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spk07: Greetings and welcome to the Viridian Therapeutics conference call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn the call over to John Jordan, Vice President of Investor Relations. Thank you. You may begin.
spk00: Thank you, Daryl. Good morning, everyone, and welcome to the Verdean conference call to discuss the initial clinical data for VRDN001 in patients with thyroid eye disease. Before we begin, I would like to remind everyone that this conference call and webcast will contain forward-looking statements about the company. These statements are subject to risks and uncertainties that could cause actual results to differ. Please note that these forward-looking statements reflect our opinions only as of today. Except as required by law, we specifically disclaim any obligation to update or revise these forward-looking statements in light of new information or future events. Factors that could cause actual results or outcomes to differ materially from those expressed in or implied by such forward-looking statements are discussed in greater detail in our most recent filings on Form 10-K and 10-Q and other reports on file with the SEC. I would now like to turn the call over to Jonathan Violin, President and Chief Executive Officer of Viridian.
spk11: Thanks, John, and good morning, everyone. We're excited to share some remarkable data from our ongoing trial of VRDN001 for the treatment of thyroid eye disease, or TED. The results are, frankly, outstanding, and I'm pleased that we can now share our plans for accelerating VRDN001 as quickly as possible to Phase III with the aim of launching a new best-in-class intravenous therapy for thyroid eye disease. We'll also share today our first data for VRDN002, more excellent results. In this case, paving the way for us to develop a best-in-class, low-volume subcutaneous product just every two or four weeks to launch shortly after our IV product. We'll share our plans in a moment. I'm joined today by Dr. Barrett Katz, our Chief Medical Officer, Christian Humer, our Chief Financial Officer and Chief Business Officer, And most gratefully, Dr. Ray Douglas, Director of the Thyroid Eye Disease Program at Cedars-Sinai Hospital in Los Angeles, our lead PI in the U.S., an internationally recognized clinician scientist, and arguably the world's foremost authority on TED. Let's get started. We have much to share with you. I'll start with a brief overview of the findings and then hand it over to Barrett and Dr. Douglas to review the data for VRDN001 in more detail. after which I'll review some new mechanistic data that we think establishes VRDN001 as unique in its class and provide the clear scientific rationale supporting the impressive clinical efficacy data we're reporting today. I'll also review the initial findings from our VRDN002 program, demonstrating the extended half-life we set out to achieve. Then I'll provide an update on the acceleration of our TED strategy based on today's results, including our Phase III program for VRDN001, which we've named Thrive. which will be initiated before year end. I'll also share our plans to develop a best-in-class subcutaneous TED therapy, something we now have increased confidence in based on today's data. Next, Christian will review our second quarter financial results.
spk12: Then we'll open a call for Q&A. So let's dive in.
spk11: As you saw in our press release this morning, we just unblinded the first 10-meg-per-kid cohort after the last patient's six-week visit. and we've seen profound and consistent signs of efficacy on all endpoints measured, far exceeding our initial expectations. Keep in mind that this is after only two infusions of VRDN-001, three weeks apart, and assessing patients at week six. Eighty-three percent of patients were overall responders, meaning they had at least a two-millimeter change in proptosis, the bulging of the eyes characteristic of TED, and a two-point change or greater in clinical activity score, CAS, a composite of TED symptoms. Eighty-three percent of patients were proptosis responders, with 2.4 millimeter change in proptosis, and the median time to response was just three weeks. Eighty-three percent achieved a maximal or near-maximal reduction in CAS to a score of zero or one, and 75 percent of patients who had double vision at baseline, diplopia, had complete resolution of that diplopia. Importantly, VRDN001 demonstrated all this while showing a favorable initial safety and tolerability profile. with no reported serious adverse events, no hyperglycemia, and no infusion reactions. This is honestly stunning. And when we look at how VRDN-001 data compares to Tepesa's Phase III clinical data, we see higher responses on every single measure. And the differences aren't subtle. On every relevant endpoint in TED, VRDN-001 shows enhanced efficacy when compared against prior studies at Tepesa at a six-week time point. Doubling the rate of overall response at TPEZA, which requires that patients respond on both proptosis and clinical activity score, meaning they improve on both the signs and symptoms of TED. 83% proptosis responder rate versus 56% TPEZA. A larger mean change from baseline proptosis by half a millimeter. Four times the proportion of patients achieving a cap of 0 or 1, with mean change from baseline cap a little more than double at TPEZA. and double the rate of patients with baseline diplopia who have that diplopia completely resolved. This isn't something we initially expected, but as you'll see in our presentation today, recent preclinical evidence showed us that VRDN001 has a differentiated mechanism of action. We learned that Tepeza and other IGF-1R antibodies we tested act only as partial antagonists. That means that even at maximal exposures, Tepeza leaves some residual IGF-1R activity. In contrast and uniquely, VRDN001 acts as a full antagonist and achieves a far more complete inhibition of IGF-1R. I will tell you more about that in a moment. We may have a uniquely powerful therapeutic in VRDN001. I'll now hand the presentation over to our chief medical officer, Barrett Katz, a neuro-ophthalmologist with a deep understanding of and appreciation for thyroid identities.
