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

Welcome to the Viridian Therapeutics Conference Call. It is now my pleasure to introduce your host, Louisa Stone, Manager of Investor Relations at Viridian Therapeutics. Please go ahead.

Thank you, operator. Good afternoon, everyone, and welcome to the Viridian Therapeutics conference call to discuss the positive data from our Phase II trial cohorts of VRDN-001 in patients with chronic test, an amendment for ongoing THRIVE Phase III trial and the latest progress in our subcutaneous program for the treatment of TED. A press release highlighting these updates and the presentation for today's call, are available on the Investors page of the corporate website at www.viridiantherapeutics.com. Before we begin, I would like to remind everyone that this conference call and webcast will contain forward-looking statements regarding our regulatory 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 recent Form 10-Q and 10-K filed with the SEC. Presenting on the call today are Scott Myers, our President and Chief Executive Officer; Dr. Barrett Katz, our Chief Medical Officer; Dr. Thomas Ciulla, our Chief Development Officer; and Dr. Kimberly Cockerham, an oculoplastic surgeon specialized in [ NPD ] as well as neuro ophthalmology, orbital oncology and oculofacial restoration at the SENTA Clinic in San Diego, California. And on [ adjunct ] of the Stanford University School of Medicine. Dr. Cockerham is also an investigator in the VRDN-001 trial. Additional members of the Viridian Therapeutics during question-and-answer session at the end of today's presentation include Kristian Humer, our Chief Financial and Business Officer; and Todd James, Senior Vice President of Corporate Affairs and Investor relations. I would now turn the call over to Scott Myers, President and CEO of Viridian.

Thank you, Louisa, and good afternoon, everyone. We are excited to share the positive data from the two dose cohorts of VRDN-001 evaluated in our Phase 1/2 trial for the treatment of patients with chronic thyroid eye disease or chronic TED. These important data established proof of concept for Viridian and Chronic TED and build upon the compelling data we previously reported in active TED during 2022 and earlier this year. In Chronic TED, we are observing profound and consistent signs of clinical activity on endpoints measured after only two infusions of VRDN-001, three weeks apart and assessed at week 6 in both the 10-milligram per kilogram and 3-milligram per kilogram dose cohorts. Both doses were generally well tolerated with no serious adverse events reported. Following consistent feedback from key stakeholders in the TED community, including key opinion leaders, our principal investigators, treating physicians and patients as well as with the discussions we had with the FDA, we are amending our ongoing THRIVE Phase III trial to include only the shorter 5-dose, 12-week treatment regimen, along with a placebo arm and we are removing the 8 infusion arm from this Phase III study. Primary and secondary endpoints will be assessed three weeks after the last dose at week 15. Our excitement of VRDN-001's differentiated mechanism as a full antagonist coupled with its ability to generate clinically meaningful results as early as week 6, gives us high confidence in attaining clinical success for this shortened treatment regimen. We believe it will potentially offer an attractive commercial profile that differentiates VRDN-001 in the market, both for patients and caregivers for an intravenous therapy for the treatment of TED. Following today's positive data in patients with chronic TED, our team is putting the finishing touches on the design of our second pivotal Phase III trial, THRIVE-2 for chronic TED, which we plan to initiate this quarter and expect top line results by the end of 2024. The low dose data support the continued development of a convenient low-volume dosing profile for our subcutaneous injection candidates for the treatment of TED. Our team has made important progress in this endeavor, and we remain on track to select our lead subcu candidate in TED by year-end. We have completed important formulation work for all three subcu candidates. We have filed the IND amendment for subcutaneous VRDN-001 as well as the initial IND for VRDN-003 with the FDA, and plan to initiate Phase I trials for both candidates this quarter. Based on our progress, to date, the team continues to build on building a blockbuster franchise for the treatment of TED through the development of differentiated IGF-1R full antagonist IV and subcu therapies. We believe our growing value of clinical data put us in a strong position to build and expand the market for active and chronic TED therapies. Today, the TED market for IGF-1R antibodies has been limited to the U.S. We believe patients in regions outside of the U.S. can benefit from the access to these therapies. While we may choose to operate independently in certain ex U.S. markets, in those regions in which we may not be able to maximize commercial opportunities, we will explore partnering with companies with the necessary infrastructure and experience to support our strategy. We believe a subcu product in TED has the potential not only to deliver valuable convenience to patients but also offers the opportunity to expand the prescriber base inside of drug administration beyond the current concentration of subspecialist treaters to more ophthalmologists and endocrinologists. Having both IV and subcu products will allow us to work with caregivers and experts, intend to establish new treatment paradigms with the potential to provide a longer-term benefit and value to patients with this vision-threatening disease. To execute our long-term vision in TED, we have focused on attracting and retaining experienced leaders to strengthen existing functions and to establish new areas necessary to drive our transition to a late-stage clinical development organization. We have established a corporate affairs team that includes patient advocacy and engagement under our Senior Vice President, Todd James. We have grown our clinical development and clinical operations organizations to execute on multiple global Phase III trials as well as the ongoing and planned development of our subcu candidates. This work is occurring under the seasoned leadership of Dr. Barrett Katz, our Chief Medical Officer; and Dr. Thomas Ciulla, our Chief Development Officer. We have established a medical affairs function led by Dr. Felix Geissler, which includes our first MSL and scientific communications team, both of which are focused on educating researchers and medical professionals throughout the TED community and raising awareness of Viridian's programs in TED. With our ongoing progress in subcu administration, our Chief Product and Strategy Officer, Dr. Deepa Rajagopalan, has hired a small team of experienced professionals focused on our subcu device product development efforts. And finally, in April, we hired Tony Casciano, Viridian's first Chief Commercial Officer. Tony and his new team are focused on pre-commercial activities, including research, on marketplace dynamics, market access and pricing. We will continue to grow as needed with a clear goal of balancing appropriate expansion with prudent allocation of our investors' capital. Now moving to the more detailed section of today's call, I will hand the presentation to our three presenters today, beginning with our esteemed guest presenter, Dr. Kimberly Cockerham, an internationally recognized thought leader in TED and an investigator of VRDN-001 trials, and then moving to Dr. Barrett Katz, our Chief Medical Officer; and Dr. Thomas Ciulla, our Chief Development Officer. I will now turn the call over to Dr. Cockerham to discuss your background and provide an overview of TED.

