Viridian Therapeutics, Inc. (VRDN) Earnings Call Transcript & Summary

Welcome to the Viridian Therapeutics conference call. [Operator Instructions]. As a reminder, this conference call is being recorded. I would now like to hand the conference call over to Ms. Louisa Stone, Manager of Investor Relations at Viridian. Please go ahead.

Thank you, and welcome, everyone. Today, we are going to discuss Viridian Subcutaneous IGF-1R program selection. Joining me on the call this morning is Steve Mahoney, our President and Chief Executive Officer; Dr. Shan Wu, our Chief Business Officer; and Peter Harwin, a member of the Viridian Board of Directors. Before we begin, I would like to remind everyone that this conference call and webcast will contain forward-looking statements regarding our financial outlook, regulatory plans, product development and commercialization plans and research activities. These statements are subject to risks and uncertainties that could cause actual results to materially differ from those forecasted. A description of these risks can be found in our most recent Form 10-Q on file with the SEC. I would now like to turn the call over to Steve Mahoney, our President and CEO.

Thank you, Louisa. Good morning, everyone. Thank you for joining us today. We are very excited to share data from our half-life extended anti-IGF-1R subcutaneous monoclonal antibodies and also to announce our plans to initiate pivotal subcu studies by mid-2024. We have selected VRDN-003 for pivotal development. 003's clinical data has exceeded our expectations and suggest that it could constitute the best-in-class half-life extended IGF-1R therapy for patients with thyroid eye disease. This is because we anticipate it being a low volume infrequent and self-administered therapy that patients can use at home. 003 shows a confirmed half life of 40 to 50 days, which is 4 to 5x that of its parent antibody VRDN-001. This is significantly longer than other first-generation IGF-1R inhibitors, including Teprotumumab and lonigutamab. 003 is the same molecule as 001, except for a 3 amino acid change that enables half-life extension. The data shows that 003 reaches 001 exposures, which gives us confidence that we can potentially dose as infrequently as Q8 weekly and still achieve clinically efficacious exposures. We expect to take 003 directly into pivotal development by mid-2024, pending alignment with regulators. Our goal for this program is twofold. First, develop best subcu IGF-1R for TED patients; and second, bring it to the market as fast as possible to meaningfully change the landscape for patients. For those who are new to the Viridian story, 003 is nearly identical to its parent antibody 001. There are just 3 amino acid changes in the Fc region of the antibody with the sole purpose of extending half-life. The binding domains or the CDRs and the rest of the antibody are identical. The performance of the half-life extension mutations was remarkable with a confirmed halfway of 40 to 50 days. As a reminder, TED, or thyroid eye disease is a large market and is only currently served by one marketed IGF-1R IV therapy. So there is no self-administered option. The marketed therapy is only available in the U.S. currently where it is annualizing close to $2 billion in sales. IGF-1R inhibition is the only clinically and commercially validated mechanism of action for thyroid eye disease. That is an exciting proposition for our company as we have the potential to develop the best version of this highly effective class of medicine. We are excited about the potential to differentiate compared to Tepro and other monoclonal antibodies. With 003, we hope to show the potential for a convenient, less frequent low-volume, self-administered auto-injector. We see significant potential within the current TED market and as well as the opportunity to expand it from there. Turning to Slide 6. We show two examples of diseases where a meaningful portion of the market converted from IV to a later entry subcu. Keep in mind that these subcu examples have the same or worse dosing frequency than their IV counterparts. That will not be the case for 003. On the left is an example of converting IV subcu with the same molecule, while on the right is the adoption of a new subcu entrant. In both examples, sales of the class grew after the launch of subcu. So subcu offerings can command substantial market share even when launching several years after an incumbent IV and can command that market share quickly. Further, subcu offerings can also grow the overall market -- grow the overall market size for their class. And importantly, none of these examples were in new start markets. TED is a new start market, which should be easier for us to break into. We think there is a significant opportunity for a long-acting convenient subcu anti-IGF-1R therapy. Moving to Slide 7. Here's a quick look at the study schematic for our healthy volunteer studies to provide context for the data on the coming slides. We ran single-dose subcu and IV at low doses for 001 and 002. And then we most recently ran a single dose subcu and IV at low and high doses for 003. Let's turn to the data that we've all been waiting for us. Here is a PK and PD comparison across all three molecules, 001, 002 and 003. We have also included the published lonigutamab PK data on the slide for reference. As you can see, 003 has the best pharmacokinetics of any of the antibodies tested with prolonged durability compared to its parent 001. Although 001 subcu looks favorable compared to other first-generation IGF-1R antibodies, 003 takes it a big step forward. We also wanted to see 003 at least match 002 on half-life, and we are very happy to see that it is superior to even 002's impressive performance. All three Viridian candidates showed excellent exposures with bioavailability consistent with approved subcu antibody therapies. We have previously shown that 001, a full antagonist of IGF-1R produces best-in-class increases in IGF-1 levels, which is a key marker of target engagement. Consistent with expectations set by 001, its parent molecule, 003 increased IGF-1 levels to a greater extent than other IGF-1R antibodies, including 002. We were hoping and expecting to see this sustained and potent pharmacodynamic effect with 003, and we see it very clearly here on the right. 