At TD Cowen, and thank you for joining us at our 45th annual healthcare conference. It's my pleasure to have with us today the team from Viridian Therapeutics for a fireside chat. We have President and CEO Steve Mahoney and Chief Business Officer Shan Wu. Thank you both for joining us today.
Thanks for having us.
Maybe if you would like to just kick things off with a bit of a state of the business, kind of what investors should be looking at this year, and obviously coming off the back of two positive phase 3 studies, having some good momentum, just like a quick state of the business, and then we'll go from there.
Yeah, great. Thanks again for having us here today. Before I get into it, we will be making forward-looking statements today, carry the risks and uncertainties spelled out in our SEC filings, so please refer to those. On cross-trial comparisons, just ask you to draw your own conclusions there. In terms of the business, we're doing great. We obviously just had two very positive phase 3 readouts at the end of last year in our THRIVE, which is the active form of thyroid eye disease study, and then THRIVE II, which studied the chronic population. Both extremely positive, really, in fact, better than expected results. There are three key endpoints for these studies. Proptosis is the first one as a primary endpoint, which is essentially bulging of the eyes, and then our ability for the drug to be able to reduce that bulging of the eyes.
That was really important. Diplopia or double vision, as you can imagine, people care a lot about if they have double vision or not. Our diplopia resolution and response were both extremely positive and encouraging for patients, particularly in light of what we've seen with the currently available drug. Finally, clinical activity score, which is really a proxy for pain, inflammation, redness, that type of thing. When you take those three parameters on the proptosis side, we were very much in line with what we've seen by the currently available drug. As I mentioned, diplopia, clear differentiation. That is when you ask patients and you ask physicians, what are the things that people care about the most? Remember, these are primarily women in their 40s and 50s who get thyroid eye disease.
How they look with the proptosis and the double vision when they're in that age range, how does that impact their life? I mean, are they able to drive, read, work, take care of families, and just live active lives? For our results to be as good as they were in both of those measurements was highly encouraging. Now we are, for that program, this is the IV program. That program is on track to file a BLA in the second half of this year. We just need the THRIVE II follow-up data to get collected and finish that up. That's what's driving that timeline. We also have a subQ program for thyroid eye disease, which is essentially the same antibody, same binding domain, same CDRs. We have a half-life extension technology on that.
Our healthy volunteer data for the subQ program was very encouraging. Try to match the exposures from the IV with the subQ to stay above CMIN. That enables us to, we expect to be able to deliver similar outcomes with our subQ program. First half of 2026, we'll have top-line readout for those programs on both active and chronic. Those programs are all on track, as we just put out in our earnings release last week. From the thyroid eye disease standpoint, we feel really good. We can talk about the competitive landscape at some point as well. We think that's very clearly in our favor now. We also have an FCRN portfolio.
We are in the clinic with the FcRn portfolio, and we have with the first program at least, and we expect to have healthy volunteer data in that program in the third quarter of this year. That'll help us figure out IgG suppression, albumin sparing, and give us some insight on dosing. Everything's on track execution-wise. We're moving things forward, executing against the strategy, and all looks really good right now.
Perfect. Great. Maybe we'll start with thyroid eye disease and break these into the two component parts of active and chronic disease. When you look at the standard of care and Amgen's Tepezza is out there, I guess in active, what is the remaining unmet need? Maybe can you pull in a little bit of the excitement around the dosing profile that veligrotug is able to offer? What are you hearing from KOLs in terms of, is it more going to be on the dosing flexibility side or on the efficacy side of your active trial or both as it might turn out?
Yeah, I mean, I think the key to keep in mind is we showed a more rapid, again, cross-trial comparison, draw your own conclusions, but we showed a more rapid response. We had statistically significant response after just one infusion for proptosis. As I said, as a patient, you want to see that. You want to feel that relief as quickly as possible. You want to see that reduction in the bulging of your eyes. That was one differentiator right off the bat. The other differentiator was the diplopia that I referred to. Our numbers, again, cross-trial comparison, but our numbers looked very encouraging as compared. Again, massive quality of life impact there. That is on the efficacy side. On the safety side, we saw, if you look at our AE tables, the two different AE tables, they look very similar.
