Earnings Call: Q4 2021

Jun 1, 2021

Good morning. My name is Daryl, 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. Pete Salzman, Chief Executive Officer of ImmunoVent. Before we begin, I would like to remind everyone that today's conference call will include certain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward looking statements include, for example, statements regarding potential efficacy and safety of Immunovance product candidate and ImmunoVance expectations regarding the timing, design and results of its clinical trial, including the timing of future data readouts and the announcement of future indications. These forward looking statements are not guarantees of future performance and are subject to various risks and uncertainties, assumptions known or unknown, which could cause the actual results to vary materially from those indicated or anticipated. For more information, investors are encouraged to review Immunovance's most recent quarterly report on Form 10 ks filed with the SEC on June 1, 2021. Now I would like to turn the call over to Doctor. Pete Salzman. Thank you, Doctor. Salzman. You may begin. Good morning, everyone, and thank you for joining me on today's conference call to review a corporate update for Immunomand. I appreciate Daryl advising everyone that this presentation contains forward looking statements for the purposes of Safe Harbor provisions. In addition, as you may be aware, in March of this year, Royvant, our 57% stockholder, amended its 13d to state that it intends to make a proposal to us to acquire the outstanding shares of the company not already owned by Royvant. In response to the filing, our Board of Directors formed a special committee consisting of independent directors to be prepared to evaluate and negotiate any such proposal from RayMed or other parties. The special committee has retained CenterView Partners as its financial advisor and Wachtell, Lipton, Rosman Katz as its legal advisor. Moving now to our corporate update. As you recall, in February of this year, we voluntarily paused dosing in our clinical trials for IMVT-fourteen oh 1 due to elevated LDL levels observed in patients treated with 1401. At that time, we shared that we were doing a program wide review and that we would come back in this quarter to share our findings. We look forward to sharing our insights and our excitement for the future. We learned a lot over the last couple of months. First, we've learned more about patient needs and refined our view of what an ideal anti FcRn agent should do. I'm going to return to these very important patient insights at the end of the presentation, but suffice to say that the strong IgG lowering observed across a range of 1401 doses matches nicely to patient needs. 2nd, we've learned a lot about 1401's profile. In addition to covering why we believe the LDL impact of 1401 is manageable, I will also share that our therapeutic window is wider than we anticipated. 3rd, we're excited to have now seen biological activity across 3 different disease states. And finally, we've pressured them to various clinical development options and we're looking forward to returning to the clinic in patients later this year or early next year. Let's start by reviewing what we've learned about 1401. In fact, we have 4 really important findings to share. 1st, at the doses we're studying, 1401 is more potent than we thought and has a broader therapeutic window. 2nd, changes in IgG, albumin and LDL are all tightly linked and this leads to predictability for individual patients. 3rd, there is a favorable trade off between desired changes in IgG and undesired changes in albumin and LDL. And 4th, the changes in LDL appear manageable for several important reasons. Let me now take these concepts 1 by 1. Regarding potency, we observed deeper reductions in IgG with 3 40 milligrams and 6 80 milligrams when dosed weekly for 12 weeks compared to the reductions we had observed previously during 4 to 6 weeks of weekly dosing. We now understand that 3 40 milligrams is a high dose and 6 80 milligrams weekly is a very high dose, while 255 milligrams weekly also reduced IgG substantially over 12 weeks. In other words, we learned that the therapeutic window of 1401 is broader than we thought. I've also noted the LDL changes at 12 weeks compared to baseline now that we have all the data in from ASCENDO-two. A 15% change in LDL compared to baseline for the 255 milligram dose and a 37% increase in LDL change from baseline for the 3 40 milligram dose. Regarding predictability, we learned that the LDL changes were highly correlated with serum albumin changes and were not correlated with thyroid hormone levels in our study data. Of course, we already understood that IgG and albumin changes were highly correlated as both reductions are mediated via non target effect of the Fc receptor. The new learning was that lipid elevations correlated very tightly with albumin changes and also therefore appeared to represent a non target effect. Based on the observed correlation between albumin and LDL, plus the lack of an observed correlation between thyroid hormone levels in LDL, the consensus of external expert consultants is that lower serum albumin stimulates hepatic synthesis of albumin and the LDL. In addition to the observed correlations during treatment, we also observed that both albumin and LDL returned to baseline off treatment, which is another important predictability characteristic. Outside of ASCEND-two, we observed dose dependent changes in LDL of a similar magnitude in a healthy subject injection site study in ASCEND MG and in ASCEND WAYHA. These observations were based on analyses of stored serum with small numbers. Nevertheless, the pattern appeared quite consistent and we believe the impact will not differ across indications. New data demonstrated a favorable trade off between IgG reduction and albumin reduction across the range of doses tested in ASCENTIN-two. Whereas IgG reduction for all 3 doses clustered near the peak of 1401's IgG reduction, the albumin reduction and therefore LDL increases for the 3 doses did not cluster. The reduction in albumin remained in the normal limits for about half the patients on 3 40 milligrams after 12 weeks in dosing. And you can see from this graph the widespread in albumin reduction between the 2 50 5 dose and the 6 80 milligram dose over a 12 week period. The reductions in albumin on the 2 55 milligram dose were mild. These mild reductions in albumin resulted in small changes in LDL as shown on the previous prior slide. Consequently, the larger reductions in albumin for patients on the 6 80 milligram dose resulted in larger increases for these subjects. So what have we learned about managing LDL increases? We've learned that we have multiple ways to manage LDL in future clinical trials and that this should provide good solutions for physicians and patients down the road, assuming approval in different indications. 