spk14: Thank you, John. This study was designed to investigate whether VRDN001 can match the precedent for powerful efficacy in TED by IGF-1R blockade, but also to enable our development program to advance quickly should we see positive results. We enrolled patients with active TED with a clinical activity score of four or higher and onset of TED signs and symptoms within the preceding 12 months. These criteria were intentionally similar to the TPEZA Phase III trials so that we could compare our results to those. Our study was randomized and double-masked. The data today are from our first cohort of eight TED patients, six of whom received 10 milligrams per kilogram of VRDN-001, two of whom who received placebo. The drug was infused twice, first on day zero, then again on day 21. The key efficacy endpoints were measured on day 42, that is week six. We are nearing completion in enrolling our second cohort, which is evaluating two infusions of 20 milligrams per kilogram VRDN001. We continue to remain masked for this cohort and plan to present its data at a medical meeting in the fourth quarter of this year. Enrollment has accelerated nicely as we continue to open more sites, with the 20 milligram cohort enrolling over three times faster than the 10 milligram cohort. And we remain on track to deliver data from a third cohort evaluating two infusions of three milligrams per kilogram in the fourth quarter of this year. We've incorporated two additional cohorts to the proof of concept portion of this study, those to evaluate to VRDN001 in chronic TED patients. We plan to begin enrolling this cohort in the fourth quarter of this year and expect to have data in the first half of 23. We also plan to incorporate chronic TED patients into our phase three Thrive Pivotal program, as you shall see. For today, we have a rich and compelling data set from this first cohort, and we will review safety and tolerability, as well as efficacy measures. To review the data, I'll turn the presentation over now to Dr. Raymond Douglas, the Director of the Thyroid Eye Disease Program at Cedars-Sinai and the key KOL for thyroid eye disease.
spk04: Thank you very much, Barrett. And let's start by reviewing the baseline patient characteristics. They were quite similar to the TPEZA Phase II and Phase III clinical trials. with similar levels of baseline proptosis, clinical activity score or CAS, and rates of diplopia. Overall, the populations had very similar disease severity. Time since diagnosis was slightly longer in this study, which is unsurprising since patients were eligible for the study if their symptoms started no more than 12 months ago. Age and sex characteristics were also similar. So overall, These are very similar populations. And this gives a good basis for contextualizing the study results within the field. So let's turn to those data now. Let's start with overall response. This is the most stringent assessment of efficacy, including both signs and symptoms of TED. An overall responder is defined as a patient who has at least a two millimeter reduction from baseline proptosis and at least a two-point change in clinical activity score, or CAS. Now remember, proptosis is the key sign of TED and was measured in standard fashion with the Hertel exophthalmometer. Clinical activity score, or CAS, is a composite of the presence or absence of seven signs and symptoms characteristic of TED. As you can see, 83% of patients were overall responders, five out of the six patients, while none of the placebo patients exhibited a response. Data for phase two and phase three trials of TPEZA demonstrated overall response rates of 46 and 44%, respectively. Turning now to proptosis. As shown on the left, there was a 2.4 millimeter change from baseline proptosis in the VRDN-001 group. In the placebo group, one patient had no change in proptosis. The other placebo patient did, which happens about 10% of the time. Interestingly, this placebo patient did not show any improvement on CAS and did not report feeling better. Now, turning to the VRDN-001 treated group, which was larger with six patients, On the right, you can see the patients treated with VRDN-01 experienced significant proptosis response. Consistent with this ex-optometer data, MRI confirmed proptosis response in the VRDN-01 group when available. Of note, the response in the placebo patient was not confirmed by MRI, and in fact, slightly worsened by this measure. 83% of treated patients, five of the six patients, had a reduction in proptosis by at least two millimeters. 67% had at least two and a half millimeter reduction, and half of the patients had a reduction of at least three millimeters. To put the VRDN-001 effect on proptosis in context, we can compare it to the mean change from baseline proptosis for tepeza at week six in phase two, and phase 3, which was 1.8 and 1.9 millimeters versus 2.4 millimeters for VRDN-001. Proptosis responder rate, defined as the percentage of patients who have at least a 2-millimeter change from baseline proptosis, is shown on the right at week 6. 83% of patients who received VRDN-001 were proptosis responders at week 6, compared to 55 and 56% for TPEZA at week six. Let's turn now to clinical activity score, or CAS, which is, remember, a composite scale of assessments of patients' experience, pain, redness, swelling. Here we see a 4.3 point change from baseline CAS after BRDN-01 treatment. far exceeding the placebo response of 1.5, which is similar to the placebo responses of 1.1 in the two TAPESA trials. Given a rapid and sizable change in CAS, it's not surprising to observe many patients with near total reduction in inflammatory signs and symptoms defined as achieving a CAS of 0 or 1. 83% of VRDN-001 patients met this criterion, while no placebo patients did. Likewise, two-thirds of patients had a five-point or higher reduction in CAS from baseline after VRDN-001 treatment, whereas no placebo patient achieved a four- or five-point change. The reduction in CAS compared with TPEZA at the same time point is shown here. The mean change in CAS score for VRDN-001 treatment at the six-week time point was robust. The percentage of patients who achieved a maximal or near-maximal therapeutic effect at six weeks was also very robust and shown in comparison to that observed for TPEZA in phase two and phase three trials. Keep in mind that the CAS is a seven-component scale, scored for presence or absence of seven different queries of pain, redness, and swelling. So the data tells us that patients are experiencing improvement in a majority of their symptoms, and in many cases, resolution of those symptoms. The last key efficacy measure I have to share today is diplopia, double vision, which is one of the most disruptive and distressing aspects of TED to patients. Analogous at TAPESA trials, about two-thirds of patients had depopia at baseline. And for those that do, the most relevant and stringent endpoint is resolution, the complete alleviation of double vision. In the four patients who had baseline depopia, the average score was two. Now, this is based upon a three-point Gorman subjective scale, so this is a rather severe depopia. Following VRDN-01 treatment, 75% of patients with baseline topopia experienced complete resolution. Once again, a rapid and very meaningful effect for these patients. The VRDN-01 data compare favorably to TPEZA at the same six-week time point. So to summarize, we've presented data in six treated patients and two placebo patients, demonstrating a positive response for VRDN-01 in overall response proptosis response, proptosis reduction, CAS change, and CAS improving to zero or one, and depopia resolution. This preliminary data is consistent and compelling, which is very encouraging for TED patients around the world. Now, let's review safety and tolerability. There were no reports of hyperglycemia or infusion reactions. Some of the known on-target IGF-1R effects were observed. We saw two cases of muscle spasm, both mild and did not require intervention. There was also a single case of hearing changes. However, on her next visit, the AE had resolved. Hearing was normal by audiogram, and she completed this treatment study course. I will now turn the presentation over to Jonathan.
