Acelyrin, Inc. (SLRN) Earnings Call Transcript & Summary

Good morning, and welcome to the Acelyrin Inc. conference call to discuss the Phase I/II proof-of-concept results in thyroid eye disease. The conference call is being recorded today, March 20, 2024. I would now like to turn the conference over to Agnes Lee, Senior Vice President of Investor Relations and Corporate Communications. Agnes?

Thank you. Good morning, everyone, and thank you for joining us. Before we begin, I'd like to remind the audience that this conference call may contain forward-looking statements such as those related to the progress of our clinical trials, including trial commencement and anticipated data readout, our future financial and operating results and investments and our ability to commercialize our product candidates. These forward-looking statements involve risks and uncertainties that could cause our actual results and events to differ materially. We urge you to review the Risk Factors section of our Form 10-Q for the quarter ended September 30, 2023, and is also available on our website at acelyrin.com, along with today's press release and our slide presentation, which identifies certain factors that could cause our actual results, performance and events to differ materially. Additionally, these statements are based on information available to us today, March 20, 2024, and we undertake no obligation to update them as circumstances may change. The presentation slides from today's call and a recording of the webcast will be archived on the Events and Presentation page of acelyrin.com for approximately 30 days. Joining us on today's call are Dr. Shao-Lee Lin, our Founder and CEO; Gil Labrucherie, our Chief Financial Officer; and Dr. Shep Mpofu, our Senior Vice President of Development. I will now turn the call over to Dr. Lin. Shao-Lee?

