Study Result

Mar 30, 2020

Press Release

Good morning. My name is Sherry, and I will serve as your conference call operator. At this time, all participants are in a listen only mode. A brief question and answer session will follow the formal presentation. As a reminder, this call is being recorded. Joining me on today's call will be Doctor. Pete Salzman, Chief Executive Officer of Aimovat. Before we begin, I would like to remind everyone that today's conference call will include forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward looking statements are not guarantees of future performance and are subject to various risks, uncertainties, assumptions known or unknown, which could cause actual results to vary materially from those indicated or anticipated. For more information, investors are encouraged to review Imovance's most recent quarterly report on Form 10 Q filed with the SEC on 02/14/2020. I would now like to turn the call over to doctor Pete Salzman. Thank you, doctor Salzman. You may begin. Thank you, Chari, for that introduction. I'd like to start off by expressing how thrilled we are about the positive clinical results we are announcing today in thyroid eye disease. As the only subcutaneous therapy in clinical development for thyroid eye disease, we believe IMVT fourteen oh one has the potential to be life changing for patients, and we couldn't be happier with the outcome of this small proof of concept trial. Prior to seeing this data, we believed there was strong biologic plausibility for using an anti FcRn agent in thyroid eye disease. Now with this data, we have the first clinical proof of concept using of an anti FcRn agent in thyroid eye disease. For those of you who are following us closely, you will note that our press release described results for seven patients. Although we initially planned to enroll eight patients in ASCEND GO one, the eighth patient enrolled in ASCEND GO two instead of ASCEND GO one at one of our four Canadian sites for this trial. All four of the Canadian sites are now converting to ASCEND GO two sites. I also want to note that following my discussion of the ASCEND GO I results, I'll provide a brief update with respect to the COVID-nineteen pandemic. I'll now turn your attention to slide nine of our deck. Slide five, excuse me. Before jumping into the data, I thought it would be helpful to provide a brief overview of thyroid eye disease, a serious autoimmune condition with an incidence of fifteen to twenty thousand patients per year in The United States alone. Also known as Graves' ophthalmopathy or Graves' orbitopathy, thyroid eye disease is characterized by a pronounced bulging of the eyes, known clinically as proptosis. Eye pain, double vision, known clinically as diplopia, and light sensitivity are also common. Thyroid eye disease isn't an ocular disorder per se. Rather, the tissue around the eye is particularly vulnerable to inflammation in patients with abnormal thyroid function due to stimulating autoantibodies. In ASCEND GO-one, we sought to minimize variability by restricting enrollment to thyroid eye disease patients who also have Graves' disease. For thyroid eye disease in the context of Graves', we believe that retro orbital fibroblast activation occurs downstream of the stimulating stimulatory autoantibodies directed at the thyroid stimulating hormone receptor and or at the insulin like growth factor receptor. On slide six, as you can see in the classic curve first described by Francis Rundle in 1945, The disease has two phases, an active phase and a static phase. During the active phase of the disease, the orbital tissue is inflamed, resulting in redness, swelling, eyelid retraction, orbital pain, and general discomfort. Following the active phase, which often lasts a couple of years, the inflamed tissue gives way to fibrotic tissue. In the inactive fibrotic phase, patients are no longer responsive to medical therapy and are left with the long term manifestations of the disease, including proptosis, diplopia, and occasionally strabismus, meaning patients cannot align their eyes in the same direction. Once a patient has reached this point, surgery is usually the only option. The best time to intervene to alter the natural history of the disease is during the active phase, as we've indicated here with the dark blue dotted line. In ASCEND GO-one, we included only patients in the active phase. Turning to slide eight, our phase two program in thyroid eye disease consists of two trials. ASCEND GO-one, the results of which I will be reviewing today, is an open label proof of concept study taking place in Canada. This study primarily uses our lower dose of three forty milligrams, supplemented by two six eighty milligram loading doses. The treatment duration in this study is short, just six weeks. Our larger phase two program, which is already up and running, is testing three dosing regimens, including a higher dose regimen of six eighty milligrams delivered weekly by subcutaneous injection. This larger study has a twelve week treatment period. As I mentioned earlier, a planned eighth patient was enrolled in AscendGo two instead of AscendGo one based on the investigators and patient's decision. Turning now to slide nine. ASENgo-one is the first trial of an anti FcRn in thyroid eye disease. We had two major objectives for this trial. First, the study was designed to test the pharmacodynamic response to a loading dose regimen. Second, the study was designed to examine the initial safety and efficacy of IMVT fourteen