Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Biopharma Conference. My name's Tom Smith, I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to welcome our next company to the stage, Viridian Therapeutics, and happy to be joined by President and CEO Steve Mahoney and Chief Business Officer Shan Wu. Thank you both for joining us. And, Steve, why don't you just kick us off here with a brief overview of Viridian for those in the audience who may be less familiar with the story?
Yeah, sure, great. Thanks for coming, everybody. We at Viridian have a thyroid eye disease franchise and a recently unveiled FcRn portfolio as well. Thyroid eye disease, we have two programs: an IV program, what we refer to as 001, and a subQ program, which we refer to as 003. They are both progressing. The IV program has two top-line phase III readouts this year, first in the active patient population for thyroid eye disease, and then that will read out mid-year, and then the chronic study for the IV program will read out top-line at the end of this year. So two big important catalysts there. On the subQ program, we have a, we are expect to start a pivotal study, or our pivotal program, I should say, this year.
We are in the process of working through FDA to lock down our trial design, and we will have our meeting with FDA come out, and provide guidance on what our trial design looks like and what our timelines look like. Our thyroid eye disease program targets IGF-1R, which is the same receptor targeted by TEPEZZA, which is Horizon Amgen's program, which has already generated close to $2 billion in annual sales in the U.S. alone. That is obviously a market that will continue to grow as they continue to penetrate both the active population and the chronic population in thyroid eye disease. Thyroid eye disease patients have three main symptoms that drive the need for treatment: proptosis, which is a bulging of the eyes, in a clinical activity score that revolves around pain, and inflammation, and then finally diplopia or double vision.
These are symptoms that are quite debilitating for patients, with respect to their quality of life, can often lead to depression. TEPEZZA, or that Amgen is now commercializing, has shown very good treatment effect size with the IGF-1R receptor. We also have that same target, as I mentioned. TEPEZZA is a program that's dosed at high levels, 20 mg per kg, 8 times. We have a different presentation or a different offering, with respect to fewer doses and lower drug exposure that we think will match the same profile. So we're looking for competitive advantages, in that next generation. The IV program, as I said, was first and followed by the subQ program, which we expect not only to penetrate the market but also grow the market.
So just quickly moving on to the FcRn portfolio, as people know, VYVGART or efgartigimod is a very safe and effective treatment. That from argenx we are developing a program that will be similar to VYVGART as an Fc fragment approach. Other companies have full-length antibodies, but the Fc fragment approach has proven to be very good. So we're gonna have a program that's similar to VYVGART. We plan to file an IND at the end of this year. And then we have a second program that's also a fragment approach but a bispecific that is intended to be half-life extended, and we think that'll be a game changer in the FcRn landscape.
So, we're really excited. We've got a lot of catalysts coming up, including the IND for the VYVGART-like program, and then the extended half-life we expect to have, non-human primate data the second half of this year. So a lot of different catalysts between the thyroid eye disease readouts, and FcRn progression.
That's great. A lot of a lot of data to look forward to here over the next 12 months. Let's talk about your pivotal phase III THRIVE trial for 001, in active TED. Maybe could you just provide an update on enrollment, sort of where you are with enrollment? Remind us regionally where you're recruiting these patients from.
Yeah, so I'll start with the last part of the question first. So this is a global study. We are in the U.S. and in Europe as well. In terms of our timelines, we've guided that we'll have a mid-year top-line readout, which is the 15-week endpoint, which is five infusions after every three weeks. So 15-week readout. We'll have that mid-year. We will have more specifics on the guidance of exactly when that is because it doesn't end with enrollment. You have to collect the data, clean the data, database lock, analyze, and then disclose. So there's components to it, but that all is being baked into our top-line readout mid-year.
Okay. Just, like, regionally where you're recruiting these patients from, is it? I know you have centers in the U.S. and Europe, but do you expect this to be mostly ex-U.S. enrollment or mostly U.S. enrollment?
We haven't gotten into that level of detail, but I think you can expect that it's a good mix. That was our intention from the beginning, so nothing's really changed.
Okay. And then you mentioned the 5 IV infusions versus TEPEZZA that's eight. This was a protocol amendment you put into place last year. Maybe if you just walk through sort of the rationale for that protocol amendment and, you know, how you went about gaining alignment with FDA on this sort of 15-week primary endpoint that's different from the TEPEZZA.