1 key lever is customizing the dose for the indication and for the stage of treatment. For indications that require an initial high dose induction, treatment may begin with a high or very high dose of 14:01, 3 40 milligrams or 6 80 milligrams given weekly. Depending on disease severity and other factors, LDL excursions over the short term during induction might be managed with anti lipid therapy or might simply be monitored. At the other end of the spectrum, 255 milligrams weekly is likely to be a standard dose during the maintenance phase of a long term extension where the goal is to maximize maintenance of efficacy while minimizing immunosuppression. At 255 milligrams weekly, we anticipate that albumin and LDL changes will be small for most patients. Recall that the median increase in LDL at the 255 dose was 15% at 12 weeks. In the middle of the spectrum, we envision both 255 and 340 milligram doses achieving a sweet spot of IgG suppression and albumin LDL changes for many patients. How will physicians handle patients who experience a modest chronic increase in LDL? This market research was designed to test physician response to increases in LDL that are higher than we expect to see for most patients on 2 55 milligrams weekly. Physicians were presented with hypothetical product profiles of an anti FcRn with either no LDL impact or with an LDL impact of 30% or 60%. They then estimated their prescribing share for such a product in their practice. We are able to test their prescribing projections across the range of disease severity and across different lines of therapy. This market research showed an increase in LDL of 30% did not really change in neurologists willing to prescribe an anti FcR medication for myasthenia gravis. For example, this group of practicing neurologists anticipated using an anti FcRn medication for about 27% of their MG patients with and without an LDL signal of 30%. For very early lines of therapy, there was a slight decrease in projected market share, but generally little change in market share for an LDL increase of 30% and suggesting very little change for an LDL increase of 15%. In fact, these physicians believe that LDL changes of this magnitude will be readily addressed by a statin or other anti lipid therapy. When presented with a hypothetical product profile of an anti FcRn that increased LDL by 60%, they did note that anticipated market share would fall for such a product in the product study and they believe that some of these patients might be less easy to control in statin or other anti lipid therapy. Similar research with physicians in other specialties also yielded a comfort with increases in LDL in the 30% range. This next slide is a post hoc analysis of patients who happen to enter 1 of our trials already on a statin. We identified 5 patients in the ASCEND VO-two trial and 3 patients in the ASCEND MG trial who are taking a baseline statin and for whom LDL could be obtained. In ASCEND-two, 3 patients were taking a statin and were randomized to 1401. 2 additional patients were taking a statin and randomized to placebo. All 5 patients had varying levels of LDL ranging from quite low to moderately elevated. LDL changes during treatment with 1401 for the 3 patients randomized to active treatment arms were small for these patients. In ASCEND MG, on the right hand side of the graph, 2 patients were taking a statin were randomized to an active treatment arm, while 1 patient was taking a statin and randomized to placebo in Ascend MG. For the patient who was randomized to 3 40 milligrams, LDL actually decreased more than 20%. On the other hand, for the patient randomized to 6 80 milligrams and the patient randomized to placebo, LDL increased by about 30%. All of the MG samples are based on post hoc analysis of stored serum. I should note that for the MG patients, all of the yellow bars show their LDL at the end of the randomized treatment period and don't relate to LDL observations during the open label extension. The same is true of the thyroid eye disease patients where the yellow bars all represent a value at the end of treatment. Although this is a very small sample of patients who just happen to be on statin, we find these data to be encouraging and also consistent with experts' views that statins will likely work in this situation. Turning now to warm autoimmune hemolytic media. We are encouraged by early findings, while also acknowledging the data are very limited. As a reminder, the ASCEND WAYHA trial is an open label study in patients with warm autoimmune hemolytic anemia who have failed the prior line of therapy. These patients are often treated with very high dose steroids to be in disease control. When steroids are tapered, the disease often recurs and other immunosuppressants are prescribed, so these are not FDA approved for the treatment of warm autoimmune hemolytic anemia. Patients like this don't spontaneously improve as a general rule. A patient who does improve their hemoglobin by 2 grams per deciliter on therapy is considered a responder. And that is the primary endpoint for this study. Prior to the pause, we had 5 patients randomized and dosed in the San Buijay 3 patients completed 11 or 12 weeks of dosing. 2 other patients completed only 2 or 3 weeks of dosing. 