003 was very well tolerated. There were no SAEs and all treatment-related treatment emergent adverse events were grade 1 and mild. No ADAs were identified. 002 and -- 001 and 002, were also well tolerated in this study with no SAEs and no adverse events of interest. Let's review the data for 001 as a frame of reference for why we are so excited about the 003 results we are reporting today. On the graph on the left, we show the 001 IV serum concentrations at the 3 different doses we evaluated in our Phase I/II clinical trial. These were 20 mg per kg, 10 mg per kg and 3 mg per kg. The 3 shaded boxes represent the exposure ranges that we saw from each of these doses from C-min at the bottom to C-average at the top. Now with that as a background, let's turn to the next slide where we can get the correlation of these exposures to clinical response. Here, we again have the serum concentrations from the three doses we evaluated in our Phase I/II clinical trial. On the right, we show the corresponding clinical responses in TED patients for 3 key end points; proptosis, CAS and diplopia resolution. As you can see, all 3 doses showed highly active clinical responses for 001 IV, including at the lowest dose of 3 mg per kg. In fact, looking closely at TED's primary endpoint of proptosis, 001 IV looks similar, if not favorable, to Tepro across all 3 doses. With this 001 IV data showing the connection between exposure levels of 001 IV and clinical responses, coupled with the fact that 003 and 001 are nearly identical antibodies, we can uniquely leverage the 001 data and rapidly advance 003 as a best-in-class half-life extended, self-administered subcu program that we expect to meaningfully change the landscape for patients. Now that we've established 003's shared sequence in pharmacology with 001, confirmed its extended half-life and confirmed its receptor engagement, what dosing regimens are available to us. Here, we've taken the pharmacokinetic data from 003 and modeled dosing intervals that have achieved or surpassed 001 exposure ranges. One exciting outcome from the surprise outperformance of 003 is that an unlocked an even more differentiated dosing regimen for patients. Dosing 003 as infrequently as Q8 weekly is predicted to achieve and consistently surpass trough or C-min levels of 001 IV dose at 3 mg per kg. This enables an incredible combination of convenience and exposure that is still expected to be efficacious and which could also positively impact the safety profile compared to the currently approved option. Dosing 003 at once monthly is predicted to achieve and consistently surpass trough levels of 001 IV dose of 10 mg per kg. Achieving exposure where we have seen clear clinical responses and then being able to extend that to once a month convenient dose is a development that we are very excited about. Finally, we illustrate that our modeling suggests that dosing 003 at a Dupixent-like Q2 weekly dose would be predicted to surpass trough levels of 001 dosed at even 20 mg per kg. So you see the properties of 003 give us a lot of headroom to work with here and give us the potential to offer patients a best-in-class, low-volume, self-administered subcu delivery option. This is a great result for patients. We expect to move quickly by moving directly into 2 pivotal registration-enabling studies with confidence, because our extensive experience with 001 effectively guides our dose selection of efforts. We want to be sure that we are keeping the endgame in mind by testing dosing regimens that we expect will provide a best-in-class product profile and maximize commercial impact, while also ensuring a successful outcome of these studies. Our 003 pivotal studies are expected to begin just as THRIVE and THRIVE-2, or completing enrollment, enabling us to leverage our clinical trial machinery and our extensive learnings, which we believe is a key advantage to Viridian. Our next step is to align with regulators on our pivotal design, and we will share more detail on our trial design and plans ahead of pivotal trial intuition. We are excited to rapidly advance a highly differentiated subcu 003 to patients. Just a quick look at our pipeline with the reminder that we are building what we believe is a world-class portfolio in thyroid eye disease. And based on today's announcement, we have the potential to bring a best-in-class IGF-1R therapy. We look forward to sharing more on our unique FcRn portfolio in 2024. To close out, we are making excellent progress at Viridian on developing our pipeline, and we are executing across the board. We are enrolling our Phase -- our 2 Phase III trials THRIVE and THRIVE-2 for active and chronic TED patients. We are on track to report THRIVE results in mid-2024 and THRIVE-2 results at the end of '24. We also recently unveiled our FcRn inhibitor portfolio, where we are on track to file an IND for the 006 Fc fragment program for self-administered subcu delivery by the end of '24, as well as advance our 008 program, which is our potentially first-in-class FcRn bispecific program into nonhuman primates in 2024 as well. With that, I'll ask the operator to open the call for questions.