spk11: Thank you, Dr. Douglas, both for your review of the data and your participation in this trial. I'd like to start by showing this slide again to reemphasize what we've seen with VRDN001. For every relevant measure, and in particular for the more stringent measures, we're consistently across the board seeing increased efficacy for VRDN001 versus what was observed for TPEZA. We believe there's a solid mechanistic rationale for why VRDN001 may be able to drive deeper and more rapid responses in TED patients. And we'd like to share some of that data with you today. We've previously shown that VRDN001 binds to the same region of the IGF-1R as TPEZA and that the binding epitopes overlap. We sought to explore this in more detail because where a drug binds is only part of the story. How it binds matters too. And we've learned from some of our recent preclinical research that VRDN001 is distinct in how it binds and how fully it can inhibit IGF-1R function. The left-hand side of this slide illustrates a set of preclinical experiments that the Viridian research team undertook to identify which IGF-1R domains and which specific amino acids are required for binding to a panel of anti-IGF-1R antibodies. VRDN001, TPEZA, and VRDN002, which we'll talk about more in a minute, all rely on the same extracellular domains for binding receptor, as we expected based on our prior epitope characterization. However, while Tepeza and VRDN002 are sensitive to changes in the same amino acids, suggesting they bind very similarly, we were surprised to learn that VRDN001 is not sensitive to these same amino acid changes, and thus is binding to the same epitope, but differently. Contrast these antibodies to lanodutamab, which binds to a different unrelated epitope than 001, Tepeza, or 002, and is sensitive to different domain deletions, as well as different amino acid mutations. Our research team has also recently evaluated each of these antibodies in assays measuring IGF-1R function to understand how changes in binding might affect activity. The data on the right shows that VRDN001 fully blocks IGF-1R function and is a full antagonist of the receptor. In contrast, TPEZA, VRDN002, and lanagutamab are all partial antagonists, each with varying magnitudes of antagonism. Even at maximal clinical exposures, these antibodies may not fully inhibit IGF-1R function. We saw very similar responses in other assays. This suggests that VRDN-001 is better at suppressing IGF-1 receptor activity than other antibodies, and the unique nature of VRDN-001 as a full antagonist may explain the dramatic IGF-1 increases in healthy volunteers we presented in May. It may also explain the rapid and profound clinical improvement seen in TED patients. I'd like to point out one more feature of today's VRDN-001 proof-of-concept data. 001 responses occur remarkably quickly and suggest faster onset than TPEZA. On the left is the onset measure used in the TPEZA Phase III trial, median time to proptosis response, which for TPEZA was a little over six weeks, and for VRDN-001 was just three weeks. On the right is the onset measure used in the TAPESA phase two trial, mean time to overall response, which as a reminder represents improvement on both proptosis and CAS, which for TAPESA was 11.2 weeks and for VRDN001 just 4.8 weeks. These findings are consistent with the higher magnitude of efficacy we just discussed at week six. And of course, a faster response is something patients would welcome. This is something the company has incorporated into its phase three plans by evaluating both a standard eight infusion treatment course, like Tepeza, and a shorter five infusion, 12-week treatment course, which can be a lot easier for patients. We now have a clear opportunity to differentiate VRDN-001 from Tepeza. We believe we have an opportunity to offer patients a shorter course of treatment and to offer them faster symptom relief and possibly greater efficacy, as well as an attractive safety profile. We already know that the last two infusions of TPEZA offer little additional efficacy, as shown in the left-hand panel of this slide. We just presented data suggesting VRDN001 delivers faster, more profound efficacy. Our phase three program will build on these findings. The program consists of two pivotal efficacy studies, THRIVE and ACTIV-TED, and THRIVE2 and CHRONIC-TED. They will read out in mid-year 2024 and by year end 2024, respectively. Each of these randomized placebo-controlled trials will have three arms, with 40 patients in each arm, as illustrated here. An eight-infusion regimen matching Tepeza, a shorter five-infusion regimen, which would allow patients to complete their treatment course in just three months, 43% faster than Tepeza, and a placebo arm. To further improve the treatment regimen, we plan to use a shorter 30-minute infusion time instead of the 60 to 90-minute Tepeza infusion. We'll come back to a detailed review of our Phase 3 program in a moment, but before we do, I'd like to share our first clinical data for VRDN-002. As some of you may recall, VRDN-002 is a distinct antibody from VRDN-001 designed to recapitulate the pharmacology of Tifesa, but incorporating half-life extension to dramatically improve pharmacokinetics and enable lower, less frequent dosing. Shown in the left panel, we've known for some time that VRDN001 and Tepoza have very similar PK in non-human primates, with half-lives of about six days, and that VRDN002 showed a doubling of that half-life in head-to-head non-human primate study. As cited at the bottom of the slide, we also know that in six different oncology trials, Tepratonumab showed a half-life of around 10 to 11 days, comparable to VRDN001, which also showed a half-life of around 10 to 11 days in oncology trials. In the middle panel, you can see VRDN001 PK and healthy volunteers. We observed a 12-day half-life for 01, similar to the PK and oncology patients. Today, in the right panel, we can share initial data for VRDN002 and healthy volunteers after a single IV dose, and it shows a preliminary half-life between 30 and 40 days, which is better than we expected, about triple the half-life of VRDN001. The safety profile for VRDN002 has also been favorable to date. with no serious adverse events, no hearing impairment, no hyperglycemia, no muscle spasms or fusion reactions reported as of last subject, last visit. We also have today plasma IGF-1 levels. This is a biomarker for systemic target engagement. When IGF-1R is blocked, plasma levels of IGF-1 increase by homeostatic mechanism. This makes plasma IGF-1 levels an excellent pharmacodynamic measure of IGF-1 receptor antagonism. The more the receptor is blocked, the higher IGF-1 levels should go. TPEZA data from an oncology study are shown on the left. TPEZA treatment resulted in a 2.5-fold elevation in plasma IGF-1 shown out to day 7. The middle panel shows IGF-1 levels after single doses of VRGN-002. We see a sustained increase of about 2.5-fold, similar to TPEZA, but staying elevated throughout the 84-day study period, even at the lowest dose, a single 3 mcg infusion. The similar magnitude of IGF-1 increase aligns with the preclinical data we just discussed. The RDN-002 closely mimics the effects of TPEZA on IGF-1R, but with more than three-fold longer half-life and therefore duration of action. Based on internal modeling by our research team, the RDN-002 PK should support a low-volume subcutaneous injection of 300 milligrams, either every two weeks or every four weeks. The either schedule would support a very strong commercial profile. comparable to some of the best-selling subcutaneous antibodies, such as Regeneron's Depixent. We plan to evaluate 300 milligrams of VRDN-O2 in 2 milliliters as every two-week or every four-week dosing in a proof-of-concept