1 of these patients paused dosing due to the program wide voluntary pause. The other short duration patient withdrew from the study for serious adverse events of recurrent ITP in a patient with a history of both ITP and WAYHOP. In terms of the patients who completed 11 to 12 weeks of open label therapy, the patients shown here had a strong response and completed 11 weeks of therapy prior to the program wide pause. With an increase in hemoglobin well over 2 grams per deciliter, and this increase was maintained during treatment. Based on expert discussions, total bilirubin is another important biomarker in Weihau, particularly in the short term, and the improvement in total bilirubin matched the improvement in hemoglobin for this subject. Note also that this patient had failed 3 rounds of potent immunosuppressants and steroids prior to entry into the ASCEND WAYHA trial. There was 1 other patient who had a modest response during 12 weeks of therapy and 1 patient who did not respond and get 12 weeks of therapy. As you know, we had to prematurely terminate our Phase IIb study at 1401 in moderate to severe thyroid eye disease due to our unanticipated program wide lipid review. Prematurely discontinuing a study is always difficult, especially for patients and investigators. And in this case, more so as only 41 of the projected 77 subjects to be randomized completed the primary efficacy evaluation at week 13, a bit over 50% of those anticipated. Consequently, the question that this study was designed to answer, that is whether a 12 week course of 1401 improves proptosis, cannot be answered with any certainty. What we do observe is that 1401 in a dose dependent manner decreases total IgG and thyroid stimulating immunoglobulins. From a clinical perspective, the power calculations used to size the study assumed a 45% risk difference in preptosis responder rates for the 6 80 milligram dose compared to placebo. On reviewing the data from early study visits, when approximately 85% of the enrolled patients were assessed for proptosis response at each visit, It appeared that this risk difference could be achieved with a 6 80 milligram dose and possibly with a 3 40 milligram dose with no or minimal observed response in the placebo group. Due to the unbalanced randomized design, 2 key subjects were assessed in the 2 55 milligram group to allow for any meaningful comment. Whether these observed response rates in the 680 milligram and 304 milligram dose groups would have persisted if the trial had gone to completion is unknown and simply cannot be determined. Efficacy trends in the prospectively defined secondary endpoints were of lesser magnitude, for example, clinical activity, score responder rate or were not evident, for example, improvement in DUKOLTELY scores. However, it is important to remember that the study was sized only for assessment of the primary prognosis responder rate and not the secondary endpoints. We believe that the 1401 induced decline in total IgG and thyroid stimulant co opulence, coupled with the efficacy trends observed at the early visits when most of the enrolled subjects were evaluated to these efficacy parameters, suggest that TED may be another disease where anti FcRn appears to work. We're continuing to discuss the rough results with key opinion leaders. Despite our disappointment in the premature discontinuation of the study, we are encouraged by our data review and we believe that continued investigation of 1401 in this indication may be warranted. We're very much looking forward to discussing potential trial designs with regulatory agencies in the second half of this year. So what's next? Where do we go concretely from here? Pending FDA agreement, we plan to return to clinic and initiate a pivotal MG trial in late 2021 or early 2022 as well as resume our trial in warm autoimmune hemolytic anemia and initiate a Phase II trial in TED on a similar time frame. Beyond these 3 indications, we plan to initiate clinical studies in 2 new indications over the next 12 months, and we believe 1 of these could be a pivotal trial. With all this activity, we are very excited that we've consolidated medical and scientific leadership under Doctor. Bill Macias. Bill brings over 27 years of pharmaceutical experience to Immunovat, including industry leading experience in early, mid and late stage drug development. Bill's impressive breadth of experience and proven track record of clinical development in numerous therapeutic areas, including immunology, fits very well with the potential of IMVT-fourteen oh 1 across multiple indications. I've had the great pleasure of working with Bill in the past. And as he's come up to speed on our programs over the last weeks, it's been a lot of fun to see him already having a positive impact. Finally, I want to note that based on our existing cash balance as of March 31, 2021, of $400, 100, 000 and our current plans as just reviewed and our timing expectations related to these development programs, we have enough capital to get us into the second half of calendar year 2023. Before opening the line to questions, I want to return to the patient insights we gained. At Avant, our vision remains unchanged, normalized for people with autoimmune diseases. This is a high bar and keeps us focused on what is most important. It guides us to really understand what people living with autoimmune diseases need and what tools physicians will require to deliver on those needs. Our recent discussions with thought leaders, advocacy groups and scientific experts yielded 1 critical insight to the question, how much IgG suppression do patients with an autoantibody driven condition need? The answer is almost certainly, it depends. Patients with new onset disease, patients with flaring disease and patients with acute conditions generally need a lot of IgG suppression. In fact, when prescribing steroids in these situations, many physicians start with very high doses to quickly gain disease control. On the other hand, patients whose condition is chronic and whose disease activity has come under control will likely need less IgG suppression. Experts agree that maintaining these disease control is easier than achieving initial disease control. They also agree that long term therapy should target the best efficacy with the least immunosuppression. Myasthenic crisis, warm autoimmune hemolytic anemia and acute rejection following solid organ transplantation are clinical examples where the standard of care begins with high dose immunosuppression and a rapid and deep IgG lowering. CIDP is another condition where therapy often begins with high doses, in this case, high doses of IVIg. On the other hand, for generalized myasthenia gravis without crisis, treatment doesn't usually begin with a high dose induction. In the case of CIDP and warm autoimmune hemolytic anemia where symptom control has been achieved for some time, then the goal of treatment switches to tapering immunosuppression and maintaining symptom control. In