Thank you so much, Scott, and good afternoon to everyone. Truly a pleasure to be joining on the call today to discuss the really exciting advances in Thyroid Eye Disease therapeutics. Thyroid eye disease, also known as TED, has been my clinical interest and research passion for over two decades. So as you can imagine, I'm thrilled that the enthusiasm for the space and the ability to offer my patients transformative intervention. So a little bit about my background. I am a board-certified ophthalmologist with subspecialty training in neuro-ophthalmology, orbital disease, plastic reconstruction in adults strabismus. In translation, that means I'm a subspecialist who takes care of all medical and surgical aspects of Thyroid Eye Disease. I have seen approximately 300 TED patients a year for quite some time. First on active duty Army at Walter Reed Army Medical Center. Then within the VA system at UCSF and then with adjunct faculty at Stanford for many years. I'm now in private practice in San Diego at the SENTA Clinic. So let's talk about the TED overview. This slide illustrates the underlying drivers of TED biology and how they impact the eye and the area behind the eye called the orbit. IGF-1 is over-expressed on orbital fiberglass in thyroid eye disease, and it's co-located and co acting with the TSH receptor. The signaling stimulates muscle and fat and this results in expansion in addition to the inflammation. Next slide, sorry -- keep going on this slide. Sorry about that. Historically, Thyroid Eye Disease has been described as a biphasic disease with an initial active phase that's characterized by inflammation. This results in pain, redness, swelling, eyelid retraction, proptosis, double vision and blurred vision. Inflammation may resolve over months to years, for some it will not improve without a therapeutic intervention. Once the inflammation recedes, the chronic phase of thyroid eye disease is characterized by a white eye, but with all the persistent symptoms and signs I just described, that altered significantly and interfere with the patient's quality of life. In both the active and chronic phases of the disease, proptosis, eye lid retraction and eye deviations combined to create facial disfigurement. In severe cases, sneezing or coughing can result in the eye getting stuck in front of the eyelid, resulting in severe pain and anxiety. Optic nerve compression can occur at any phase of the disease and can cause complete blindness. Thyroid eye disease affects all ages and ethnicities, but it affects women more than men at a ratio of approximately 5:1. The typical thyroid eye disease patient is a woman who are in 30s, 40s, 50s and the facial deeply affects her psychosocial health, interfering with social interactions, relationships at home and affecting her ability to drive, read, work on the computer and be productive. Next slide, please. I touched on this in a previous slide. But here you can see the different categories of the visual impairment. So almost all patients have dry eyes as seen in slide -- of the slide left. And many patients go on to develop double vision, especially when they first wake up in the morning, there's like a blur image when they go to read their paper. In addition to diplopia and double vision, you can have photophobia or light sensitivity due to corneal breakdown and [ interior ] film alterations. They can get actually decreased vision in straight ahead and/or visual fields in the periphery -- visual field defects. They can have reduced color. And then worst of all, an optic neuropathy can develop that is permanent and irreversible. Next slide, please. As I was previously describing, TED has had this historical view as a biphasic disease. However, we now understand that the transition varies from patient to patient. Some patients never have an inflammatory phase. Others have very prolonged inflammatory phase that can last for decades. Patients who have been chronic for several years can even relapse or become inflamed again. Of therapeutic importance, the chronic patients, their quality of life remains impacted for years and even decades. Despite the improvement in the inflammation, they continue to have significant symptoms and signs. Prior to 2020, chronic thyroid eye disease patients endure decades long persistence of bulging, double vision, pain and dry eye symptoms that disrupt the tasks of daily living. Next slide. So what are the current treatments for thyroid eye disease? So the current treatments vary depending on the patient. So in some patients, and these are mainly patients that see general ophthalmologists or optometrists. Patients have very mild, minimally symptomatic thyroid eye disease. And there's some supplementation with Vitamin D and selinium-recommended, artificial tears without preservatives, and they may be recommended a SleepMask, and a little ointment if their eyelids don't close completely while sleeping. In contrast, the patients that are referred to me are -- tend to be moderate to severe, where their -- sorry, the thyroid eye disease is interfering with their social interactions and tasks of daily living. In those cases, I discussed the following therapeutic options with my patients. So the first 3: intravenous steroids, orbital radiation and off-label immunosuppressive are items that we utilize in patients with active thyroid eye disease. Corticosteroids are widely used to combat inflammation, topical are not helpful, oral have a lot of side effects, and IV works to relieve the redness and fluid accumulation. They're only helpful in active thyroid eye disease, whether it's active inflammation. There is no clinically significant improvement in muscle size, fat volume, proptosis or double vision. External beam radiation is controversial and typically used in conjunction with corticosteroids. Radiation is only helpful again in the active thyroid eye disease patients. Radiation like steroids does not restore the structure and function of the extraocular muscles. So it can't improve proptosis or double vision. Now let's jump down to the bottom. Surgical management is reserved for chronic thyroid eye disease patients unless there's optic nerve compromise or corneal breakdown, which prompts urgent surgery. The surgical options are to remove bone to make more space for the enlarged muscles and fat, this bone removal is called orbital decompression. Unfortunately, this procedure can cause worsening of the double vision as the muscles fall into the hole that was created and that creates a permanent and tractable double vision, not responsible -- nonresponsive to surgery. The strabismus surgery can improve double vision when looking straight ahead, but it doesn't restore structure or function. And finally, eyelid Surgery can improve eyelid position and the ability to close. Going back to the off-label immunosuppressive agents, I really have not ever found these to be of any help. And they're also extremely difficult to get authorized due to the fact they are not FDA-approved. Since the winter of 2020, intravenous IGF-1 has been my friend. So this inhibitor just came on the market and has done amazing things for these patients. So the FDA approved this -- proposals to all patients with thyroid eye disease. And unlike any of the therapies I've just discussed, this works independent of activity or duration of disease. Let me say that again. We currently have no other options on the market that work independent of the activity or duration of disease. It works in all forms of the thyroid eye disease, whether it be active chronic or relapsed, all thyroid eye disease. So very impressive. So as far as the other differences, unlike therapeutic options where that just treat the inflammation, Tepezza enables tissue remodeling that restores the extraocular muscles and fat back to the normal free state. So it doesn't overcorrect. So if you have a little bit of proptosis, it will improve you a little bit and won't make you sink too far in. I'm not just clearing up the redness or breaking bones, I'm helping patients address the cause of their symptoms and signs. But this intervention does not come without a cost. The treatment regimen is burdensome in and of itself. And the adverse events are well known from hearing impairment, hyperglycemia and more. Next slide, please. The level of unmet need for thyroid eye disease patients remains very, very high. My colleagues in neuro-ophthalmology oculoplastics, endocrinology, I've been thrilled with the increased focus on the development of thyroid eye disease therapies over the past several years. As this is a rare disease or a relatively rare disease, and it's been ignored for decades. At this point, I've been involved in the care of over 200 patients treated with the only FDA-approved therapeutics, yet there is a substantial need to ease the treatment burden. In addition, the side effect profile, especially in at-risk populations such as elderly, those with preexisting hearing conditions, pre-existing inflammatory bowel disease, or poorly controlled prediabetes or diabetes have led some patients and their clinicians to choose to avoid this impactful therapeutic option. So what would be ideal? Well, ideally, there would be a more convenient dosing regimen that will minimize the dose of the drug delivered, shorten the infusion duration and decrease the frequency of delivery. This would potentially minimize the side effects, save on cost and allow more patients to get authorized for this medication. Secondarily, it would be very nice to have a similar efficacious subcutaneous treatment option, which would dramatically reduce treatment burden for patients by allowing them to administer the treatment themselves in their home at approved dosing intervals. And finally, we really need to develop new treatment regimens that deliver longer benefit for patients. Thyroid eye disease is a chronic disease so treatments or protocols with the potential to safely extend clinically meaningful improvements for duration of their lives would represent another important advance. And with that, I will turn back over to the presentation to Barrett to provide some background on VRDN-001 and the trial work done to date before I review today's data in the chronic thyroid eye disease studies. Barrett, you're up.