study, which we'll initiate by year-end. And we expect to have top-line data in the second half of next year. So let me sum up the lessons we've learned from today's data. First, VRDN-O01 delivers rapid and profound improvements in signs and symptoms of TED. with all efficacy endpoints surpassing prior TPEZA studies, often by two-fold or more. Second, VRDN-002 produces more complete IGF-1R inhibition via a unique receptor interaction, providing a mechanistic rationale for the remarkable clinical observations we presented. Thirdly, VRDN-001 continues to be well-tolerated with a strong safety profile. Fourth, VRDN-002 half-life extension provides a longer-than-expected extended activity in humans, tripling the half-life of first-generation IGF-1R antibodies, and its PKPD profile paved the way for our proof-of-concept study of two milliliters containing 300 milligrams subcutaneous injection, either every two weeks or every four weeks. So, with these lessons in mind, I'd like to share our strategy in TED and next steps in our development programs. Tepesa launched two years ago. and will sell about $2 billion in the U.S. this year, almost entirely to newly diagnosed patients. And peak sales are estimated to be $3.5 billion, not including the EU. There are only so many markets of this size in biotech, $2 billion in annual sales, growing, and not yet including chronic patients, where Tepeza is restricted, or any ex-U.S. patients. Recall, this is not a switch market where you have to attempt to take a patient off of another therapy. This is a new start only market. Every single year, 20 to 25,000 patients in the U.S. will choose the best product to treat their thyroid eye disease every year. Think about that. It's exceedingly rare to have a new start market this big where new patients choose the best therapy for themselves each year. In light of this unique opportunity and the compelling initial clinical profile for VRDN-001 presented today, We're accelerating our plans so that most TED patients can choose one of Viridian's therapies. Beyond this established portion of the market, there are another 75,000 or more patients in the U.S. with chronic TED who represent a major upside to this market opportunity because there isn't yet randomized controlled trial data supporting access and uptake for this population. Importantly, there's a similar picture in the EU and UK where there are 35,000 to 40,000 patients diagnosed each year. and we estimate more than 150,000 chronic patients and no approved therapies. We're designing our phase three program to support a marketing authorization application for the first approval of a TED therapy in Europe, which we anticipate to significantly expand our revenue opportunity. The likely endpoints are either CAS or overall response. We have seen some differentiating data from us today. Our data enabled two approaches to satisfy an unmet need in the TED market, which we're now committing to as corporate objectives. Our first goal is to sprint to market in the US and the EU with a best-in-class IV product in VRDN001 using the trial design we mentioned a moment ago. We just told you about this large incidence market, a new start market, and we think we have an advantage. Our second parallel corporate goal is to develop and launch a durable best-in-class subcutaneous therapy. So let's look a bit closer at our development plans for VRDN-001, the Thrive program. Here are some key features. This is a global registration program. We'll generate robust evidence in both active and chronic TED, and the registrational program is designed to enable approval in the US, the EU, and other major and emerging markets. We have a number of potential improvements over TPEZA. An accelerated 12-week, five-infusion course of therapy, 43% shorter than TPEZA. Shorter infusion times, 30 minutes for VRDN001 versus 60 to 90 minutes for Tepeza. And as you've seen today, the potential for faster onset and higher efficacy. And we're in a strong position to execute on rapid timelines to enter this large market. Our phase three program will initiate by the end of this year. We already have 17 sites active with 30 expected by the end of the year, expanding beyond 50 in the first half of next year. We expect a Phase III active TED data by the middle of 2024 and Phase III chronic TED data by year-end 2024. In summary, we're designing a development program that we hope will deliver a VRDN-001 product profile with superior efficacy, faster time to symptom improvement, fewer treatment visits, and shorter administration time with a highly attractive safety profile. We think these attributes sum to a highly differentiated and valuable product profile. Now, let's turn to our second parallel corporate objective, launching the best possible low-volume subcutaneous TED therapy as rapidly as possible. The key to this approach is half-life extension, something no other company currently has in development for an IGF-1R antibody. As we just shared, the VRDN-002 epitope, binding, and in vitro profile are very similar to Cepeda. The key difference is that 002 achieves triple the half-life of first-generation IGF-1R antibodies. We have 30 to 40 days. We know we have in hand a compelling profile, 300 milligrams and two mils, dosed every other week, maybe even every four weeks. In addition to VRDN002, we now have a second opportunity to deliver on our subcutaneous goals. Today we're unveiling VRDN003, which is the half-life extended version of VRDN001. It retains the unique VRDN001 binding and antagonist properties while incorporating the same half-life extension technology as VRDN002. Based on non-human primate data, we expect OO3 to match VRDN-002-PK. This program isn't new. We've had OO3 in our corporate presentation for a long time. Today, we're accelerating this program now that we've seen the VRDN-001-TED proof-of-concept data. We're well into IND-enabling studies and expect to file an IND in second quarter 23, with phase three enabling healthy volunteer PK PD data in the fourth quarter of 23. We'll launch our subcutaneous product with a patient-friendly pre-filled pen, at a minimum, something like Regeneron's Depixent, which is 2 mils, 300 milligrams every other week. We've got a lot of confidence in achieving this profile, but we may be able to go further. The upcoming efficacy data for 3 mg per kg VRDN001 will inform an every 4-week or longer profile for both VRDN02 and VRDN03. Overall, this approach gives us two shots on goal for a best-in-class subcutaneous TED product. And clinical data in the second half of 23 will tell us which of VRDN002 or 003 is best to move forward to phase 3, which will be ready to start early in 2024. We think this puts us in a very strong position to make good data-driven decisions to select the best possible molecule while advancing multiple options. This ensures we have a best-in-class product to launch as soon as possible after our IV VRDN001 product launch. I'd like to close by summarizing where Viridian is headed next. On the basis of today's very strong data, we now have plans that advance our mission to deliver better options to patients suffering from TED and other serious diseases. We have an incredible news flow over the next few years, representing major milestones for the company. We're excited to execute on these plans, and I'd like to thank everyone who's contributed to what you've heard today, the patients who volunteered for our trials, the investigators in our trials, particularly Dr. Douglas for his leadership in the TED field, his productive partnership, and for joining us today, and the Viridian team for all the hard work that's driven the progress you've heard today. Before we open the call for questions, Christian will review our financials.