Thank you, Agnes, and thank you, everyone, for joining us today. As we approach the 1-year anniversary of our initial public offering last May, we've been working hard to ensure a strong start to 2024. Last week, we highlighted positive views for our lead program, izokibep and a path forward. And today, we are delighted to share positive proof-of-concept results from lonigutamab, the first reported clinical responses with the subcutaneously delivered anti-IGF-1 receptor treatment in patients with thyroid eye disease or TED. Today's results are meaningful for TED patients and the clinician community and also for myself and many members of our Acelyrin team, having had the great privilege of leading the development and approval of the first available therapy for TED and for our company. We are excited about achieving these proof-of-concept results as they represent the opportunity to continue to advance therapy duration. Our goal is to address the unmet needs of depth and durability of response, safety liabilities and convenience in a manner that we believe has the potential to be paradigm shifting for these patients. While lonigutamab is a clear example of our business model, where we seek to identify drug candidates we believe are diamonds in the rough, where based on molecule characteristics, our collective experience and expertise and the evolving scientific and medical understanding, we can establish a development plan that test our hypotheses around clinical differentiation and the potential benefits for patients. Combined with the izokibep use -- last week at HS and PsA, today's announcement is another step forward in advancing our late-stage pipeline in immunology and inflammation. For izokibep, we just shared the top line results of the Phase IIb/III trial in PsA, and we expect to be the first of two registrational fronts. For HS, Uveitis, we have Phase III trials ongoing that we also believe will be the first of two registrational trials in those indications and both of which we expect to readout top line results within this year. And with these positive data for lonigutamab, we will be planning to initiate the first of two registrational trials for thyroid eye disease within the second half of this year. We believe both of these programs are in the forefront of development for the next generation of each mechanism with potential to provide a clinically meaningful difference for patients. I want to thank all of our trial participants, clinical investigators, investors and employees for continuing to stand with us in our mission to bring transformative medicines to patients. Now let me start by taking a moment to talk about thyroid eye disease. Thyroid eye disease is a vision-threatening autoimmune disease in which there is both inflammation as well as expansion of the tissues behind the eye, resulting in eye bulging known as proptosis, and the subsequent inability to close the eyelids. Double vision or diplopia can occur as well as the potential for compression of the retinal nerve, which can lead to blindness. As such, TED is a progressive chronic inflammatory disease where longer term treatment has the potential to improve depth and durability of response. I'm proud to say that the first approved therapy was a major step forward for managing this devastating disease, providing the potential to move patients from a surgical to a medical intervention as a fixed dose course of IV administration of this anti-IGF-1 receptor treatment. As we continue to observe real-world evidence in TED, it's clear that there's a clinicity to the disease that can be treated longer term. There have been updates to the label in the past year that included both effectiveness of this mechanism on treating more chronic disease, as well as an update on the potential for severe and even permanent hearing impairment associated with the current treatment paradigm. Although there have been explorations of other mechanisms in the treatment of TED, existing data, including clinical response rates, has suggested this mechanism as likely most central to the disease and may see the need to optimize benefit/risk for TED patients, which we believe the characteristics of lonigutamab enable us to do. Let's take a moment to talk about the characteristics of the molecule and how they suggested to us a hypothesis that it could lead to something clinically meaningfully different for patients. Lonigutamab is a humanized IgG1 monoclonal antibody, targeting the IGF-1 receptor and is delivered subcutaneously. Relative to standard of care, lonigutamab binds to a distinct epitope, which results in internalization of the receptor within minutes. In a preclinical binding and functional laboratory assays it has been shown to be 75-fold more potent. The characteristics of lonigutamab that enables subcutaneous delivery also enable the potential for longer-term dosing, which we believe can improve depth and durability of clinical response. Based on our preclinical and pharmacodynamic data from our completed single ascending dose study with lonigutamab, we can optimize the therapeutic window utilizing the subcu route of administration. The characteristics of lonigutamab also allow the potential to minimize exposures relative to IV therapy. IGF-1 is neuroprotective to cochlear cells of the inner ear and serves to repair damage that can occur over time. We hypothesize that high concentrations of anti-IGF-1 receptor due to the maximal concentrations or Cmax for IV administration, can penetrate the blood-labyrinth barrier and interfere with this normal function. Our current study cohorts are designed to provide data to allow us to choose a subcutaneous dose and frequency that optimizes the potential to improve depth and durability of response while minimizing safe use. We are pleased that today's positive data demonstrates proof-of-concept for the first subcutaneous anti-IGF-1 receptor product candidate in thyroid eye disease. Across two of the cohorts, patients with active TED experience rapid and meaningful proptosis and clinical activity score responses as well as the diplopia response. The placebo-adjusted responses observed in Cohort 1 showed that by the first clinical assessment, which was within 3 weeks after the first dose of lonigutamab, patients achieved responses that were in line or better than what has been previously reported for IV therapies, representing the potential for an exciting paradigm shift for TED patients. While Cohort 1 demonstrated proof-of-concept, we also are sharing the current cut of Cohort 2, which is consistent with and supports the observations for Cohort 1. Based on the strength of these data, we plan to initiate a Phase IIb/III trial in the second half of this year, designed to be the first of two registration studies. This is the design of the Phase I/II trial evaluating subcutaneous lonigutamab in TED patients. It was designed to have a size and shape consistent with what others have shared as proof-of-concept for their candidate TED therapies. Cohort 1 was placebo-controlled with a randomization of [ 6 to 2 ]. Patients received 2 doses of lonigutamab, one at baseline and one at 3 weeks. The demographics and baseline characteristics in Cohort 1 were consistent with other test studies and were otherwise unremarkable. At the first assessment, which was within 3 weeks of receiving the first dose of lonigutamab, 50% of patients achieved a proptosis response, defined as a greater than or equal to 2-millimeter reduction in proptosis. This is actually the registrational endpoint for TED because it is approximately the amount of bone that an osteoplastic surgeon can scrape over way from behind the eye before jeopardizing the brain in an attempt to reset the globe back into its orbit. We know from our studies that patients often have much more than 2 millimeters of proptosis, sometimes 10, 15 or even more than 20 millimeters. And this is why we think it is important for us to strive for longer-term dosage to have the potential to enable greater depth and durability of response. Remarkably, in this cohort, even with the last dose being administered at 3 weeks, responses seem to be holding out to 12 weeks. This is just the durability of effect that could factor into dosing decisions in the future. Clinical Activity Score, or CAS, is another important measure of disease activity for TED, where patients are scored based on pain, redness and swelling around the eye. A greater than or equal to 2-point reduction in CAS is considered clinically meaningful improvement for patients. As you can see from these data, there are rapid and deep responses with 50% of patients receiving lonigutamab achieving a clinically meaningful reduction in CAS within 3 weeks and 100% within 6 weeks. As was observed with proptosis, these responses were again maintained through week 12. Ultimately, the goal for patients with chronic disease is resolution of all signs and symptoms to achieve a normal -- as normal a life as possible. It's core to our mission to strive for transformative benefits for patients and this is what we're trying to achieve by treating TED more like a chronic disease with longer-term dosing. In TED, CAS of 0 or 1 is a hurdle that approximates the sentiment. As you can see from the data, CAS 0 or 1 was achieved by 50% of patients by week 6. Based on all of these data, we believe that proof-of-concept has been demonstrated within this first cohort of treating TED patients subcutaneously with lonigutamab with speed and magnitude of these responses at least comparable to the IV approaches. Now I'd like to turn it over to Shep, who will walk through our Cohort 2 data. We're sharing data from the current cut of Cohort 2, which is consistent with and supports the observations from Cohort 1. Shep?

