Avidity Biosciences, Inc. (RNAM) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining us today. My name is Geoff Grande. I'm the Vice President of Investor Relations and Corporate Communications for Avidity. And we're very happy to have you with us for volume 8 of our investor and analyst event series. We're excited to share with you our long-term data from our MARINA-OLE study as well as plans for our global Phase III HARBOR trial. As always, following our prepared remarks, we'll leave time for Q&A. So please feel free to submit any questions via the box on your screen. Before we get started, just a reminder that this presentation does contain forward-looking statements as defined under applicable law. Forward-looking statements involve risks and uncertainties and both known and unknown, which may cause actual results to differ from the forward-looking statements contained in the presentation. You're cautioned to not place undue reliance on these forward-looking statements and to refer to the more detailed cautionary language in this slide and in the Risk Factors section of our annual report on Form 10-K filed on February 28, 2024. And with that, I will turn the call over to our President and CEO, Sarah Boyce.

Thank you, Geoff. Our vision at Avidity is to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. We can deliver RNA to muscle cells. We can also deliver RNA to heart cells. Today, though, we're going to be focused on our muscle pipeline, and I could take you to the next slide, please. This is a big year for us. We have 3 data readouts for 3 different clinical programs in 3 different rare diseases. In the second half of this year, we'll be looking forward to sharing data from AOC 1044, which is being developed for boys and young men amenable to exon 44 skipping. In Q2, we're really looking forward to sharing data from AOC 1020 in FSHD. And this will be the preliminary data for about part of the participants in the FORTITUDE study. Today, we're focused on the MARINA open-label extension study and the HARBOR study. And if we can go to the next slide, please. So our goals for today, we're going to be sharing with you the Phase III HARBOR study design. We have regulatory agreement on the study design, and we are now pulling forward our guidance for initiation of the study. Previously, we were guiding to initiating midyear. And we're now bringing that guidance forward to Q2 of this year. We're going to be presenting long-term data from the MARINA open-label extension study. And what you'll see is consistent and durable improvements in multiple measures. They include the video hand to opening time, which is the measure from myotonia; hand grip; muscle strength; and activities of daily living, all of which are key end points in the HARBOR study. We also see the very favorable long-term safety and tolerability profile. We'll be debuting for the first time data from the END-DM1 natural history study. We're incredibly grateful to the END-DM1 group who have given us permission to share this data for the first time. So what you'll see is a luck of 1-year progression. What we've been able to do is match a patient population in END-DM1 with MARINA and the MARINA open-label extension study, specifically the 4-milligram group. So what you'll see is a comparison of a 1-year time point of natural history versus treatment with del-desiran. When we look at this, what we were able to see was reversal of disease progression when compared to natural history. We also now have the generic name, which is delpacibart etedesiran. The delpacibart refers to the transferin antibody and etedesiran refers to the siRNA. It is a mouthful. So we shortened it to del-desiran. And we will now refer to it as del-desiran throughout this presentation. We can go to the next slide, please. I am joined today by my colleagues from Avidity, and we're also delighted that Prof. John Day has agreed to join us today who is a world expert in neuromuscular medicine. We can go to the next slide, please, our agenda for the day. Dr. Steve Hughes will take you through the Phase III HARBOR study design. He will then hand to Prof. Day who will take you through the MARINA long-term safety and efficacy data, and then we'll hand back to Steve to close out. As always, we look forward to engaging with you in Q&A as well. And with that, I'll hand over to Steve.