spk10: Thank you, John, and good morning, everyone. I would like to give a brief summary of the Q2 items. Cash, cash equivalents, and short-term investments were $161 million as of June 30, 2022, compared with $197 million as of December 31st, 2021. We believe that our current cash balance, in addition to our $75 million credit facility, will be sufficient to fund our operations into 2024. During the second quarter of 2022, we entered into a debt financing agreement with Hercules Capital for up to $75 million. Under the terms of the agreement, we drew an initial $5 million at closing. As of August 12, 2022, Viridian had approximately 43 million shares of common stock outstanding and on an as-converted basis, which includes 28 million shares of common stock outstanding and an aggregate of approximately 14 million shares of common stock issuable upon the conversion of 194,000 and 23,000 shares of Series A and Series B preferred stock, respectively. Please refer to our earnings press release for a more detailed Q2 financial update. With that, we can open the call up for Q&A. Thank you.
spk07: Thank you. We will now be conducting the question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for your questions. Our first questions come from the line of Chris Howerton with Jefferies. Please proceed with your questions.
spk13: Great. Thank you so much for taking the questions, and a hearty congratulations on the excellent data. So, I think maybe just two questions from me. and then I'll hop back on the queue. So first, I know that there was obviously most of the profile extremely clean, but there has been some concerns around hearing loss. So just curious if you have any more thoughts on that observation and how, if anything, you're doing to monitor that further. And then the second question that I have, I think is just more of a clarification in terms of strategy. So for the subcutaneous formulation, What information specifically are you waiting for, and I guess, like, to make the final decision to move forward? It sounds like it'll be O2 information, the 3-mig-O1 IV formulation, and then I guess, Jonathan, just the little tack I'll add on there is, are you considering a 3-mig-per-kig subcutaneous O1 dose group at this point? Thank you.
spk11: Great. Thank you, Chris. Appreciate the questions. Why don't we start with the adverse event question? I'll ask Barrett to comment on our observations, and maybe Dr. Douglas can provide some additional color, and then I'll answer the other two questions.
spk14: Thank you for your question. I think you've heard Dr. Douglas speak to the safety profile, which really is very strong, very tolerable. We did have one patient who described a ringing in their ears. This was transient. It resolved very quickly over a week or so. The audiometric analysis of this patient showed normal audiometric function at the resolution of this, and we believe it is something that we see in clinical practice and is not so terribly uncommon.
spk12: And Dr. Douglas, if maybe you'd like to provide your views on the hearing loss ease.
spk04: Yeah, to reiterate what Barrett said, it was a tinnitus, and typically we've seen those in other IGF molecules to have resolution. And as Barrett also mentioned, this patient was being followed by audiometric analysis, and I think that that's very important as we move forward of making sure that we are actually following these patients and clarifying. both the type and potential issues associated with hearing.
spk05: But as noted, this did resolve.
spk11: Then I'll answer the question on the subcutaneous strategy. So the question is, what more information do we need? The short answer is nothing. We already know with VRDN002 that we have that Dupixent-like profile in hand. The reason that we're advancing OO2 and OO3 in parallel is that, well, OO2 seems to really do everything we hoped it would. It matches the TPEZA profile pharmacologically in every way we've measured. It has a phenomenally increased half-life, so it gets us to a compelling subcutaneous product profile. What we've learned recently is that OO1 seems to have a unique and potentially superior pharmacologic profile. So why not take the opportunity to combine the benefits of OO1 and the benefits of OO2 in what we're now calling BRDN-OO3. And because we now know so much about sort of the PK and PD of these molecules, we can move these two programs forward in parallel so that by the second half of next year, we'll have our subcutaneous proof of concept data for BRDN-OO2. We'll have a healthy volunteer PKPD for OO3, which is effectively proof of concept, again, given everything we know about OO1. And on the basis of that data, we can choose whichever molecule looks best, and we're running the programs in a way that we can then start phase three early in 2024. So we really like this strategy. We think it allows us to make data-driven decisions on the basis of clinical results. And then finally, you'd asked about, would we consider, I actually missed the question about the 3 mcg per kg.
spk13: It's really not that important. I guess I was just like, is there any scenario where a O1 subcutaneous formulation makes sense, I guess, is the real crystallized question.
spk11: Oh, I think so. You were asking about the upcoming 3 mcg per kg data for IV VRD and O1. So that's going to be informative in a number of ways. We already, with high conviction, know that we can achieve in every other week sub-Q with O2 and O3. If we see that lower doses of OO1 deliver a similar benefit, then that puts every four weeks very much not just on the table, but it would give us confidence in that profile, maybe even longer. So that's kind of the key value that we'll get from the three-minute pre-K cohort coming up. But you're right. There is, of course, still the potential of OO1 itself could achieve sub-Q. But honestly, with the outperformance of half-life extension that we saw today, we really think that 02 and 03 are our best bet to achieve a very difficult-to-beat commercial profile.