[Operator Instructions] Your first question comes from the line of Michael Yee from Jefferies.

Congrats on the data. I appreciate that. We had 2 questions for the team. One was trying about your view a perspective of the every 4-week option and every 8-week option. And when you look at your PK for those, it looks like you could cover both bases. But I just wanted to understand your confidence around the efficacy, given the fact that comparing the coverage to 001, for example, I think, which is on slide 22, and how you think about those 2 different ones. And then related to that is by using PD data. And so if you look at the PD data, I just wanted to understand your thoughts around that, because I think around after 40 days or so, I think the IGF-1R 4, one of the doses starts to fall off a little bit. So I just wanted to think about, again, comparing and contrasting your confidence on every 4 weeks and every 8 weeks.

Thank you, Michael. Yes. So first, just to anchor the discussion here. We can achieve or surpass exposures of the 10 MPK IV, which is the dose we are evaluating in our Phase III THRIVE pivotal studies. Our Q2 weekly regimen is Dupixent-like, and it matches 10 mg per kg IV on the C-avg and is far above 10 mg per kg on the C-min. Now we would only need this level of exposure if the lower exposures didn't work, which would mean competitor molecules wouldn't work either. So we include that arm or we're thinking about including an arm like that, to ensure success. So although we highly doubt that those levels would be necessary for 003 when it's all said and done. Now just to take the second part of the question, just to reinforce that we have a range of clinical activity that's helpful from our 001 IV studies where we've showed clear activity at low exposures to the 3 MPK with similar activity at the 10 MPK levels. So we want 003 regimens across the exposure range of 001 IV where, quite frankly, maybe the most exciting regimens are those in the middle or near the bottom end of that range, 3 mg per kg or somewhere in the middle, where we might have the ability to improve safety with the same IGF-1R efficacy while at the same time, maximizing convenience. So just to reiterate the data that's in the slide specific to your question, as I said, Q4 weekly, we achieved 10 MPK IV C-min and C-average is right between right between 3 MPK and 10 MPK. So that's a good place to be. On the Q2 weekly, as I mentioned, above C-min for 10 MPK and actually in line with more 20 MPK for C-min. And then we match C-avg for 10 MPK, we're actually a little bit higher. So that just gives us a lot of confidence, again, I mean just to reinforce. It gives us a lot of confidence, because we're in those exposure ranges where those exposure ranges correlated to clinical response with 001, and 003 and 001 are nearly identical antibodies. On the IGF-1 question, Michael, IGF-1 biomarker is a good biomarker, it tells us if 003 is acting the way it's supposed to be. You can see that 003 just like 001 raised IGF-1 levels to similar peak levels, 4x baseline after a single dose. What we knew before today that TEPEZZA and 002 had IGF-1 increases more in the 2- to 3-fold range. And quite frankly, we haven't seen a [indiscernible] IGF-1 data. So we're not sure what drug is capable of doing. We just haven't seen it. But IGF-1, a fourfold increase with 001 combined with the clinical data for 001, that got everybody really excited about what we could do and have a potential to differentiate on efficacy. So -- and then I would just point out the second characteristic about IGF-1 that is exciting for us is that it confirms the durability of target engagement. And you can see that 003 nicely sustains that elevation in line with this extended half-life, which again is up to approximately 50 days.