this phase of the treatment cycle, physicians and patients are striving for a lower effective dose or longer intervals between doses in order to minimize immunosuppression while maintaining clinical benefit. During the maintenance phase of their treatment, patients may also place an even higher premium on a convenient delivery mechanism such as a simple subcutaneous injection. These insights, which we believe apply to many autoantibody driven conditions, have important implications for the development of a class leading anti FcRn. Specifically, the ability to provide a wide range of IgG suppression with an easy to administer subcutaneous delivery device will be key. With that, I want to thank you for your attention and I'll ask the operator to open the line for questions. Thank you. We will now be conducting a question and answer session. Our first questions come from the line of Robin Karnauskas with Truist. Please proceed with your questions. Great. Thanks, guys, and thanks for all the color. I'm trying to I'd like to sort of understand the comments at the very end and sort of what all this data you've shown means for where the most likely uptake will be for your drug. Are you saying that like TED will maybe more challenging because even though you don't have the full proptosis data that likely is a high dose induction so that even though it's an acute therapy from what we've done with doctors, it sounds like you're going to see you may need higher doses to see the proptosis level achieved, reduction achieved, maybe high doses and maybe some prognosis. I'm trying to understand what you said at the end. So maybe help me understand, like, where do you think the most likely what are the most likely indications that we should be modeling? And then do you think that TED is less likely now because you have to use higher doses? And then for the lower dose amount, like what indications do you think will be that will work with that for the 255, if that's really the dose that you take forward? The other question I had was like, what about less frequent dosing? We know that Ardentax is doing less frequent dosing, gives you lower IgG and then it fully comes back. Is that sort of what you're seeing with 255 where you're sort of maintaining a lower dose? Or could you go even less frequent so you don't see a sustained cholesterol decrease? So a Yes. Thanks, Robin. As always, a great set of questions. Yes. Thanks, Robin. As always, it's a great set of questions. So let me start with the second 1, which is the concept at the end. And really the concept is quite simple, which is that different patients have different needs for IgG suppression. Some are going to need deep IgG suppression, some are going to need strong IgG suppression. And we've shown now that 1401 across a range of doses can deliver both. So for those patients who need a deep IgG reduction, and I mentioned a few conditions where that could be the case, the higher doses or very high dose of 1401, 3 40 milligrams or 6 80 milligrams can provide that. And over a short period of time or when there is a very high unmet need, then the changes in albumin or LDL are less important. On the other hand, there's going to be many patients who are going to be seeking maintenance of disease remission or improvement in symptoms that they've achieved during the acute phase. And in speaking with experts across a range of conditions, there's a belief that the degree of IgG suppression needed for that chronic phase will be a little bit less, maybe more in the 50% range instead of the 80% range. So, what we learned in from this data is that our lower doses, 255 milligrams as an example, potentially 340 every other week, as you mentioned, can provide that sweet spot of 60 ish percent IgG reduction with minimal changes in albumin and LDL. So that's really the concept at the end that we see 1401's profile is really competitive across a wide range of indications and in both the acute and chronic setting, which is important for a lot of those patients. In terms of thyroid eye disease, the what I reviewed there is really the efficacy data is inconclusive because of the study had to be stopped before it was anywhere close to completion and that makes interpretation very challenging. We were very encouraged by the improvement in biomarkers and an apparent correlation between biomarkers and clinical impact. At the same time, I want to be transparent that the degree of efficacy which we observed fell a bit short of our expectations. So based on that, we have some ideas for a Phase II trial to really optimize who we're studying thyroid eye disease and where we can deliver a clinical efficacy that's meaningful and competitive. And we plan to start that trial in the second half of this year after discussion with experts and regulators. That would be my follow-up question. It's like, so in what population do you think this that you deal what population would you go after and what might be the design of the Phase 2? Help us sort of narrow in like what the percentage might be for the percentage population that might be eligible for your therapy versus Verizon? Yes. That's a great question and something we're working on. I mean, we do see I see opportunities on both ends of the spectrum actually patients with a little bit more mild disease and patients who've already as we've discussed in the past, who already had a course of TAPAZA and haven't achieved full remission of their symptoms. Got it. Okay, great. Thank you very much. Thank you, Robin. Thank you. Our next questions come from the line of Derek Archila with Stifel. Please proceed with your questions. Hey, good morning, everyone, and thanks for taking the questions and thanks for the comprehensive update. So just a couple from us. Just can you give us a sense on your choice to continue at MG given the competitive landscape there? I guess, where do you feel your differentiation is in that indication? And then for the patients that you provided some data that were on statins and receiving 1401, can you talk about the dose of statins they were on? Were they on kind of the max dose for the statins or were they kind of on lower mid range doses? Thanks. Hey, thanks, Derek. Those are some really good questions. So with regard to myasthenia, I think competitiveness in myasthenia will be similar to competitiveness in many other indications that will be driven by efficacy, safety