Thank you, Kim, for sharing your perspectives and background on TED. Good afternoon, everyone. I, too, am delighted to share in today's data announcement and for what it could mean for our patients and my colleagues in the field. I'm going to begin by providing some background on VRDN-001 and our proof-of-concept work before turning things back over to Kim to prevent and present the top line data from our chronic TED cohorts. VRDN-001 is a humanized antibody that targets the insulin-like growth factor 1 receptor, IGF-1R. It is differentiated by its binding and engagement with IGF-1R as a full antagonist. Preclinical studies have shown that VRDN-001 binds to a distinct epitope of the IGF-1R and binds longer than teprotumumab. VRDN-001 affects near complete inhibition of IGF-1 ligand binding to IGF-1R and blocks IGF-1R, both proximal and distally. We believe the impact of this binding activity is being seen in the clinic. VRDN-001 achieves a rapid onset of action in the first six weeks of treatment, driving significant clinical changes by a full target engagement in both low and high doses that we tested. This has the potential to provide important differentiation in the treatment of TED with a short course of therapy, 5 infusions over 12 weeks compared with a 21-week 8 infusion regimen. We are also able to administer at a lower dose and 10 milligrams per kilogram, which when combined with our shorter course of therapy, could result in an optimized safety profile. With VRDN-001 30-minute infusion time, there is also the potential to shorten the patient's time and costs at the infusion center. With today's announcement, we've now established proof-of-concept in patients with both active and chronic TED. The key difference between our two trials inclusion criteria was the clinical activity score or CAS. In the active TED trial, participants had a CAS of 4 or higher. While in our chronic trial, any CAS, including 0 was acceptable for participation. Additionally, active TED was defined as having onset of signs and symptoms within the past 12 months, whereas chronic TED was characterized as having more than 12 months of signs and symptoms. Following the active TED data, that was announced throughout 2022 and earlier this year, we've had the privilege to present our data to researchers and clinicians throughout the TED community and multiple medical congresses, including NANOS, the American Academy of Neurology and ARVO and at major meetings both here and across the world. Our data has been well received and most recently, our VRDN-001 presentation in active TED was selected as the winner in the end of 2023 Annual Meeting in the presidential competition as best poster. Turning to our proof-of-concept trial design in chronic head. The trial was quadruple [ masked ] and included two dose cohorts. 10 milligrams per kilogram and 3 milligrams per kilogram, each randomized 3:1 in favor of VRDN-001 versus placebo with the aforementioned inclusion criteria. Target enrollment with 8 patients in each cohort, the 3-milligram cohort was over-enrolled allowing all patients who had consented and were eligible to be randomized following screening to participate in the trial. In the 3-milligram per kilogram dose cohort, 7 patients were randomized to receive VRDN-001, and 3 patients were randomized to receive placebo. One patient randomized to receive VRDN-001, 3-milligram per kilogram, discontinued the trial due to needing to leave the country for a family emergency, prior to receiving their second dose of VRDN-001, leaving 6 patients treated with VRDN-001 3-milligram per kilogram evaluation at the week 6 clinical endpoint analyses. The pharmacokinetics we found were consistent for both doses throughout the study. As in our findings in the active edge cohort, we saw multi-focal sustained increases in IGF-1 levels in the chronic patients, suggesting full target engagement for both 10 and 3-milligram per kilogram cohort. I will now turn the presentation back over to Dr. Cockerham to present the patient's baseline characteristics and the top line data from the trial. Kim?