So on a follow-up comment...

Michael, I'll just add a quick one there for you, in case it's helpful. So every 8 weeks since you were zoning in on that with your question, it's clearly at or above the 3 mg per kg 001 IV exposures on C min and C avg, which led to remarkable clinical benefits. So we're really confident about that. And then you asked about the IGF-1 levels. The IGF-1 levels, the magnitude increase clearly matches between 001 and 003, which just connects everything back beyond just the pharmacology to the efficacy data with 001. The IGF-1 data that you see on the slide is, of course, from single dose, right. And there'll be a 600 mg loading dose in that regimen followed by only 2 more doses. So 3 administrations of 003 for that every 8-week regimen. So we fully expect that to link back to that 3 mg per kg or better IV 001 efficacy.

Your next question comes from the line of Laura Chico from Wedbush Securities.

I guess I wanted to take a step back and maybe just clarify on the regulatory strategy. Does this remain a filing for the IV 001 program first and then pursuing a follow-up sNDA or a separate NDA for the subcu results? I guess I just wanted to clarify that. I didn't see that on the milestones. And then, Peter, I think you just mentioned that you would be pursuing a loading dose. Does the 600 mg load, is that a single shot? And would that be regardless of whatever regimen you're advancing, whether it be Q8, Q4 weeks?

Laura, I can take the first part of the question. Yes, the intention is to file 001 IV first. We -- as we stated in the press release, the 001 subcu program has been deprioritized just in light of how great the 003 data is and the speed in which we think we can bring 003 through pivotal studies. And that 003 is a new molecular entity and would require a separate PLM. And then, Peter, if you want to ask a question on loan.

Yes. Yes, just to add color to that. And the 003 just is moving so fast and it's so differentiated, Laura, that it ends up just making sense for the company to go all in on it, right? It's really that simple. And on the modeled exposures, yes, it's using a typical loading dose regimen actually in all 3 of the modeled regimens. And given we're at 150 mg at least per mL, a standard 2 mL injection would be 2 injections for the load followed by a single injection thereafter.

Your next question comes from the line of Thomas Smith from Leerink Partners.

Congrats on the data. Just a quick one on the 003 safety. I was wondering if you could provide any additional color on the one case of liver enzyme increase and the injection site reaction there? And then just on the subcu formulation, if you could just remind us where you are with the subcu device? I know you just signed a deal for an auto-injector pen back in October. Is that something you're looking to implement into the 003 pivotal studies next year? Is that part of a longer-term life cycle management strategy?

Thanks. Yes, so just -- we'll talk about the safety on the 003 just to just to set the stage, very well tolerated, no SAEs, all treatment-related treatment-emergent AEs were grade 1 mild, no ADAs detected. On the hepatic data point there, that is a single data point. We haven't seen that in our 001 trials, healthy volunteers, Phase I/II. So that is not concerning to us. On the ISR, I think it was mild and it resolved. And what was the second question with respect to auto injector?

Yes. I just wonder if you could provide an update on where you are with the auto-injector and if you intend to use that in the pivotal studies to start next year?

Yes. Our goal is to launch with an auto-injector. We have been working on it for quite a while. It's all on track. There's your normal blocking and tackling you have to do when you develop an auto-injector. But it's on track, and we intend to have that available at launch. And so we'll introduce it into the pivotal studies as soon as practicable.

Your next question comes from the line of Gavin Clark-Gartner from Evercore ISI.

Congrats on the great data. So first, I know that you haven't aligned with regulators on the pivotal 003 trial design yet. But maybe you could just lay out the different scenarios or what your base case assumption is for the amount of dose ranging work that may be required with that trial?

Thanks, Gavin. We do not anticipate any need for dose ranging. I mean the bottom line is we know our doses. Given the similarities between 003, the shared pharmacology with its parent 001, we have more information and have a higher comfort level with our data than you would probably otherwise have as a typical program. And just as a reminder, the exposures for subcu are already in the range that is being studied in, with 001 in its pivotal studies. So again, we know what our doses are and we are confident that, that's going to move right into a pivotal study.