Thank you, Sarah. So just very quickly before I share with you the design of the HARBOR study. Just a quick reminder of the disease that del-desiran is designed to treat. So myotonic dystrophy type 1 is a significant rare disease with a high burden on the patients and also a very high unmet need, with about 40,000 patients living with this disease in the United States, and there are no currently approved therapies. As with many neuromuscular diseases, it's underrecognized and often takes a long time to diagnose despite the fact that it's a progressive disease that's often fatal. It primarily affects skeletal, cardiac and smooth muscle. Unlike other genetic diseases, it tends to get worse from generation to generation as well as core anticipation. And as you would expect, from a disease such as this, there is a significant impact on the quality of life not just in the patient, but also their families and carers. And it's not unusual to find patients that are caring for other family members that are affected by DM1. del-desiran is designed to address the root cause of myotonic dystrophy type 1 by targeting mutant DMPK mRNA as causative in this disease. And Prof. Day will talk to you a little bit more about that later on. We can move to the next slide, please. So I'm really excited today to be able to share with you the design of our Phase III HARBOR study. We've had this design in our back pocket for quite some time now. As we shared at the end of last year, we were very well advanced in our protocol and not thinking about the study, and we submitted the study for discussions with several regulators globally. We've now reached the end of that regulatory discussion. And as a consequence, we're now able to bring up, as Sarah said, the guidance for study initiation from midyear up to Q2. What that also tells us is that in the background, we've been working really hard with sites to get the study ready to start fairly quickly. Now today, we'll walk you through the data from the MARINA study later on. And what you're going to see is a drug that, as Sarah said, reverses the course of the disease in comparison with natural history. And with that comes a great responsibility to get this drug to the broader range of patients as quickly as possible. And with that in mind, we've designed the HARBOR study for efficiency, speed of execution and operational feasibility. And there are a number of design elements that talked to this. For example, we don't have any MRI scans. We don't have any muscle biopsies. This is a functional story. We're not focusing on biomarkers as we move through to late-phase development. This increases the number of sites that can potentially participate in the Phase III study and also makes the study far more attractive to patients as they don't have to undergo painful procedures in order to participate in the study. If we focus now to the schematic at the bottom, as you would expect, for a Phase III study, this is double blind, randomized, placebo controlled. We'll randomize about 150 participants in a 1:1 ratio so del-desiran and placebo. Placebo-controlled period for the study is about a year. The reason for this is that the regulators like to have a year of placebo-controlled data for assessment and safety. But we're going to be cutting the primary analysis, which is our primary endpoint and our key secondary endpoints at week 30. And the reason we're able to cut the primary endpoint so soon is because we're having a tremendous impact on patients' disease. And we're improving the disease. Therefore, we don't have to wait for the placebos to get worse in order to see the separation between the active treatment arm and the placebo arm. Cutting the data at week 30 also allows us to potentially file early based upon the week 30 data and then to provide the remaining safety data during the review process. So this is another design element for efficiency that potentially allows us to file considerably sooner than we would otherwise be able to. At the end of the placebo controlled period, all patients will have the opportunity to go into an open-label extension trial where they'll immediately receive active drug. If we can move to the next slide, please. So just a few more points on the Phase III study design. We'll start on the left. As we've communicated already, 4 milligrams per kilogram is our dose in Phase III. We're going to be giving it every 8 weeks in this study, with the first dose at 2 mg per kg. You'll remember that the MARINA study was in adults. That's 18 and up. In this study, we're extending that into the pediatric range, so bringing in adolescent patients and the age rate for this study is 16 now. We anticipate needing about 40 sites globally in a sort of longer study and timely fashion. The primary endpoint for the study is going to focus on myotonia. We measure myotonia with a video hand opening time in the hand, but myotonia doesn't just affect the hand, it's just where we can best assess it. Myotonia is a multisystem disorder that has many, many different impacts on the patient. It can impact just about any muscle in the body, so they can affect the tongue, it can affect jaw, it can affect swallowing, it can affect the gut, it can affect skeletal muscles. So this early is an important and limiting center for patients. The key secondary endpoints are the ones which we'll test statistically after the primary endpoint, and these focus on muscle strength. So we're measuring hand grip strength as a stand-alone. And hand grip strength together with the video hand opening time gives us a very nice assessment of overall hand function. Then we'll be looking at quantitative muscle testing, or QMT, as a composite of lower limb muscles. And this tells us how the patient is improving in terms of their total body strength. And finally, we'll be looking at the DM1-Activ, which is a patient-reported outcome that's disease-specific and focuses on activities of daily living. So what this essentially tells us, almost in the patient's own words, is how the changes in myotonia and improvements in muscle strength are translating into improvements in how the patient can go about their daily lives. We can move to the next slide, please. So without further ado, it's my great pleasure to introduce Prof. John Day. Prof. Day is a professor of neurology, pediatrics and pathology at Stanford University School of Medicine. He's also the Director of the Division of Neuromuscular Medicine and is one of the investigators on our MARINA open label study. So without further ado, I'll pass it over to you, Dr. Day.

