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

Good morning, everyone. My name is Lalita Sundarrajan, and it's my pleasure to introduce Viridian Therapeutics speakers for today: President and CEO, Steve Mahoney, joined on stage by Chief Business Officer, Shan Wu. With that, Steve, I'll turn it over to you.

Thank you very much, Lalita. Good morning, everyone, and thank you for joining us. I'm pleased to be here today to tell you about Viridian. We are very excited about 2024, the year ahead. Viridian is building what we believe to be a world-class portfolio in 2 key areas: thyroid eye disease, with a best-in-class -- potential best-in-class therapy for thyroid eye disease, and a portfolio of FcRns that are differentiated from and improved upon current products and those that are also in development. Before we get started, I'd like to mention that we will be making forward-looking statements today. They are subject to risks and uncertainties, and we refer you to our recent SEC filings. For those of you who are new to the Viridian story, our strategy is to identify market opportunities where there is a way for us to differentiate. We then engineer the best possible biologic for patients and then move rapidly to solidify our position in the market. On Slide 4, we're showing our pipeline, where we have applied our strategy to both the clinical pipeline in TED and our preclinical pipeline with the FcRns. We believe that we have a world-class portfolio in thyroid eye disease, with both a potential IV best-in-class, what we refer to as VRDN-001, followed by a potentially best-in-class IGF-1R, with subcu VRDN-003. 001 showed robust clinical activity in a Phase II clinical studies in TED, and features a shorter infusion time and fewer infusions compared to the currently marketed IGF-1R inhibitor. 001 is currently in 2 Phase III clinical trials for active and chronic TED patients, with readouts that are expected this year. In December, we announced the selection of subcutaneous VRDN-003 for pivotal development in TED, pending regulatory alignment. We have designed 003 to be a low-volume, infrequent and self-administered therapy that patients can use at home, and we'll touch more on this a bit later in the presentation. We are also developing a novel portfolio of FcRn inhibitors, VRDN-006, which is an Fc fragment, which is very similar to efgartigimod, and VRDN-008, with an extended half-life that could achieve the goal of combining deeper and more persistent IgG suppression. Before diving into our programs, I'd like to briefly highlight the great progress we have made in the second half of 2023 and the exciting catalysts that we have ahead of us in 2024. As I mentioned, we recently disclosed clinical data and selected VRDN-003 as our potential best-in-class subcu program for TED. And we are continuing to enroll our 2 Phase III trials for VRDN-001 in active and chronic TED. We also unveiled our FcRn portfolio, and closed a $185 million pipe that puts us in an outstanding financial position. I joined as CEO at the end of October, and I'm proud of what we've accomplished in just the last several months and excited for what is to come this year as well. 2024 is a big year for Viridian, as we expect 001 top line results from both global Phase III studies. We anticipate starting the pivotal development program for 003 in the middle of this year, pending regulatory alignment. And for our FcRn portfolio, we expect to file an IND for our 006 program by the end of this year, and then generate nonhuman primate data for the 008 program in the second half of this year. Now let's take a closer look at thyroid eye disease in the IGF-1R. Thyroid eye disease is a rare debilitating autoimmune disease in which the tissue surrounding and behind the eye are inflamed and as a result, expand. This leads to symptoms, including proptosis or bulging of the eyes, redness, swelling, double vision and retraction of the eyelids. In severe cases, TED can be sight-threatening. An estimated more than 95,000 people in the U.S. alone are living with moderate to severe TED. And these patients are only currently served by one marketed IGF-1R IV therapy. This one approved IGF-1R therapy is annualizing close to $2 billion in revenues in the U.S. alone. We see opportunities for growth within the U.S. market as well as a possible ex-U.S. strategy, and we believe growth can also come from the introduction of subcutaneous -- a subcutaneous option for patients. 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 proven and highly effective class of medicines, including a subcutaneous option with 003, with the goal for patients to self-administer their therapy on a convenient schedule at home. Viridian is developing 2 anti-IGF-1Rs: VRDN-001 and VRDN-003. 