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

Good morning, and thank you for joining us today for Volume 10 of our Investor and Analyst Event series. We are excited to share with you today a first look at patient data from our EXPLORE44 trial. But before we get started, I will be sharing an excerpt of our forward-looking statement. This presentation contains forward-looking statements as defined under applicable law. Forward-looking statements involve risks and uncertainties, both known and unknown, which may cause actual results to differ from the forward-looking statements contained in this presentation. You are cautioned not to 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 recent reports filed with the SEC. And now I would like to hand over to our President and CEO, Sarah Boyce.

Thank you, Mike. Good morning, everybody. I'm delighted that you've joined us for this morning's webcast. Our vision at Avidity is to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. The data with del-zota that we're going to share with you this morning is a further example of how we're delivering on that vision. We go to the next slide, please. So the purpose of the update today. We're going to be presenting you the initial data from the Phase I/II EXPLORE44 study. This is data from the 5-milligram cohort given every 6 weeks, and this is data from the 4-month time point in the study. You'll see five things: unsurpassed delivery to muscle; robust exon skipping; statistically different difference in dystrophin production and also the exon skipping; a profound reduction in creatine kinase; along with a favorable safety and tolerability profile that we'll also share. In terms of what's next for del-zota, we're looking forward to regulatory interactions and understanding on how we can carve the most expeditious path to accelerated approval. We'll also talk about what this means for our global DMD franchise DMD44, and the fact that, that is now almost in full steam ahead. Now looking towards the data, and I'm going to show you sort of highlights of what we're going to talk about today, and then we'll get into it in more. First and foremost, what we're seeing is unsurpassed delivery to muscle. We are delivering more PMO to muscle cells than anyone has ever done before. And that's about 200 nanomolar. That's about 3 to 5x what any other delivery technology has been able to achieve. We know for DMD and with exon-skipping with PMOs, it's really all about delivery. When you get that delivery, then you see results like we've seen. Significant exon skipping, a 37% increase in exon skipping and up to a 66% increase in exon skipping measure Digital Drop PCR. We've, also then, in turn, see a significant increase in dystrophin production. And that's a substantial increase of 25% of normal in dystrophin production. So I'll refer to you to the graphic that's also on this slide, and it's at 25%. That's the delta. So baseline was 7%, 25% increase, taking people to 32%. And actually, the restoration was up to a total of 54% normal. At 32%, that takes us clearly well into Becker's range, which is considered to be over 10 and starting to move closer and closer to more and more production of that normal dystrophin protein. With that, then also what we see is a profound reduction in the creatine kinase biomarker. Creatine kinase is very elevated in people living with DMD. It is a key marker of muscle damage. And what we're seeing is these levels reduced to near normal with a greater than 80% reduction when compared to baseline. And we'll also share with you the favorable safety and tolerability profile. So let's get into it. So joining me today are my colleagues, Steve Hughes; Michael Flanagan; and Michael MacLean who introduced us. We will now move into -- I'm now going to hand over to Steve, who will take you through aspects of design, safety, next steps. Mike will take us through the data, and then we'll come back for Q&A at the end, which will be facilitated by Mike MacLean. And with that, I'm going to hand over to Steve.