Thank you, Barrett. Before I jump into the data, I would like to review a few of the measures to help everyone better understand process of evaluating a thyroid eye disease patient in the clinic and for the clinical trials. For proptosis or eye bulging, the Hertel Exophthalmometer is the gold standard. It's an [ office-based ] measuring device to quantitate proptosis, specifically how far the eyeball itself protrudes in front of the bones that form the box that holds the eye, known as the Anterorbit. And it's measured by placing the Hertel on the orbital [ rooms ] , as you can see demonstrated here. In contrast, the MRI determination of proptosis is an exploratory tool in thyroid eye disease clinical trials, but not yet a validated measure. The MRI's objective and more precise than Hertel and provides us with a second proptosis data point to confirm or reject the proptosis change measured by the exophthalmometer. Hertel is known for variability. MRI in contrast, the MRI data allows us to measure and analyze activity within the orbital cavity identifying potential treatment-related changes to orbital muscle and adipose tissue volumes. The evaluation of the symptoms of thyroid eye disease is performed by using the CAS score. So next -- another way to reevaluate signs and symptoms. It is the CAS, this composite scoring ranges from 0 to 7, quantifying redness, swelling and pain based on the presence or absence of these 7 signs and symptoms that are characteristic of thyroid eye disease. We add one point to the patient's CAS score for the presence of each of the following signs and symptoms. And you can see the signs are listed as swelling of the eyelids, redness of the eyelids, conjunctival injection and chemosis, which is the galantis covering of the eyeball itself, inflammation of the caruncle or plica. That's a medial tissue closest to the nose. And then the symptoms, pain or pressure sensation in the area around the eye or behind the eye and then pain with upward, downward or lateral a movement. It's important to note that the severity of CAS is not a predictor of overall severity of thyroid eye disease in any individual patient. For example, some patients with a score of 0 can have devastating visual loss, constant disabling diplopia or even severe proptosis with corneal exposure. In contrast, a patient with a higher CAS could have normal vision, no double vision, and minimal proptosis that doesn't impact the quality of life. We strive to reduce the CAS for patients as lower CAS is clinically meaningful, but is not the best way to classify patients from a disease severity perspective when compared to proptosis. In truth, the CAS is not widely used by clinicians not involved in clinical research. The impact of thyroid is on social interactions, work performance and CAS of daily living such as driving and computer use are much more clinically relevant and meaningful. That said, the CAS data is very strong and compelling for VRDN-001. Next slide. So what were the baseline patient characteristics? in this slide we'll go through each of these. I want to highlight a few points. So beginning with the mean baseline proptosis. In the VRDN-001 treated group, the mean baseline proptosis was, in fact, much lower than placebo in this trial and also lower than the level of proptosis seen in patients enrolled in the Phase IV teprotumumab trial. It's important to remember that the baseline proptosis correlates to some extent with the patient's potential proptosis response to the drug based on previous studies in this space. So as I discussed earlier with the Hertel, so a patient with more proptosis can have more room to improve to get back to their baseline compared to a patient that has not so much proptosis at baseline. You wouldn't want them to have a big change because that would be an overcorrection. So to see such dramatic results in this 10-milligram per kilogram cohort is especially compelling. So basically, it's a tougher population to show improvement in the teprotumumab trial. So stated another way, VRDN-001 causes a restoration of muscles and fat volume towards baseline. When you reduce the size of the muscles, reduce the volume and the fat you get improvement in proptosis but less severe proptosis will return towards baseline with less change in the measured proptosis. With respect to the half, remembering that the inclusion criteria did not have specific requirements, the mean task scores range from 2.5 to 4.0 points compared to the teprotumumab Phase IV clinical trial, where the inclusion criteria specifically was just two cast scores, either a 0 or a one, the duration of disease among our chronic patients was approximately 94 months, very model. That's 7.8 years, which is significantly longer than the 5.4 years of disease among the patients enrolled in the Phase IV teprotumumab trial. As a tenet of clinical medicine, the earlier history of a disease therapy has initiated the better the clinical outcomes. Our population had their disease for a much longer duration than that in a teprotumumab chronic study. Again, a type of population to see changes in. Enrollment considered primarily of female patients with approximate age of 50, which is typical for the thyroid eye disease clinical trials, and we've seen in the teprotumumab chronic trial 2. Next slide. So on this slide, we have a summary of the clinical activity measures evaluated at week 6. On the summary table you can see the data separated by each dose cohort. So we can see 10-milligram per kilogram and the 3-milligram per kilogram with the combined dose data for each of those clinical activity endpoints listed above. So if you look at this for proptosis, 42% overall response, but for 10 milligrams per kilogram, it was 50%. The mean change in proptosis was a 1.6 millimeter. If you pull the data for the 10-milligram per kilogram group is 1.8 millimeters. For the mean change by MRI, it was minus 2 millimeters and the 10-milligram per kilogram was 1.5. Those achieving a cap of 0 or 1 was 40% overall, but 50% in the patients receiving the 10-milligram per kilogram. The CAS, the mean change was minus 2.3%, but in the 10-milligram per kilogram was minus 2.8%. In all groups, no patient had complete resolution of their diplopia after at the 6-week mark after two infusions. Next slide. On this slide, we are taking a closer look at the proptosis response from baseline to week 6. If you look at the chart on the left, we have a waterfall plot of individual proptosis change within dose cohorts. The response at week 6 ranged from 0 millimeters change up to 4 millimeters reduction for the 10-milligram per kilogram treated patients, with a mean change of 1.6 millimeters across both cohorts. With only two infusions, a majority of the VRDN-001 patients achieved a reduction in proptosis at week 6. Teprotumumab data at that same point at week 6 was 1.2 millimeters. So a nice reduction in proptosis that exceeded the proptosis reduction noted by teprotumumab at the same time point. The middle chart shows the individual proptosis change by MRI. And to the right is the mean proptosis change. Valuable, readable MRIs are available both at baseline and week 6 for all 5 placebo patients and for 8 of the 12 VRDN-001 treated patients. Or 4 of 6 from each dose cohort. two patients from the 3-milligram per kilo cohort did not undergo a week 6 MRI and two patients from the 10-milligram per kilogram cohort have week 6 MRIs that were not interpretable due to poor image quality, most typically the patients moving during the MRI. When looking at the individual proptosis changed by MRI, two placebo and one VRDN-001 treated patients who were responders by exopthalmometer were not confirmed by MRI analysis. As you can see from the MRI data, VRDN-001 treated patients achieved a mean proptosis reduction of minus 2.0 millimeters compared to a reduction of 0.2 millimeter in the placebo-treated group. So whether you're looking at the hotels or the MRI, there was a significant reduction. As found in previous active TED cohorts, the ability to confirm or refute the exopthalmometer data with more precise MRI measures of proptosis is very valuable, given the small sample size and the proof-of-concept studies. Next slide. So let's look at the CAS details. Turning now to the chart on the left shows the individual CAS changes for all VRDN-001 treated patients. The top axis shows the baseline cap. The y-axis shows change from baseline and the x-axis and bar color identifies the dose cohort for each patient. As you can see, individual CAS changed changes ranged from 0 to 4-point reduction, which is achieved by three patients. The four patients with a change of 0 were, either 0 at baseline or 1, which provided little or no room for improvement with treatment. The chart on the right shows the mean change for CAS for patients with a baseline of greater than 0. So those ones you can see on the plot on the left that had 0 are not included on the plot on the right. Placebo came in at minus 1.2%, whereas the VRDN-001 had a change of minus 2.3 points of the CAS. Next slide. This next slide is my favorite slide. This slide shows a summary of the reported adverse events in that were occurring in more than 10% in the chronic TED cohorts. You can see that five of the safety events listed were in the placebo cohort and two were in the VRDN-001 treated patients. Mild back pain was reported by two patients, while two patients reported muscle spasms. The muscle spasms are not surprising with IGF-1 receptor antagonism as there are known class effect of this antibody. Leg cramps seeing to resolve spontaneously without treatment, and there were no discontinuations due to safety. Importantly, no serious adverse effects. Notably, very much notably, especially to clinicians who have treated patients with teprotumumab. Among the patients treated with VRDN-001 no hyperglycemia or hearing -- hearing impairment events were reported. let me say that again. In the treated patients, no hypoglycemia or hearing impairment events were reported. As many of you know, both of these adverse events have been recorded in other clinical studies in investigative therapies for thyroid eye disease and also seen with teprotumumab. Okay. Let's go to our final slide. So to summarize the data and to provide my perspective, VRDN-001 resulted in clinical efficacy and demonstrated excellent safety when compared and when utilized in chronic thyroid eye disease subjects with superior outcomes when compared to the Horizon Phase IV clinical trial. When looking at these two cohorts with their 6-week outcomes after two infusions. VRDN-001 reduced proptosis as measured both by Hertel and MRI measurements and improved CAS. The safety profile was excellent, with mild back pain and leg spasms noted and no hearing impairment or hyperglycemia adverse events and no infusion reactions. These results confirm that VRDN-001 should be effective in all thyroid eye disease, independent of severity or duration of disease. And the safety profile of lowering dosing and fewer infusions is promising for at-risk populations. I will now turn the call over to Dr. Thomas Ciulla, Viridian's Chief Development Officer to continue the presentation. Tom?