Sure. So the rationale for 5 doses versus the 8 doses of TEPEZZA is that, just to back up a bit, TEPEZZA was an old oncology drug, where they had not done when they dropped it into the thyroid eye disease population, there was no dose ranging that was done. So the field doesn't really know; there's never been any evidence of exploring the therapeutic index, which is what we intended to do. So when we looked at 3 mg per kg, 10 mg per kg, and 20 mg per kg, we decided on 10 mg per kg.
The reason we went to five doses versus their eight doses is, because they didn't do dose ranging, when you look at their phase III placebo-adjusted data, it really looks like they've addressed the disease in the first five doses, and there's no real incremental benefit after those five doses. So we feel really confident that our five doses with our program will match our 15-week endpoint versus their 24-week endpoint. We expect to have a similar profile both on the safety side and on the efficacy side, based on just those five doses.
Okay. Yeah, I guess in terms of expectations, like matching sort of the 24-week time point for TEPEZZA, I think that makes sense on the efficacy side of it. On the safety side of it, like, are you expecting to see safety tolerability benefits because you're using the shorter course of therapy and the lower dose?
Well, it certainly could be upside. But in terms of our expectations should be that it's a similar profile on safety. The safety profile of teprotumumab or TEPEZZA is very benign. The common AEs are, or AEs that have been reported are mostly muscle spasms, hypoglycemia, and then hearing. But all of those are mild and infrequent. So it's got a good benign profile to start, to the extent that our lower exposures, by virtue of dosing less and less frequently, where we come in at about a third of the dose, exposure, cumulative dose exposure that TEPEZZA delivers, to the extent that that translates into an even better safety profile, that would be great. That would be upside. And it would be a correlation between lower exposures and safety in that case. So that would be upside.
Understood. And so, yeah, I guess just to be clear, so match TEPEZZA, you at 15 weeks, them at 24 weeks on efficacy and safety, that would be win.
Yeah. And efficacy is proptosis or the bulging of the eyes, CAS score, which is your, you know, clinical activity score that's mainly pain and inflammation and redness, and then your diplopia, which is your double vision. So yeah, we're expecting a similar profile across those endpoints.
Got it. Okay.
We expect that to be a win because this is a new, new start market. So whether a patient has been newly diagnosed or if they've had thyroid eye disease for a while and they're flaring up with their symptoms, they're coming back into the physician's office to evaluate their treatment options. They're not otherwise on therapy. So in that space where they have two options, one is ours, that 10 mg per kg versus a 20 mg per kg, 30-minute infusion versus TEPEZZA 60-90-minute infusion, and just 5 doses versus 8 doses, we think that's a side-by-side that we have a really high confidence in being able to win that choice between patients and physicians. And all of these patients are coming in, in this incipient space market, in a new start market to make that choice.
Got it. That makes sense. And, maybe if you could just clarify, I guess, the amount of data you expect to have with the top-line data release, and then is it gonna include any follow-up? There's obviously a follow-up period associated with the study. Is the top-line gonna include any of that follow-up?
The top-line won't have the follow-up, but we'll have that 15-week endpoint, and that'll tell us, you know, what we expect to see in terms of confirming what we expect to see across those endpoints. And then we'll have other opportunities to disclose the follow-up data.
Got it. Okay. Wanted to turn to Chronic TED, and you had really strong results that you toplined back in July 2023. And then obviously we've seen TEPEZZA with pretty good results in that setting in the sort of phase III, phase IV setting. Maybe if you could just kind of put the data that you have in context within Chronic TED versus the TEPEZZA data, kind of similarities, differences, and how you think about, you know, studying that patient population with THRIVE-2.
Sure. I, so yeah, I think, just to back up a bit, TEPEZZA or Horizon did not run a phase III in chronic patients itself. It and, and I know you said this, but they, they ended up doing a more in-depth look at the chronic population in a post-approval setting. I think primarily that was to convince payers, and so there's still some work there to be done on the payer side, that they have talked about that they are in the process of doing. But we felt really good about our chronic data, across those endpoints, proptosis in particular, and as compared to TEPEZZA. So that gave us a lot of confidence going into this chronic study. Shan, do you wanna add anything to that?