Thanks, Sarah. So if we can go to the first slide. Duchenne muscular dystrophy or DMD is a severe disease with reduced to absent dystrophin causing progressive muscle weakness and disability, loss of ability to walk quietly early teens and a significantly reduce life expectancy. Overall, there were about 10,000 to 15,000 people living with Duchenne the U.S.A. with a similar number in Europe. It's an X-linked disorder, so it primarily affects males. Del-zota is or DMD44, our drug AOC 1044. Del-zota is specifically designed to skip exon 44 in order to restore dystrophin production, and there are about 900 patients in the U.S.A. and a similar number in Europe with DMD amenable to exon skipping or Exon 44 or DMD44. Today, we'll be presenting data from the 5 milligram per kilogram cohort of the EXPLORE44 Phase I/II clinical trial in people living with DMD44. So I'd just like to spend a few moments reminding you of the high-level design of this study. So EXPLORE44 is a Phase I/II study. It's actually our first in human study for this drug. It's a multiple dose study. It's also a dose escalation study. So we're testing multiple doses of 5 mgs per kg that actually we're sharing today is the lowest dose of patients. Targeted enrollment is 24 participants, and we have a broad age range from 7 to 27, which means that we've enrolled both ambulatory and non-ambulatory patients. All patients in all cohorts have biopsies, a muscle biopsies from the biceps muscle and their [indiscernible] biopsies. And all participants on completion of EXPLORE44 will eligible to roll over into an open-label extension study. And this is a first in human study, the primary objective is focus on safety and tolerability. Secondary is look at PK, PD, exon skipping, and dystrophin levels, and then the functional endpoints, patient-reported outcomes, and the quality-of-life are exploratory objectives. If you could go to the next slide. [indiscernible] are generally well balanced on the baseline characteristic, but I'd like you to cast your eyes down to the second mode from the bottom. You will notice that both groups are very high creatine kinase levels. And as Sarah mentioned, this is a characteristic of Duchenne muscular dystrophy and is caused by the extensive muscle damage that's going on. Next slide, please. As with our other program, del-zota has shown favorable safety and tolerability. There were no related AEs going in more than one patient. There was one serious AE leading to discontinuation. This was a case of two anaphylaxis analysis that occurred at the lowest 5 milligram per kilogram dose level. The patient experienced a [indiscernible] infusion. This result rapidly on discontinuation of the infusion and administration of epinephrine and the patient actually was able to go home just a few hours later without going hospitalization. FDA was informed and didn't place any restrictions on the study. We were able to continue dosing the 5-milligram cohort and dose escalate to the higher 10 milligram per kilogram dose. This is the only time we've seen this in any of our programs, including at the high dose of 10 mgs per kg in this program. There was also one other event that resulted in stopping the study drug. This was a classical and future-related reaction, that was moderate in severity. This also occurred at the lowest dose of 5 milligrams per kilogram, and we've not seen any similar reactions at the 10 milligram per kilogram dose. Just as a reminder, we're not using any premedication routinely across any of our programs. Importantly, there have been no symptomatic hemoglobin changes, no hypomagnesemia, and no renal events. As Sarah alluded to earlier, the data we'll be showing you in just a moment is truly remarkable, once again demonstrating the power and consistency of our AOC platform. These remarkable data and yet another where neuromuscular disease provides an imperative for us to move del-zota to DMD44 patients as rapidly as possible. And in this slide, I'm going to walk you through the changes we're making to the EXPLORE44 program in order to achieve this goal. Firstly, we've determined that we do not need to dose escalate above 10 milligrams per kilogram. This study originally had three patient cohorts with a cohort B3 at 20 milligrams per kilogram. We removed the 20-milligram per kilo our cohort. The dystrophin levels that we're seeing at 5 milligrams per kilogram are well within the Becker's range, and we know that we don't need to go uptick. This means at the moment is now complete for the randomized placebo-controlled EXPLORE44 study. Patients from the EXPLORE44 study rollover into the open-label extension study, EXPLORE44 LLE, and we'll actually be amending this open-label extension study to involve an additional 10 to 15 new patients in order to gain more experience at both doses. Completion of enrollment of the EXPLORE44 study allows us to move up our regulatory interactions. And accordingly, we've now initiated interactions with FDA to discuss the fastest route to an accelerated approval, and we're moving as quickly as possible to secure regulatory alignment. I'm now going to pass it over to Mike, who will share the data from the study.