Thank you, Shao-Lee. Indeed, the results from Cohort 1 are impressive and clearly demonstrated proof-of-concept for lonigutamab in thyroid eye disease with the subcu treatment. I am super excited and thrilled to share further supporting evidence from Cohort 2 that validates the proof-of-concept and helps us to further understand how we might optimize embedded risk of lonigutamab. Here, you see the demographics and baseline characteristics for Cohort 2, which were as expected and consistent with Cohort 1. In Cohort 2, we are looking at the next six patients at 6 weeks, and the data are entirely consistent with Cohort 1 in the 6 weeks treated patients. Depicted on this slide, on the left, the line graph shows rapid improvement in proptosis response achieved by 67% of patients by week 4, the first assessment point, which is maintained through week 6. The middle bar chart shows clinically mean proptosis responses for both Cohort 1 and 2 at a 6-week time point. Finally, on the right side, you can observe reduction in clinical activities score with 83% of patients achieving a clinically meaningful reduction in clinical activity score by week 6 for Cohort 2. It's important to note that one of the most debilitating symptoms of thyroid eye disease is diplopia or double vision. Diplopia is measured by severity on a 4-point scale that ranges from constant to intermittent to diplopia only with far left to right case and to non-diplopia. As you can imagine, a single grade reduction on this scale will be important for patients and is what is called the diplopia response. In Cohort 1, 25% of patients with a valuable diplopia at baseline achieved response and this improved to 40% in Cohort 2. These diplopia responses are remarkable as they represent a level of response at 6 weeks in this difficult-to-treat manifestation that seems at least comparable to the 39% placebo-adjusted response observed at a later time point. It's 24 weeks in the teprotumumab registrational program. So to summarize, across response measures and in both cohorts, lonigutamab demonstrated very early, clinical meaningful and durable efficacy. Now turning to safety. Our experience to date demonstrates lonigutamab has been well tolerated with favorable safety profile, which supports our ability to test our hypothesis for both the greater depth and durability of responses as well as the potential to limit safety liability. In this trial to note nothing was confirmed or noted with the majority of events being mild. There were no interruptions to study drug except for optic neuropathy in the placebo patients. There were no events of hearing impairment or hyperglycemia recorded and with no serious adverse events. Now I turn over back to Shao-Lee.