The difference in the key AE of interest in this field is hearing impairment. It's not hearing loss, it's hearing impairment. And the hearing impairment includes a number, it's a composite term for a lot of different subcategories like tinnitus or autophony, which is like an echoing in your ear. And so those are for Tepezza as well. I mean, these are generally considered, they're generally mild, they're considered, they will resolve on their own without intervention. That was really great to see. The key difference for us was we were actively monitoring for hearing impairment because by the time we ran our studies, it was a known AE of interest. We were taking baseline assessments and we were taking assessments at every visit. Now, Tepezza did not do that because it wasn't known at the time.
In spite of all that, we still had lower rates, even though we were looking. I think that's really encouraging. That very well might be, it's always hard from a biological standpoint to really pinpoint stuff. One of the main strategies of Viridian was when Tepezza was originally developed, there were no dose ranging studies. They have this 20 mg per kg dose that came out of oncology at some point, and they just dropped it into thyroid eye disease. We looked at that and said, I think, and if you look at the dose response curve, there really isn't any incremental benefit to know after dose five. Doses six, seven, and eight do not really make a ton of sense from a Tepezza standpoint. We took advantage of that.
We ended up putting in a lot less drug, like 70% less drug to achieve the differentiated outcome that I already explained. That very well may have some relation to the hearing impairment as well because it's just less drug. Obviously, if you're some people have referenced the CMAX spike as an AE driver, our CMAX in our IV program is half just because we're half the dose. Now you have differentiated efficacy, you've got a differentiated safety, and on top of all that, you get less infusions, less drug, less infusion time. It's a better profile, what we think is a better profile for patients, make it easier for them.
Perfect. Maybe jumping over specifically to the chronic opportunity, obviously in Amgen studies, they did not study the full disease spectrum of clinical activity. You did in your phase three program. Can you kind of talk a little bit about, I guess, why you decided to study that whole program, what you saw, and how you think that could be differentiating? Obviously, Amgen had a little bit of an issue with getting some chronic patients on therapy. Do you think you'll have more success?
Shan can answer.
Sure, I can start with an answer to that. The chronic patient population we studied in THRIVE II is inclusive of all CAS scores from the whole spectrum of zero to seven. We know that chronic patients can have higher CAS, they can have lower CAS, and there is no reason to limit the study of chronic patients to any one particular number or a subset of those patients. What we think we ran with THRIVE II is the most comprehensive study, a most robust study that is the most representative of the chronic patient population. We generated results that were really better than expected and spectacular. Not only robust efficacy on the proptosis side, but it was the first global phase three study to demonstrate a statistically significant result on diplopia, on both diplopia resolution and diplopia improvement.
This is an area that for even KOLs, when we were speaking to them before the chronic data readout, they were skeptical that chronic patients can have diplopia be addressed. They're much longer in their course of disease, maybe fibrosis has set in. The average time from onset in our THRIVE II study was six years, and that's actually longer than the baseline characteristics for patients who are in the Tepezza study. With these being true chronic patients on THRIVE II and the level of efficacy that we saw, we were just really thrilled with the outcomes that we had. On the safety side, similarly low rates of hearing impairment, again, that key AE of interest that Steve talked about.
We think that this could be a game changer for patients, really address the unmet needs for chronic patients, still saw rapid onset of treatment effect after three weeks, has statistically significant impacts on proptosis, and after six weeks, statistically significant impacts on diplopia. Again, this double vision that contributes so much to the debilitating nature of the disease. Patients and physicians really care a lot about it. We will have this data in our label as well. Because we ran THRIVE II as one of our registrational studies, we would expect to be able to have the chronic data in our label, which is different from the approved therapy currently where that chronic study was run after approval.
In addition, just the strength of the data, and we had a number of conversations with KOLs after the chronic data came out who really talked about this changing how they think about the benefit risk for chronic patients. One particular instance of an oculoplastic surgeon had kind of moved away from treating chronic patients with a therapeutic instead of opting for surgery. She took a look at our data, both efficacy and safety, and said, wow, this is phenomenal. I'm going to start trying VELI for my patients again before putting them on surgery. I think we really are bringing something that is addressing a true unmet need for these chronic patients.