Great. Thank you very much, Dr. Hughes. It's very exciting to be here today with you all and to discuss these exciting new results. If we go to the next slide, I think it's important to level set and make sure everyone understands myotonic dystrophy. Like, Dr. Hughes just reviewed, it's distinct from most forms of muscular dystrophy in several ways as was demonstrated more than 100 years ago, when it was first identified that it's a dominantly inherited disorder. So in this family, all of these individuals are affected, but you can see that the older brother and sister are affected less than the younger brother and sister who are affected less than this woman's recent infant. So it increases in severity, but it's dominantly inherited. And compared to the most other forms of muscular dystrophy that are missing some important gene, this is caused by a dominantly inherited toxic gain of function. Next shows one of the key features which, again, Dr. Hughes mentioned, which is this myotonia, or the tendency of muscle to remain in a contracted state after it's activated. So these individuals are trying to open their hands rapidly but can't do so because muscle has persistent tone that doesn't relax quickly. We measure that. We can see it most dramatically, we measure it most easily in the hand. But this is a feature muscle throughout the body as, again, Dr. Hughes mentioned, as we can indicate next slide -- next image there of myotonia. So we can actually measure this electrophysiologically. We can put a needle into the muscle and see that this can be happening almost continually in muscles throughout the body. One muscle fiber will do this. This is an indication of action potentials from a single muscle fiber. That muscle fiber just continues to fire action potentials and continues thus to contract. In the next slide, you can see the effects of all of this. Because of that ongoing muscle activity, the muscle tends to be stiff, fatigued, there's increased aching or discomfort or pain oftentimes, and that leads to ultimately a loss of muscle function. So you eventually develop weakness, loss of muscle bulk and ultimately, dystrophy or the replacement of muscle by connective tissue. So it is a muscular dystrophy, but it is much more than that. There's a distinction with other muscular dystrophies because of this myotonia. But if you go forward, again, you can see all the other features. So this isn't the disorder limited to muscle, it's a disorder that affects the skin, the eyes; it affects the heart seriously. These are direct effects of the genetic change. And it really defied understanding before the gene was identified, which was found almost 30 years ago, more than 30 years ago, on the next slide. And when that was identified, it unfortunately did not shed a lot of light on the path of physiology because it was caused by the CTG expansion in the 3 prime untranslated region of a previously unknown protein kinase. So there was a lot of gnashing of teeth and work to try to understand how this non-coding expansion could actually cause this multisystem disorder. And clue came up shortly thereafter in the next image, which was the identification that the RNA, including those repeat expansions, tend to accumulate in the nuclei. So the pink clumps here are actually the RNA that contain those expansions in the muscle nuclei as evidenced by RNA fish here. And that's identified, but it wasn't at all clear how that could lead then to the downstream effects of the expansion. But a clue again came several years later, if you advance to the next image, where we've shown that a particular RNA binding protein, in this case, muscle blinder, MBNL, is sequestered by those repeat expansions. And so that led to the understanding that MBNL sequestration and mislocalization led to the disease. So if you go to the next slide, you can see the underlying pathophysiology where the CTG expansion or CUG expansion in the RNA tends to form hairpins, which then are stabilized and persist by the binding of this muscle blind protein, thus taking muscle blind out of the rest of the cell and causing a loss of its effects. So muscle blind is, we believe, directly involved in the vast majority of symptoms associated with myotonic dystrophy leading to then this therapeutic approach with del-desiran where, once into the cell, can bind specifically to that mRNA target and destroy it. So it can bind to the RNA target, cause siRNA mechanism, the destruction that target, thus liberating MBNL. And that's dramatically shown in a poster that will be presented at the FDA conference, that there is this very clear dose-dependent increase in MBNL levels as inferred from the plexopathy that results from the MBNL sequestration. So it's a very dramatic evidence of this change where the use of del-desiran liberates MBNL, and you can see this relative dose-dependent increase then in MBNL content. And then the effects of that will be measured on the myotonia that we talked about, the video hand open time, as well as looking at strength and activities daily living. So if we go ahead, not laid the groundwork for this long-term safety and efficacy trial of the open-label extension from the MARINA trial. And as we go forward, next slide, we were gratified to see that in this study now with an N of 37 patients, that there really were no serious long-term safety or tolerability signals so that there were no SAEs related to the drug. No one dropped out due to the treatment and no serious effects related to the drug, as I mentioned. There were the adverse events associated mostly with the disease itself with some nausea and headaches, possibly related to the drug. But otherwise, it was very well tolerated and no patients needed to drop out of the study. So given that, we're interested in showing the efficacy of the treatment. If you go forward into the next slide. We did that by comparing results of the open-label extension to the END-DM1 natural history study that is still underway, which is a noninterventional natural history study, looking at ultimately more than 700 patients for 2 years in 20 centers really around the world, 12 or so in the United States, as well as many in Europe and in Australia and New Zealand. So that we can all work together to develop methods to study these patients and define the natural history. That's all done by the Myotonic Dystrophy Clinical Research Network and has the funding as noted there. So in the next slide, this points out the value of this is that we're looking using the same centers that have been doing the END-DM1 study in the United States for this MARINA open-label study. We looked at the same endpoints that have been used, and we have the natural history from the END-DM1 to compare that to the open-label results. And so we believe that this was a very strong setup in which to look for the effects of del-desiran in this trial. So if we go forward, we can see the result now for the first time of the natural history study over 1 year. And what you can see is that there's a slight variability but very little in the video hand opening time or the myotonia. There's also very little change in the quantitative muscle strength. This is a very precise way of measuring the strength at selected muscles. There is some drop in the hand grip which is consistent with the known early effects of myotonic dystrophy on the volar forearm musculature and also some loss of function picked up by the activity of daily living scale, the DM1-Activ. So that's the natural history. And so now the big question is, what did we see with the open-label extension? And if you click forward, you can see the results where there's a nominally significant difference for all of these measures where there's a definite improvement in the myotonia, with the lessening of the time that it takes for the hand to open. There's improvement in the quantitative muscle strength. There is improvement in the hand grip, and there's an improvement in the patient's own assessment of their ability with regard to the activities of daily living. If you go forward, we can break that down a little bit more in the next slide, looking at the improvements in myotonia, of the treated patients in purple here versus the gray patients that are placebo, showing a significant decrease or improvement in the duration of the myotonia and the video hand open time that persisted during the early 6-week dosing, 3-month dosing and then clearly dosing of the open-label extension. Furthermore, if you go to the next slide, you can actually see this effect. Again, this is looking at the same individual treatment at baseline and then a year after treatment in the open-label extension at the 4-milligram per kilogram dose. So if you run the video here, you can hear and see the test. [Presentation]