001 is the IV. 003 is the subcu. As you can see here, 003 and 001 are nearly identical antibodies. There are just 3 amino acid changes in the Fc region of 003 from its parent, 001, which resulted in 003 having extended half-life in the range of 40 to 50 days or 4x to 5x the parent, 001. With 001, we hope to have a fast-to-market differentiated IV therapy for patients with fewer doses, a shorter infusion time than the currently available option. With 003, we're developing a convenient, less frequent, low-volume, self-administered therapy that patients can take at home. We see significant potential within the current TED market as well as the opportunity to expand it. So let's start with 001 and what makes us excited about our upcoming Phase III clinical trials. On this slide, Slide 11, you could see that we have already shown robust clinical activity in a Phase II clinical trial with 001 after just 2 doses in the key areas of proptosis, clinical activity score and diplopia. 001 meaningfully reduced across each of these endpoints at all dose levels in thyroid eye disease patients, including at the lowest dose of 3 mg per kg IV. The clinical responses we saw with 001 are as good, if not better, than TEPEZZA at all dose levels in our cross-trial comparison. We think the potential clinical profile of 011, with fewer infusions, shorter infusion times and lower cumulative drug exposure, can be very competitive with TEPEZZA. The TED market is almost entirely a new start market where newly diagnosed patients or even chronic patients who are flaring will have the ability to choose from the available options at that time. That is a good position for 001. 001 was well tolerated. And as you can see on this slide, no infusion reactions, no serious adverse events. We saw safety in line with TEPEZZA in these Phase II studies. These results set us up nicely for our Phase III study called THRIVE in active TED, which is ongoing. In addition to active TED, 001 also showed clear clinical activity in a Phase II study of chronic TED, which we previously presented. Our second Phase III study called THRIVE-2, where we are evaluating chronic TED patients, and that is a trial that is ongoing. We are on track for top line results in mid-2024 for THRIVE and year-end 2024 for THRIVE-2. We are -- with the validated IGF-1R target for TED and the robust clinical activity that 001 has already shown, we are very excited for the upcoming pivotal readouts. Now I'll turn to our subcutaneous program, 003. We know from market examples that a later-entrant subcu therapy can convert meaningful portions of an IV market, and we've included 2 of those examples here. Keep in mind that these subcu examples have the same or worse dosing frequency than their IV counterparts, which would not be the case with 003, which is designed to have a superior dosing profile to the currently marketed IV product. In addition, neither of these examples are in new start markets. TED is almost an entirely new start market, which means that every new patient or new flaring chronic patient will have a choice to make as to which product profile works best them. And that is a good market dynamic for us. So there's precedent for subcu offerings to command substantial market share even when launching several years after an incumbent IV, and that can command market share quickly. Further, subcu offerings can also grow the overall market size for their class. We believe 003 has a significant potential to do the same to the IV TED market as a convenient, less frequent, low-volume subcutaneous IGF-1R that patients can take at home. Now let's turn to the data that we shared in December, which led us to selecting 003 for pivotal development and makes us excited for its potential in thyroid eye disease. We studied the pharmacokinetics and the safety of these 3 subcu molecules, 001, 002, 003 in healthy volunteers. Here's the PK and PD comparison across all 3 of those molecules on the slide. 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 huge step forward. Consistent with the expectations set by 001, its parent molecule, 003 increased IGF-1 levels to a greater extent than other IGF-1R antibodies. We are excited to have selected 003 as our lead subcutaneous program and expect to start in a pivotal program in mid-2024, pending our alignment with regulatory authorities. 003 was very well tolerated. There were no serious adverse events, and all treatment-related, treatment-emergent adverse events were grade 1 and mild. No ADAs were identified. On Slide 18, we briefly review the 001 clinical responses in TED that I shared earlier, and layer those on top of the 001 exposures that were associated with clinical responses. On the right, there are 3 key endpoints: proptosis, clinical activity score, or CAS, and diplopia resolution. And as I shared earlier, all 3 doses of 001 showed highly active clinical responses, including at the lowest dose of 3 mg per kg. On the left, we show the 001 serum concentrations achieved by each of these 3 doses. This clinical data in TED patients shows the connection between our highly active clinical response rates and the exposure levels for 001. Because 003 and 001 are nearly identical antibodies, we can uniquely leverage this 001 data in rapidly and confidently advance 003 as a best-in-class, half-life extended, self-administered subcu program that we expect can meaningfully change the landscape for patients. So what potential dosing regimens could we have with 003? On