o one in thyroid eye disease. Patients were treated with two weekly six hundred and eighty milligram loading doses followed by four weekly three hundred and forty milligram maintenance doses for a total of six weeks of treatment. For the study protocol, all patients included were positive for antibodies directed at the thyroid stimulating hormone receptor. To measure clinical improvement in thyroid eye disease, we used three scales. Proptosis is really the hallmark feature of this disease and can be measured using a device called an exophthalmometer, pictured here at the top of the slide. To measure double vision or diplopia, we used a standard clinical assessment called the Gorman diplopia scale. To capture improvements in other dimensions, such as pain, eyelid abnormalities, and redness, we use the clinical activity score, which is also a standard assessment conducted by a trained health care professional. One point is given for each of seven abnormalities. Slide 11 is just to show you the baseline characteristics for the seven patients in our study. Note that our patient sample was very similar to the patient populations that have been studied in other recent trials for novel agents to treat thyroid eye disease. In particular, the average CAS or CAS score and the average proptosis value are very similar to other studies. On slide 12, we've provided a high level summary of our clinical observations from the treatment phase of the study. Note that all patients have entered the follow-up phase, and we will be sharing much more data when the study is complete. Fifty seven percent of patients improved by two or more points on the clinical activity score, or CAS. Forty three percent of patients were CAS responders, defined as having achieved a CAS score of zero or one. Forty three percent of patients were also proptosis responders, defined as improving two or more millimeters in proptosis in the study eye without significant deterioration in the fellow eye. At the bottom of the slide, you see that six patients had baseline diplopia, and four of these six patients with baseline diplopia saw an improvement. In addition, two of these patients achieved a status of no diplopia. I want to emphasize that we are very encouraged by the forty three percent proptosis response rate. The three proptosis responders were also CAS responders, and all three showed improved diplopia. This consistent clinical effect across different parameters really speaks to a biological response. Turning to slide 13. As a reminder, the primary endpoints of the study were safety and tolerability, change from baseline levels of antithyroid stimulating hormone receptor antibodies, total IgG levels, and IgG by subclass. Of these primary measures, the anti TSHR antibodies and IgG subclass results are not yet available. We're looking forward to presenting those laboratory results at an upcoming medical meeting once the study is complete. What we do have available today to report is that the average reduction in total IgG levels was 65% from baseline to the end of treatment, right in line with where we had modeled it for the regimen used in this trial, indicating that thyroid eye disease patients responded similarly to healthy volunteers on this parameter. We are also pleased to report that the safety and tolerability profile we observed in ASCEND GO-one was in line with our expectations from our phase one study in 99 healthy volunteers. We saw no serious adverse events or SAEs, no withdrawals due to adverse events, and no headaches were reported in this trial. All adverse events were mild or moderate. For albumin, we observed an average reduction of 24%. Albumin changes were asymptomatic in this trial, as they were in phase one. Finally, I wanted to use this opportunity to briefly address the global COVID nineteen pandemic. Many clinical trial sites in North America and Europe have halted new enrollment in nononcology trials. At these same sites, visits are generally proceeding for patients who are already enrolled in the clinical trial. However, in certain cases, a key staff member or the principal investigator or the patient may not be able to go to the site, and this can interrupt the schedule of events in a trial. So what are we doing to ensure patient safety and to ensure trial quality? Several things. First, we are ensuring communication lines remain wide open between our sites and our staff. Our clinical operations team has a great depth of experience and is proving to be a valuable resource for our sites. Second, we are monitoring our trials very granularly. Our team understands where every patient is on the clinical trial journey. They know which visit is coming up, which tests are needed, and what is going on in a particular geography. Third, we're staying abreast of evolving guidance from regulatory agencies that emphasizes patient safety, flexibility within certain guardrails, and very good documentation. Finally, we are working with our partners to ensure we have backup services in place, working to get ahead of the needs as much as we can. Understanding the situation is still fluid and subject to change, our current estimates with respect to programs are as follows. For the myasthenia gravis phase 2a study, earlier this month, the trial was on track to easily hit our q two guidance based on actual enrollments plus scheduled randomizations, plus patients in screening and prescreening, even accounting for some prescreen failures. However, based on the current environment, we now expect a Q3 