Thanks, Steve, and good morning, everyone. Thanks for joining. We're really excited about sharing the data today. And what I'd really like you to focus on, once again, is the robustness and consistency of our data from unsurpassed delivery, PMO delivery to muscle to a 37% increase in exon skipping to significant 25% increase of newly produced dystrophin compared to baseline and restored total dystrophin to as high as 54% of normal. This dramatic increase in dystrophin results in profound decrease in creatine kinase to near normal levels, suggesting the improved health of muscle tissue. So once again, we connected the dots, unsurpassed delivery to muscle, robust exon skipping, meaningful production of dystrophin, leading to profound decrease in creatine kinase biomarker. Now the one differentiating feature, differentiating feature of exon skipping technology and of del-zota is that it produces near full-length dystrophin. In the top panel, it's full length dystrophin, in the middle panel is a representative del-zota produced nearly full-length dystrophin. And on the bottom is an example of gene therapy encoded micro dystrophin. We believe that the near full-length dystrophin retains many of its biological activities and may lead to better muscle function. So the first step in producing this near full-length dystrophin is delivering PMOs to the muscle. And that's shown on the next slide. So what we've seen is unsurpassed PMO delivery to muscle at 1 month following three doses of del-zota at 5 mgs per kg. Just to orient you to the graph, the Y-axis shows concentration of PMO in the muscle. The X-axis shows the different dose groups, healthy volunteers in the dark and DMD44 participants in blue. Following a single dose of del-zota at 5 mgs per kg, we measured 40 nanomolar of PMO in muscle biopsies in healthy volunteers. This was 1 month after dosing. We presented these data last December. And at that time, this was unsurpassed delivery of PMOs to muscle. And now in DMD participants following three doses of del-zota, we observed 200 nanomolar mean levels of PMO in the muscle. These data really highlight the robust delivery afforded by our AOC technology, featuring our anti transferrin receptor monoclonal antibody that we use across all our programs. It's with this unsurpassed PMO delivery that we really were interested in seeing what the effects of exon skipping. Here, we show statistical significance of 37% increase in exon 44 skipping compared to baseline, following treatment with del-zota, with skipping as high as 66%. On the Y-axis shows exon skipping and on the X-axis are the placebo group or the del-zota treated participants at baseline in 4 months. Not surprising, the placebo cohort in gray shown on the left, show no change in exon skipping between baseline and 4 months later. In contrast, in the far right bar, you can see DMD exon 44 participants treated with del-zota, saw mean exon skipping of 44% and a change from baseline biopsies of 37%. These were statistically significant changes in exon skipping. Now these participant biopsies were collected from the biceps and analyzed using Digital Drop PCR for exon skipping. Part of that biopsy was also used for immunoblotting or western blot for dystrophin production, and that's shown next. Here we show a statistically significant increase of 25% of normal in dystrophin production compared to baseline, following treatment with del-zota, with total dystrophin production as high as 54% of normal. On the Y-axis is the dystrophin levels as shown as percent normal dystrophin. On the X-axis are the placebo group and the del-zota-treated participants at baseline in 4 months. Again, the placebo group is shown in gray, and we saw no changes in dystrophin during the 4 months. While participants treated with del-zota as shown in the blue bars, saw a mean total dystrophin production of 32% and a significant increase by 25% of normal of newly produced dystrophin compared to baseline. So what does this mean? So we tried to provide a figure on the far right that helps illustrate the change in dystrophin observed after del-zota treatment. Now this -- the range of normal dystrophin is calculated as 0% to 100%. Generally, people living with less than 10% dystrophin are diagnosed as having Duchenne muscular dystrophy. As you can see, our average baseline was 7% in this population. And following del-zota treatment, we saw a significant mean total dystrophin of 32%, which is starting to approach healthy levels of dystrophin. The absolute change is a significant increase of 25% normal levels of dystrophin. With this significant increase in nearly full-length dystrophin, we are interested to see how it would translate to improvements in muscle health as measured by creatine kinase. As shown here, we see a dramatic decrease of 80% in creatine kinase levels that approach near normal levels. On the Y-axis is creating kinase levels on the X axis are the study days, and the arrows indicate dosing of either placebo or del-zota. Showing gray are the mean values of the placebo group and shown in blue are the mean values of the del-zota group, the dotted line denotes the upper limit of normal for creatine kinase. As you can see in the placebo group, the creatine kinase levels hover around 7,000 units of enzyme. In the del-zota group shown in blue, following the first dose, we observed a marked drop in creatine kinase. That continues to fall to near normal levels 1 month after the third dose. These significant changes in creatine kinase strongly suggests that del-zota treatment is improving muscle health. With these positive data, next slide. With these positive data, we're now focused and committed to pushing forward additional exon skipping AOCs to advance our growing DMD portfolio. So this morning, once again, we've connected the dots from unsurpassed delivery to muscle, to a significant increase in exon skipping, leading to an increase in dystrophin that's resulted in a profound decrease in creating kinase biomarker, suggesting an improvement in muscle health. And with that, I'll pass it back to Sarah.