Thank you, Kim. We are really excited about this new data in chronic TED for VRDN-001, so we really appreciate you joining us today to present these results and share your insights. Now let me provide an update on our Phase III trials and our recent progress and upcoming priorities for our subcutaneous candidates in development. As Scott mentioned earlier, we are amending the ongoing drive Phase III trial evaluating the safety and efficacy of VRDN-001. This slide shows the updated trial schema following the amendment. Previously, Thrive included three arms: VRDN-001, 8 infusion regimen, VRDN-001, 5 infusion regimen in placebo. Patients were randomized 1:1:1 between the arms and the primary and secondary endpoint evaluation was at week 24. As you can see on the slide, the updated trial design has removed the 8 infusion regimen arm and now only has the VRDN-001 5 infusion arm and the placebo arm. Patients will be randomized 2:1 in favor of the VRDN-001 arm. The primary endpoint evaluation will occur 3 weeks following the last infusion at week 15. We continue to expect top line results in the middle of 2024. The THRIVE Phase III trial amendment reflects our growing confidence in the clinical success of the 5 infusion treatment course of VRDN-001, our assessment of its potency and key stakeholder feedback from the TED community. Based on the rapid onset of clinical activity prior to 6 weeks and the limited benefit that standard of care provides from the 18 to 24 weeks, we believe that our 5 infusion treatment regimen at a dose of 10 milligrams per kilogram has the potential to improve benefit risk for patients. This 5 infusion regimen has potential to provide clinically meaningful improvements by week 12 and minimize any potential safety risks to which longer durations of therapy subject patients. Our team has spent a lot of time interacting with KOLs, principal investigators and treating physicians. They have provided clear feedback that they view the 5 infusion treatment regimen as a significant improvement, and it also reflects where they believe intravenous treatment standard is already evolving to. Finally, for patients, a 5 infusion treatment standard could increase convenience and decrease cost by eliminating three trips to the infusion center. Following the chronic TED data today, our team is very close to finalizing the THRIVE-2 Phase III trial design. Similar to THRIVE, it is a global quadruple masked placebo-controlled Phase III trial. THRIVE-2 is evaluating the safety and efficacy of VRDN-001 in patients with chronic TED as defined by proptosis of 3 millimeters or more for race and gender 15 or more months since onset of signs and symptoms in any CAS. There will be two arms, VRDN-001, 10 milligrams per kilogram and placebo every three weeks. Additional details, including target enrollment and randomization will be provided closer to the start of the trial this quarter. We expect top line results by the end of 2024. Moving now to our subcutaneous candidates. As a reminder, we have three subcutaneous candidates currently under development. We have VRDN-001, VRDN-003 and 002. All three candidates are humanized monoclonal antibodies that target the IGF-1 receptor. VRDN-001 and VRDN-003 share the same binding domain and act as full antagonist of the target, while VRDN-002 acts as a partial antagonist to the IGF-1 receptor. VRDN-003 and VRDN-002 share the same half-life extension technology, which provides the opportunity for more convenient dosing intervals every 2 to 4 weeks relative to VRDN-001, which will be weekly or every other week. Now let's review our latest progress and upcoming priorities for our subcutaneous candidates. Earlier this year, we completed the formulation work for all 3 subcutaneous programs, allowing for a concentration of 150 milligrams per milliliter for administration of a 300-milligram per 2-millimeter dose in subcutaneous clinical trials. In June, we filed with the FDA the initial IND for VRDN-003 and an IND amendment for subcutaneous VRDN-001. Following the submission, we plan to initiate Phase I trials of subcutaneous VRDN-003 and VRDN-001 in healthy volunteers in the third quarter of 2023 with initial data expected in the fourth quarter of 2023. We completed enrollment of a Phase I healthy volunteer trial of VRDN-002 in single intravenous and single subcutaneous dose cohorts. Upcoming priorities also include initiation of a 10-device supply agreement with an experienced drug delivery device manufacturer in the second half of 2023. Viridian expects to select its lead subcutaneous program by year-end 2023 and to advance the program into a pivotal Phase II/III trial in the middle of 2024. I'll now turn the presentation over to Scott to close our presentation today, and then we look forward to taking your questions. Scott?