spk13: I tend to agree. And thanks again for just taking the questions and your excellent data set.
spk05: Congratulations.
spk07: Thank you. Thank you. Our next questions come from the line of Thomas Smith with SVB Securities. Please proceed with your questions.
spk05: Hey, guys. Good morning.
spk03: Thanks for taking the questions, and let me add my congrats on the really strong early data here. Just, I guess, first, to follow up on the safety, with respect to the muscle spasm and hearing impairment, can you just kind of remind us of the time course of when these AEs are typically seen with the PESA treatment? I know it's not explicitly on the AE slide, but can you confirm that there haven't been any cases of hypertension seen in the TED patient cohorts debate?
spk12: Great. Thanks, Tom.
spk11: Barrett, why don't you address the muscle spasm question and then the time course of adverse events first. Certainly.
spk14: The muscle spasms are common in real life situations. In fact, there's a way to mitigate them by giving volume and magnesium. Dr. Douglas has shown that and shared it with the rest of us. They can occur at any time. They occur early. The hearing loss is something we thought occurred later, but as the experience has increased with DEFESA, we recognize that the hearing loss can occur at any time. The truth of the matter seems to be that the hearing impairment is usually reversible. The interesting thing, as you talk to these patients and even the ones that complain of hearing impairment, they say, oh, gosh, I want the drug. I'd much rather go deaf than change what I'm having done to me because the efficacies are so strong. And that's been our experience as well so far.
spk11: Maybe Dr. Douglas can comment a little further.
spk04: Yeah, so the hearing impairment occurs in one of two forms, typically a tinnitus or a plugging of the ears. And that appears to be 100% reversible. Typically, it can occur mid-treatment during this course of therapy and then resolves either during or after therapy. Then some notice of audiometric and high-frequency hearing impairments, not loss completely, but just impairments. And we're still waiting to see how those in a much smaller segment of patients and see if those are also reversible. The muscle spasms typically occur early in the treatment course, and again, are more of a nuisance than anything else, typically have not impaired continuation of treatment, and as Barry suggested, can be highly reversible.
spk11: Great. And maybe so I can then address the adverse event question on hypertension. So for VRDN002 first, the There were only three adverse events for VRDN002 that were deemed related to treatment. There was a mild transient dizziness. There was one case of asymptomatic hypotension that resolved the same day without treatment, and one case of asymptomatic hypertension that resolved the same day without treatment. These are just the kinds of things you observe in a Phase I study. And then with respect to VRDN001, There's nothing that we've seen in temptations with respect to blood pressure.
spk05: Okay, great.
spk03: That's super helpful context. Thanks. And then just a couple of questions on the phase three plans, and then we'll hop back in the queue here. But just can you talk about the need for FDA engagement to confirm how you're thinking about the THRIVE program? elaborate a little bit on how you're thinking about enrollment here, specifically with respect to how you're thinking about patient targeting relative to PESA and, you know, some of the other companies who are contemplating pivotal studies. You know, what specifically gives you confidence in meeting the enrollment timelines you've laid out? And I guess any early thoughts on the cost, anticipated cost of the phase three program?
spk11: Okay, great. Yeah, thanks, Tom. So first, the regulatory question. So we'll formally meet with the FDA later this year, but based on conversations to date, we think our plan will actually exceed what the FDA needs. Keep in mind that Horizon had two studies with a narrow population and only ever studied one dose for approval. We have a lot more than that, right? We'll have acute patients, chronic patients. We're studying two different courses of treatment, right, different total cumulative dose. And we've also done some dose ranging. So we think we're going to have a very, very strong package. And that first study, the THRIVE study, is very much following the precedent that TAPESA set. So we really don't see a lot of risk here. And then with respect to enrollments, the THRIVE study, the active disease phase three, is leveraging the flexibility that we built into the current study. We're adding cohorts directed to be registrational using sites we already have open. We already have 17 sites open. We're expanding that quickly. We've been in the U.S. and Canada for phase three. We've long planned to go broader than that. We'll be in the U.K. and Europe. We'll have 30 sites open by year end. So this is a very robust plan to enroll patients. Interestingly, we've seen once sites are open, we are enrolling at the rate that we had projected. And that was before we had any clinical data. With today's data, you can imagine how excited we are about this data. We think that that's going to be shared by the investigator community as well. So we're actually really confident that this can move forward quite briskly.
spk05: Okay, great.
spk03: And then just, yeah, any early thoughts on how you think about cost for the registrational program?
spk11: Oh, yeah. I'm not going to go to details of costs, but as Christian said, we're very well capitalized, and we know what we need to do and are poised to execute.
spk05: Excellent. All right, guys. Thanks for taking the questions. Appreciate it. Congrats again on the data.
spk07: Thanks, Tom. Thank you. Our next questions come from the line of Gavin Clark-Gartner with Evercore ISI. Please proceed with your questions.
spk02: Hey, good morning. Congrats on the great data, and thanks for taking the questions. Just had a couple. First, on the 20 mg per kg, 001 safety data that you're still blinded to, do you know how many doses have been given?
spk12: So, we are nearly done enrolling.
spk11: So, I guess the answer is most, but I don't have the exact number before me. But the safety data was as of August 9th, so a recent safety read for that cutoff. And as you saw, very promising so far, but data collection is ongoing. We're pleased that we're not seeing any hyperglycemia, no hearing impairment, no muscle spasms, no infusion reactions, and of course no SAE. So we're really going well so far.
spk02: Yeah, got it. And then do you plan to pursue any studies showing the benefit of re-treatment, maybe in capacity responders who have kind of relapsed months or years later?
spk11: Yeah, the re-treatment question is a really interesting one. Well, look, the first thing is first for us, right? We think we have some really exciting plans to deliver a differentiated product profile. I do think the re-treatment question is important. It will take some time to answer. It also reflects the state of the field, right? This is a young and rapidly evolving field of clinical science, and we're excited to participate in advancing the knowledge. So questions like this, I think we'd love to be a leader in figuring out how best to treat patients and build up our commercial product profile as we do so.