By having it in our label as one of our registrational studies, I think we'll be able to have the payer conversations upfront and be in as good of a position as possible for when we launch in terms of those coverage decisions from payers.
I think it's worth noting again or reiterating that these are the two, THRIVE and THRIVE II are the two largest phase three studies ever run in this disease. If you look at the curves in our deck, you could see just the robustness, but the consistency of the curves. That's really encouraging to see versus some of the others where you see a lot of ups and downs. Like we have nice smooth curves across every endpoint and every time point. That just gives us a ton of confidence in the data itself.
Perfect. You mentioned earlier that the BLA is on track for an H2 submission of this year. Can you kind of just walk us through what's remaining? Obviously, we need the longer-term follow-up data, but if you could touch on your readiness on the CMC side of things. Will we see the long-term data or is the next kind of point we hear from you that the BLA is submitted?
Yeah, so the BLA timing, as I referenced in the beginning, is dictated by the THRIVE II follow-up period. Everything's on track. We've been consistent about this timing for a year now that we knew this would be the driver. That's still the case. CMC all set, everything's on track there as well. It's really just waiting for that THRIVE II follow-up data to get in-house so we can drop it into the BLA.
Perfect. When you think about XUS opportunities here, is the opportunity in Europe kind of as exciting as it could be in the US? Where are the cadence of your interactions with Europe?
Yeah, so we've talked to Europe for several years now. We designed THRIVE and THRIVE II with Europe in mind. I mean, there's an overall response rate endpoint in there as well, which is specific to Europe. That's what they like to see. That's been all planned out. Now, Amgen, so Horizon never filed XUS. I think that was a big part of Amgen's investment thesis or acquisition thesis was that they could expand beyond the US, which we 100% agree with. They now are approved in Japan for the active form of the population. They got a great price, which is really encouraging, really just validates the market for us over there as well. In Europe, they filed and they filed towards the end of last year, I think it was probably sometime in the fall.
That's a good sign too. Our expectation is they wouldn't have filed if they didn't feel like they were going to get the price. We benefit from seeing all that type of activity. We benefit from them educating payers, but not only payers, they're educating physicians and patients on IGF-1R. We get to come along and differentiate, but we don't have to start from square one. Yeah, just another advantage that we get to take.
Perfect. You mentioned kind of the payer dynamics and pricing. Obviously, we've seen the data, the shorter course of therapy and able to get less to patients. How are you thinking about pricing maybe relative to Tepezza?
Yeah, as you can imagine, we haven't come out and really talked about that in detail just yet. It's a bit early. We've got time, but in this, it's relatively well understood what their price is. We are not, again, trying to reinvent the wheel here. We'll see where we end up, but we've got a clear range to shoot for.
Perfect. Maybe as you're building out your sales force, I guess when is the ideal time to start doing that? Second, what's the ideal call point? It seems like Amgen and Horizon have kind of tried a few different things here. Is ocular surgeons where you're going to see the most? Is it ophthalmologists? Is it something else? What's the ideal call point?
Yeah, well, and endocrinology too. There is a mix of those three. Now, on the endo side, which is what Amgen is emphasizing currently, and that is maybe a function of the fact that they have an endo sales force. They never had an ophthalmology sales force until acquisition Horizon. They did not get all the Horizon reps. We know that for a fact. On the endo side, it depends on who you talk to. You think there is probably a subset of KOLs who feel comfortable with starting the diagnosis and completing it to treatment, but most endos are not trained in the ophthalmology side of the world. They will refer. Ophthalmology is still probably the key endpoint or the key call point. Oculoplastic surgeons obviously are very important here because they get consulted all the time as well.