this slide, we have taken the pharmacokinetic data for 003 and model dosing intervals that achieved or surpassed 001 exposure ranges. Dosing 003 as infrequently as every 8 weeks is predicted to consistently achieve and even surpass trough or Cmin levels for 001 IV dosed at 3 mg per kg. That enables an incredible combination of convenience and exposure that is still expected to demonstrate robust clinical response and could also improve upon the safety profile of the currently approved option through lower overall drug exposure. Dosing 003 once monthly is predicted to achieve the consistently -- and consistently surpass trough levels of 001 IV dosed at 10 mg per kg, where we have seen clear clinical response as well. Finally, dosing 003 at a Dupixent-like Q2 weekly would be predicted to surpass trough levels of 001 dosed at even 20 mg per kg. So all 3 potential doses every 8 weeks, every 4 weeks or every 2 weeks give us a lot of optionality as we move toward the final design of our potential pivotal studies for 003, and importantly, gives us the potential to offer patients a best-in-class low-volume, self-administered subcu delivery option. In terms of next steps for 003, this year, we expect to move quickly into a pivotal program in mid-2024 pending alignment with regulators because our extensive experience with 001 effectively guides our dose selection. We expect this program to include 2 pivotal registration-enabling studies, evaluating at least 1 active arm. Our 003 pivotal studies are expected to start at a time that will allow us to leverage our clinical trial infrastructure that we've already built through our 001 program, 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 that pivotal trial. So let's turn to the FcRn franchise, which we recently disclosed. FcRns are a large market. The first FcRn, efgartigimod, is approved for myasthenia gravis and already annualizing over $1 billion in annual sales. Myasthenia gravis is a large market, with projected sales of over $4 billion by 2028. As you can see from the slide, there are additional sizable autoimmune indications that would meaningfully add to this opportunity. Consistent with the Viridian strategy, we are excited to bring forward a portfolio of potentially best-in-class anti-FcRns to address the unmet needs of patients living with myasthenia gravis and other auto -- and autoantibody-mediated autoimmune diseases. Let's take a look at our FcRn portfolio. As I mentioned, we have 2 assets in our franchise, 006 and 008. Beginning with 006, this is the only other known Fc fragment in development other than efgartigimod. Argenx has proven that the Fc fragment is special, achieving substantial efficacy while sparing an effect on albumin or LDL and showing better tolerability than full-length antibodies. We are excited to be the only other known Fc fragment in development, and we have something that we believe is as good as efgartigimod. On the right here, 008 is a first-in-class molecule where we are developing that is targeting FcRn, with the potential for extended half-life. We think if we can demonstrate greater IgG suppression and persistence of that effect with this half-life extended molecule, we could have something really special on our hands. Here's a brief look at our preclinical data for 006 and 008 today, and we'll share more with this later as these programs progress. Here for 006, in vitro and in vivo NHP data shows our Fc fragment acts like efgartigimod in every way. 006 has comparable potency and the key IgG PD effect is the same. And on the next slide, the lack of albumin effect is the same and the lack of LDL effect is the same. Now on to 008. Our protein engineering efforts identified a molecule derived from Fc fragments that both dramatically extend the half-life and persistence and generate meaningfully deeper IgG reductions in animal models. As you can see in this mouse model, we are showing clearly deeper and more durable IgG suppression over efgart. And we will move -- next move this program into NHPs, with the goal of confirming these results that we saw in the mice. We're excited to bring forward this next generation of FcRn programs. We believe that by improving persistence and the depth of suppression, we can improve the efficacy and other -- and offer a more convenient dosing profile compared to the current weekly IV or subcu infusions. To close out, we are making excellent progress on developing our pipeline, and we are executing across the board. In TED, we are on track to report THRIVE results in mid-2024 and THRIVE-2 results at the end of '24. In FcRn, we are on track to file an IND for 006 Fc fragment program, and we look forward to nonhuman primate data for our 008 program in the second half of this year. We are well capitalized through our anticipated key catalysts into 2026. And we thank you again for coming today. And before we move on to questions, I'd like to sincerely thank the patients who are participating in our clinical trials and all of the employees at Viridian who are working really hard to bring these potentially best-in-class medicines to patients. So thank you.