spk02: Yeah, got it. And just the last one for me. How are you thinking about the pricing of 001, given that it could have five infusions and, of course, a treatment instead of eight with Copeza?
spk11: Yeah, so the way we think about our products is way too early to get into pricing, but generally, we're focused on what value we can deliver to the market. And, I mean, you've seen the clinical data, you've seen our plans to deliver something that could be highly differentiated and add a lot of value above and beyond what what exists now. So we think this will be really exciting for us, and we're focused on delivering that value.
spk05: Yeah, that's really helpful. Congrats again. Thanks, Gavin.
spk07: Thank you. Our next questions come from the line of Rami Kapkuda with Lifesize Capital. Please proceed with your questions.
spk15: Hey, guys. Congrats on the data, and thanks for taking my questions as well. Dr. Douglas touched upon this briefly, but can you talk to the differences between MRI and hurdle exophthalmometer measurements when looking at proptosis in these patients? And how do these measurements kind of compare for the patient in the placebo arm that had the 2-millimeter reduction in proptosis as well as those treated with 001?
spk11: Sure. Why don't I start, and then maybe Barrett and Dr. Douglas can comment further. So, the Hertel Exophthalmometer obviously is a validated measurement, works great. We've been very pleased with it, but we do know that in a very small sample size, like two placebo patients, you do sometimes see a patient with a change despite having no active drug on board. So, the interest in MRIs, this is an objective measurement, right? It doesn't require the kind of device and manual reading of the Hertel X-up thermometer. We do not have all the data for MRI measurements, but we take these images and then analyze the changes pre- and post-treatment to get an objective measure of how much the proptosis has changed. We have four patients. with MRI measurement pre- and post-treatments, so at baseline and at week six, who received drugs. So those four patients that received drugs, in every case, the millimeter change by exophthalmometer was slightly exceeded by MRI. So the MRI is reporting a slightly bigger change in proptosis, a bigger reduction in proptosis. And then as you heard, that placebo patient, where we saw minus two, so two millimeter improvement by the exophthalmometer, proptosis worsened by 0.58 millimeters by MRI. So it just underscores why it's so nice to have multiple measurements of the same thing. And when we think broadly, when we think holistically about our data, it's just an incredible consistency at the direction and magnitude of response that we are outperforming both TPEZIS Phase II and Phase III trials across the board. And we think the MRI is an important piece of that, and we'll be excited to have the full data sets in the future. Barrett, you need to add?
spk14: If you think about the measurement of proptosis, as we use the exophthalmometer, we're having the site investigator in each of the sites do that measurement. The power of the MRI scan, or a CT scan for that matter, is that the scan is done with the same section at each site, and then sent to a central reading center and read in a masked fashion. So you have one center reading the entirety of the data set for these orbital scans. And in fact, it should be more objective. And what we're seeing, interestingly enough, is the exophthalmometer underestimates the proptosis response of our drug. The MR measurements and the CT measurements tend to suggest that the proptosis improvements with these superior results are, in fact, underestimated on exophthalmometry.
spk15: Got it. Makes sense. And then really quickly, just to confirm a point you made in the presentation, is the more complete antagonism of IGF-1R with 001 the reason why we saw more robust PD effects and increases in IGF-1 levels in healthy volunteers versus TPEZA?
spk11: Yeah. Obviously, the pathophysiology is not totally understood here, but we can start to connect the dots, right? So, we have a couple partial antagonists in TPEZA, VRDN-002. They increase IGF-1 by about two and a half fold, and we know the TPEZA clinical efficacy results. And then with 001, we've got more full antagonism in multiple different in vitro systems, and Then in terms of IGF-1, we see almost twice as high an IGF-1 increase, right, a six-fold or so increase in plasma IGF-1 levels compared to two-and-a-half fold for TPEZA. And then you saw the clinical results, right, the outperformance compared to prior TPEZA data on all these different measurements. So starting to look like a pretty nice correlation and something that we hope to build on. And again, I think highlights that with VRDN-001,
spk05: we might have something truly special on our end. Awesome. Thanks so much, guys, and congrats again. Thanks, Rami.
spk07: Thank you. Our next questions come from the line of Laura Chica with Wedbush Securities. Please proceed with your questions.
spk01: Good morning. I actually have one or two for Dr. Douglas first. Dr. Douglas, I'm curious, in light of this data, could you just remind us, in practice with your TED patients today, How are you evaluating proptosis response, and do you actually incorporate MRI data in assessing that? And also, could you speak to kind of defining disease severity in practice? Are you using primarily CAS scores, or how are you categorizing patients as moderate-severe? And then I will follow up.
spk12: Thanks, Laura. Please go ahead, Dr. Douglas.
spk04: Great. Thanks so much. So in practice, you know, I think one thing to bear in mind is in practice, it's always a balance between what's practical and what is most robust. So in practice, I tend to use exophthalmetry data. But when I treat patients either with surgery or TPEZA, I usually use a before and after scan of some type, typically either MRI or CT scan. It's kind of like the difference between a very crude test point diagram versus an entire painting. The MRI and CT can give you an entire painting of what that orbit looks like in a very objective manner. So I'm very excited about the MRI data. And I do, to answer your question very directly, do use it as a supplement to my exophthalmometry measurements with Hertel. In regards to severity, severity is actually defined as the amount of disease burden for patients that I use when thinking about treatment for patients. And so, for example, if a patient has profound proptosis above normal limits, typically three millimeters or more, and disease that either is active or is quiescent, I will often opt for tepezin therapy and IGF-1R therapy. Because what I've seen over our data and we've published in both, you know, active and chronic patients is that they have a dramatic improvement of their proptosis and of their disease. So severity for me in guiding my therapeutic use of Tepeza thus far has been based upon their disease burden. And moderate to severe is often three millimeters or more, as was, you know, as suggested. you know, the criteria for their disease burden.