twenty twenty data readout. Warm autoimmune hemolytic anemia phase 2a study. Results are currently still possible for the high dose cohort by the 2020. We expect to have more clarity on the timing for this study by Q3 of this year. Thyroid eye disease phase 2b study. Results are still possible in the 2021. This study does have a meaningful number of European sites, which could prove challenging depending on how the enrollment environment evolves there. However, I expect the positive results we're announcing today to be a tailwind. In other words, now that our Phase 2a initial results are available, we are hopeful we'll be able to reaccelerate enrollment once our sites in Europe and North America recover. We expect to have more clarity by Q3 of this year. To conclude my remarks on ASCEND GO-one, I just want to say again that we're absolutely thrilled with these results. Ophthalmologists are not generally equipped to deliver intravenous infusions, but we think a safe and effective subcutaneous therapy would fit their practice patterns well. Of course, patients prefer convenience too. Yesterday, we had only we had the only subcutaneous therapy in clinical development for thyroid eye disease. Today, we have that plus a strong proof of concept across a range of important safety and efficacy parameters in thyroid eye disease. With that, I will ask Chari to open the call for Q and A. Thank you. If you would like to ask a question, please press star one on your telephone keypad. Our first question is from Jibola Amusa with Chardan. Please proceed. Hi, it's Jibola Amusa. Thanks for taking my call and congrats on the hit here with the top line. Just a quick question on clinical meaningfulness of the results with regards to CAS, proptosis response and diplopia. Can you talk a little bit more about what these signals mean at least to patients? And then second is just, does this go against natural history? We saw the Randle's curve, etcetera, but for the duration of this study, do these results on those endpoints go against natural history? Thanks, Paula, for those questions. In terms of the clinical meaningfulness, patients experience a tremendous amount of morbidity due to, the pain and proptosis and also due to the double vision or diplopia. Double vision in particular, think is maybe under recognized as a source of patient morbidity outside of the ophthalmology community. Ophthalmologists clearly recognize it. But when you're not able to remove double vision from your daily life, it just really impacts your ability to work, your ability to spend time with your family. It's probably one of the higher impact symptoms from a quality of life perspective. Obviously, the proptosis is something that patients complain about from an appearance standpoint, but it can also impact the ability of it can cause them to have an inability to close their eyelids and that can cause drying of the eyes or even corneal abrasions if they scratch their eyes. So there's a lot of patient morbidity caused by the proptosis as well as the diplopia. Those two features are measured across the clinical scales. So, obviously, the diplopia scale and proptosis directly measure those two features, but the clinical activity score also includes two elements of pain and then a variety of elements of swelling and redness. So improvements across these clinical scales, I think, really correlates to tremendous improvement in the in how patients are feeling, And I think that's been validated by other agents in development for thyroid eye disease. In terms of the natural history of thyroid eye disease, I think it's a really interesting question whether the natural history will be altered or postponed. What I mean by that, and I think this is getting at your question, Bola, is whether when interventions during the active phase of treatment have an impact, does that mean that Brundle's curve is shifted out to the right so that withdrawal of therapy, there will be a return of the active phase? Or will the initial active phase be flattened and that chronic phase will occur at the same time period but with a lesser impact? Practically speaking, what that means is I think there's an open question with regard to whether patients will need a shorter term of therapy or a longer course of therapy in order to really achieve what they're looking for, which is a long term result. The nice thing about having a medication that's available by subcutaneous infusion is it will allow us in our phase three program to test that hypothesis and treat patients for a longer period of time to determine if that makes a bigger difference in terms of their long term benefit. Great. Thanks. Just a really quick question on COVID nineteen. I know these are unprecedented times, but when you complete enrollment on future studies, might you, put out a release, showing that a trial is complete or to be determined? Yeah. I think that's, that's to be determined. I think we'll see how things evolve over the next, you know, even the weeks weeks or short months and we'll see where we're at. Great. Thanks and congrats again. Yes. Thanks, Paul. Our next question is from Thomas Smith with SVB Leerink. Congrats on the data. First, can you just give us a sense either quantitatively or qualitatively of how quickly you're seeing the proptosis responses observed in these patients? Yeah, great question. So for the patients who achieved a proptosis response, so they achieved that two millimeter or greater improvement, What we saw in those curves is essentially a