Thank you, Tom. And as you can see from the presentation this afternoon, you can understand why we are so thrilled by our data in chronic TED, which establish proof-of-concept and provide additional momentum for us as we drive our late-stage development towards potential approval. Our vision and goals are clear. We plan to launch with the best-in-class IGF-1R antagonist, followed by a convenient, self-administered that will have the potential to be the first and best-in-class subcu pen device in TED. Our IV and subcu programs are the foundation of our plan to create a blockbuster franchise in TED. Our long-term vision remains building a fully integrated biopharmaceutical company based on our success in TED. In addition to our work in TED, we have multiple preclinical programs and look to replicate our drug development and launch success in TED in autoimmune and rare disease areas. We expect to unveil at least one of these preclinical programs later this year. With that, I'll now turn it over to the operator for questions. Operator?

The floor is now open for your questions. [Operator Instructions] Our first question comes from the line of Gavin Clark-Gartner from Evercore ISI.

So I had 3. Actually, all on the subcu program. First, the INDs were just filed in June, and it seems like they're not cleared yet. So I'm just wondering what the gating factor for filing those was?

This is Scott. Derek or Tom, would you like to handle that question?

Sure. So we've completed work on our PK and PD for our IV program. And we currently have a lot of programs that are in process, and we're just going through the normal course of action of filing the IND for one and the amendment for the other. So there's no particular issue with any of this. It's all proceeding as planned.

Got it. For the -- yes, go ahead, sir.

This is Todd. They're just on the normal 30-day clock that we're waiting for clearance with the FDA. So more to come on that.

Yes, that makes sense. And for the initiation of the pen device supply in the second half of this year, is that for the clinical use or the commercial use or both? Maybe just like any formal update on our formulations would be helpful.