So a very clear result. And I think that it's important to realize that these tests are done by video and then scored independently by a blinded observer who can measure the time that it takes for the fingers to open. So that I believe this is a very objective measure and very qualitative sure of the benefits of treatment in the use of myotonia. But remember that the myotonia is not just present those hand opening but that it's present throughout body and consequently affects the painting in myriad ways in terms of their motor function. That's further on the next slide where we can actually look at the strength of patients. So the strength here can improve really quite quickly. In just a matter of a few months, you can see some improvement in function, again, the purple being treated as opposed to placebo, and that, that improvement in strength is persistent throughout the quarterly dosing of the open-label extension. That's true for hand grip in the top and for the quantitative muscle testing that involved muscles at the elbow, the knee, the ankle and hand grip on the bottom. So there's a clear benefit here showing improvement in strength. And if you go forward, you can see that this is also reflected in the patient's own assessment of their ability to perform activities of daily living in this DM1-Activ scale. So going forward, and to just summarize, I just want to point out that the 4-milligram per kilogram dosing over the 1-year period of the open-label extension demonstrated safety and tolerability as well as showing that there was a significant improvement in function for multiple measures of myotonic dystrophy as compared to the natural history that would have been obtained in the END-DM1 natural history study. So we think that we have reliable measures that are going to be valuable in the upcoming Phase III HARBOR trial. And with that, why don't I pass it back to Dr. Hughes.

Thank you, Prof. Day. So over the next 3 slides, I just want to let you hear in the patient's own voice exactly what a difference del-desiran has been making to their lives as these patients have participated in the MARINA study and have through the open-label extension. We have 3 slides. Each slide is a different participant in that study and all 3 have been receiving 4 milligrams per kilogram of del-desiran since the beginning of the MARINA study. So if you can move to the next slide; if you could play, please. [Presentation]

This patient's narrative here is really talking to what we've been saying for quite some time now, which is that once patients start to improve with the myotonia, and that was the first thing that we saw improve, they can start to do more, their muscle strength then starts to improve. As they get stronger, they can mobilize more, then mobility starts to improve. So this really is a snowball effect of being able to do just a bit more at the beginning, over time becomes an ability to do quite a bit more. So if we can move to the next slide. [Presentation]

And for improvements in this participant, I just like to draw your attention to the very last thing that she said regarding the tongue cramping up. So that's myotonia of the tongue. And as Prof. Day elucidated, myotonia doesn't just affect the hand muscles, it could affect any muscle in the body pretty much. And tongue myotonia is pretty common in people living with myotonic dystrophy. And the tongue, of course, isn't just important to speech, it's also important to swallowing. And this is a genetic disease. Many, many people living with DM1 have experienced family members that died from choking. And when we sat down and spoken with these individuals, they actually live in fear of choking, in many instances. They fear of dying from something that they have to do every day, which is to eat. So now just going to move on to the last one of those patient testimonials, if we can play please. [Presentation]

So we've shown you 3 of the participants in our medical trial, each with their own story of what a difference del-desiran has made to their lives. And I think you'll agree that the common way of running through all of these stories is that it's made a tremendous difference to what these individuals are able to do. So with that, I'd like you to pass -- I'd like to pass you back to Sarah Boyce for closing remarks.