I think in the chronic study, because we've designed it similarly to how TEPEZZA studied the chronic population, but a broader, and more robust study there to be more inclusive of the chronic patients. And so we're really excited about that as one of our pivotal studies for registration to demonstrate evidence in the chronic population. And similar to THRIVE, which is for active, we would expect the safety as well as the efficacy to be comparable to TEPEZZA there.
Got it. That makes sense. So the chronic population we think of as this much larger, prevalent patient pool. Maybe you could just walk through or describe a little bit the enrollment dynamics there and how they compare versus the Active TED study and how enrollment's going in THRIVE-2?
Yeah. It's interesting because in the real world, physicians don't often distinguish between chronic and active, but there's certainly been a number of patients. There's a large number, a large population of what is called chronic, simply from the standpoint that they've historically been diagnosed, and then may not have even had access to TEPEZZA in either the trials or commercially. So those patients are out there. There's certainly a larger number of them. But what's interesting there, and this goes to Shan's point about the new start market, is a chronic patient may have been diagnosed years ago, but then they present with symptoms. They get a flare of their symptoms, and they come back into the physician's office or the ophthalmologist or endo's office and say, "You know, my symptoms have reemerged.
I need to be treated for my proptosis," or, you know, whatever level of CAS, or clinical activity score they have, plus possibility of diplopia. So when they come in, they're very much just like an active patient as far as the physician's concerned, and which is great for us because we can, as Sean mentioned, patients and physicians will have a choice when that chronic patient comes back in, as to what type of therapy when we're all on the market, you know, with our IV and our sub-Q, they'll have choices to make that we think we're gonna have best in class in both cases. So, we think that's a good opportunity for us to switch that revenue stream at that moment that they're making the choice.
Okay. That makes a lot of sense. Let's switch gears and talk about the sub-Q program, the Viridian 003. And we've got starting a pivotal program for TED later this year. I guess, like, what are the plans for meeting with FDA? What are the gating factors to getting the pivotal program off the ground, and how should we be thinking about the design of that study?
So more to come is the short answer. We have guided externally that we are in the process of the FDA timeline for a Type C Meeting. So we'll get through that meeting. We have to wait for the minutes. It's not always a really good idea to come out and give your interpretation of the meeting without the minutes. So we wanna see the minutes. And then we'll come out, and we'll describe what the final trial design looks like, and what our timelines look like.
Got it.
That'll happen roughly middle of the year, is probably a good expectation.
Okay. So we'll stay tuned for that. And, obviously, the 003 has an extended half-life, roughly 40-50 days, and potential for less frequent dosing. I guess, how are you guys thinking about what sorts of dose frequency intervals to evaluate in a pivotal?
Yeah. And when our PK, so, historically, what we ran essentially a bake-off between three sub-Q programs, what we called 001 sub-Q, which basically was the conversion of the IV into the sub-Q, which is the normal life cycle management. And then we had an 002 molecule, which was different, had different binding domain than 001, but was half-life extended with the YTE mutation. And then we had the 003 program, which is the one we've advanced, which essentially emerged as the winner, when we compared those three programs. And what's important is that 003 and 001 are essentially the same molecule, with the same binding domain, the only difference being the 003 having the half-life extension with YTE.
When we ran the PKPD study in healthy volunteers, we were able to see that we could match IV exposures in the range of 3-10 mg/kg IV, which we know from our prior studies correlates to clinical response. Therefore, we now have an opportunity with the sub-Q program to explore that therapeutic index between 3-10 mg/kg, and that's, that's a pretty exciting place to be. When we match 3 mg/kg on the Cmin, which is where we think what drives efficacy is, is staying above that Cmin level on the IV, and that we could match the 3 mg/kg could go out to Q8 weekly under the PKPD modeling. That was really exciting to us.
We also saw that we could fall between 3-10 mg/kg IV in on Cmin and, and take that out that could be a Q4 weekly, so once a month. And then we also explored, obviously, like a Dupixent-like dosing regimen of Q2 weekly. So we have options. And this is what I mean by we'll go to the FDA. We'll lock down, we, we get to choose what our doses are, and we feel really we know what our doses are, so we don't need, you know, your traditional phase II dose range study. So we're gonna we fully expect to go into a pivotal, and we'll, we'll come out and say which dose regimen we chose. But we have good options in front of us.