spk01: Okay, that's helpful. And then maybe for the Meridian team, could you remind us, you briefly touched on the ex-U.S. market and seeking patients outside the U.S. Can you remind us on how you're planning to approach commercialization ex-U.S.? I guess in light of the data you're seeing, would this be a market that you can commercialize on your own? Thanks.
spk11: Yeah, too early to really go into details on our commercial strategy. Obviously, we're thinking about that, but for competitive reasons, just don't want to get into it yet.
spk01: Sounds good. Congratulations on the data.
spk05: Thanks, Laura.
spk07: Thank you. Our next question has come from the line of Kalpit Patel with B. Riley Securities. Please proceed with your questions.
spk06: Yeah, hey, good morning. Congrats on the data, and thanks for taking the question. Maybe just a quick one for Dr. Douglas, and I think you touched on this a little bit, but how common is it to get greater than three millimeters of proptosis reduction in the real world with TAPEZA?
spk12: Thanks, Cal, but yeah, Dr. Douglas, please go ahead.
spk04: Yeah, so, you know, I think one thing that we've observed, you know, with TAPEZA, and it really speaks to IGFR therapies in general, is that what we've seen in the clinical trials has translated exceptionally well to real world experience. So my real world experience, and we just published a large review, has been that we're achieving on needs much greater than three millimeters reduction in proptosis in the majority of patients. So it all depends on the disease burden, you know, when patients present. But what you're seeing, I think, from the clinical trials translates exceptionally well to real-world experience.
spk11: Thank you, Dr. Douglas. Maybe I'll just add to remind everyone that the changes we're seeing are just two infusions at week six, right? And the TPEZA course of treatment is eight infusions over 24 weeks. So, when we think about magnitude effect, we're looking very early on in the course of treatments. I just want to make sure everyone keeps that in mind. Okay.
spk06: And then a couple questions on the design of the registrational studies. I guess what went into the decision-making for selecting five doses of 001 versus maybe four or six for one of the cohorts?
spk11: Sure. Yeah. Well, we already knew based on the TPEZA data that the last two infusions, the seventh and eighth, are not delivering much of any additional benefit. And then given the data we've seen today, right, the speed of onset, the magnitude of efficacy, what we know about the PK and PD of the drug, we landed on five as the sweet spot. So, we really like this regimen. We think that a three-month course of treatment is going to be truly compelling for patients.
spk05: Okay.
spk06: And, John, just to be clear here, can you confirm that the THRIVE-2 study will only include that 10-milligram per kilogram dose and results for the other, you know, three and 20 milligram per kilogram doses will not necessarily inform the design of that trial.
spk11: Yeah, so we're moving forward with 10 mg per kg in the Thrive program. We think the data is outstanding. The dose is half, a 50% reduction from the Tepeza dose. And by testing both the 5 infusion and 8 infusion, regimens, we're still testing two different cumulative doses with the upside of this dramatically shorter treatment period. So, we think this is a really great place to be.
spk06: Okay. Thanks so much for taking the questions.
spk05: Thank you.
spk11: I just want to point out we are running a little short on time, so we'll try to keep our answers brief, and maybe we could ask for just one question from whoever's still in the queue.
spk07: Thank you. Our next question comes from the line of Jason Butler with the JMP Securities. Please proceed with your question.
spk09: Hi, thanks for taking the question. Let me add my congrats. I'll keep it brief. Just on the chronic trial, can you just give us some, you know, initial thoughts on how you think about patient baseline characteristics here compared to the, you know, the acute treatment population? And then on the, I guess, a follow-up to that retreatment question, would you allow patients who had previously been treated with Tepeza into the chronic trial? Thanks.
spk11: Thanks, Jason. So the chronic study is we're using 15 months since diagnosis as the cutoff between active and chronic. So that means that the Thrive program in total will enroll patients regardless of how long ago their symptoms began. In the chronic study, we will allow any CAS score to enter. Now, chronic patients tend to have lower CAS scores, so we expect the population to have lower CAS. But it will be quite a broad population. We will not allow a prior treatment with IGF-1R therapy in the study. So it will be naive to IGF-1Rs.
spk05: Great. Thanks. Thank you. Our next question comes from the line of Trevor Allred with Oppenheimer.
spk07: Please proceed with your questions.
spk16: Hey, guys. Good morning, and my congrats as well. So, yeah, just real quick from me. With Viridin-001 being a full antagonist, do you have any thoughts on why you've also shown an apparent safety profile seen thus far?
spk11: Yeah, well, so what we're learning is that the biology has some subtleties to it, right? What we can say is that between the TED patients and the healthy volunteers, we've exposed more than 20 people to VRDN001 at these doses, even higher doses with 20 mgs per kg, and the safety profile looks great. So, we think we're in a really good position.
spk05: All right. Thanks, guys. Thank you.
spk07: Our next question comes from the line of Michael Higgins with Leivenberg Zalman. Please proceed with your question.
spk08: Thanks, Alfred. Good morning, guys. Congrats from me, as well, to impressive results. question for you on the use of methotrexate in these Phase 1s or before the BLA filing. Do you have any comments to that, if you've used it or plan to?
spk14: Thanks, Michael. Barak, go ahead, please. We do have inclusion criteria that disallow for any recent such intervention, so it's not part of our plan to change that going forward.
spk05: Thank you. There are no further questions at this time.
spk07: I would now like to turn the call back over to Jonathan Violin for any closing comments.
spk11: Great. Thank you, everyone, and thanks for the good questions. Data like this really doesn't come along every day, and it doesn't happen without the support of a large multidisciplinary team dedicated to the success of these programs. I'd like again to thank the investigators who worked on our studies, the patients who volunteered, and the rating employees who've worked diligently, tirelessly, and with purpose to build the opportunity we have before us. And thanks again to Dr. Douglas for joining us. We really appreciate it. And thank you, everyone, for joining us this morning. With that, we'll close the call.
spk07: This does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.
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