Thank you, Steve. And thank you also to Prof. Day for your presentation as well. I began with a vision, to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. I hope what you've seen today is that we're already making an impact on people's lives. Our goal now is to recruit the Phase III study as quickly as possible and get del-desiran to the people who need it. I would also, in closing, like to thank the participants in the MARINA open-label extension study, all of the investigations in this study, all the teams who are involved in the study and also to the END-DM1 study group for giving us their agreement to share the END-DM1 data with you for the very first time. It is an incredibly exciting time for the myotonic dystrophy community. And we couldn't be prouder to be part of it. And with that, I'm going to open up for questions. Geoff, if you would like to moderate our questions.

Great. Thank you, Sarah. Thank you, everyone. All right. We've got a number of questions in already, so we will jump right into it. Our first question is from Ritu and Anvita at Cowen. Steve, I think this question is for you. What effect size on vHOT did you power your HARBOR study on? Any color on the statistical analysis plan? What the vHOT effect size would get physicians excited to use it.

Thanks, Geoff, and thanks, Ritu. As you can imagine, it's quite a competitive space at the moment. So we haven't been giving guidance on the specifics of how we power the Phase III study. What I can tell you is that we use the data from the MARINA study as part of that powering together with the data from the END-DM1 natural history study and triangulated all of those data points. We made relatively conservative assumptions in terms of what we see. And we have quite a lot of power for the primary endpoint and our key secondary endpoints, certainly, the kind of power that you would expect for a registrational clinical trial. In terms of what changes in health will get everybody excited, I think you can see from the video that we are making a substantial difference to people's ability to function in terms of their video hand opening time. We've heard them in testimonials exactly what a difference the changes in vHOT as well as muscle strength are making to patients' lives. And that's not in our words, that's in the patients. So we are really confident that the changes that we'll see in the HARBOR Phase III study are going to be meaningful and convincing to the regulators.

Great. Thank you, Steve. Dr. Day, a follow-up from Ritu and Anvita for you. Based on the natural history data and functional benefits seen in the MARINA studies, what minimum PBO-adjusted improvement on vHOT would get you excited?

Yes. Thanks for directing that to me because I wanted to follow up on Steve's response as well. Because I think a very modest improvement would actually get me very excited because I know the mechanism of action here. So this is not directed just at eliminating myotonia. This is -- the mechanism of action here is really the primary source of the problem, so that I think that the vHOT needs to be looked at as an indication of what's going on in the muscle more generally that were improving muscle function. I think most patients with myotonic dystrophy have a combination of myopathy where the muscle is present but not working well and then muscular dystrophy, where the muscle has been replaced by connected tissue and fat as well as the myotonia. And what you can see is that we're already seeing improvements in strength in individuals very, very quickly. That's not reversing muscular dystrophy, but it is reversing the myopathy in addition to the myotonia. And so we're very excited to see this fundamental improvement. And I think demonstrating an improvement in myotonia is an indication of the overall symptoms improving in the patients. We look for more improvement actually as we follow them longer.

Thank you. Next question is from Joe Schwartz at Leerink. Congratulations on all the progress. My first question is about the clinical meaningfulness of the clinical benefits we're seeing in the MARINA patients. Is the natural history data or any other data to provide context with the magnitude of benefit on the primary and secondary endpoints? And then a couple of follow-ups. Are the patients who shared testimonials representative of the mean response? Where would they rank on a responder analysis relative to a minimally clinically relevant change? And what proportion of the patients would clear such threshold? I think, Steve, maybe you want to start there.

Well, that's a lot of questions. So maybe I'll start, and Prof. Day could jump in and talk to some of the clinical meaningfulness questions as well. We've heard from the patients in their testimonials, what the differences is making to their lives. We've seen consistent improvements across multiple functional endpoints. So we know that the changes that we're seeing in the clinical trial are meaningful and clinically meaningful to patients. Obviously, there's a regulatory burden of proof that's required as well in determining minimal clinically important differences. That's actually something that's typically determined as you go through more later phase development, when you got a relatively large number of patients and you can use different anchors to actually determine based upon quality of life changes what is clinically meaningful. And we will, of course, be doing that as part of our Phase III program. We haven't given any or shared any details on individual patient at this particular disclosure. I know we have on previous disclosures. As we move forward into the Phase III study, our focus has really been on providing totality of data as opposed to the last presentation. Obviously, there's a range of responses in any clinical trial. Some patients are absolutely tremendous responders, some patients respond slightly less as well. And of course, that's what we've seen in this clinical trial as well. Maybe I can hand over to Prof. Day to share his thoughts on the clinical meaningfulness of the data.