steady, steady improvement. The curves just kinda keep going down, and, it looked like at the end of treatment, you know, they were still headed in the downward direction, which is not surprising because that's what's, seen in other trials as well. Okay. And then, I guess if you could just give us your thoughts about how you're thinking about dosing going forward. This is obviously a pretty unique, dosing regimen, and you're using a different dosing regimen in the Phase IIb study. But can you just give us your thoughts on how you're thinking about dosing going forward? Yeah. For sure. So I think the phase 2b program is closer to how we're thinking about dosing going forward. And what I mean by that is a a straight dose during the treatment period. Obviously, that program also tests a higher dose regimen. The two a program is really closer to the lower dose regimen. It does have a two loading doses of six hundred and eighty milligrams, which more quickly get the patient to the, to the trough level. But the, the total IgG reduction was modeled to be very similar to what we saw in the three forty cohort in the multiple ascending dose trial in healthy subjects, and that's in fact, what we saw. Why did we do the loading dose regimen in this two way trial? I think it was as much to learn, more about our pharmacodynamic profile as a way to consider loading dose across a range of different indications. It wasn't so much specifically geared to provide insight into the treatment only of thyroid eye disease. So long story short, you know, we're not gonna make any changes to the two b program. I think we wanna see in that program if there's a difference in efficacy with longer therapy, which we expect, but also with a higher dose, the six eighty compared to the three forty. And I think that study will really be much more informative in terms of what is the appropriate long term dosing regimen for patients with thyroid eye disease. Right. Okay. Thanks. So maybe, just one last question. Just as you're looking through kind of the baseline characteristics, for these patients, is there anything that jumps out as to why some patients may have responded better than others with fourteen oh one? But were there any response trends in patients who didn't achieve clinical response? Right. So, in terms of the hard metrics of proptosis responder and clinical activity score responder, meaning those patients who achieved either zero or one on clinical activity score or two millimeters or more on proptosis, right, that's where we had a forty three percent response. However, the response on more leading indicators such as an improvement of two or more points on the clinical activity score, or for that matter, any improvement on the clinical activity score, there were more patients who fell into that category of achieving some response but not meeting the hard endpoint. So we had fifty seven percent or four out of seven who achieved a two point improvement on CAS and actually six out of seven achieved at least a one point improvement on the CAS. And each of those clinical activity score metrics is a meaningful symptom to reduce. So I think based on all that, plus the natural history we've seen from other trials, we would expect that with longer duration of therapy, you're likely to see the number of patients and percentage of patients who hit those hard endpoints go up. In terms of being able to predict who, you know, responds and who doesn't, I think that's a very interesting question. We'll be very interested to see the results of the anti thyroid stimulating hormone receptor antibody titers and whether there's any correlation there. Of course, in a relatively small study like this, it's gonna be somewhat hard to tease out the difference between responders and nonresponders, particularly because you clearly wouldn't expect anywhere close to 100% responders in a short study like this anyway. Right. No. Thanks very much. That's very helpful, and, congrats again on the data, guys. Thanks, Thomas. Our next question is from Christopher Marai with Nomura Instinet. Please proceed. Hey, good morning. Thank you for taking the question, and congrats on the data. I was wondering first if we could touch upon the IgG reductions. I was wondering, you saw a mean of 65%. How does that compare to the trough level that you observed? And I have a follow-up. Right. So, just to that's a great question, Chris. Just to be clear, the, the mean is the mean at the end of treatment, which is the trough. So for these seven patients, the mean change from baseline from treatment initiation to the end of treatment was a 65% reduction, which is what we expected for this particular dosing regimen based on pretrial pharmacodynamic models. Great. Then Did I get your question there, right, Chris? Yeah. I think so. I guess we were wondering if perhaps you saw lower levels at time points prior to the end of the study. But but I suppose how many data points do you have between, baseline and and the the end of the, the study period? Yeah. So we have weekly values. And what you see again with that six eighty milligram loading dose is you get faster to that, sort of 60 to 65%, reduction range than you would if you had, given three hundred and forty milligrams the whole time based on models. And then that three forty milligram weekly dose, maintains the 65%, response. Again, recall from our multiple ascending dose, trial in healthy subjects in phase one, we saw a 63% reduction from the three in the three hundred and forty milligram cohort. So