Yes. The only thing -- and we're giving some detail on sort of how we're thinking about it in the slides, and you heard in the prepared comments that we're probably going to take more than 1 dose regimen forward. But we just want to make sure that when we give the design to the investor community that we say it once. So that's how we're thinking about it.

Got it. And maybe just a quick housekeeping question confirming that 003 doesn't fall under the Xencor partnership?

It does not.

Our next question comes from the line of Gregory Renza from RBC Capital Markets.

Congrats on the data this morning. Maybe, Steve, certainly commenting on the commercial opportunity up at the top of the call. And as you mentioned, the global opportunity, obviously, the convenience as well as several other factors. I'm just curious if you could just maybe put into context the hierarchy of where you see that reach extending and would this necessitate the need of maybe a partner sooner than later when you think about commercialization? And then my second question is just related to the intellectual property as it comes to 003 and 001, just remind us of the intellectual property portfolio, how the overlap and the contrasting of both assets?

Okay. Yes. So look, I think what we see as the commercial opportunity, I think you've got TEPEZZA at 20 mg per kg in the market there, it's already annualizing close to $2 billion. We think our IV -- our 001 IV has a very solid place in that market, and we look forward to the THRIVE results and possible differentiation there, which would be great. And IV will have a place in the market. But the introduction of a subcu, like 003, we would expect to have assist with penetrating the active population further is gaining more access or more penetration in the chronic population as well. But also, we would expect it to grow the market. And we have some examples in the slides that show that the introduction of a subcu can grow the market. Now that's just the U.S. market. We are also looking at other market opportunities outside the U.S., and we'll have -- we have more work to do there and see what those opportunities present. But we think we're set up very nicely with 001 IV followed by an 003 subcu in terms of both penetrating the existing market and also being able to grow.

Got it. And just on the property portfolio.

Yes, I can take that. Actually, this is Sean. We have coverage IP-wise across all of our molecules into 2040.

Your next question comes from the line of Alex Thompson from Stifel.

Thanks for taking my question. I guess first one on 003. I guess is your current expectation that you would run the active and chronic pivotals in parallel? Or do you expect to stagger them in a similar way as you did with 001? And then maybe for 001, maybe you could set the stage for expectations around the mid-'24 data for THRIVE, I guess, in terms of efficacy and then also safety in terms of some of the AU like hearing loss, et cetera?

Well, on the first question, I think we'll -- we haven't locked down the studies yet, but we would expect that they'd be staggered. We'll start the first one as soon as we can. And -- but we'll get more details on that. The second question was what about?

I guess could you just set the expectations for THRIVE data in mid-24, like what should we expect? What do you think the bar is for efficacy and safety at the top line?

I could chime in that. I mean, I think we'll set that up more fully. We might do some sort of a Capital Markets Day ahead of that event, to set that up possibly with KOLs as you've seen some other companies do. Just as a refresh, 001 efficacy across all endpoints, and we put the data back in the deck today is also in the appendix. On CAS, proptosis diplopia, it looks as good or better than TEPEZZA at that week 6 endpoint comparing across studies. You'll also recall that if you look at the TEPEZZA studies, whether it's active or chronic the efficacy gets maxed out right around that 5 dose time point. And that's why we're super excited about our 5 dose schedule for 001. Also that gives us the potential for differentiation on safety, which was the other point of our regimen and we're really excited about that readout. We don't want to set any expectations that, that will be superior, but it is very exciting that all of the efficacy endpoints were as good or better and sometimes clearly better than TEPEZZA when you compare to cross studies.

Our next question comes from the line of Jason Butler from JMP Securities.

Just a quick one on -- understanding you still have to align with regulators on the Phase III design, should we still think about 15 weeks as the timing for the primary endpoint? Or given the different dosing duration options you have, could the primary endpoint timing be different?

Yes. Great. Thanks. So yes, we expect to run just to say, we expect to run 2 pivotal studies, one in active, one in chronic. We expect to bring forward at least one active arm. And we're looking at a 24-week endpoint Again, we haven't locked everything down, and we'll update on specific details once we get confirmed alignment with regulators. But that's our current thinking. As Peter said, we want to say this once and say it right, and not have to go back and change things. So we're essentially following what we did for THRIVE. And just across the board, we're just going to move as quickly and as aggressively as we can.