Yes. Thanks, Steve. I think that it's a very sophisticated question. And I think it's one that we look forward to diving into in more detail as we go forward and collect more data. I think that, that degree of statistical evaluation is going to depend on gathering more data and determining what those clinically significant and clinically important differences are. But I'd just point out that, again, some patients don't show as much of a change, obviously, if they have more dystrophic change in their muscle. If the muscle is already end stage, we don't expect to see much improvement in that. We do expect that we will blunt the progression of the disease, but we are looking at here some actual improvement in function. So we expect both of those to happen as we go forward, that we could see some improvement of the reversible elements of the disease while we also slow down and hopefully stop the progression of the more destructive elements of the disease. But I look forward to having more data and more opportunity to explore the statistical elements of it and come up with better answers for that question.

And then a follow-up from Joe, and he says it's great to see the HARBOR trial weighing anchor. And this is for you, Steve. Has the FDA signed off an end-of-Phase II meeting? And are you clear to enroll patients in the U.S. at the 4-milligram dose right away? Where does the FDA stand with regards to the partial clinical hold?

A great question again, another multifaceted question. Maybe I'll work backwards. The clinical hold actually now is not gating at all on the Phase III study initiation. We're working as quickly as possible to get the study up and running. And in fact, while we were going through the regulatory discussions, we've been working with sites to get the sites ready, and we're very well advanced in our preparations. As you would expect, given we're going to be initiating the study next month, that includes sites in the United States as well as Europe and other countries globally as well. At this point in time, the partial clinical hold has been completely lifted. As I said, it's not gating on the clinical trial in a way now, and we anticipate movement of the whole closer to initiation of the Phase III study.

Thank you, Steve. All right. I'm just getting our next questions. [Operator Instructions] Our next question is from Yanan at Wells Fargo. What are the gating items on the Phase III initiation? Do you need any additional FDA approval for dosing patients in the U.S.? Does the partial all need to be lifted before patients can be dosed in the Phase III in the U.S.? Any requirements for the secondary endpoints to hit statistical significance for the study to be considered successful by regulators? And then I'll leave the last one for a follow-up.

Wow, I'm not sure I'd be able to remember all of those. There's no additional requirements or hoops that we have to jump through in order to initiate the study. In the United States, FDA has agreed with all the elements of our study design. And so now it's just a matter of getting the sites up and running. As you can imagine, that involves submitting to the IRBs, getting IRB approval, going through the contract negotiation process at the sites. And that just takes a couple of months to work through before we get our first sites up and mining. So from where we are now, it really is all systems go to get the study initiated in the second quarter, and we're well on track. Did I miss anything?

No, I think...

I think you got everything.

You got it all, well done. One follow-up for you. Based on your PK/PD work with the Q 8-week dosing frequency result in better efficacy than the MARINA's 12-week dosing.

So that's a great question. There are a few reasons why we moved the dosing every 8 weeks. One of those was because we could. Our safety data is really clean, and that's enabled us to make the dosing more frequent than we have been doing in the MARINA-OLE study. Efficacy is certainly part of the reason as well. If there's any more efficacy to be had in these early months and dosing more frequently should allow us to do that, so we may see even better improvements in the HARBOR study than we've seen in the MARINA study. And then the last reason was that we were getting some anecdotal feedback that for some patients in the last couple of weeks at the dose interval, they are seeing some fading of their improvement. And so by dosing more frequently, that allows us to prevent that from happening. So any improvements that patients are seeing are well maintained for the entire doses.

Great. Thank you. Next question is from Steve Seedhouse at Raymond James. Mike, this is for you. The dose-dependent increase in MBNL that you're showing on Slide 16, can you talk about that assay, how reliable it is and why wouldn't that be a good of a biomarker assessment as splicing index for DMPK? We're curious why that hasn't been emphasized before today.

