you think about ILD that big pharma has. This is a space where steroids -- patients need to get off steroids. We need to do better than steroids. Steroids are not helping with that progression of fibrosis.

So efzofitimod right now has the most advanced therapy closest to the market, has the ability to tap into this kind of market opportunity, $2 billion to $3 billion. And that includes not only sarcoidosis but other fibrotic lung diseases where right now we need something better outside of IPF. Even within IPF, those patients, remember, are just sort of keeping their lung function just at bay, but they are progressively getting worse. There has been quite a bit of interest with our data set to also potentially look at efzofitimod in those patients that are flaring, have inflammatory response.

So we feel really good that efzofitimod is going to play an important role in fibrotic lung disease for years to come if we can actually get this drug approved. And as I said, the market opportunity is something that is large. We will be talking a lot about -- a lot more about it as we get closer to the market here over the next year or 2.

Great. And then last question. I don't want to front line your ATS data, and I'm sure you don't want either. But, look, between the data readout last year and now, you've had the time to talk to the FDA, you've had time to talk to patient-representing groups, clinicians, patients. I'm sure you spent a lot of time looking at the data and how people have felt about it. What are the things that usually want us to try to pay attention to? Not specific data points at ATS, but what is it about ATS that, from all of your talking to patients, clinicians, regulators that really kind of excites you as you head into that conference?

Yes. I think as a preview to ATS, the point here is, our therapy I think now will really be -- when you're in an earlier clinical trial, you're not sure novel agent, what is it going to do. But now that we are the furthest advanced therapy and we have seen efficacy just across the board, steroid reduction, force vital capacity improvement, symptom improvement, inflammatory biomarkers also well controlled, very, very well controlled by 3 and 5 milligrams, it's a consistency of response. Now we've just got to show that durability in a longer trial, in the next trial.

And I think what you're going to see from experts out there in the field is how can efzofitimod really be a frontline therapy for not only sarcoidosis, but for really all fibrotic lung disease. Because steroids -- as I said before on more academic calls with some of the experts, steroids are poison. In 40 or 50 years, we'll be looking back at the medical textbooks and talking about it as though why did we give this poison to patients. With all the cardiovascular metabolic effects, the health economics of steroids are horrible for patients, the day-to-day quality of life.

So we think we have a real winner there. And then wrapping it all up, make sure the drug is safe and thus far, we're tracking really well with that with the last couple of years of work. So I think it's going to be a real coming out moment for efzofitimod. If we can launch at American Thoracic Society, we expect to receive quite a bit of buzz from the medical community because we know how important it is to have a game-changing therapy for these patients.

And we have no further questions at this time. I will now turn the call over back to Mr. Sanjay Shukla for closing remarks.

Great. Well, great questions today. I know there's a lot of interest. We're right around the corner here from, hopefully, really getting this, as I said, getting this trial on track here in the third quarter, initiated. Just a few more things to accomplish here with our friends at the FDA. But great questions today, I appreciate the interest, and we really look forward to keeping you up to date here in the coming months. Thanks again, everyone.

And this concludes today's conference call. Thank you for participating. You may now disconnect.