that's essentially spot on what we would have expected with the with the lower dose regimen. Okay. Great. And then just with respect to some of the clinical data, the diplopia, I was wondering if if you could comment on how response was was defined. You I guess you presented that patients saw an improvement in it. But but how did you find define that improvement? Yeah. Great question. So we define improvement as a change of, one or more grade, and that's the same, definition of response that that has been used in other trials when they report an improvement in diplopia. So one one one grade or more change on the Gorman diplopia scale. Great. And then with respect to the proptosis, the the the change the median change, in in millimeters, did did you have that data? I don't recall if it was We haven't reported that yet. We're saving that for the more robust, complete data package that we'll, share at an upcoming medical meeting. Excellent. And just on safety, the albumin, we saw an expected reduction. I thought we saw that come back up in in prior prior trials. Are you have have you started to note that recover as well? And at what time point might you expect that to recover? Thank you. Right. So, you know, not everyone has has gotten fully through the follow-up phase, and a few folks are relatively early in that follow-up phase. But there are two patients that have gotten all the way out to eighteen weeks or or close to it. And the curves in terms of the recovery of albumin were similar to what we saw in the phase one trial. So you see a recovery, you know, in about four to six weeks after dosing has completed back to normal. Great. Thanks, and congrats on meeting your guidance. Yes. Thanks. Our next question is from Sam Slutsky with LifeSci Capital. Please proceed. Hey, everyone. Thanks for taking the questions and congrats on the update. Most of my questions were asked, but just looking forward to the Phase 2b readout. It'd be great to get your take on expectations when using the six eighty mg dose consistently versus three forty. And then you if could just remind us on, any information out there that may support greater IgG reductions, leading to better efficacy? Thanks. Yeah. Thanks, Sam. So I think the first, question, there's really sort of two dimensions to that. One, in terms of what we expect with the two b trial. The first, as you pointed out, is we do have that higher dose regimen in the two b trial. We also have a longer duration of therapy. So I think we're gonna be looking at what we see over this trial in more detail to try to create an estimate there. But that six eighty milligram cohort in the two b trial is predicted certainly to have a deeper IgG reduction and then that deeper IgG reduction will last longer. Why might that matter? And that gets to your second question. There published published literature showing that the absolute titers of the anti thyroid stimulating hormone receptor antibodies, autoantibodies, correlates with clinical severity. And although we don't have complete information yet back on our own autoantibody titers from this trial, what I do know is that there was variability at baseline and in some cases, a pretty significant variability in the titers of those stimulating autoantibodies. So you might expect that patients who have a higher baseline absolute titer of antithyroid stimulating hormone autoantibodies are gonna require a greater relative reduction in order to get them below whatever threshold you need to be below in order to see a clinical response. So that's that's I think the the reason why there's likely to be a better response at the population level in the six eighty milligram cohort versus a three hundred forty milligram cohort. Got it. Okay. That's helpful. I'll jump back in the queue. Thanks. Thanks, Sam. Our next question is from Brian Snorfney with Baird. Please proceed. Hey, thanks guys for taking the question. Congrats on the data. I guess maybe I missed it in your comments on, the albumin reductions, but did you see a trough on treatment or was there a continuous decline over the course? Right. The curse, again, don't have the full curse for everybody, because some patients, are just into that, follow-up period. We wouldn't expect the albumin to continue to decrease, of course, in, after therapy, but I don't have the complete curves. That said, the shape of the curves that we do have is pretty similar to what we saw in phase one. You know, you have a reduction a over the first three weeks or so, then you have flattening of the response. Then once therapy is withdrawn, then the albumin recovers. Great. Then just big picture. I've been getting some questions just in terms of kind of COVID and eventuality that hopefully wind up with a vaccine here. Just general thoughts on the risks of IgG reductions and infectious risk and how that kind of impacts use of FcRn's in the background of eventually us having a SARS CoV two vaccine. Yeah. It's a great question, Brian. And obviously, it's really, really early days to to, provide any type of specific answer to that. I think there's a few fundamental elements of biology though that are important to consider. So whereas there's not much information available on the immune response to COVID, it's it's coming it's being published, you know, almost daily, but there's not that much out there. There is a fair amount of information published on the immune response to SARS, which is a a RNA virus that's very similar to COVID. And what you see in terms of the immune response