Thank you, Shep. In vision to establishing the clinical proof-of-concept with favorable safety profile, observed exposures from Cohorts 1 and 2 are represented on this slide and of note the Y axis is a long scale. The most important takeaways are that the clinical responses achieved were exposures below the Cmax for lonigutamab is an important consideration for testing our hypothesis of limiting safety liability seen with IV administration. We are extraordinarily pleased to have achieved the level of clinical responses seen in both cohorts. The 40-milligram Q3-week dose gives us confidence that we can achieve monthly Q4-week dosing. And the durability of clinical responses out to 12 weeks further suggest the possibility of even less frequent dosing. Overall, the exposure response relationship demonstrated provides the evidence needed to choose a dose to optimize efficacy while determining the potential to minimize safety risk. And so to wrap up on lonigutamab, we are pleased to be the first to present proof-of concept for subcutaneous anti-IGF-1 receptor treatment in thyroid eye disease patients. We are excited with the strength of these results and look forward to initiating a Phase IIb/III trial designed to be the first of two registrational trials in TED in the second half of 2024. In closing, I'd like to highlight between the lonigutamab program and our lead program, izokibep, we have a robust late-stage pipeline, covering a number of indications with a catalyst-rich year ahead of us. Similar to lonigutamab data shared today, we have the data shared last week from izokibep in HS and PsA that continue to suggest the potential for the unique characteristics of izokibep to differentiate in meaningful ways across indications. For PsA, we've seen response rates across disease manifestations include high [indiscernible] of response that appear to be at least as good as the best agents available today or in development without the safety liabilities and with the potential to further differentiate in resolution of enthesitis and with longer-term exposure. Similarly, for HS, the potential differentiation has been demonstrated with earlier resolution of abscess and nodules relative to what has been reported by other agents as well as clinically meaningful improvements across disease manifestations. This is without evidence of increased risk of infection, especially fungal or suicidal and behavior in a patient population predisposed to infection and clinical impression. I am pleased to update that we are seeing faster than expected enrollment in our ongoing Phase III trial in HS and currently, we anticipate these top line results in the second half of 2024. Based on our end of Phase II interactions, we anticipate our ongoing Phase III trial in HS and the recent Phase IIb/III trial in PsA to be the first of two registrational trials for each of these indications. With all of this important work ahead of us, we are extremely fortunate to be in a strong financial position. We expect that our cash will enable us to fund the company's business over multiple years and through key data milestones for registrational studies for multiple indications and across programs including the planned Phase IIb/III for lonigutamab in TED. In closing, we had a strong start to 2024. With lonigutamab, we have the opportunity to change the practice of medicine for TED patients and similarly with izokibep. And that's the goal, the pursuit of helping patients achieve as normal a life as possible through resolution of their disease. Thank you for the opportunity to provide these exciting updates. Given the close proximity of this call to what would be our normal year-end earnings and business update, we will forego that earnings call and issue a press release and file our annual report on Form 10-K next week. I'm grateful to your belief in our vision of accelerating the development and commercialization of transformative medicines for patients. And we look forward to speaking with you all again soon. And now, we are ready to open up for questions. Operator?

[Operator Instructions] And our first question will be coming from Yasmeen Rahimi of Piper Sandler.

Congrats on the data. Team, I think first question is around -- it's exciting to see that there was no hypoglycemia or hearing inabilities or [ dispairments ] reported. But questions that clients have for us is like is maybe 6 weeks too early pick up any differences? Would love to get your thoughts on how -- what type of analysis were conducted to really ensure that those two safety limitations are overcome with loni? That's sort of question one. And then question two is given Cohort 1 and cohort data, could you provide some glimpse on how you're thinking about which doses you would be moving forward into a registrational study? And I'll jump back into the queue.

Thank you so much for those questions. They're both really, really important ones. I think absolutely, we shared the safety with regards to the first two cohorts, reporting no hearing impairment and no hypoglycemia seen because those are obviously events of the interest for the pathway. But you're exactly right. These sorts of safety events, especially hearing impairment are really going to take the longer-term treatment in larger numbers of patients to be able to have a good point estimate in terms of what's really happening. With those what we really want to communicate today that's the most important that we have the opportunity to do -- to test the hypothesis, to do that experiment because of the data that we're seeing. And so really, the takes on here are that, number one, we are administering this potential therapy at this point as a subcutaneous administration in TED patients. We think that we're the first ones to be doing that. And we are seeing response rates that are at least on par with where we would expect those therapies to be. But at exposures that are well below, at least a half log below the Cmax of what we saw with teprotumumab, which is what we're trying to avoid. And that was exactly the parameters that we were hoping to be able to achieve. With this data set, we've achieved that in a way that I'm extraordinarily pleased about because to be frank, I thought we would have to go to weekly dosing in order to narrow that therapeutic window enough to be more below the teprotumumab Cmax. And at this point, it's -- I think we've demonstrated that we can do that even with monthly dosing and perhaps beyond. So your next question was about what do we expect in terms of dosing moving forward. I think we can safely say that we'll, at a minimum, include a monthly dosing cohort within the context of the IIb/III trial that we stated that will begin in the second half of this year. And the rest of the dose -- specific dose levels, et cetera, we will refine. But the purpose of that trial will be to enable us to look at the potential to improve not just convenience, but also the potential to improve efficacy as well as safety, efficacy with depth and durability of response, perhaps with longer-term dosing within the context of that study and then safety by limiting our exposures relative to the maximal concentration of teprotumumab, which we feel like we currently can do. So we're excited because the overall data that we're seeing is completely consistent with what we had hoped we would see in terms of responses and from a pharmacodynamic perspective allow us to proceed with actually better experiment than we would be able to do. We thought we'll be able to do.