Your next question comes from the line of Rami Katkhuda from LifeSci Capital.

Congrats on the update. I guess a couple of quick ones. First, will you wait for the THRIVE results before initiating a pivotal study with 003 or is it just whatever comes more quickly? And then in the future, do you imagine assessing retreatment with either 001 or 003 in patients who don't kind of achieve full efficacy based on the clinical trial perspective?

Yes. So the answer to the first question is we do not intend to wait. We're going to move quickly. Again, we have extreme confidence in 003 based on what we've seen and based on its similarities to 001. So there's no reason to wait on that. With respect to retreatment, we haven't really kind of dove into that yet in terms of disclosing our plans for that. It's certainly an option. There's certainly things that are out there that we want to consider and probably the opportunity is available to do that, but we just need more time to kind of sort through that. But we'll definitely update the market on that at another time.

Your next question comes from the line of Derek Archila from Wells Fargo.

Congrats on the update here. Just one from us. I guess, is there any consideration for maybe looking at the every 8-week dosing as potential like a maintenance post monthly dosing, kind of looking more at an induction period, would that be a consideration in the Phase III?

Yes. I think you've got to give us a little bit more time to kind of lock down exactly what we're going to do. I can tell you that we have a lot of faith in that Q8 weekly dose, I mean, matching 3 mg per kg in that lower end of the activity range, where we saw -- it's at the lower end of the range, where we saw quite a bit of clinical activity at 3 MPK. So that's a pretty exciting place to be. So give us a little bit of time, and we'll come back on that one.

Yes. I would assume a standard way of treating the patients that you've -- we've all become used to. And Steve just mentioned that we're probably going to run a 24-week period. I mean every 8 weeks, you've got the potential for this IGF-1R efficacy that's just dramatic that we've all come to know. You've maximize differentiation. It's -- I mean one of the coolest things about that one, it's 3 administrations and you're done. And there's also the potential to uniquely test whether we can improve upon safety as well. So it's a really exciting regimen.

And then I just wanted just one for clarification. Just on the loading dose. Is it just a single loading dose? Or are there multiple? I just wanted to be clear on that.

Single. It's a standard load. There's nothing unique about it. Dupixent, lebri, there's STELARA and SKYRIZI have different ways to load. This is a standard load.

And your final question comes from the line of Kalpit Patel from B. Riley Securities.

Maybe one follow-up on the liver enzyme elevation in that one patient. Can you characterize how soon after this AE occurred and how quickly it resolved? And was it in the 600-milligram dose or the 300-milligram subcu dose in the liver enzyme obligation?

Kalpit, this -- so I don't think we've looked at it that closely. This was a spurious finding. I mean, the safety was outstanding across the board. And if you look at you got to recall as well, 003 is an almost identical antibody to 001. So we have 001 data in TED patients and healthy volunteer patients in IV and subcu and across 003 and 001, the safety looks outstanding. So I wouldn't overthink this one.

Okay. Okay. And you sort of touched on this earlier, but how confident are you that no additional data will be required for 003 since this is a new molecule, new entity, you can go straight into the pivotal development without any data in patients?

Yes. I mean, look, we're really confident in that. I mean, just again, there are nearly the identical antibodies. The only difference is the half-life extension, same binding domain, CDRs. So -- and as I said, we're already testing those exposures in the pivotal studies. And so that's already been through regulators. So we feel really confident that that's -- and we know what our doses are. So we're -- we feel really confident that we'll be able to move into a pivotal.

Yes. Just to put an exclamation point on that, confident enough to talk about it as an accelerated program going into pivotal today. We just want to make sure that when we put out the precise design that you guys see at once and that it doesn't change.

At this time, we have reached the conclusion of the question-and-answer session. I would now like to turn the call back to Viridian's President and CEO, Steve Mahoney, for some closing remarks.

Thank you, operator, and thanks to everyone for your time this morning. We are thrilled to be ending the year on a high note, and we are preparing for an exciting 2024 for Viridian. We wish everybody a happy holidays, and thank you again.

This concludes today's conference call. You may disconnect your lines. Thank you for participating.