Now, what's critical for a company like us is that we don't need a big infrastructure here. We think there's roughly 2,000 core prescribers in the U.S. made up of that mix that you just referred to. You think about the Horizon experience, they launched with roughly 80 reps, and then they grew to about 140 at one point. I think it got bigger after that. We think 100 reps can cover 2,000 core prescribers with 20 HCPs and Ps. That's very manageable. We have said that. We haven't said exactly what our numbers are going to look like. Your question about when we would hire the field force closer to bonufidate. That's not an expense that would hit us this year anyway.
Perfect.
What we have now already is a core commercial leadership team that's in place. We've had a Chief Commercial Officer. We are well on our way to building those readiness. Actually, we've built the readiness plans, well on our way to the readiness activities themselves, but well ahead of launch, obviously. The heavier spends, like hiring a sales force and tactics that are really driving launch, will come closer to the bona fide date.
Perfect. Maybe jumping over to 003, is this completely de-risked? How much does veligrotug de-risk the upcoming H126 readouts for 003? What can you take either from the patient population enrolled or the activity level? Just your thoughts there would be helpful.
Yeah, that's a great question. We think that the VELI data, both THRIVE and THRIVE II, as well as phase two data that we generated with 3 mg per kg and 20 mg per kg, so different doses than what the IV doses, which all of that was very clinically active, are de-risking for 003. The way that we design 003, it has the same binding domain as VELI IV. And so the molecule should interact. We would expect it to interact with the target in the same way because it has the same CDR, same binding domain. We have engineered it to have an extended half-life, which was confirmed in a phase one PK and PD study.
Not only does it have an extended half-life, but it sustains that IGF1 level, which is the PD biomarker for IGF1R antagonism, and sustains that also beyond what the non-half-life extended VELI could do. From that healthy volunteers data, we did PK/PD modeling to show what levels of exposure 003 could get to with Q4 weekly and Q8 weekly dosing. That is why we've decided to take those two doses into the phase three studies of Reveal One and Reveal Two, two active doses. Both would be really great regimens for patients from a convenience standpoint. It has already been formulated to fit into a two-mill auto injector, low volume auto injector that we would anticipate mailing to a patient's home for them to self-administer at home. Every four weeks or every eight weeks.
Both of those from a PK standpoint and exposure standpoint match back to the phase two exposures that we saw with veligrotug IV, which again was very clinically active at 3 mg per kg as well as 10 mg per kg. I focus on those two in particular because the Q4 weekly dosing regimen from an exposure standpoint really matched back to that 10 mg per kg IV. The every eight-week dosing regimen matches back to the 3 mg per kg IV from a CMIN standpoint. From an AUC standpoint, we are right up in that same range as well. We feel really good about the exposure levels that we are achieving with 003 in the two active arms of the Reveal One and Reveal Two studies.
Of course, now with THRIVE and THRIVE II, we've significantly de-risked the 10 mg per kg IV dose as well. To the extent that a subQ, both having a lower Cmax, that smooths out all of the Cmaxes versus an IV infusion, as well as that every eight-week dosing regimen having an overall lower exposure, again, more similar to 3 mg per kg IV, to the extent that these lower exposures can lead to an even better safety profile, we're really excited about the opportunity to test in the Reveal studies, the ability to preserve the efficacy, which is really strong determination of adoption for patients with moderate to severe thyroid eye disease to preserve that strong efficacy of IGF-1Rs while improving the safety even further for this class.
Perfect. Steve, you mentioned earlier some comments on the competitive dynamic and the competitive landscape here. Obviously, we've seen updates from Acceleron. We've seen some private updates on oral. We have the FCRNs out there. I guess how do you think about the competitive landscape here? I guess what gives you confidence that 003 is ahead of the pack here?
003, not only 003, VELI is ahead of the pack too. I think the competitive landscape for those who were watching earlier this year really cleaned up nicely in our favor. The Sling data that you referred to, which was the oral small molecule, came out not much. I mean, in our view, it doesn't look like a competitive profile. Hard to really understand where that fits in. 31% discontinuation rate in the study. They had liver tox. I mean, small molecules have their own tox profile that they bring on top of whatever the target profile, the target for IGF-1R, there's a target safety profile there. When you add small molecules on top of that, we expected that, to be honest. We had been looking at small molecules ourselves, so we kind of expected to see what they showed.