to SARS is that both the hyperimmune response that can be damaging as well as the positive immune response that confers a benefit longer term is primarily a t cell based response for these respiratory RNA viruses. And primarily actually a c d eight, but both t cells, c d four and c d eight playing a role. Of course, there's some b cell t cell crosstalk in maintaining that or creating that immune response. And then the memory is primarily through, memory t cells. There will be, you know, measurable circulating antibody titers that'll probably be helpful in determining whether or not someone has immunity, But the the memory the initial response and the memory response is probably, if SARS is a good analogous virus, is probably gonna be more through t cells. B cell functionality is gonna be important and there's not evidence that anti FcRn therapies impact b cell functionality. And circulating free IgG may not be the primary contributor to that that immunity long term if, again, if the SARS mechanism of immunity transfers to COVID. So a lot of a lot of unknowns, but I think there's reasons to be optimistic that anti FcRn won't be a have a lot of interplay with COVID. Great. Thanks. That's really helpful. You're welcome. Our next question is from Robin Karnauskas with SunTrust Robinson Humphrey. Please proceed. Great, thank you and congrats. I know the mood is very dire out there, but it's great that you are are hitting your time line. I guess my question to two of them. First, on the IgG reduction data, when will we, do you think, get that data, and how will it be presented? Would it be in a format like this? And then second, compared to tepro, could you just give us some you know, people are gonna make the the comparison even though it's small study, small n to tepro. Could you just put into context what you know about, like, the baseline characteristics of that study versus this study and, like, also, the other metrics beyond, proptosis? Like, what the benefits were and what they weren't. I was looking through the data this morning. I was a little confused about how to assess it. Any any help you can would be gratefully appreciated. Thank you. Yeah. Thanks for those questions, Robin. They're really good ones. So our initial plan was to present the detailed analysis at the May ATA meeting in New York. That meeting has been canceled, and, it's not yet clear whether there'll be a virtual component or not. So at the moment, we're looking we wanna make sure that we get the data out in a robust fashion, as soon as we can, but also in a good format. So we haven't made a final decision yet given that, that May ATA meeting in New York has been canceled, that will be. In terms of the comparison to the, tepro trials, I think maybe some of the most important baseline characteristics are the average clinical activity score and average proptosis of the patients entering the trial since both of those speak to the activity and severity of the patients in the trial. And our average clinical activity score was five and our average proptosis was about 23 millimeters. Those numbers are very similar to the baseline characteristics in both the two b and the phase three trial for tepro. If you look those up, they're really, really close. In terms of the clinical parameters, so I think it's important to look at all three of them. It's also, of course, important to note that, you know, cross trial comparisons need to be done with caution. And as you're well aware, the teprotumumab trial had their primary endpoint, in both of them at twenty four weeks. They did report some six weeks data post hoc, but again, primary endpoint was at twenty four weeks. All that said, if you look at what they reported in their 2b trial and their phase three trial at week six, you'll see that for clinical activity score responders, so patients who achieved a zero or one, it was twenty one percent in one of the trials and twenty two percent in one of the in the phase three trial. We had forty three percent on that dimension. Proptosis response was in the fifty percent range for both of us in six weeks. And then in terms of diplopia, they had about a two thirds response at week twenty four. We're seeing that again with small numbers at week six. So I think the efficacy that we have here compares very favorably, of course, with the caveat that this is a small sample. Great. Thank you very much. I appreciate that. And then one other question. When you think about disruption, and thank you for clarifying, you know, potential for that for MG. For for, Ted versus MG, are there differences in in where these trials are running or or even the patients that might lead one to be less disrupted than the other? And are there any other challenges that you're facing as far as the clinical work that you're working on, getting enough reagents so that preclinically, as you move these drugs forward, there isn't an innovation gap approaching us in the future? Yeah. Thanks for those questions, Robin. They're really good. I'll get the step hit the second one first because that's really easy. We don't have any supply supply chain issues at the moment. We're we've our our partners, Samsung and Catalent are doing a a tremendous job, and we've been planning ahead fortunately there. We have drug substance and drug product in supply, so no issues there. In terms of the differences between the myasthenia the impact on the myasthenia gravis trial and the impact on the two b trial in thyroid eye disease, the difference there is really more based