And I think kind of a couple of questions for you, based off of your presentation. So one, you mentioned that you have a few exciting readouts coming out this year and -- including the Phase III data. What are you expecting to see? And how do you think the data will stack up against TEPEZZA?

Great. Thank you. Yes. So we will have more opportunities during the year to get into the specifics and more of the details and guidance on these upcoming TED readouts. But it really boils down to at a high level that we want to see comparable efficacy and safety profile to TEPEZZA with our 5 doses versus their 8 doses. And that's on a placebo-adjusted basis. For efficacy, that means that we want to hit the relevant key endpoints that I discussed in the presentation, which is proptosis, clinical activity score, CAS, and diplopia. As you saw, our confidence is based on the fact that we are hitting the same target as TEPEZZA, IGF-1R, and the data that I showed in the Phase II results, where we looked as good, even better in some cases than TEPEZZA. On the safety side, again, we want to see a comparable profile. So the key is we want to see a comparable profile to TEPEZZA on both efficacy and safety. On the safety side, IGF-1R, as shown by TEPEZZA and in our own studies, is a benign safety profile. The AEs that are commonly associated with it are muscle spasms, hyperglycemia and hearing impairment. But again, these are infrequent and mild, and we would expect the same for our 001 program when that reads out. So we're looking forward to those 2 readouts this year. And again, we hope -- we expect them to be similar profiles to TEPEZZA in both cases.

And then noting that, do you -- can you elaborate a little bit on how you think you'll be differentiated against TEPEZZA? And maybe speak to the competitive landscape a little bit?

Yes. Great. Thank you. I'll ask Shan Wu, who's our Chief Business Officer, to answer that question.

Yes, that's a really great question. I think, first of all, with 001 IV, we believe we have an improved product profile with comparable, safety and efficacy as Steve has just mentioned with what our expectations for the clinical data to be, and we would be able to achieve that, we believe, with 5 doses versus TEPEZZA's 8 doses. And for each infusion, these are every 3-week infusions, we are at 30 minutes per infusion versus TEPEZZA's 60 to 90 minutes in infusion time. And we believe this is a really meaningful difference and differentiation for the patients that are driving to infusion centers to get these therapies every 3 weeks. Now let's talk about 003 as well, our subcutaneous program, which we have designed to be a long-acting subcutaneous and a low-volume, infrequent injection. We think that this could be a game changer for patients to be able to administer their anti-IGF-1R at home and potentially as infrequent as every 8 weeks and achieve same efficacy profile and perhaps, at lower exposures, be able to improve even further on the benign safety profile that -- excuse me, that anti-IGF-1Rs have. As for the competitive landscape, we really believe that IGF-1R is the mechanism that is the driving mechanism behind the pathology of thyroid eye disease. TEPEZZA has shown very, very robust remarkable efficacy and treatment effect with their pivotal studies and real-world experience since their launch back in 2020. And of course, we showed in our Phase II studies very nice efficacy as well. So IGF-1R really is getting to the heart of thyroid eye disease. We're encouraged by the other mechanisms that are being pursued. We think it's great to look at different mechanisms for any disease, not just thyroid eye disease. But the question would be whether these broader mechanisms, such as IL-6, FcRn, can achieve the same effect size as the anti-IGF-1R. And finally, another IGF-1R antibody that is in pipeline development is through Acceleron, and they are anticipating clinical data in first half of this year -- or excuse me, first quarter of this year. And we are looking forward to that data. It will be their first data in thyroid eye disease patients. We'll be looking at that just as everyone else. We still believe we have a great profile with 001 IV as well as, in particular, 003 subcutaneous because of the half-life extension, which we show to be 40 to 50 days to enable infrequent dosing at home, low-volume injections and preserve the efficacy potentially of IGF-1Rs.

And as you just touched on 003, it seems like a very exciting program. And congrats on your recent positive data there. What gives you the confidence to move straight into pivotal studies for that program?

Yes. Great. Thanks. So first and foremost is the fact that these are nearly identical antibodies as I mentioned in the presentation. The only difference between 001 and 003 is the YTE mutation in the Fc region of 003 for extended half-life. So that allows us to leverage the 001 data where we saw -- as I mentioned, as where we saw that range of clinical -- of exposures that correlated to clinical response. So that's a really good spot for us to be in from an efficacy standpoint because we can -- if we can have our subcu match those exposure levels, that gives us a great deal of confidence, given the similarities between the antibodies. On the safety side, we saw the health of our tier study, the safety profile looked great. And even on the -- as mentioned, the IGF-1R profile for safety is already benign. And again, we'd be looking to match that with our subcu program. And just as a reminder, our subcu program, as we showed in the -- with the exposure ranges, we can -- we will be exploring those ranges that are already within the range that the IV program is showing in THRIVE. So we're already -- we dose at 10 mg per kg in the THRIVE studies, and we're exploring -- we are going to potentially explore the range between 3 and 10 on the subcu. And that trial design will be finalized. We'll give more details on what that trial design looks like before we start that study. But really, it boils down to the -- essentially the same antibody. We know what the -- what our doses look like, and we feel good about where they fall into the safety range.