I mean, their discontinuation rate was really high, as I said, liver tox. And then just on the efficacy side, it wasn't that great either. I mean, it was less than half, I think, of what we saw or about half. That doesn't seem like a real go-forward profile. I know they're trying to position to figure out where that would fit into. For moderate to severe patients, they want that rapid onset of effect, and they need that proptosis and diplopia resolved. That is on the Sling side. Acceleron, really hard to say what's happening with Acceleron now with the Alumisteel. Not really sure the profile or the data that they put out with Loni was the proptosis levels or proptosis response was lower than ours quite significantly.
I just don't, I think that they were kind of pivoting towards a more maintenance dose. They had this phase three study design that we thought, and again, I don't even know if I'm talking about them in the present or in the past now, but their phase three was going to be a problem in terms of they were asking 350 patients to take a dose every two weeks for a full year. I think that would be a problematic study to execute on. It wasn't clear from the endpoints that they were going to get the readout that they were hoping, that the readouts that they were going to get were going to actually help them differentiate on the story. A little bit messy there. Immunovant came out because the other mechanism was FcRn.
People were saying, well, that could be a threat, a competitive threat. The issue with Immunovant, though, is they came out in January and said that they were not going to try to compete with IGF-1R, and they were going to focus on a more mild population. That kind of takes them out of the moderate to severe population that we are targeting. You see all three of those fall off. We feel really good about where we stand on the companion. If it is just us and Tepezza on the market, the key to this market that everyone has to keep in mind is this new start concept. We are not asking people to switch off of Tepezza or any other therapy. They come in, they are symptomatic, whether they are active or they are chronic. They come in and they say to the doctor, what are my options?
I can get you more rapid onset, better diplopia numbers, a good safety profile. Again, cross-trial comparisons, I get it. I could do that with five infusions versus eight, 10 mg versus 20 mg per kg. A lot less drug and a lot more convenient profile. If that is in a new start market, that's a critical piece of the puzzle. We feel really good about the competitive landscape in that respect.
We think that our subQ, our 003 subQ program has the best profile out there now. It is subcutaneous first and foremost. I mentioned that we've already formulated it into a two-mill auto injector, and it's infrequent dosing at home and administration every four weeks or every eight weeks. Just to give an example, with every eight-week dosing regimen, it would be two doses upfront as a loading dose, very typical subQ regimen, and then another dose at eight weeks and a third dose at 16 weeks, and the patient is done. There's no other profile out there like that.
Perfect. Maybe jumping over the FCRNs quickly in the last minute here, but we are going to have the 006 data in the third quarter. I guess what would you be looking for in that data set to give you confidence to move the program forward? Do we need to be differentiated at this point? Do you just need to enter this large market? How are you thinking about that?
Yeah, so we're not getting really into the differentiated side of it just yet. Suffice it to say that we know what to shoot for. We're the only other Fc fragment in development that we know of. Vivguard is the gold standard. They're an Fc fragment. We like that positioning. We like being in the other fragment because the folate antibodies have been trying to compare against it. Obviously, there's still more to see, but so far, Vivguard looks like the gold standard. We like that positioning. We don't have to go through all the steps that they did. We can skip right towards the end. We're targeting a subcutaneous formulation or approach.
We have not really got into specifically how we think we are going to differentiate, but in terms of this data that is coming out in Q3, we want to see the IgG suppression in the range that Vygart saw. We want to see that albumin sparing. Again, if you look at the history of FcRNs, NHPs has translated to healthies, healthies has translated to disease patients. We are on the right track.
Perfect.
We have our follow-up 008 program as well, just to make a final comment there. This is where we think could be potential best in class half-life extended FcRn. We saw really encouraging data that we reported out last November in primates, which again, is very translatable, has been historically very translatable to humans. Confirming that extended half-life, and we'll have more preclinical data from that program this year with the IND expected by the end of this year.
Perfect. Unfortunately, we are out of time, so we have to keep things going. I appreciate both of you joining me today.
Thanks for having us.
Thank you so much, Joe.