Yes. So we finished the -- Gavin, we finished the formulation works at 150-milligram per milliliter, so we could show that we also had for the 302 ml pen. This would be certainly for the commercial put-up, and then we'll be considering whether we can use that pen device early on or we would use some sort of vial syringe in the early stage and then do a crossover to the final form factor.

Okay. Got it. And for the subcu healthy volunteer data in the fourth quarter. How many healthy volunteers will that be? And will that also include serum IGF-1?

I don't believe we disclose how many healthy volunteers, but I do believe the PK/PD data will be included.

Okay. Got it. Actually, sorry, my last one. I'm just wondering how you're thinking about endpoint for the subcu program in the pivotal trial. I mean you moved the IV dosing from 8 to 5 doses only now, and you've kind of alluded to longer maintenance style dosing for the subcu before. So I'm just wondering what the latest thoughts on that are.

Tom, would you like to take that question?

Well, I think as you can see from our results today and from our active MAD study that we released throughout last year, that we hit on a whole variety of endpoints, including proptosis responder rate, mean change by exophthalmometry, mean change by MRI, CAS improvement. Safety was excellent. So I think we have a lot of latitude. And obviously, we haven't bought in great detail about the endpoints for trial design in subcu. So more to follow. But I think we've seen the potential efficacy with these -- with our assets, and I think we have a lot of potential to show efficacy with these endpoints.

Just to add to what Tom suggested. We don't anticipate any new endpoints to be included in these studies. We take our direction from the tradition at the agency and the success of what's been shown beforehand. The question is in terms of timing, but that will be worked out as we learn more about our compound and assets.

Our next question comes from the line of Michael Yee from Jefferies.

First question was around thinking about the placebo response. I know that you cite the MRI data, which looks fantastic and clearly a huge separation from drug. Can you just comment on thoughts around the placebo response when you're seeing exophthalmometry. I want to pronounce that right. And the 2 folks that were excluded, how to think about that? And then my follow-up was for Dr. Cockerham if she's still on there. How to think about trying to compare and contrast the chronic population and efficacy with Tepezza versus here given the different cash definitions and how you would compare the 2, given the 2 different patient populations.

Thank you, Michael, for the question. Tom, and maybe you will follow up with Barrett to speak about the placebo, and then we'll have Kim address the different test course.

Sure. With Hertel exophthalmometry, there's some inherent variability to this approach in measuring proptosis. And importantly, in this trial was a very small sample size that actually amplifies the variability. So although Hertel exophthalmometry is a standard device to measure proptosis by clinicians and it's used as a primary endpoint in approval for Tepezza, for example, it's subject to inherent durability amplified by our small sample size. And this is why we use the MRI to confirm because it's a much more precised measurement. Our Phase III trials will be strengthened by the larger patient numbers in both the active arms and the placebo arms. And we expect that variability too should be diminished by this larger sample size. So again, we view MRI as a -- although we view it as an exploratory end point, it's a much more precise measure and allows us to really assess proof of concept.

Makes sense. I think small numbers, but also just looking at the totality of the drug arm versus placebo arm, you clearly see pretty much responds in the drug arm. So I think that makes sense. And then maybe comparing and contrasting the efficacy given slightly different patient population definitions and for example, if you had just low CAS scores, what would you have seen with those patients more comparable to Tepezza's study versus yours similar all-comer, and we clearly see efficacy, but how does the doctor think about those 2 populations?

So the thyroid eye disease is a continuum. Cutting it up into little pieces is not what I've seen in real world. So like Tepezza has been effective in white chronic eyes, which would be 0 to 1 CAS. But it's also been effective in patients who have more of a persistent inflamed state with higher CAS scores despite years or decades of disease. The IGF-1 receptor has increased expression in all flavors of thyroid eye disease. So although we are comparing slightly different groups in that one had a longer duration, that would be the Viridian and Viridian study, and the other had a higher CAS, I think that there's no reason to think that this molecule will be different than Tepezza or less effective than Tepezza. If anything, things are pointing towards improved efficacy, lower dose, fewer infusions. So yes, I don't -- I agree with you. We're not comparing apples-to-apples. But if anything, we're comparing an easier apple to deal with in the Tepezza chronic study to be a little bit more complex in our study.

Just Barry here. I just want to add something to what Kim has just shared. It's important to recognize that in Horizon Phase IV study, there were 2 phrases for their inclusion criteria. The first phrase was the CAS 0-1. But then there's an or there. And so there's a second phrase. And any patient who had stability of their diplopia and of their proptosis for year was admitted with any CAS score. And so what I believe we're seeing is in fact, there were patients in the Horizon study that did have CAS scores greater than 1. And so I believe our definition what we chose to use for inclusion, exclusion criteria is a much more real-world experience of what the clinician sees for chronic patients. Recall that in North America, clinicians have not been using CAS to analyze or categorize the disease state. That is something that is new and just people are learning about because of these trials. I believe what we've seen in our chronic definition is exactly what the clinician does in his or her office.

I totally agree. Yes. And I think that really the key is the CAS, whether it's the CAS or the Hertel, what it comes down to is when I'm talking to my patients is this disruptive, is there thyroid eye disease, not when it happened or how red their eye is, but is it impacting their quality of life and their ability to be productive. And that's what pushes me and other clinicians to decide to use Tepezza or another intervention. This CAS is very -- is not utilized clinically by almost anyone. And so it's just getting -- it's the same with the Gorman score, the diplopia score. That's something that clinicians have not used prior to this, these clinical trials.