Yes, it's a great question. And we weren't able to do the assay before today because we didn't have the RNA seq data. So now with a number of all the patients coming through MARINA having those data and having all the RNA seq data, then we were able to look at the muscle finite protein inferred levels. But that's really big on the slope of a number of different transcripts. So if you think about the 22-gene panel, that panel has really devised for disease severity. This other panel, and you saw the reference is from the Wagner -- from Stacey Wagner. It was back in 2016 in PLOS Genetics, where they identified a set of transcripts that really help you understand muscle like proteins in muscle cells and at what level that you have. And they related it to a number of different disease rarity as well as treatments. And we used that as our starting point and then used the RNA-seq data to then infer muscle blind. And what you saw, as Dr. Day showed it really nicely, is that there's a nice dose dependency from compared to placebo, then 1, 2 and 4. And we really now have been able to connect the dots. I mean, remember, we're working with a genetic medicine, right? del-desiran is a genetic asset medicine. We can look at DMPK knockdown. We showed that in MARINA trial where every patient dosed with del-desiran doesn't show DMPK knockdown or inhibition. That then relates to releasing muscle blind-like protein or muscle blind like protein. And now we're able to measure that or be able to infer the concentration on the cell with this new set of genes. So it really is a nice like connecting the dots for a genetic medicine from the DMPK knockdown. To release the muscle blind, you saw the splicing for MARINA trial. And now using this new panel, we show changes in splicing there that then gives you the functional data that you're now seeing. And as you recall from Steve, we're not going to be doing biomarkers in our Phase III because we've really -- and I think that reflects kind of the regulators working with us and also reflects their confidence in our ability to demonstrate the market or underlying molecular mechanism. So I think it's great for our drug. It's great for patients not to have to undergo biopsies. And we're looking forward to the HARBOR trial and getting it underway.

Great. Thanks, Mike. Our next question, Sarah, I think this is for you. With this data and a clear path forward to a pivotal trial, what does this mean for the pipeline and the company strategically?

Yes. So in terms of -- as Steve and Mike have spoken to, we're incredibly excited to get the HARBOR study up and running. This now takes us into a transition as being what we believe will be the first of our muscle programs to go into a pivotal study. And we have been getting ready for some time around initiating the HARBOR study and have all of that in place as well as also the work around AOC 1044 and 1020. From a strategy perspective, as we have said from the very beginning, it is our goal to develop and commercialize our pipeline in rare diseases ourselves, and we're now building towards that.

Great. Thank you. next question is from Joey Stringer at Needham. Could you provide more details on the plan for training sites on vHOT? What are the details around the central reader and adjudication for vHOT? Thank you. Steve, for you.

Thanks, Geoff, and thanks, Joe. So as you would expect, getting reliable endpoints in these studies is incredibly important. And so we do, of course, train the sites on how to do the measurements to ensure that the measurements are being performed consistently from site to site. And we did that with the MARINA and MARINA open-label studies as well these end points that you're seeing, the sites have been trained on how to do the assessments via centralized busy ethos. And we'll be doing the same for the HARBOR study. All of the sites will be trained. They will be trained in a consistent fashion, have to be a certain quality standard before they're further up and able to enroll participants. Specific to the vHOT measurement, the sites there are requested -- what they have to do is basically ensure the correct hand placement of the patient when the test is performed. You heard on the video, there's a squeeze, squeeze and open. That's prerecorded. So that is coming from the one's administering the test and they take a video recording. That video recording then goes to a central adjudication panel. That's a standard type of adjudication that you'd expect to see for any kind of registrational study where we have 2 independent adjudicators. Each one use a time-based calipers to measure the hand opening time. They have to score within a certain range of each other. If they score outside of that range, then we have a third adjudicator that acts as a tie breaker. So all very standard for a registrational study. And in fact, we used exactly the same procedure for vHOT in the MARINA-OLE extension study as well to ensure consistency of data and also that the measurements and estimates that we have from the MARINA study can be generalized into a Phase III study.

Great. Thanks, Steve. The next question is from Gavin at Evercore. To clarify for HARBOR, the primary analysis is done at 30 weeks and there's no alpha allocated to any analysis at 54 weeks. Is that correct? Hypothetically, what if there was no benefit at 54 weeks, does that represent any regulatory risk. Steve?

So as you can imagine, this is a rare disease, 150 patients. There's not a lot of patients for a Phase III study. We're well powered for the assessment at week 30, if we were to try to set out for cost and the final end point, we need a much larger sample size than the 150 patients that we've got. So one of the efficiencies that I spoke of is conducting the time point at a single time point and using all of our alpha there. We will be, of course, measuring all of those endpoints as well at later time points, including the end of study, so that we can show that the things that we see at the primary endpoint time point are maintained until the end of the study. But in those later assessments, we don't test them statistically. We are extremely well powered for our endpoints. And you've seen from the MARINA study that we're seeing very early improvements in all of the measures that we're seeing. And they continue to improve even further out. They have the label extension study. We've made fairly conservative assumptions about the improvements that we would anticipate seeing as part of calculations, and that gives us a great deal of confidence that we are going to have our property end points and secondaries at week 30 time point.