and tolerability. And in myasthenia, in particular, something we talked about back in August when we released our results is, I think that in addition to the responder rate, the other percentage that's maybe equally or even more important is the deep responder rate. Remember, we talked about those patients who didn't just have a 2 point improvement in their MG ADL, but had a 6, 7, 10 point improvement in their MG ADL. Those patients have a tremendously different body of life with treatment than they had during a little bit into the trial. And although our trial was too small to conclusively validate a link between deeper IgG reductions and those deep clinical responses, I think that link is pretty logical and was also suggested in the nipocalumab data. So this gets to this the point that Robin asked me about as well, which is the concept at the end there, because sometimes you need a deep reduction, sometimes you need a strong reduction. For patients who really are looking to achieve a big, big change in the symptom control, we think we have maybe the best shot of achieving that given the deep IGT reductions we can deliver. Then, as we also discussed in the past, as patients move into a long term extension or in the clinical setting move into a chronic maintenance phase, we believe that many of those patients will be able to taper down to, lesser levels of IgG suppression. And as they do that with 1401, then the albumin and LDL changes become much less significant. So the changes in albumin and LDL that they might experience in the short term in the front end are probably a reasonable trade off for a deep improvement in clinical symptoms. And then as they move into the chronic phase, those adverse events either go away or become much less important in their magnitude. In terms of the statins, there were a range of statins, but they were sort of mid range statins. Several of the patients were on atorvastatin 20 milligrams, 1 was on Crestor at 5 or 10 milligrams. They weren't super high doses, but they weren't low doses either. 1 person was on at least 1 or maybe 2 were on atorvastatin 40. None of them were on atorvastatin at like 80 milligrams. So they were sort of mid range. And you saw the even the LDLs coming into the trial on the statins varied, some were had their LDL at 100 or less. Others, even with the statin therapy, were more in the 150 to 160, 70 range at baseline. Got it. That goes. Thank you. Our next questions come from the line of Yatin Suneja with Guggenheim Partners. Please proceed with your questions. Hey, guys. Thank you for taking my question. A couple for me. Number 1, do you have to do more dosing work? Do you have to establish even a lower dose before you move into pivotal or other studies? And then the second question is on the TED study. You were pretty excited about the 7 patient data that you had generated in the past, but we're not really hearing that same level of excitement now that you have 40 patients. So give us a little bit more sense into the TED data. Thanks, Jan. Those are 2 excellent questions. I'm really glad you asked both of them actually because on the first 1, the we do not believe that additional dose finding studies are on the critical path. We may do some dose finding in the context of a Phase 2 trial in a disease population where we can correlate that with biomarkers or potentially in a Phase 1 setting where we could examine concomitant anti lipid therapy or things like that. But those studies are not on a critical path to returning to the clinic in disease populations. And the reason we believe that is that the PKPD models for 1401 and probably for anti FcRn in general are really quite predictable. We've shown a very, very tight correlation between IgG and albumin and albumin and LDL. And now having data from 3 different doses and to some extent different intervals because we do have every other week dosing in the open label extension of the MG trial. And we had a different we had every other week dosing in our healthy injection site study completed recently. All that data allows us to build much more robust computer models of PKPD than we had in the past. And those again, they show a nice range of IgG reduction as well as impact in albumin and LDL. So that allows us to go back to the agency with trial design that we feel confident in that will test a range of doses, which will have a meaningful difference in terms of their effect on those parameters. Got it. And then just 1 more. Go ahead, Gavin. Okay. 1 more question I have is on the relevant offer. Can you maybe also talk about how that is going to play out? Who decides the price? If they are the majority holder, can they force a transaction? And then are you also running a proper process where you are engaging other parties who might be interested in the asset? Right. So thanks for that question. As with any M and A transaction, and in particular, in an M and A transaction with the majority shareholder, there are many specific regulations governing that how that process works. And I shared on the first slide, which I've sort of put back up here on the webcast, if you're following the 1 that I'm controlling, really the important parameters, which is that in response to what Anne's amended 13D, our Board of Directors formed a special committee consisting of independent directors. And that special committee, their charge is to be prepared to evaluate and negotiate any proposal that could come from Roy Vent or any other party. And that special committee has engaged Senergy Partners as their financial advisor and Wachtell, Lipton, Rosen and Katz as a legal advisor. So the machinery is all in place. Given the really tight regulations around these types of situations, I can't comment on any anything else about the process or the activities of the special committee. Yes, and you asked about TAD and I didn't answer that question yet. I think it's an important question. So we were absolutely very excited about the data that we presented from the 7 patients in the open label trial. And there are elements of this IIb trial that are exciting as well, including at the early time points where we had improvements in proptosis that were of a similar order of magnitude to what we saw in the 2A trial. We definitely don't have definitive data from this trial because it stopped early and it was unblinded and people are at different stages of finishing