And just to be clear again, Barry here. Remember that if one carefully reads the advisory committee for the original Horizon approval, it was clear from the agency's perspective, they don't differentiate chronic from active disease and strongly felt clinicians cannot differentiate chronic from active disease. That is why the initial label was so broad. And in fact, with Horizon's Phase IV study, they reiterated that statement in the sense to reiterate the fact that they're saying chronic and active is but 1 disease. In the active, the inflammation is in the front of the eye. In the chronic state, it's behind the globe in the orbit.

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

This is Adam on for Derek. Congratulations on the data. Very encouraging. So just a few from us. We were wondering what is the rate of response you were seeing on proptosis? And can you put today's data in context relative to Horizon's chronic data from like a baseline characteristics in efficacy standpoint? And then just really quickly also, how should we interpret the differences in dose response for proptosis between the Hertel and MRI methods, particularly given you were just highlighting that the MRI method is a more precise approach?

So, Tom if you can take these on the rate of response.

Sure. So we had a -- as you saw from the slide deck, we had a proptosis responder rate of 42%. And that was after only 4 infusions, and that was at 6 weeks. And that compares favorably to what we saw with Tepezza after 2 infusions at 6 weeks peers with 36%. cross-trial comparisons really aren't valid. But numerically, ours is slightly ahead. So I think that was your first question. And then you asked about baseline characteristics, and I think that's a really important point that I think we discussed in our prepared remarks. But I just want to reemphasize that we had, in our 10 mg per kg cohort, the baseline proptosis measured 21.1 millimeters, and that compares to 24.4 in the Phase IV chronic TED trial. So we are going up against a relative for effect. And as Kim and Derek mentioned in their prepared remarks, this created a higher hurdle for us. Furthermore, we had much more chronicity than was encountered in the Tepezza Phase IV trial. For example, our main number of months since the onset of TED symptoms and signs is 94 months versus their -- 63 months. And that also creates a higher hurdle. And yet we had a result that was excellent. We had an improvement overall of 1.6 millimeters, which again, cross-trial comparisons aren't valid, but that compares quite favorably than the 1.2 millimeters we saw after 2 infusions in the Tepezza trial. So I think the baseline characteristics created a bit of a floor effect with respect to baseline proptosis and a higher hurdle with respect to clinicity, yet we had a really excellent response.

Yes, I just want to add to what Tom said. We actually began by luck of the draw with our cohort in the 10-milligram per kilogram group. We had 2 strikes against us. Those patients had relatively low proptosis and they had much longer disease. The fact that we saw the results we did suggest that it's especially compelling because we had a difficult group to see results in because of their level of proptosis and the longevity of their signs and symptoms.

And I think the final question was around dose response by exophthalmometry versus MRI. If you look at the values numerically, one, they don't seem to -- they're not consistent with respect to dose response. They do show a consistent, impressive improvement. And I think the answer to that is that they're small sample sizes here. And so I think the MRI is important to us because it corroborates a measure that is somewhat variable, as I mentioned earlier. So I think both doses showed really compelling clinical effect after only 2 doses at 6 weeks. And furthermore, I think the lower dose, the 3 mg per kg dose, gives us confidence that we have a path forward with a low-volume subcutaneous injection.

Great. And maybe if I could just get 1 more in on the subcu. Could you confirm whoever you choose for the [ pent bite ] partnership, will they have a validated product with like an existing drug that's already approved with that device?

Yes. Yes, Adam, this is Scott. I can take that. Yes, it is the day of head marketed products before.

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

Again, congrats on the data. I guess 2 for me. I guess to follow up on the proptosis by exophthalmometry. I guess understandable that the data are small and there's variability. But by not disclosing it, should we assume that the reduction is at least the same as the low dose, around 1.5 millimeter mark? I guess why not just disclose it? . And then on the Phase III trial. Can you comment on how the enrollment is going and if the change from the 2-dose cohorts to the single dose cohort had anything to do with slower enrollment than expected? I think you produced the overall end of the study now and the primary endpoint, but the timeline has remained the same.

So Tom, if you'd like to handle the first one, the [ proptosis ] exophthalmometry and...

Sure. As I mentioned earlier, there's a lot of variability inherent in Hertel exophthalmometry. And the sample size is exclusively small, right? It's 2 in 1 cohort and 3 in the other. And it almost -- the first with such high variability and such small sample size, it's almost a meaningless value. What's really important here is the response by MRI. So as we disclosed in our slide deck today, the improvement by MRI was 2 millimeters in the treated subjects after only 2 infusions. And by -- in the placebo group, there's essentially no change. It was a minus 0.2. And I think that level of separation with a precise test like MRI gives us lots of confidence that we're seeing a very potent biologic effect.

Let me add something there, too. I totally agree with Tom. Proptosis is one metric of the disease. It is not the entirety of the disease. In fact, it's healthy to think of it as a proxy for the disease. You've got to look at the totality of the data here. These patients showed improvement in proptosis, improvement in CAS and at some point in the future, we'll be sharing additional data as we get it more an analysis of it, of how they've changed in their quality of life and facial appearances. So what we're seeing is significant changes in multiple metrics is just 2 infusions in a chronic cohort.

And I guess just to add to that. As an investigator that's supposed to be masked, it's very obvious who's getting the drug. The patients are thrilled. They -- within the first infusion, after the first infusion, they're getting improvement. After the second, there are often no pain. Dry eye symptoms are better. They're just doing much, much better. So I want to really emphasize what Barrett just said that this is to look just at proptosis in a very multifactorial disease like this where quality of life is so impacted, it's just a little snapshot of the whole process.