[Operator Instructions] Our next question will be coming from Tyler Van Buren of TD Cowen.

Congratulations on the initial MAD data for loni here. So my primary question would be -- so obviously, the proptosis response rate of 50% at 6 weeks looks consistent with what TEPEZZA showed at the same time point. But can you say anything about the depth of response or change from baseline in proptosis? And the follow-up to that would be also with TEPEZZA, there are meaningful improvements in responses on the various endpoints from week 6 to week 24. So would you expect a similar dynamic with loni with continued dosing in terms of improvement on these various endpoints? Or how might this dynamic differ with subcutaneous dosing versus IV?

Yes, thank you so much, Tyler, for that. Really all terribly important questions and very central to what we frankly, help to be able to offer patients. So remember the top of heat in terms of what we're trying to improve for patients is, number one, efficacy, then number 2 safety and then number three convenience because that's the typical order of importance as we're developing, frankly, any drug. And exactly to your point, what we've been able to provide to you so far as top line data is our proptosis response rate. So remember, that's the registrational endpoint, and therefore, what we felt was both important as well as enabling us an opportunity to sort of compare apples-to-apples across, as best we can, in early days of small dataset. But we feel very good about what we saw. The -- one of the very most important things is that moving from an IV administration to subcu, the ability to see that as rapidly as we have that is at least consistent with the IV therapies is part of what's been so remarkable. Here, one could imagine that if you deliver something subcu, it might take long to get up to the IV levels of response. And so we're not seeing that happen. And then there's no reason that once you get up to an efficacious or therapeutic level, that if you're able to maintain that, and we think you can maintain that actually with a more optimal therapeutic window or therapeutic level, if you will, by delivering itself. There's no reason to believe that you wouldn't continue to maintain that efficacy like others have with the same mechanism of action so -- or at the same target, at least, not exactly the same molecule. So exactly to your point, we do expect to see that continued benefit over time. We are looking for that in our longer-term next trial to determine whether or not we can get that efficacy benefit, not just the 2 millimeters of response. But really, when we talked about patients having 10, 15, even 20 millimeters of proptosis really striving towards resolution of proptosis for patients. And that's going to have to be tailored on a patient-by-patient level, giving physicians and patients the flexibility to be able to dose for longer term. We think it's going to be important. We think that, that's actually already been demonstrated and updated in the potential label within the context of last calendar year in terms of treating more chronic patients who have had the disease for multiple years and shows the efficacy of this pathway or this mechanism for those patients. And so really, it's a fundamental tenet of what we're trying to achieve, longer-term dosing for these patients, starting some of the safety liability as well as providing the convenience of subcu.

[Operator Instructions] Our next question will be coming from Akash Tewari of Jefferies.

This is Amy on for Akash. Just a quick one. In terms of the doses that you tested, I think in some of your earlier MAD studies, you were looking at higher doses. In your clinical trials you had a monthly dose option? Just wanted to see if you had any of those data on file and how that looked in terms of safety and efficacy?

Yes. Thanks for that, Amy. Yes. So in addition to Cohort 1 and Cohort 2, we do have a Cohort 3 that's ongoing and that is a monthly dose. And we don't have those data for you. In fact, for Cohort 2, we provided you the sort of current cut of that data set. And those 6 patients to 6 weeks is what we have available at this time...

[Operator Instructions] And our next question will be coming from Emily Bodnar of H.C. Wainwright.

I kind of wanted to follow up on one of the previous questions about longer-term treatment. Since the Tepezza is used for only 6 months, are you planning to evaluate any endpoints looking at time periods further than 6 months to kind of see if there might be additional efficacy beyond that time period? So what time periods might you look at? And given the Tepezza phase III study, was that large, I believe it was like 80 patients. Is there a potential to use the first Phase IIb/III study as just the registrational study and the second one for confirmatory purposes?