their treatment and all those complications of a failed trial when you have to unexpectedly unblind it. Nevertheless, there's more data in this IIb trial than in the IIa trial. And the data that we do have doesn't suggest the, as strong of a magnitude of impact as we were hoping for based on the 2a trial. So that makes us want to ensure that any future study is in the right population where we can really demonstrate a not just a significant statistically significant impact, but a really clinically and ultimately commercially significant impact. Thank you. Our next questions come from the line of Daniel Perrault with Raymond James. Please proceed with your questions. Danielle, could you check if you're on mute, please? Hi, guys. Can you hear me? Sorry about that. Yes. We can. Thank you for the question. So I just wanted to first clarify that the magnitude of LDL impact was in fact consistent across all indications. And then curious if you have any thoughts as to why competitor programs with similar albumin impacts haven't reported similar findings? And then, Pete, the new IgG reduction data you presented looks slightly different from the Phase 1 data in healthy volunteers. I believe the magnitude of IgG reduction you saw with the 340 milligram was in line with what you're reporting here for 255 milligrams. Just curious how many patients were included in this data site and what gives you confidence that what you're seeing here in the low dose is actually real? Thank you. Yes, those are really good questions, Danielle. Thanks for that. So with regard to the consistency of the LDL findings across indications, the degree the magnitude of change and the correlation with dose and albumin reduction was consistent across all the indications, Caveated slightly by the fact that we're dealing with small numbers and that when we looked in the other indications or in the healthy subject study, which was an injection site study, those are post hoc analysis. They weren't pretty specified. They were run on stored serum. Cholesterol is a pretty standard test, but it's not as standard to run the cholesterol on stored serum. So we do need to view those slightly cautiously. But when we ran stored serum on the thyroid eye disease patients, it was very consistent with the cholesterol findings that had been specified and run prospectively. So all those things triangulated to give us a sense that the change in LDL in terms of magnitude is really similar across all the indications. The other thing that bolstered that was we were which we were a little surprised is that we just didn't find any correlation between thyroid hormone levels and LDL. There's a well described relationship between those 2 in general, but in our data, we were not observing that correlation. So we're pretty confident of this consistency across indications in terms of LDL impact and the difference in terms of degree of LDL change by dose and by degree of albumin change. In terms of the magnitude of the IgG changes, I think these are generally consistent with what we've seen before, but a little bit deeper at the later time points. I have the slide up right now, which shows the IGG curve. And you can see with the 340 arm and even to some extent with the 680 arm, there's just a little bit of additional reduction that you get after 6 weeks. We saw that also in the albumin curves, which were a little deeper for 680340 at 12 weeks compared to 680. So those both being on target effects, both being consistent across 2 different biomarkers give us confidence that these are good estimates of the degree of IgG suppression that we would see with the different doses. As I mentioned, those computer simulation models that we've been building allow us also to estimate the IgG reduction that we might see with different dosages or different dosage frequencies. That's really helpful in picking the best dose going forward. Thank you. Our next questions come from the line of Thomas Smith with SVB Leerink. Please proceed with your questions. Hey, guys. Good morning. Thanks for the updates and for taking the questions. I appreciate some of the early market research you presented, Pete. Did you conduct any market research that contemplated the presence of multiple FcRn agents in the marketplace? And if so, what was that feedback? And then just in terms of how you're thinking about study timing, can you help us understand some of the outstanding gating factors to getting these clinical studies going again later this year? Absolutely. Thanks, Tom. Great questions. We did do a lot more market research than I'm showing here. I kind of picked what I thought was maybe 1 of the most important themes, but we double clicked on that theme in ways as you described. And that was interesting having physicians choose different profiles. We did see that the benefit of a simple subcutaneous injection format can counteract the disadvantage of a modest change in LDL, recognizing that the change, the modest change in LDL wasn't perceived as that big of a disadvantage actually. So for physicians, I should have been around this data, but we did similar work with different specialties and pretty much across the board when you're looking at changes of 30% or so in LDL. And we didn't ask actually about less than that. They really didn't view that as something that would significantly impact their prescribing at the margin. It was kind of something they have to address and may start a statin here and there, but they have a lot of patients on statin. So when you're at that 30% rate, it's just sort of 1 of many factors that they consider. And I think they'll go back to the efficacy they're achieving and the points I was making within myasthenia and the ability to achieve deeper Saunders and things like that are going to be the real drivers. In terms of timeline to getting back in the clinic, so for myasthenia, each study is a little bit different. So for myasthenia, we had a very, very productive end of Phase 2 meeting with the FDA back in January, just prior to the pause, the voluntary pause in our program across all the trials. And based on that, we gained good alignment with the FDA on a design for MG and many other features of the pivotal trial. We believe most of those will be able to carry forward into the actual pivotal trial that we're planning. So as we're finishing up our computer modeling, that will allow us to come forward with