One follow-up from Ritu at Anvita at Cowen, Mike, this is for you. Based on the MARINA-OLE data thus far, do we now understand what range of CTG repeat links correspond to the best responders to del-desiran?

Yes, that's a great question. And we've been looking into it. And the answer is no. We don't -- we're not planning -- while we haven't really given a lot of data or information on the inclusion/exclusion, it will be very similar to MARINA. So we haven't pared down inclusion to a certain CEG repeat or CTG repeat. It's a great question. Yes, we haven't been able to really understand it deeply. I think things just as a kind of -- when you think about it, and the caveat, it's kind of -- it's interesting to think as just general repeats of CTG repeats, just in a row. But oftentimes, what you'll find is that there's insertions in those repeats that break up the secondary structure. So it's hard sometimes to really understand the number of CEG or CTG repeats compared to what's really finding muscle blind light. So that's why we've gone back. And with what we can relate muscle blind to see CEG repeats, it's really hard to be able to select the patient population based on that. And I think as you can see from the MARINA trial, we have a wide range of CTG repeats. The patients had pretty high levels, I think it was around 600 repeats for some of our population as a mean. And we have the activity across a range of the CTG treatment piece. So we haven't been able to nail down what would be what is that kind of relationship with muscle blind. But we're confident that del-desiran works across a number of CEG repeats because it decreases DMPK. If you don't have DMPK, it doesn't really matter how many have because you'll release most of them.

Great. Thank you. And Steve, one follow-up for you. Apart from the late adolescent inclusion in HARBOR, how else is the inclusion/exclusion criteria going to be different from that of MARINA?

MARINA was actually a pretty inclusively in terms of the patients that we allowed in. We had very few disease-specific eligibility criteria. The HARBOR study is also going to be really inclusive and we're loosening up the eligibility criteria a little bit further from the MARINA study. We haven't gone into specifics at this stage of the exact eligibility criteria, but the study won't be inclusive.

Great. Thank you. And our last question is for you, Dr. Day. How should we understand the 1-year data from the natural history study? And how do you view the data from the MARINA-OLE in comparison?

So the END-DM1 study is ongoing. So we will have continued data acquisition and data release, and I think we can look forward to more refinement of the features. But I think what we can see is that there is no dramatic change in the quantification of either the myotonia or the overall strength of the patients in that 1-year period. I think we can see the progression of the hand grip weakness. And as I mentioned, that's consistent with our understanding that the volar forearm muscles that are responsible for hand grip are early affected in this disease. So that all makes sense. And I think that as we go forward, we'll probably see more refinement of that. But it speaks to the value of the trial wherein we're looking at the improvement in function rather than just halting that progression. So we've known all along this is a slowly progressive disorder. And consequently, if we're going to need to power this on the basis of stopping that progression, this could be a very big study in order to come up with significant change in that slope of loss of function. But I think since we're actually seeing improvement, versal of the myopathic function, reduction of the myotonia, those features are really indicative of significant change. And I think that's optimistic; it gives us optimism for the entire field that this is going to be amenable to these trials because we're going to be able to see some improvement in function and reversal of disease elements. So I think it's all congruent with what we were hoping for, and I'm very excited by the results.

We actually did have one other question coming from Keay at Chardan. He asked, at what point could we expect to see efficacy data for the patients who were dose-escalated up to 4 milligrams per kilogram within the MARINA-OLE study? Steve, would you be able to take that?

So we haven't guided as to when we'll be able to share that data. One of the difficulties has been that in order to do the dose escalations as quickly as possible, it's very important to not have to make major changes in protocol because those major changes to the protocol would have affected the contracts at the sites and rescheduling patients who have already had their schedules figure that. So we just dose-escalated everybody at their next dose. What that meant was that some people were having dose escalation just after they had an efficacy assessment, others were having dose escalation just before they had an efficacy assessment. And of course, in the open-label extension study, the efficacy assessments was less frequent than we did in the MARINA study. So we just need to follow these patients out for a little bit longer. So that their changes in terms of where they sit on their schedule at the time of the dose escalation have time to even out. Of course, the safety data that we shared today does include all of those patients that are dose-escalated so far. I know the data cut was from January of this year. So it's a very recent data cut of the safety.

Great. Thank you, Steve. And that was our last question. And right on time. We've concluded. I'm going to turn it back to Sarah for closing remarks. We thank everyone for joining us today.

Thank you, Geoff, and thank you, everyone, for joining us today. We were incredibly excited to share the data with you and also around in terms of really looking forward to initiating the Phase III study, the Phase III HARBOR study in Q2 of this year, and ultimately being able to get del-desiran to patients because they need it. Thank you.