on where the trials are in their life cycle. So the MyastheniaGravis trial was just about to finish up. In fact, we had a couple people who two patients in Canada who were scheduled to have their baseline visit within the last two weeks when their institutions, made a decision to, not temporarily not enroll any new patients. So assuming that we get our clinical trial sites back up and running and for myasthenia, those are in Canada and in The US, we've got a good pipeline of patients ready to go at a variety of sites. There are other sites that are still enrolling. I just mentioned those two as an example. The same impact is happening for some sites in the thyroid eye disease trial, which by the way are in Canada, The US, and in Europe for the two b. The difference in for the thyroid eye disease trials, we just have more time to, you know, to put mitigation steps in place. That trial is still ramping up. There's still some slight activations going on. And so we have there are things we can do now, I think, to be really well prepared for a fast restart in thyroid eye disease and potentially make up some time. Whereas in the case of myasthenia, there's just not a runway to make up the time, which is why we're now guiding to q three for that trial. Great. Thank you very much. Yes. Welcome. Our next question is from Jason Gerri with Bank of America. Please proceed. Hey, good morning, and thanks for taking my questions. Just wanted to confirm, do you guys just say that on CAS zero to one at week seven, you were at 43%? Because I didn't see that number in the PR, and I didn't wanna confuse that with the proptosis responder rate. And then your just general thoughts on whether you'd expect proptosis to improve over time just based on the mechanism, just helping us bridge the gap in terms of the different durations of follow-up with this drug and tepro? And then lastly, just in terms of what is the FDA really focused on in terms of, the laboratory, safety data that you'd be presenting at a future medical meeting just to give us a sense of bridging the gap to a safe and easy patient self administered therapy? Thanks. Great questions, Jason. So with regard to the CAS or clinical activity score responders, you're correct that there were forty three percent, three out of seven patients who achieved a zero or one score on the clinical activity score. That's the same actually number, and it's actually the same patients who achieved a proptosis responders response defined as two millimeters or more improvement in their proptosis. So forty three percent for both of those both of those metrics. In terms of proptosis improving more over time, I think that's, very likely based on the natural history of the disease and also the natural history of treated disease from other trials with, innovative therapies. The you know, again, six weeks is a really short period of time. I would even get commonly questions leading up to today. Did we think that six weeks was enough to show any impact given that you have to reduce the inflammation and then that inflammation has to regress and then you have some shrinking of the tissue and then the proptosis goes down. So there's gonna you know, that's not something that happens in days. It's more a matter of weeks, and I would absolutely expect that with longer therapy, you're gonna get more patients achieving a proptosis response. Again, that's what's been seen in other trials. In terms of what the FDA looks at, I think on the efficacy side, they've been very clear that preptosis responder rate is the preferred primary endpoint, that is the primary endpoint in our 2b trial. Clinicians on the other hand, I think really appreciate the fact that this is a multifaceted disease and that the clinical activity score captures many elements of patient morbidity beyond just proptosis. Of course diplopia, as I mentioned earlier in the call, is also really, really important. I think on the safety side, you know, the FDA is gonna look at the full range of of a of a data package for any asset that's submitted. I think what we're really encouraged by in terms of our data to date is that all the adverse events that have been reported both in our phase one trial with healthy volunteers as well as in this trial were were just mild or moderate. We haven't had any SAEs. And although the FDA, I don't think would be particularly concerned about headaches, patients certainly would be, and so we're really encouraged to see no headaches in this trial, which is consistent with, the type of data we presented from phase one as well. Thanks. Yeah. You're welcome, Jason. There are no more questions in the queue. I would like to turn the conference back over to Doctor. Salzman for closing remarks. Thank you very much. I'm just going to repeat briefly my concluding remarks and say that we're just absolutely thrilled with these results. I know that having spoken to a lot of ophthalmologists recently, they're very, very excited about the chance for patients finally to have some new therapies that impact the, preptosis, the double vision, and the swelling and redness of the eyes. And to be able to potentially deliver that benefit with a therapy that has the chance to be given as an at home injection, think is really exciting. So we're really excited about these results and I appreciate very much the engagement of everyone on this call. Thank you very much. Thank you. This does conclude today's conference. You may disconnect your lines at this time and thank you for your participation.