the dosing recommendation and then we're here with experts to develop cholesterol monitoring guidelines and things like that, which would be pretty straightforward. So that's what we need to do there with regard to myasthenia. Warm autoimmune hemolytic anemia, that trial is sort of more or less paused since it was an open label trial. It didn't have to be totally it didn't have to be terminated like the thyroid eye disease trial. So that 1 we're looking forward to starting back up on a similar time frame with roughly the same existing protocol, just the addition of the monitoring for LDL. And then of course, for both trials, we've gotten a lot of data over the last couple of months. And so we need to lock that data, add it to an updated investigator brochure and share that with the FDA as well. And then thyroid eye disease, because that trial had to be soft because of the unblinding, there we'll be proposing a new design that will likely be a Phase II design. So that's all work that's at the top of our priority list right at the moment. Okay, great. Thanks, Steve. And maybe just 1 other clarifying question. You provided some really good color just on the albumin reduction seen at 680340. I guess can you clarify, did any of the patients who received the 255 dose fall below the lower limit of normal regarding albumin? Right. So in the 255 dose, we have such a small number that the I'm not sure it's useful to provide the individual patient level data, but the average right in the middle there was quite well above the lower than normal of 3.5. The average was 4. So we're confident that patients on 255 when we have a large population, they're not going to have issues related to albumin and the LDL changes that they'll have as a group is going to are going to be low and manageable. You do see that with the 3 40 milligram dose, the average patient is kind of right on the line there. So in the 340 arm, there was there were patients who go obviously below the lower limit of normal. And then in the 680 group, there's the average is already pretty low. It's a point I made during the presentation, but I'll just make it again, which is that the difference in albumin reduction by dose is large. So the PKPD modelers talk about albumin being on the steep part of the curve and what that means is as you reduce the dose, you have a big change in the reduction in albumin, whereas IgG is on the flat part of the curve. So as you reduce the dose, you don't have as much loss in IgG suppression. And this really makes the 255 dose a very, very favorable dose. And for many patients, the 340 will be a favorable dose because this individual variability patient to patient for some people, for some individuals, the 340 performs like the 255 and others. So between those doses, that's a really nice set of options I had on the slide here with the different dosage options. The 255 and the 340, we think will provide a really nice balance of IgG and suppression with minimal changes in albumin and lipids for most patients taking those 2 doses together. Got it. Got it. Okay. Thanks Keith. I appreciate the color. Yes. No problem, Tim. Thank you. Our next questions come from the line of Brian Skorney with Baird. Please proceed with your questions. Hey, good morning. Thanks for taking the question. My 1 question is really on just kind of the thoughts on your plans for lipid management. Has there been any thought to basically starting patients on statins at baseline or is it purely interventional? And if you're kind of thinking about it as a purely interventional basis, maybe in terms of the MG Phase 3 study, how do you kind of ensure study conduct and that patients aren't being unblinded, provided that 1 would expect to see LDL increases probably more heavily in the treatment on placebo? Thanks. Yes. A couple of really great questions there, Brian. So first of all, with regard to our approach to lipid management, 1st and foremost, it's to get people in the for longer term dosing in the sweet spot where most of them aren't going to have more than a modest increase. And some of those modest increases are going to occur on a background of a relatively low LDL to start with. So we're not thinking that we're going to need to start everybody in the statin or something like that, but rather have for the few patients that fall outside of a normal guideline, they may have a statin started at the discretion of their physician or there might be some rough guidelines and that can translate through ultimately to the label where many other products that have similarly modest change in LDL have a note in the adverse events warning precaution section, along the lab abnormalities that cost draw increases can happen and a recommendation that physician manage those according to regular guidelines. In the short terms studies where we may be using higher doses and they those may result in a change in not just LDL but albumin, we have several things in place to ensure that there is not unblinding, including having separate physicians or healthcare professionals who do the medical monitoring versus those who do the clinical assessment. So there's some standard things we can do there. We've done that even in the prior trials because albumin can be unwinding. But it was important to have a physician involved in the treatment of the patient understand where the albumin was at any given point. So there's that. And then we don't think that in the short term, patients are going to need to start statins during the blinded treatment period or something like that, that might add an extra level of unblinding complexity. So that's our thought with regard to MG and more generally in terms of staffing management. Great. Thanks, Steve. Yes. No problem, Brian. Thank you. Our next question comes from the line of Sam Zlotsky with LifeSci Capital. Please proceed with your question. Hey, good morning, everyone. Thanks for the questions. I guess, first, just building on Ryan's question a second ago. So the 15% or so increase in LDL at the 255 mg dose, Just help us understand the clinical significance of this as it relates to needing an intervention. Right. So that's a great question, Sam. And it ultimately comes down a lot to the absolute level more so than the percentage level. So at the population level, the percentages are important to kind of get a sense for the magnitude of the issue and 15% is it's a low magnitude