Thank you, Mike. As Mike said, we are now committed to full steam ahead with our DMD franchise. We're also deeply aware of the partnership with the DMD community that will be needed to advance treatment options. And that's both patients themselves, their families, patient advocacy organizations and all of the people at the clinical trial sites who brought us to where we are today with this data. I would also like to make sure that we thank all of the sites involved in EXPLORE44, but most importantly, the families who are participating in the study and the boys and the young men who are part of the study. As a reminder, FDA has granted orphan drug status, Fast Track and Rare Pediatric designations to del-zota, and EMA has also granted orphan drug designation. Enrollment in EXPLORE44 is complete. And as Steve also talked to, we plan to enroll an additional 10 to 15 patients in the EXPLORE open-label extension study. Part of our next steps is also looking forward to regulatory interactions to discuss about what is the most expeditious path to accelerated approval. When we have updates around that, we will provide them. And if we can go to the next slide, please. I'll just close reminding on our vision, which is to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. I hope what you've seen today is another example of the work we're doing and the data that we're seeing that is bringing us further and further towards that vision. I'll now ask my colleagues to join me, and we'll move into Q&A.

Okay. So we have lots of questions coming through. The first question comes from Cantor, Eric Schmidt, Eric smit and Josh Schimmer. First of all, they congratulate us on the unprecedented data. There's two parts to this question. I'll split this up. The first is, is there anything about exon 44 that would make it more or less difficult to achieve high levels of full-length dystrophin expression. Mike, do you want to start on that one?

Yes, I can take that question. Yes, it's an interesting question because it has a number of different layers that I really appreciate it. That's a good first question. So when we looked at the landscape, we really felt, of course, we want to go where there's no therapeutic and really high unmet medical need, which I think is clear for or Duchenne muscular dystrophy and exon 44. So we started there. And we were told by a number of luminaries in the field and others that don't do exon 44, like it is going to be too hard. There's background expression of dystrophin, you're not going to be able to see any increase above that has some intrinsic skipping. But we really felt that it was just such a high unmet medical need and very few people are working in this space. And we thought that our AOC technology could really have an impact here. So we kept plugging along and kept moving forward with nonhuman primate data selecting sequences. We had very interesting mouse data that we've shared before that really showed that we could have an impact on skipping and dystrophin production. And it's really what has led us today to show that unsurpassed delivery. I think that's really the key thing with our technology. And once you have that delivery, everything else falls into place. You get the skipping, the skipping obviously results in dystrophin production, and these are levels that really others have not seen. So they're early advice to avoid exon 44, while we appreciate advice, sometimes we just don't follow it, and we just push forward. So I don't think there's anything easy about Duchenne muscular dystrophy. People have been working on it for decades. And I think finally, we're starting to see progress, meaningful progress that we hope will really transform people's lives, both the boys and young men as well as their families. So we're focused and committed to pushing the whole portfolio forward, not just exon 44, but everything and as go as fast as we can because we know people are waiting.

And the second question, and I think, Steve, you could probably start to give the answer here. Can you remind us of the data packages, the number of patients, follow-up biomarkers that led to other approvals in the exon skipping field.

That's also a multi-lead question. It's a few PMOs that have been approved in this field and the range of patients involved for those individual programs as very a little bit from not far moved from the number of participants that we have on the EXPLORE44 program up to -- with the earlier approvals had more patients in the range of 76 to 100, if might memory serves me right. The other thing is that regulatory expectations around the number of participants who enrolled at least to satisfy things like safety database requirements does vary according to the size of the patient population that you're serving. And for some of the other exons, such as exon 51, and those have larger patient populations than the exon 44 skipping. So this is really an ultra-orphan indication. And so we would anticipate that the regulatory expectation may will not be as high as for some of the other exons in terms of total safety baseline.

And our next couple of questions come from Ritu Baral with Cowen. And Steve, I'm going to stick with you here for a minute. The first question is what functional endpoints of data do you plan to show eventually from this data set?