Yes, both absolutely fabulous questions, Emily. Thanks for those. So I'll start with the second one first because it's easier and that one is yes. We're intending to design the study that will start in the second half of this year as a IIb/3 with the potential to utilize this as part of the registrational package definitely. And in terms of longer term dosing, absolutely. That's the point of what we're trying to achieve. Because of the 6-month, 6-regimen and IV administration of Tepezza there were a couple of things that we were hoping to address or a couple of things that we understand from that patient population. Number one is that, again [ terribly ] trial because it's made a tremendous difference for patients. And we feel that that's been an important -- obviously, a tremendously important advancement for patients. We also know that after 6 months of therapy, not everyone is -- certainly not to full resolution of their disease and a significant percentage of patients in the publication specifically about this new response over time or need additional rounds of therapy. And so -- and we know from, again, the studies and label update within the context of the last year in more chronic patients, patients still had disease for years, we know from biopsy samples that they have continued receptor express, that they have continued cytokines in the context of those tissues and studies have shown that treatment can actually improve them in a way that resulted in the label updates to ensure that, that was also described. And so we think that the potential to provide patients with longer-term treatment is terribly important that's only enabling a fixed dose regimen in months and will have the kinds of limitations that we've seen. And so we would expect that within the context of our IIb/III that all of the primary endpoint may be -- will be earlier. The study as a whole will be run out for a year of treatment for patients. That's the paradigm that we've used within the context of other automating chronic inflammatory diseases to enable us the potential for longer-term chronic dosing for patients. Exactly how long that in, I think is something we're going to need to determine for these patients in the population over time. But certainly, it's unlikely to be months. It's more likely to be a year or more.

[Operator Instructions] And our next question will be coming from Vikram Purohit of Morgan Stanley.

We had one as a follow-up to the last question. But on a broader commercial note on TED, and your view on lonigutamab's prospects, given the data you have in hand today. I know there are some open questions you'll be looking to understand through later-stage studies for lonigutamab. Just based on the KOL feedback you received from the space and any market research you may have done recently, how compelling do you think a subcu option would be versus an IV option for TED prescribers and patients? Again, keeping in mind the data profile you have in hand today. We'd be curious to hear any thoughts you might have at this point on what portion of patients on IV you think would represent a share shift to subcu and how you think lonigutamab may end up settling versus other agents in the space, both IV and subcu that could be available by the time lonigutamab get into the market?

Yes. Thank you so much for that, Vikram. I think in a word, we're ecstatic. We're ecstatic with the level of results that we've seen across the manifestations of disease. We're ecstatic at how quickly that's happening. We've tried to compare apples-to-apples for you within the context of our slide presentation to give you a flavor of why we use the word ecstatic. And we've shared with you since before these data, ultimately, that we were after not a me too and not a piece of bigger pie, but really to try to make something that we thought would advance the therapeutic options for these patients, really to bring something clinical, meaningfully different. Everything we understand from the disease state, from the patient advocates, from the opinion leaders and experts out there is that longer-term treatment is necessary and important to bridge the gap in terms of what we're seeing from a fixed-dose regimen perspective. Certainly, people are after the convenience of subcu and that's going to be necessary or will help tremendously with regards to the potential to provide longer-term treatment. And then for this particular molecule and its unique characteristics, we think we have the ability to test this hypothesis around hearing impairment or the most significant safety liability within the context of this mechanism that could limit it moving forward. And it is a hypothesis versus the ability to test that and actually can test that in a convenience way, which is so monthly instead of weekly, again back to the word ecstatic about all of this. So I think fundamentally, as I said earlier, we think that this has a potential to really change the practice of medicine for these patients. And fundamentally, that's what we're after.

Understood. And if I could ask a follow-up, and apologies if you mentioned this and we missed it. But at what time point would you expect to see hearing impairment show up in your trial results? And at what time point rather would you -- if you didn't see hearing impairment, would you have confidence that it's not a signal that you're seeing associated with this molecule?