versus something like 60%, where if that were chronic, if that were a chronic, if you're using that as a large population chronically and then 60% increase, you definitely have to have a broad based program. But at 15%, as I was describing the volume, we don't think that we're going to need a broad based prescriptive anti lipid regimen. So how will physicians make decisions about individual patients? They'll make those primarily based on the absolute LDL of that patient. We should in this if you look at the slide that has the statin, a few patients who are on statins, which I have up now. I'm just looking in the middle here. There's a patient who is randomized to 255. And you can see that they had a LDL of about 90. Now this person didn't change their LDL on therapy with 1401 and also with the background statin. If they had gone up 10% or 15% on a background of 90%, the physician is unlikely to be doing anything. They're going from 90% to 1 105 or something. On the other hand, you see the patient on the far right, who's was randomized to 3 40 milligrams. They came out of statin more like about a baseline of about 170. That person, even before they had an increase of 7%, probably their statin dose increased or their lipid management optimized. So, the when you're looking at these relatively small single digits or teen increases in LDL, the decision making is going to be much more based on the absolute and that's probably there's some variability in the patients who have started higher may need intervention almost regardless of 14:1 in the people who are lower or won't. So that's just 1 more factor why we think it is not going to have to be a large anti lipid component to our trials. Okay. So I guess based on the data you have then, it's expected to be a kind of smaller percentage of patients who might need that. I guess it differs as well by indication a bit. Right, right. Yes, there's some difference, obviously, in the age and the population in terms of risk factors. And then as you look across a broad swath of autoimmune diseases as we're doing as we prioritize our next indications, Some of them are younger patients with few cardiac risk factors, some are a little bit older with more cardiac risk factors. So there will be differences in indication to indication. Okay. And then lastly, too, just on the kinetics of the increase, what time point did you start to see this show up and this defer at all by this level in terms of at what time point you saw increases? Yes, we're getting a very thin data there. And the little bit of data that we do have from most of the data that the really solid data comes from the thyroid eye disease trial where cholesterol was prospectively measured at 0, 12 20 weeks and we saw the data that you're familiar with now. The percentages in this that we're reporting today are a little bit lower as we've gotten more data in and ensured that it was all accurate. But what happened between 12 weeks? So we did have some patients who had some intermediate time points where we could look at stored serum. And the increase was mostly apparent in the first 6 weeks or so. So they kind of went up to where they were going to go in about 6 weeks and then were generally stable there. And then similarly, when they came off therapy or went to every other week in the MG open label trial, the LDL dropped over a similarly relatively rapid timeframe. Okay. But all that's based on small data, Sam. So it triangulates pretty well, but I'm not showing it here because it's just it's small data and each patient is a little bit different. Got it. Okay. Thank you. Our next questions come from the line of Douglas Tsao with H. C. Wainwright. Please proceed with your questions. Hi, good morning. Thanks for taking the questions. Just trying to confirm your comments. So do you just given sort of magnitude of effect that you anticipate seeing, you don't expect to just have a need to put patients on statins during the blinded portion of the study? Correct. Okay. And in terms of afterwards sort of in the open label in the extension period where patients would potentially need to be put on to statin therapy, will there be sort of a management? Thank you. Yes. That's a great question, Doug. I could imagine there'll be a little bit of both depending on the trial and the disease population and some other factors. I think 1 of the things that came out of the market research with physicians is that they are very interested to have some data. I showed some very anecdotal data today that we found very interesting. And physicians are going to want to know what happens when I prescribe a statin to a patient treated with 1401 whose cholesterol has gone up a bit or who's at risk of more risk of cardiovascular risk and they're wanting to keep their LDL lower. So I think we'll probably have some designs where we are a little bit prescriptive, which will allow us to create sort of some predefined data sets to answer some specific scientific questions that will help clinicians understand how to treat their patients. But I think there will also be other trials where we will leave it to physician management and judgment and that will also create a different type of data that will be useful. So I'd imagine that we'll end up with both designs over time. Okay, great. Thank you. And I was talking about the long term extension there, the most advanced. Okay. There are no further questions at this time. I'd like to hand the call back over to Pete Salzman for any closing comments. Thanks for that. So, I really appreciate everybody's attention and just a lot of great questions. We have completed as I review today, pretty extensive review of our program, looking at data from a lot of different trials. And we're excited by what we see. We see a lot of potential for 1401 given its broad therapeutic window and given the insight that the LDL signal that we have seen is modest at the doses where most patients will be treated and should be manageable for the vast majority of patients. So based on those learnings, we're excited to get back into the clinic and we've got a team that's working hard to get that done. And I look forward to more discussions with all of you about our future plans and the indications we'll be announcing in the future. Thanks everyone. Thank you for your participation. This does conclude today's teleconference. You may disconnect your lines at this time.