Okay. Yeah. That makes a lot of sense. I guess, what, if any, data are still being generated for 003 and whether that's, like, preclinical tox work or, I know there was a cohort five that was kind of like a multidose cohort. Like, are there plans to present those data? Just how should we think about, obviously, the regulatory update's gonna be really important, but how should we think about, like, additional data that could come for 003 in 2024?
Yeah. So we got the information that we needed for the PKPD modeling. We got that from the single ascending dose. We had four cohorts of that. And then we did a fifth cohort, which had two doses in it. That all completed enrollment, of course. But the data's still coming in from that fifth cohort. But we don't necessarily need that data for the modeling. It's not really gonna have an impact on the modeling. I mean, we've already seen some of it, so it doesn't really impact. We'll find an opportunity to possibly put that data out at a later time.
But the most important thing, the thing to keep in mind is that it informs the data that we got from all of those cohorts, allows us to pick those doses based on the IV exposure, what we're trying to match on the IV exposure. So we know what we wanna do now. And now it's simply a matter of, you know, having our Type C Meeting with FDA and then moving on to the pivotal.
Got it. That makes a lot of sense. Okay. How should we think about just general timelines between 001, the IV program, and 003, the sub-Q program, right? Like, we could have these in-registrational studies at, like, roughly similar timelines. IV would be first, sub-Q coming. Like, what, what do you think the lag is, I guess, on the sub-Q program actually getting to market?
Yeah. Well, I mean, I think if you back out from our top-line data on the IV, and if we're gonna put that top-line out, that means that we won't be the studies won't really overlap that much. And so we do look forward to starting the pivotal program for the 003 sub-Q, in the middle part of this year.
Okay.
And it won't. We don't expect a lot of overlap.
Got it. Okay. Let's talk about competition in TED in general. There's a number of programs that are also pursuing IGF-1R. There's a number of programs that are pursuing alternative mechanisms, FcRn, IL-6. Just, like, take a step back, I guess, and how do you see this market evolving over the next, like, five to 10 years as you have all of these various treatment alternatives that become available?
Yeah. I first of all, I think we need to see some data from these different mechanisms. I remember that IGF-1R is really goes to the heart of the disease. I mean, that's where the cell signaling is taking place in that receptor complex with IGF-1R, and TSHR. So you have to if you're gonna get the treatment effect size that you need and these are patients that, as I described earlier, their quality of life is really bad. It translates into depression, because they don't like to go outside. They have trouble, you know, reading and driving and working. And so when a patient, like, comes in with symptoms of that nature, they wanna be treated with the most impact. And so that's IGF-1R. The other mechanisms are not at that heart of the disease kind of target.
That doesn't mean that they won't progress in thyroid eye disease. It's just where will they, where will the different mechanisms fit in the broad thyroid eye disease patient population? Possibly, there's a mild population that might benefit from a broader anti-inflammatory like an IL-6. FcRn remains to be seen. I think we've seen some data that suggested that they didn't meet the proptosis endpoint. And then only in a post-hoc analysis, did they start to piece it together and try to make the case. So I think there's more needed from all of these different mechanisms. The other IGF-1Rs that you referenced, again, we need to see the data. We haven't seen it. One's a small molecule. And we're still waiting to see what that looks like. And we model all this stuff in.
Like, we're not discounting anybody, or dismissing anyone. But the main point is IGF-1R is where you wanna be to get that treatment effect size. The moderate to severe patient population needs that treatment effect size. So we feel really well-positioned in the competitive landscape.
That makes sense. Among the IGF-1R landscape, like, what do you think is the most important driver of long-term share? Like, do you think it will be convenience, either with, you know, duration of dosing or the ability to get to low-volume sub-Q? Will it be kind of like first to market? Is it all gonna come down to, like, you have a bunch of different options, and it becomes, like, an access game somewhere down the line?
I think it's again, I mean, just given the nature of the symptoms, it's gonna be best in class. Like, what is really driving the efficacy that you need with, you know, with again the continued benign safety profile of IGF-1Rs? So I think that combination and then you add on top of that I mean, just take our sub-Q program, for instance, the ability to have an autoinjector pen delivered to people's houses so they don't have to drive to an infusion center. They may not live near an infusion center. They could be 2 or 4 hours away from an infusion center. That makes it incredibly difficult and burdensome on patients versus having an autoinjector delivered to your house so you can self-administer. And we think we have that best-in-class sub-Q. We think that's gonna grow the market. We think that's gonna take significant market share.