So we do have a number of functional end points. Let's remember that the study is enrolling both ambulatory and non-ambulatory patients. So we have included the North Star Ambulatory Assessment, but we won't be able to do that in every one. We've also included the PUL upper limb assessment. We're assessing other measures of muscle strength and then a number of patient reported outcomes, focusing on various different farmers, including quality of life.

Okay. And then Ritu's second question for you, Mike. When could we see the first 10 mg data? And would you expect to see dose response on exposure, skipping and dystrophin levels?

Yes. So as Steve indicated, we've fully enrolled the 10 mg per kg data, and we're just waiting for those data to come through. We're going to look at the totality of the data, both at 5, as you saw already, that looks remarkable and at 10 mg per kg and then we'll decide what makes the most sense for people living with DMD44 and look at the total increase in dystrophin. I think based on our previous studies based on some nonhuman primate data as well as our mouse model, it may be difficult to get much higher than what we have. But of course, we're going to need to complete the clinical study, the Phase I/II EXPLORE44 and look at the data and then make that decision. Yes. So it's a first -- it's our first program. I wish I could give you a great answer, but it's our first program in the space, and we're just going to have to see as it comes along. And that will help set us up to move faster for the other programs.

Yes. I mean I would just add, as always, we'll make data-driven decisions. As we've said, the study is fully enrolled, and it is still ongoing. So -- and people are still receiving placebo in the study as well. When we get the data, we'll make a data-driven decision. And what really, I think, just to echo Mike's point, we're covering a whole new space here essentially with the type of data that we have. So we'll review the data and make a data-driven decision. With regards to enrollment of the additional participants into the open-label extension study, our plan is to enroll both of 5 and 10.

Thank you, Mike, and Sarah. Now the next question is -- or a set of questions, I should say, are from Joe Schwartz at Leerink. On first, making a hockey reference in the summertime, he says, congratulations on achieving a hat-trick with our three clinical programs. So thank you for that, Joe. And some of these questions, I think, have been asked and answered. So I'll move it to the question on CK reduction, see this is very impressive. Are you evaluating time function tests and our NSA in these patients? If so, when might that data be reported? Steve, do you want to start with this one?

Yes. So we are evaluating the North Star, we are evaluating other measures of ambulation as well. We haven't given guidance on when we're going to report on the functional endpoints in the study. Obviously, it's very remarkable to see changes in creating kinase and particularly near normalization of that from very high levels that really hasn't been seen before least with sustained reduction over time. So that gives us great confidence that we're affecting the biology of the disease in a very positive way. It's just a little early right now to be expecting changes in the clinical endpoint. I would say we've seen some encouraging trends, just nothing that's quite mature enough at the moment to share.

Sticking with you, Steve, what is your strategy to execute clinical development in an environment where gene therapy is available?

So talking about the market as a whole or to patients as a whole, gene therapy really isn't for everyone. There are contraindications to gene therapy around patients that have through existing antibodies to the bolus factors. Patients -- not all patients choose to have gene therapy and gene therapy doesn't work for everybody. So there's definitely a patient who out there that will be available to us for further clinical development. And actually, with these data, these states are so remarkable that could really change certainly within the DMD44, DMD, people's perception or desire to have gene therapy as opposed to enrolling in our clinical trial with the PMO.

Okay. Last question from Joe, and I'm sticking with you, Steve. How much have you investigated potential immunogenicity in the two patients who discontinued?

So first of all, I would say that the two patients that discontinued didn't have any particular underlying factors that would lead us to believe that they were at risk of this -- of the events that they had. Typically, evaluation of things like antidrug antibodies, the samples from the earlier stage clinical trials are banked until the assays have validated and then they get analyzed at a later time point. So we don't have data on antidrug antibodies in these participants. But from the other labs that we've seen, there is really nothing very remarkable. I would add that this is a biological, so DMD44 is a biological drug. And these kind of reactions are completely expected with biologicals. It's just part of the profile of these kind of drugs. And that includes all go. In fact, you can see the source of reactions even with corticosteroids. Our FDA were made aware of the event as pretty much as soon as it happened and didn't place any restrictions on the clinical trial at all. We were able to continue enrollment at 5 week dose, and we were also able to dose escalate to 10 mgs per key. And of course, we haven't seen any similar events across the rest of our program or at the high dose on this poor.