Yes. That's a fabulous question, Vikram. So we saw within the context of the TEPEZZA registrational program, the hearing impairment typically comes up -- came up in around the third or fourth dose. So for that program as Q3, with dosing after the third or fourth month, which is sort of consistent with the hypothesis for what you think -- what we think might be happening, which is the IV exposures with the big saw-tooth pattern, if you will, for what those exposures look like and at some point, having an exposure high enough to penetrate the blood-labyrinth barrier. We gave medicines IV in oncology all the time specifically to push them across the blood brain barrier to enable us to penetrate and treat in the brain and about 0.1% of your biologic therapy gets across. And so there's a threshold by which this will cross the blood-labyrinth barrier, which is just like the blood-brain barrier and have the potential to be toxic, if you will, or to interfere with the normal function of IGF-1 in the hair cells of your inner ear. So we're -- our hypothesis is that what happens is happening over time. It takes some time for that to develop because you have insults all the time to your inner ear, your hair cells, you need that pathway to regenerate and you're not able to do that because we're blocking it. And so we're hoping and no one will know for sure. So this is the hypothesis that we're testing at this time that we -- if we can get as far away from the different Cmax if possible and still have efficacy and still have convenience that hopefully we can improve that safety, maybe not make it go away completely, but at least improve that benefit-risk ratio in a way that's meaningful for patients.

[Operator Instructions] And our next question will be coming from Derek Archila of Wells Fargo.

Just first, I just wanted to confirm the safety data is the new 12 weeks? So that's question number one. And then second question, I guess, can you just remind us if the trial exclude patients with hearing impairment? And I guess, to the three tinnitus AEs seen in the trial, I guess, can you just talk about the magnitude of when they appeared and when they resolved?

Yes. Thanks so much, Derek. Let me try to break that down. So in terms of the safety overall, we have -- the Cohort 1 has been followed through 12 weeks and Cohort 2 through 6 weeks. In terms of the hearing impairment, this study included patients that could have some degree of hearing impairment at baseline and -- but no audiology changes at baseline. And in terms of the tinnitus cases, there were three cases of individuals who had reported mild tinnitus. Ultimately, they resolved without intervention and there were no audiology changes in any of those subjects. And you can imagine the difficulty within the context of any studies, frankly, where we are obviously informing patients appropriately of the potential risk given the mechanism of hearing impairment and therefore, they are sort of a bit hypervigilant about hearing impairment. And really that highlights the importance of audiometry at baseline as well as moving forward through these studies, which we have implemented and will continue to implement moving forward.

Understood. And then maybe just one follow-up. Just in terms of the introduction of a subcu into the TED marketplace, I guess how much do you think that -- do you think that's more of an expansion through longer duration of therapy as we talked about more chronic dosing? Or is it more deeper penetration into the market just because it's maybe easier to treat patients, they're more apt to do with subcu? Like how do you think about that once these are introduced into the market?

Yes. A little bit early days for some of the details of that. Obviously, we need to fully understand the benefit risk here. And obviously, the full understanding of the benefit risk is really going to drive ultimately what that market share looks like. So I think more to come there as we get into longer-term studies.

[Operator Instructions] And our next question will come from Samantha Semenkow of Citi.

Two for me. Shao-Lee, you mentioned this a few times in your prepared remarks and also in the Q&A. It seems that what you're seeing meaningfully quicker responses in proptosis, at least compared to the TEPEZZA dataset. I'm curious your thoughts on what's driving this? Is this purely a difference of the formulation? Or some other differentiating aspect of lonigutamab? And then secondly, could you just remind us of the type of administration here? Was it a prefilled syringe or some other form of subcutaneous administration?

Yes. Thanks so much, Samantha, for those questions. So with regards to the speed of response, I would say the important takeaway is that we're seeing responses within our first measurement, both in Cohort 1 and Cohort 2. So it's happening rapidly. And then the levels of responses that we're seeing are at least consistent with what we've seen for this mechanism. It's not numerically better. Again, small sample size, but early days for sure, but all within the ballpark of where we would like to be. And therefore excited and across all of the important measures, proptosis, clinical activity score as well as diplopia. So super excited about all of that, including the speed aspect. And the speed aspect is where we would have thought we might have taken the biggest hit moving from IV to subcu, and that's not what we're seeing. That's an important part of the takeaway there. In terms of the mode of delivery, ultimately, we expect this to be available at launch in an auto-injector, kind of a single injection, super easy standard auto-injector without a prolonged period of time for administration, et cetera. At the moment, this is proof-of-concept in a Phase I/II trial, and we are in drug and vial, in syringes. And so it's not a prefilled syringe as yet, we anticipate being able to introduce those as single injections moving forward in our later stage studies.

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