Got it. That makes sense. And you mentioned the autoinjector pen. I guess, where are you with sort of incorporating that into the 003 development program?
Yeah. We have a device. We have the autoinjector pen that's already clinically and commercially validated. So we're not reinventing the wheel on the device itself. But devices, as you know, have to have their own timeline associated with their development. They have validation, human factor studies, all this kind of stuff that needs to go into it before you introduce it into your studies. So we're working on that in parallel with getting the pivotal program for the sub-Q up and running. And then we'll come out with some more clarity as to when we expect to introduce the autoinjector.
Got it. Okay.
The plan is to launch 003 in the autoinjector. At launch, we would have a self-administered infrequent pen that patients can take at home and self-administer.
Got it. Okay. I feel like, historically, I mean, this has been a U.S.-built market. But when we think about Europe, I mean, how important is Europe to you? You guys are enrolling patients from Europe in your pivotal studies. I guess, what's your sense of sort of timing for accessing and building the market in Europe, and how important is that to the Viridian story?
Yeah. We certainly started to work on that. I think, we will certainly pursue that. Europe is, as you know, highly segmented. It's got a centralized payer system. And then the patient journey in Europe can be a lot different than what it is in the US just because it's central because it is centralized. It's hospital-centric. So we're looking at that. And obviously, the reimbursement and the pricing will come into play as to where we end up going. We're also looking at ex-Europe in terms of Asia and Japan in particular. So these are things that we've been working on and but we're, you know, we've got a little ways to go as well.
How do you think about potentially, I guess, scaling in some of those regions? Like, is this something that you're planning to do yourself, or are you looking at regional partnerships to tap into, you know, something like Japan?
Yeah. We're still going through that analysis. But I mean, I, I honestly, I think we could do this ourselves if we chose to because Japan might be a little different. Just 'cause although I've done that I mean, in a prior company, we built a Japanese team, and it was and worked out great. And so we could do that because, because this is a rare disease and, you know, relatively speaking, and your call points are defined.
You could build a small infrastructure in Europe or Japan and commercialize it yourself if you chose. So we're gonna go through that analysis. It's not an obvious one where you have to partner it out to be successful because you've got a massive infrastructure that you need to build in these areas. And we just don't think you necessarily would need to. We're still going through the analysis on that.
Got it. That makes sense. Just in the last couple minutes, let's talk about the preclinical FcRns and what maybe just like high-level outline the strategy behind these, I guess, where you see the potential for these to fit in in a world of VYVGART. But then you have a number of other companies that are obviously also angling for a piece of the FcRn market.
Right. I mean, I think, efgart has proven as I stated in the beginning, but efgart has proven to be a pretty powerful molecule with respect to its efficacy and safety. It's been very hard to match safety and efficacy of efgart. The other approaches that other companies have taken with respect to full-length antibodies, and even the ones that have been designed to be albumin-sparing, they've had their issues. I think there is also a component of what is the proper level of IgG suppression that translates into efficacy. You know, I think there is even we've seen evidence now, clinical evidence, where even deeper IgG suppression doesn't always translate into, like, take myasthenia gravis, active daily living scores. It didn't necessarily translate into a positive, or better than efgart. So I think there's still a lot to learn there.
But we are really excited about having what we think is the only other Fc fragment in clinical development, because that's a real special molecule. And then to the extent we can improve upon that with our 008 program by half-life extending it because, as people know, FcRns clear very quickly. And so to the extent you can maintain that effect without additional dosing or, you know, more or less frequent dosing, that would be really powerful in that market.
So we feel really good about where we are. And we look forward to getting the IND on file for 006, which is the FcRn-like fragment, and getting some healthy volunteer data in the early part of next year. And then, on the 008, we'll have our non-human primate data in the second half of this year. That NHP data has been very translatable in the past for FcRns. So that's an important catalyst for us to have on the radar screen as well.
Yep. Okay. It's a lot coming. And we'll, we'll stay tuned on the FcRn front. And I think we're running up against time. But,
Perfect.
Appreciate it. Right, right, right on the nail. Thank you, Steve. Thank you, Shan. We'll stay tuned to the Viridian story.
Yeah. Tom, thank you very much for having us.
Thanks.
Appreciate it.
Thank you.