Thank you, Steve. So the next question comes from Steve Seedhouse at Raymond James, and I'm going to give you a break, Steve. We're going to move it over to Mike Flanagan. Can you please elaborate on the normalization method to myosin heavy chain 7? And what the unadjusted, unnormalized data are as well to help contextualize data among competitive landscape?

Yes, that's a good question, Steve. So just to give you I'll go a little bit on the inside we'll stick with the baseball or I guess we were doing hockey. But anyway, the...

As a soccer reference just to say...

We're going to do football and trying to hat-trick as football reference. Anyway, just to get back to the question, so just to give you an insight, so we take an open biopsy from the bicep. Part of it goes to Digital Drop PCR, which we think is the gold standard to evaluate all exon skipping. So we've used digital drop PCR. Another part of the biopsy then goes to immunoblotting which is also called western blotting. And this is where you run the protein from the biopsy on a gel and then you look to see how much is produced dystrophins produced compared to a controlled, controlled set of dystrophin and then is calculated as a percent of normal. And then within that gel, you also have internal controls. So the internal controls are muscle-specific proteins. That would be myosin heavy chain is used as well as alpha actin in. So those two controls allow you to control for muscle content and loading onto the gel. So the way that we presented our data are just straight up normalization to those internal controls. There's no additional multiplication due to muscle content. Sometimes you've seen in press releases or presentations, a muscle content factor, we have not included that. We believe that the addition of that factor is like double dipping. So if you normalized on a gel, that already normalizes the amount of muscle content that you have with myosin heavy chain. There's no need to multiply it by a muscle content factor later on. So that's the way that we presented the data. The data are represented as essentially zero would be no dystrophin to 100%, which is normal. So the normal is calculated by taking samples from healthy individuals and then loading them on a gel for basically a quantitative analysis. So that's the way that we've calculated. We use a common lab AGADA, which is the leader in as a determination of dystrophin, majority of people that are running trials use data. So they're well-known and respected FDA inspected, confirmed. So that's the lab that we use. Hopefully, that answers Steve's question, probably more than he wants to know.

Good job, Mike. Thank you. Okay. Now the next question or a couple of questions come from Yanan Zhu at Wells Fargo. First of all, he does also congratulate us on the data. Steve, I'm coming back to you. Given the high levels of skipping and dystrophin expression, curious if you have seen any functional changes in del-zota patients.

As I alluded to a little earlier, we've definitely seen some encouraging trends in the data that we've looked at. This is actually quite an early time point for this disease. And so we didn't feel that the data at this point was mature enough to share externally. But as I also mentioned, the very profound changes and early changes that we've seen in creatine kinase to indicate that we're affecting the disease biology in a very positive way, and we would anticipate that we'll see changes in the functional endpoints as we follow the patients a little further out in time.

Okay. And sticking with you, Steve, a follow-up question from Yanan on the safety, how would you mitigate this AE in further studies?

So I'm assuming that Yanan is referring to the anaphylaxis event.

Yes.

And really, anaphylaxis is one fully expected with biological drugs. It's been seen with many, many facts. Specifically just about every drug that's on the market anaphylaxis type reaction. So these are really idiosyncratic reactions. There wasn't anything that you can do to mitigate against them. Most drug labels would include a caution or contraindication to the patients that have a known higher sensitivity to the drug or any component any components such as the constituents of the drug. But in clinical trial setting, these are just things that happen. I think it's important to remember that this is most likely to be due to the antibody component of the drug. RNA are pretty -- and particularly PMO are charge-neutral and have a very good track record with regard to hypersensitivity type events. So this being almost certainly attributable to the antibody allows us to look across all of our safety experience. And we dosed over 100 patients now with this platform on the del-desiran program. Everybody is through 18 months of continuous dosing with many patients through 2 years of dosing on the 42 program. We've got several patients now whether for at least 1 year of continuous dosing. And we haven't seen any such events on other programs, and we've ensued one event on the del-zota program.

Thank you, Steve. And now just back to whether hat-trick is a hockey term or a soccer term. Steve Seedhouse reminds me that there is an NHL hockey player last name is Del Zotto. maybe it's a hockey team. Okay. Moving to the next question from Gavin Clark-Gartner from Evercore. Another question on the anaphylaxis, could there be any mechanistic link?

No, not at all. So anaphylaxis type reactions are typically mediated through IgE patients just that experience and just have a true, I'll probably use allergy for one of a better word, but they're just hypersensitive to the drug. It triggers muscle degranulation by IgE. It's a very well-known mechanism and there isn't really any component of the drug that would place any participants at higher risk for this.

Thank you, Steve. So this next question, I'm not sure if it goes to Mike or Steve or both, but it comes from Tazeen Ahmad from Bank of America. Given the background expression of dystrophin in these patients, how would you define their clinical manifestations of DMD symptoms at baseline for patients with more severe exon feedbacks.

Steve, Steve, do you want to take that as kind of a...

Yes. Can you just read that back.

Given the background expression of dystrophin in these patients, I'm assuming meeting DMD44 patients, how would you define their clinical manifestations of DMD symptoms at baseline versus patients with more exon -- to severe exon detect, which I'm assuming is lower dystrophin.

Yes. So that's actually quite a difficult question to answer because it's not really an apples-to-apples comparison. In our study, we've enrolled a broad range of patients from 7 years of age all the way up to 27 years of age. Typically, that isn't done in other clinical trials. So the baseline characteristics of the patient in terms of their ability to walk, their weakness in muscles beyond the legs, et cetera, is driven by how long they had the disease. Generally, patients with exon 44 with DMD that's amenable to exon 44 skipping because they do have some background skipping and some background low-level dystrophin production, their disease does move just a little bit slower than other forms of DMD. So for example, they lose ambulation a couple of years later. That said, it's still a disease where just about everybody is going to end up using angulation completely. So they become [indiscernible] dependent and DMD44 is still former causes a considerable reduction in life expectancy. So definitely a severe disease, but it does just move a little bit slower than the -- than some of the other exon skipping tools.

Steve, I'm going to come back to you, a question from Joey Stringer at Needham, which is just given the discontinuances, is there a chance that we would modify our protocols in additional studies such as using pretreatments?

No. Across the platform, we've really not seen a high incidence of infusion reactions. And as I said earlier, this is the only case of anaphylaxis that we've seen, and these are entirely expected with biological drugs. We don't mandate free treatment across the program, but we do allow our investigators if a patient has, for example, an infusion-related reaction and increase in temperature during the infusion, et cetera, to administer free medication at their discretion. So it's something that the investigators can do if they want to, but we don't feel the need to have this given routinely across the platform.

Okay. We're at time. There is one last question from Ritu at Cowen. Was the 7% mean baseline at placebo higher than expected.

I think based on the literature, it was thought to be around 3% to 7%. So I think it's in the same range that we would have expected for exon 44. And as Steve had indicated, we -- it's known that those patients have slightly more exon skipping, like intrinsic exon skipping and production of dystrophin. And that's why a number of people have told us to that, that was going to be really hard to demonstrate increases above that. But as you saw today, we've seen dramatic increases in both Exxon skipping, well above background statistically significant as well as statistically significant dystrophin production. So the data for the placebo are right in line with our expectations and treatment with del-zota provided that increased improvement in skipping and dystrophin production.

Okay. So with that, I want to thank everybody for the questions and turn it back over to Sarah.

Thank you, everybody, for joining us this morning. As you can see, we're thrilled with the data that we have observed both from a delivery to exon skipping to the increases in dystrophin production to the changes in serum creatine kinase. And our job now is to execute and to complete the study. And then also, we're really looking forward, as we said, to regulatory interactions to understand what can be the most expeditious path to accelerated approval. Once again, we've connected the dots. With data with del-desiran, with data del deletion, we've done it with del-brax, and now we've done it again with del-zota. Our vision and mission remains the same, to make a profound impact in people's lives by revolutionizing the delivery of RNA therapeutics. Today, we'll even one step further with that vision. Thank you so much for your time this morning. And with that, we'll close out the call.